phytochlorin and Neoplasms

Chlorin e6 (Ce6) has been extensively researched and developed as an antitumor therapy. Ce6 is a highly effective photosensitizer and sonosensitizer with promising future applications in photodynamic therapy, dynamic acoustic therapy, and combined acoustic and light therapy for tumors. Ce6 is also being studied for other applications in fluorescence navigation, antibacterials, and plant growth regulation. Here we review the role and research status of Ce6 in tumor therapy and the problems and challenges of its clinical application. Other biomedical effects of Ce6 are also briefly discussed. Despite the difficulties in clinical application, Ce6 has significant advantages in photodynamic therapy (PDT)/sonodynamic therapy (SDT) against cancer and offers several possibilities in clinical utility.

Topics: Cell Line, Tumor; Chlorophyllides; Humans; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins

Conventional cancer treatment modalities are often associated with major therapeutic limitations and severe side effects. Photodynamic therapy is a localized noninvasive mode of treatment that has given a different direction to cancer research due to its effectivity against a wide range of cancers and minimal side effects. A photosensitizer is the key component of photodynamic therapy (PDT) that generates cytotoxic reactive oxygen species to eradicate cancer cells. As the therapeutic effectivity of PDT greatly depends upon the photosensitizer, great efforts have been made to search for an ideal photosensitizer. Chlorin e6 is a FDA approved second generation photosensitizer that meets the desired clinical properties for PDT. It is known for its high reactive oxygen species (ROS) generation ability and anticancer potency against many types of cancer. Hydrophobicity is a major drawback of Ce6 that leads to its poor biodistribution and rapid clearance from the circulatory system. To overcome this drawback, researchers have designed and fabricated several types of nanosystems, which can enhance Ce6 solubility and thereby enhance its bioavailability. These nanosystems also improve tumor accumulation of Ce6 by selectively targeting the cancer cells through passive and active targeting. In addition, Ce6 has been employed in many combination therapies like chemo-photodynamic therapy, photoimmunotherapy, and combined photodynamic-photothermal therapy. A combination therapy is more curative than a single therapy due to the synergistic effects of individual therapies. Ce6-based nanosystems for combination therapies have shown excellent results in various studies and provide a promising platform for cancer treatment.

Topics: Cell Line, Tumor; Nanomedicine; Neoplasms; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species; Tissue Distribution

As one kind of redox active layered transition-metal dioxide nanomaterials, single-layer manganese dioxide (MnO

Topics: Animals; Antineoplastic Agents; Biosensing Techniques; Cell Line, Tumor; Chlorophyllides; Colorimetry; Contrast Media; Doxorubicin; Drug Carriers; Electrochemical Techniques; Humans; Manganese Compounds; Nanostructures; Neoplasms; Oxides; Photosensitizing Agents; Porphyrins

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Chemistry, Pharmaceutical; Chlorophyllides; Clinical Trials as Topic; Drugs, Investigational; Humans; Neoplasms; Photosensitizing Agents; Porphyrins; Radiation-Sensitizing Agents

Drug targeting is an attractive new approach to killing cancer cells while leaving normal tissue unharmed. Recently we have developed a new generation of antibody-targeted immunosuppressive (cyclosporin A) and cytostatic (daunomycin, doxorubicin) drugs and photosensitizers (chlorin e6) effective in vitro and in vivo. The drugs and the targeting antibody (polyclonal and monoclonal) are conjugated to the oligopeptidic side chains of a water-soluble synthetic carrier, copolymer of N-(2-hydroxypropyl)methacrylamide. The composition of the side chains ensures the stability of the linkage between the drug and the polymeric carrier in the bloodstream and its intralysosomal degradability which is a prerequisite for the pharmacological activity of the preparation. Antibody-targeted polymer bound drugs show considerably decreased hepatotoxicity, cardiotoxicity, myelotoxicity and nephrotoxicity. Two adriamycin-HPMA copolymers are in Phase I/II clinical trials in United Kingdom.

Topics: Acrylamides; Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antineoplastic Agents; Chlorophyllides; Clinical Trials as Topic; Cyclosporine; Daunorubicin; Doxorubicin; Histocompatibility Antigens Class II; Humans; Immune System Diseases; Immunoconjugates; Immunosuppressive Agents; Lysosomes; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Polymethacrylic Acids; Porphyrins; Radiation-Sensitizing Agents; T-Lymphocyte Subsets; Thy-1 Antigens; Tissue Distribution

Topics: Animals; Cell Line, Tumor; Fluorodeoxyglucose F18; Goats; Milk; Neoplasms; Photochemotherapy

Photodynamic therapy (PDT) can generate reactive oxygen species (ROS) to cause cell apoptosis and induce immunogenic cell death (ICD) to activate immune response, becoming a promising antitumor modality. However, the overexpressions of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand 1 (PD-L1) on tumor cells would reduce cytotoxic T cells infiltration and inhibit the immune activation. In this paper, a simple but effective nanosystem is developed to solve these issues for enhanced photodynamic immunotherapy. Specifically, it has been constructed a self-delivery biomedicine (CeNB) based on photosensitizer chlorine e6 (Ce6), IDO inhibitor (NLG919), and PD1/PDL1 blocker (BMS-1) without the need for extra excipients. Of note, CeNB possesses fairly high drug content (nearly 100%), favorable stability, and uniform morphology. More importantly, CeNB-mediated IDO inhibition and PD1/PDL1 blockade greatly improve the immunosuppressive tumor microenvironments to promote immune activation. The PDT of CeNB not only inhibits tumor proliferation but also induces ICD response to activate immunological cascade. Ultimately, self-delivery CeNB tremendously suppresses the tumor growth and metastasis while leads to a minimized side effect. Such simple and effective antitumor strategy overcomes the therapeutic resistance against PDT-initiated immunotherapy, suggesting a potential for metastatic tumor treatment in clinic.

Topics: Cell Line, Tumor; Enzyme Inhibitors; Humans; Immunotherapy; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Tumor Microenvironment

Topics: Cell Line, Tumor; Humans; Hydrogen Peroxide; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins

Dual- or multi-modality combination therapy has become one of the most effective strategies to overcome drug resistance in cancer therapy, and the optimized ratio of the therapeutic agents working on the tumor greatly affects the therapeutic outcomes. However, the absence of a facile method to optimize the ratio of therapeutic agents in nanomedicine has, at least in part, impaired the clinical potential of combination therapy. Herein, a new cucurbit[7]uril (CB[7])-conjugated hyaluronic acid (HA) based nanomedicine was developed, in which both chlorin e6 (Ce6) and oxaliplatin (OX) were co-loaded non-covalently at an optimized ratio via facile host-guest complexation, for optimal, combined photodynamic therapy (PDT)/chemotherapy. To maximize the therapeutic efficacy, a mitochondrial respiration inhibitor, atovaquone (Ato), was also loaded into the nanomedicine to limit consumption of oxygen by the solid tumor, sparing oxygen for more efficient PDT. Additionally, HA on the surface of nanomedicine allowed targeted delivery to cancer cells with over-expressed CD44 receptors (such as CT26 cell lines). Thus, this supramolecular nanomedicine platform with an optimal ratio of photosensitizer and chemotherapeutic agent not only provides an important new tool for enhanced PDT/chemotherapy of solid tumors, but also offers a CB[7]-based host-guest complexation strategy to facilely optimize the ratio of therapeutic agents for multi-modality nanomedicine. STATEMENT OF SIGNIFICANCE: Chemotherapy remains the most common modality for cancer treatment in clinical practice. Combination therapy by co-delivery of two or more therapeutic agents has been recognized as one of the most effective strategies to improve therapeutic outcome of cancer treatment. However, the ratio of loaded drugs could not be facilely optimized, which may greatly affect the combination efficiency and overall therapeutic outcome. Herein, we developed a hyaluronic acid based supramolecular nanomedicine with facile method to optimize the ratio of two therapeutic agents for improved therapeutic outcome. This supramolecular nanomedicine not only provides an important new tool for enhanced photodynamic therapy/chemotherapy of solid tumors, but also offers insights in using macrocyclic molecule-based host-guest complexation to facilely optimize the ratio of therapeutic agents in multi-modality nanomedicine.

Topics: Cell Line, Tumor; Humans; Hyaluronic Acid; Nanomedicine; Nanoparticles; Neoplasms; Oxaliplatin; Oxygen; Photochemotherapy; Photosensitizing Agents; Porphyrins

Coronavirus represents an inspiring model for designing drug delivery systems due to its unique infection machinery mechanism. Herein, we have developed a biomimetic viruslike nanocomplex, termed SDN, for improving cancer theranostics. SDN has a unique core-shell structure consisting of photosensitizer chlorin e6 (Ce6)-loaded nanostructured lipid carrier (CeNLC) (virus core)@poly(allylamine hydrochloride)-functionalized MnO

Topics: Bionics; Cell Line, Tumor; Chlorophyllides; Contrast Media; Drug Delivery Systems; Humans; Immunotherapy; Manganese Compounds; Nanoparticles; Neoplasms; Oxides; Photochemotherapy; Photosensitizing Agents; Polyamines; SARS-CoV-2

Accurate diagnosis of cancer cells directly affects the clinical treatment of cancer and can significantly improve the therapeutic effect of cancer patients. Cancer cells have a unique microenvironment with a large amount of peroxide inside, effectively differentiated from relevant microenvironment normal cells. Therefore, designing the high-sensitive probes to recognize and distinguish the special physiological microenvironment of cancer cells can shed light on the early diagnosis of cancers. In this article, we design and construct a fluorescence (FL) contrast agent for cancer cell recognition and imaging analysis. Firstly, luminol-gold NPs (Lum-AuNPs) have been initially built, and then successfully loaded with the fluorescent receptor Chlorin e6 (Ce6) to prepare the luminescent nanoprobes (Ce6@Lum-AuNPs) with green synthesis, i.e., with biocompatible agents and mild temperature. The as-prepared fluorescent Ce6@Lum-AuNPs can efficiently and sensitively realize FL bioimaging of cancer cells. The relevant bio-sensing mechanism pertains to the presence of hypochlorite (ClO

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Gold; Humans; Hydrogen Peroxide; Hypochlorous Acid; Luminol; Metal Nanoparticles; Mice; Neoplasms; Photochemotherapy

Folic acid-conjugated nanophotosensitizers composed of folic acid (FA), poly(ethylene glycol) (PEG) and chlorin e6 (Ce6) tetramer were synthesized using diselenide linkages for reactive oxygen species (ROS)- and folate receptor-specific delivery of photosensitizers. Ce6 was conjugated with 3-[3-(2-carboxyethoxy)-2,2-bis(2-carboxyethoxymethyl)propoxy]propanoic acid (tetra acid, or TA) to make Ce6 tetramer via selenocystamine linkages (TA-sese-Ce6 conjugates). In the carboxylic acid end group of the TA-sese-Ce6 conjugates, FA-PEG was attached again using selenocystamine linkages to make FA-PEG/TA-sese-Ce6 conjugates (abbreviated as FAPEGtaCe6 conjugates). Nanophotosensitizers were fabricated by a dialysis procedure. In the morphological observations, they showed spherical shapes with small diameters of less than 200 nm. Stability of the aqueous FAPEGtaCe6 nanophotosensitizer solution was maintained (i.e., their particle sizes were not significantly changed until 7 days later). When H

Topics: Cell Line, Tumor; Chlorophyllides; Folic Acid; Humans; Hydrogen Peroxide; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Polyethylene Glycols; Porphyrins; Reactive Oxygen Species

Photodynamic therapy (PDT) damages cancer cells via photosensitization using harmless laser irradiation. We synthesized a new photosensitizer, mannose-conjugated-chlorin e6 (M-chlorin e6), which targets mannose receptors that are highly expressed on M2-like tumor-associated macrophages (M2-TAMs) and cancer cells. In our previous study, we demonstrated that M-chlorin e6 PDT reduces tumor volume and decreases the proportion of M2-TAMs. Whether M-chlorin e6 PDT-treated cancer cells activate tumor immunity remains unclear, although the decrease in M2-TAMs is thought to be a direct injurious effect of M-chlorin e6 PDT. Calreticulin (CRT) is exposed at the surface of the membrane of cancer cells in response to treatment with chemotherapeutic agents such as anthracycline and oxaliplatin. Surface-exposed CRT induces phagocytosis of CRT receptor-positive cells, including macrophages, inducing anticancer immune responses. In the present study, we found that M-chlorin e6 PDT increases CRT on the surface of cancer cells, leading to macrophage phagocytosis of cancer cells. Furthermore, M-chlorin e6 PDT increases CD80

Topics: Calreticulin; Chlorophyllides; Humans; Macrophages; Mannose; Neoplasms; Phagocytosis; Photochemotherapy

Copper-based photosensitizer nanoparticle has high potential clinic translation potency for its extensive physiological effects such as anti-cancer progression, anti-bacteria and accelerate tissue regeneration. However, copper excess or improper coordination can induce toxicity or reduce drug efficacy. To get proper copper-photosensitizer complex nanoparticle, a portion of chlorin e6 covalently conjugated with low molecular weight fish collagen fragments-collage tripeptides (CTPs), and Cu

Topics: Animals; Bacteria; Cell Line, Tumor; Chlorophyllides; Collagen; Copper; Molecular Weight; Nanoparticles; Nanospheres; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins

Sono-photodynamic therapy (SPDT) which is the combination of photodynamic therapy (PDT) and sonodynamic therapy (SDT), could exert much better anti-cancer effects than monotherapy. The combination of chemotherapy and PDT or SDT has shown great potential for cancer treatment. However, the combination of SPDT and chemotherapy for cancer treatment is rarely explored.. We utilized a natural hydrophobic anti-cancer drug oleanolic acid (OA) and a photosensitizer chlorin e6 (Ce6) through self-assembly technology to form a carrier-free nanosensitizer OC for combined chemotherapy and SPDT for cancer treatment. No studies involving using carrier-free nanomedicine for combined chemotherapy/SPDT have been reported yet.. After fully characterization of OC, the in vitro and in vivo anti-cancer activities of OC were investigated and the mechanisms of the synergistic therapeutic effects were studied.. OC were synthesized through self-assembly technology and characterized by dynamic light scattering (DLS) and an atomic force microscope (AFM). Confocal microscope was used to investigate the intracellular uptake efficiency and the penetration ability of OC. The cell viability of PC9 and 4T1 cells treated with OC under laser and ultrasound (US) irradiation was determined by MTT assay. Furthermore, flow cytometry was performed to detect the reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential (MMP), cell apoptosis and cell cycle arrest. Finally, the anti-tumor therapeutic efficacy of OC was investigated in orthotopic 4T1 breast tumor-bearing mouse model.. OC showed an average particle size of around 100 nm with excellent light stability. OC increased more than 23 times accumulation of Ce6 in cancer cells and had strong tumor penetration ability in three-dimensional (3D) multicellular tumor spheroids (MCTSs). Compared with other therapeutic options, OC showed obvious synergistic inhibitory effects under light and US irradiation in PC9 and 4T1 cells with a significant decrease in IC. Self-assembled carrier-free nanosensitizer OC could be a promising therapeutic agent for synergistic chemo/sono-photodynamic therapy for cancer treatment.

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Humans; Mice; Nanoparticles; Neoplasms; Oleanolic Acid; Photochemotherapy; Photosensitizing Agents; Porphyrins

Gold nanoparticles (AuNPs) were surface-engineered with a cationic corona to enhance the incorporation of photosensitizers for photodynamic therapy (PDT). The cationic corona composed of poly(2-(dimethylamino)ethyl methacrylate) was atom transfer radical-polymerized on the surface of the AuNPs. The cationic corona of the engineered surface was characterized by dynamic light scattering, electron microscopy, Raman spectroscopy, and mass spectroscopy. Chlorin-e6 (Ce6) incorporated onto the surface-engineered AuNPs exhibited higher cell incorporation efficiency than bare AuNPs. Ce6-incorporated AuNPs were confirmed to release singlet oxygen upon NIR irradiation. Compared to Ce6, Ce6-incorporated AuNPs exhibited higher cellular uptake and cytotoxicity against cancer cells in an irradiation time-dependent manner. Near-infrared-irradiated animals administered Ce6-incorporated AuNPs exhibited higher levels of tumor suppression without noticeable body weight loss. This result was attributed to the higher localization of Ce6 at the tumor sites to induce cancer cell apoptosis. Thus, we envision that engineered AuNPs with cationic corona can be tailored to effectively deliver photosensitizers to tumor sites for photodynamic therapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Chlorophyllides; Female; Gold; Humans; Infrared Rays; Metal Nanoparticles; Methacrylates; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Nylons; Photochemotherapy; Photosensitizing Agents; Polymerization; Singlet Oxygen; Xenograft Model Antitumor Assays

To improve the tumor-targeting efficacy of photodynamic therapy, biotin was conjugated with chlorin e6 to develop a new tumor-targeting photosensitizer, Ce6-biotin. The Ce6-biotin had good water solubility and low aggregation. The singlet-oxygen generation rate of Ce6-biotin was slightly increased compared to Ce6. Flow cytometry and confocal laser scanning microscopy results confirmed Ce6-biotin had higher binding affinity toward biotin-receptor-positive HeLa human cervical carcinoma cells than its precursor, Ce6. Due to the BR-targeting ability of Ce6-biotin, it exhibited stronger cytotoxicity to HeLa cells upon laser irradiation. The IC50 against HeLa cells of Ce6-biotin and Ce6 were 1.28 µM and 2.31 µM, respectively. Furthermore, both Ce6-biotin and Ce6 showed minimal dark toxicity. The selectively enhanced therapeutic efficacy and low dark toxicity suggest that Ce6-biotin is a promising PS for BR-positive-tumor-targeting photodynamic therapy.

Topics: Antineoplastic Agents; Biotin; Cell Survival; Chlorophyllides; HeLa Cells; Humans; Neoplasms; Photochemotherapy; Photosensitizing Agents

Topics: Animals; Cell Line, Tumor; Cell Survival; Chlorocebus aethiops; Chlorophyllides; Cytochromes c; Drug Synergism; Female; Mice, Inbred BALB C; Nanostructures; Neoplasms; Peptides, Cyclic; Photochemotherapy; Photosensitizing Agents; Polyethylene Glycols; Reactive Oxygen Species; Serum Albumin, Bovine; Tissue Distribution

Chlorin e6 is a chlorine-based porphyrin containing photosensitizer mainly used for the therapy in cancers like neck and head, early-stage lung cancer, and topical skin cancers. The present study provides a comprehensive account of a highly sensitive, precise, and validated method for the quantification of chlorin e6 in its liposomal formulation. This method is based on the systemic study of the fluorescence action of chlorin e6 in acetonitrile solvent. This experiment follows the analytical method validation parameters as per the International Conference on Harmonization (ICH). Chlorin e6 molecule exhibits strong fluorescence at a wavelength of emission 665 nm, upon excitation at a wavelength of excitation 400 nm in acetonitrile. The linearity of the fluorescence concentration plot was observed over a concentration range of 50 to 1000 ng/mL. The developed and validated method was successfully applied for the estimation of encapsulation efficiency in in-house developed stealth liposomes. Also, stock solution stability and photodegradation study of chlorin e6 were further conducted.

Topics: Chlorophyllides; Humans; Liposomes; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins

Photosensitizer-based photodynamic therapy (PDT) can not only kill tumor cells by the generated cytotoxic reactive oxygen species (ROS), but also trigger immunogenic cell death (ICD) and activate an immune response for immunotherapy. However, such photodynamic immunotherapy suffers from major obstacles in the tumor microenvironment. The hypoxic microenvironment greatly weakens PDT, while the immunosuppressive tumor microenvironment caused by aberrant tumor blood vessels and indoleamine 2,3-dioxygenase (IDO) leads to a significant reduction in immunotherapy. To overcome these obstacles, herein, an engineered photosensitizer nanoplatform is designed for amplified photodynamic immunotherapy by integrating chlorin e6 (Ce6, a photosensitizer), axitinib (AXT, a tyrosine kinase inhibitor) and dextro-1-methyl tryptophan (1MT, an IDO inhibitor). In our nanoplatform, AXT improves the tumor microenvironment by normalizing tumor blood vessels, which not only promotes PDT by reducing the level of hypoxia of the tumor microenvironment, but also promotes immunotherapy through facilitating infiltration of immune effector cells into the tumor and reversing the immunosuppressive effect of vascular endothelial growth factor (VEGF). Moreover, 1MT effectively inhibits the activity of IDO, further reducing the immunosuppressive nature of the tumor microenvironment. Therefore, this nanoplatform demonstrates an amplified photodynamic immunotherapy via tumor microenvironment modulation, exhibiting outstanding therapeutic efficacy against tumor growth and metastasis with negligible side toxicity. The current concept of engineering photosensitizer nanoplatforms for overcoming photodynamic immunotherapy obstacles provides a promising strategy against tumors.

Topics: Animals; Antineoplastic Agents; Axitinib; Chlorophyllides; Dendritic Cells; Enzyme Inhibitors; Female; Immunity; Immunotherapy; Indoleamine-Pyrrole 2,3,-Dioxygenase; Light; Mice, Inbred C57BL; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Protein Kinase Inhibitors; Tryptophan; Tumor Microenvironment

Photoacoustic (PA) technology can transform light energy into acoustic wave, which can be used for either imaging or therapy that depends on the power density of pulsed laser. Here, we report photosensitizer-free polymeric nanocapsules loaded with nitric oxide (NO) donors, namely NO-NCPs, formulated from NIR light-absorbable amphiphilic polymers and a NO-releasing donor, DETA NONOate. Controlled NO release and nanocapsule dissociation are achieved in acidic lysosomes of cancer cells. More importantly, upon pulsed laser irradiation, the PA cavitation can excite water to generate significant reactive oxygen species (ROS) such as superoxide radical (O

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Chlorophyllides; DNA Damage; Infrared Rays; Lysosomes; Mice; Nanocapsules; Neoplasms; Nitric Oxide; Nitric Oxide Donors; Peroxynitrous Acid; Photoacoustic Techniques; Polymers; Porphyrins; Reactive Oxygen Species; Superoxides; Theranostic Nanomedicine; Transplantation, Homologous

Topics: Animals; Antineoplastic Agents; Betulinic Acid; Chlorophyllides; Density Functional Theory; Drug Synergism; Female; Glutathione; Light; Mice, Inbred BALB C; Models, Chemical; Molecular Dynamics Simulation; Nanoparticles; Neoplasms; Pentacyclic Triterpenes; Photochemotherapy; Photosensitizing Agents; Porphyrins; Prodrugs; Singlet Oxygen; Stigmasterol

Owing to the hypoxia status of the tumor, the reactive oxygen species (ROS) production during photodynamic therapy (PDT) of the tumor is less efficient. Herein, a facile method which involves the synthesis of Mg-Mn-Al layered double hydroxides (LDH) clay with MoS

Topics: Animals; Biomimetic Materials; Catalase; Chlorophyllides; Disulfides; HT29 Cells; Humans; Hydroxides; Magnetic Resonance Imaging; Mice; Molybdenum; Nanostructures; Neoplasms; Photochemotherapy; Photosensitizing Agents; Photothermal Therapy; Porphyrins; Reactive Oxygen Species; Theranostic Nanomedicine

Photodynamic therapy (PDT) is widely used in cancer treatment; however, several challenges compromise its efficiency. We propose a synergistic action between PDT and ferroptotic cell death. PDT acts as a source of reactive oxygen species for the Fenton reaction, which may reinforce ferroptosis induction and increase PDT efficacy in anticancer therapy.

Topics: Animals; Carbolines; Cell Line, Tumor; Chlorophyllides; Ferroptosis; Humans; Mice; Nanoparticle Drug Delivery System; Neoplasms; Photochemotherapy; Photosensitizing Agents; Piperazines; Reactive Oxygen Species; Sorafenib; Treatment Outcome

Sonodynamic therapy (SDT) has good targeting and non-invasive advantages in the treatment of solid cancers, and checkpoint blockade immunotherapy is also a promising treatment to cure cancer. However, their antitumor effects are not sufficient due to some inherent factors. Some studies that combined SDT with immunotherapy or nanoparticles have managed to enhance its efficiency to treat cancers.. In this work, an effective therapeutic strategy that can potentiate the antitumor efficacy of anti-PD-L1 antibody (aPD-L1) is developed by the use of cascade immuno-sonodynamic therapy (immuno-SDT). Titanium dioxide (TiO. The characterization tests showed that the nanosonosensitizers are polycrystalline structure with homogeneous sizes, resulting in a good drug loading efficiency. The innovative nanosonosensitizers (TiO. In this study, we present an effective strategy for tumor treatment by combining nanosonosensitizer-augmented SDT and aPD-L1 checkpoint blockade. This work provides a promising strategy and offers a new vision for treating malignant tumors.

Topics: Animals; Cell Death; Cell Line, Tumor; Chlorophyllides; Combined Modality Therapy; Dendritic Cells; Endocytosis; Female; Humans; Immune Checkpoint Inhibitors; Immunity; Immunotherapy; Mice, Inbred BALB C; Mice, Inbred C57BL; Nanoparticles; Neoplasms; Oligodeoxyribonucleotides; Porphyrins; Reactive Oxygen Species; Titanium; Ultrasonic Therapy

Developing novel activatable photosensitizers with excellent plasma membrane targeting ability is urgently needed for smart photodynamic therapy (PDT). Herein, a tumor acidity-activatable photosensitizer combined with a two-step bioorthogonal pretargeting strategy to anchor photosensitizers on the plasma membrane for effective PDT is developed. Briefly, artificial receptors are first anchored on the cell plasma membrane using cell-labeling agents (

Topics: Animals; Cell Line, Tumor; Cell Membrane; Chlorophyllides; Cyclooctanes; Drug Delivery Systems; Humans; Mice; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Receptors, Artificial

Nanozymes, as a kind of artificial mimic enzymes, have superior catalytic capacity and stability. As lack of O2 in tumor cells can cause resistance to drugs, we designed drug delivery liposomes (MnO2-PTX/Ce6@lips) loaded with catalase-like nanozymes of manganese dioxide nanoparticles (MnO2 NPs), paclitaxel (PTX) and chlorin e6 (Ce6) to consume tumor's native H2O2 and produce O2. Based on the catalysis of MnO2 NPs, a large amount of oxygen was produced by MnO2-PTX/Ce6@lips to burst the liposomes and achieve a responsive release of the loaded drug (paclitaxel), and the released O2 relieved the chemoresistance of tumor cells and provided raw materials for photodynamic therapy. Subsequently, MnO2 NPs were decomposed into Mn2+ in an acidic tumor environment to be used as contrast agents for magnetic resonance imaging. The MnO2-PTX/Ce6@lips enhanced the efficacy of chemotherapy and photodynamic therapy (PDT) in bearing-tumor mice, even achieving complete cure. These results indicated the great potential of MnO2-PTX/Ce6@lips for the modulation of the TME and the enhancement of chemotherapy and PDT along with MRI tracing in the treatment of tumors.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Survival; Chlorophyllides; Contrast Media; Humans; Hydrogen Peroxide; Light; Liposomes; Magnetic Resonance Imaging; Manganese Compounds; Mice; Nanoparticles; Nanostructures; Neoplasms; Oxides; Oxygen; Paclitaxel; Photochemotherapy; Photosensitizing Agents; Porphyrins; Theranostic Nanomedicine

Multifunctional theranostic nanoplatforms integrated of imaging function, multi-modality therapy, stimuli-responsiveness, and targeted delivery are of highly desirable attributes in achieving precise medicine. However, preparation of multifunctional nanoplatforms often involves laborious, multiple steps and inevitably utilizes low-biocompatible or non-functional components. Herein we report a facile, one-step self-assembly strategy to fabricate hyaluronic acid (HA)-based multifunctional tumor theranostic nanoplatform by employing magnetic resonance imaging (MRI) agent Mn

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chlorophyllides; Doxorubicin; Drug Carriers; Histidine; Hyaluronic Acid; Light; Manganese; Mice, Inbred C57BL; Nanogels; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Precision Medicine; Singlet Oxygen

A chlorine e6 (Ce6) and curcumin (Cur) based self-delivery nanomedicine (CeCu) is prepared for chemotherapy sensitized photodynamic therapy (PDT). The chemotherapeutic agent of Cur could inhibit the TrxR activity to destroy the cellular ROS-defence system for enhanced PDT, which provides synergistic effects for tumor precision therapy in consideration of the unfavorable tumor microenvironments.

Topics: Animals; Cell Line; Cell Survival; Chlorophyllides; Curcumin; Humans; Mice; Microscopy, Confocal; Nanomedicine; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Reactive Oxygen Species; Thioredoxin-Disulfide Reductase; Transplantation, Heterologous; Tumor Microenvironment

The combination of photothermal therapy (PTT) and photodynamic therapy (PDT) has attracted attention due to its enhanced tumor therapy effect. This study proposes a novel nanoenzyme-based theranostic nanoplatform, IrO

Topics: Animals; Biocompatible Materials; Catalase; Cell Line, Tumor; Chlorophyllides; Female; Hydrogen Peroxide; Iridium; Light; Mice; Nanocomposites; Nanoparticles; Neoplasms; Oxygen; Photochemotherapy; Porphyrins; Silicon Dioxide; Tumor Microenvironment

Photodynamic therapy (PDT), a typical reactive oxygen species (ROS)-dependent treatment with high controllability, has emerged as an alternative cancer therapy modality but its therapeutic efficacy is still unsatisfactory due to the limited light penetration and constant oxygen consumption. With the development of another ROS-dependent paradigm ferroptosis, several efforts have been made to conquer the poor efficacy by combining these two approaches; however the biocompatibility, tumor-targeting capacity and clinical translation prospect of current studies still exist great concerns. Herein, a novel hypoxia-responsive nanoreactor BCFe@SRF with sorafenib (SRF) loaded inside, constructed by covalently connecting chlorin e6 conjugated bovine serum albumin (BSA-Ce6) and ferritin through azobenzene (Azo) linker, were prepared to offer unmatched opportunities for high-efficient PDT and ferroptosis synergistic therapy.. The designed BCFe@SRF exhibited appropriate size distribution, stable dispersity, excellent ROS generation property, controllable drug release capacity, tumor accumulation ability, and outstanding biocompatibility. Importantly, the BCFe@SRF could be degraded under hypoxia environment to release BSA-Ce6 for laser-triggered PDT, ferritin for iron-catalyzed Fenton reaction and SRF for tumor antioxidative defense disruption. Meanwhile, besides PDT effects, it was found that BCFe@SRF mediated treatment upon laser irradiation in hypoxic environment not only could accelerate lipid peroxidation (LPO) generation but also could deplete intracellular glutathione (GSH) and decrease glutathione peroxidase (GPX4) expression, which was believed as three symbolic events during ferroptosis. All in all, the BCFe@SRF nanoreactor, employing multiple cascaded pathways to promote intracellular ROS accumulation, presented remarkably outstanding antitumor effects both in vitro and in vivo.. BCFe@SRF could serve as a promising candidate for synergistic PDT and ferroptosis therapy, which is applicable to boost oxidative damage within tumor site and will be informative to future design of ROS-dependent therapeutic nanoplatforms.

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Drug Liberation; Ferroptosis; Hypoxia; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Nanotechnology; Neoplasms; NIH 3T3 Cells; Photochemotherapy; Photosensitizing Agents; Porphyrins

Immunological adjuvants are essential for successful cancer vaccination. However, traditional adjuvants have some limitations, such as lack of controllability and induction of systemic toxicity, which restrict their broad application. Here, we present a light-activable immunological adjuvant (LIA), which is composed of a hypoxia-responsive amphiphilic dendrimer nanoparticle loaded with chlorin e6. Under irradiation with near-infrared light, the LIA not only induces tumour cell lysis and tumour antigen release, but also promotes the structural transformation of 2-nitroimidazole containing dendrimer to 2-aminoimidazole containing dendrimer which can activate dendritic cells via the Toll-like receptor 7-mediated signaling pathway. The LIA efficiently inhibits both primary and abscopal tumour growth and induces strong antigen-specific immune memory effect to prevent tumour metastasis and recurrence in vivo. Furthermore, LIA localizes the immunological adjuvant effect at the tumour site. We demonstrate this light-activable immunological adjuvant offers a safe and potent platform for in situ cancer vaccination.

Topics: Adjuvants, Immunologic; Animals; Antigens, Neoplasm; Antitussive Agents; Cancer Vaccines; Cell Line, Tumor; Chlorophyllides; Dendrimers; Dendritic Cells; Humans; Hypoxia; Immunotherapy; Light; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nanoparticles; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; NIH 3T3 Cells; Porphyrins; Transcriptome; Vaccination

Tumor hypoxia, as a hallmark of most solid tumors, poses a serious impediment to O

Topics: Animals; Cell Line, Tumor; Cell Survival; Chlorophyllides; Drug Liberation; Lasers; Mice; Microscopy, Confocal; Nanoparticles; Neoplasms; Oxygen; Photochemotherapy; Photosensitizing Agents; Porphyrins; Reactive Oxygen Species; Tumor Hypoxia; Tumor Microenvironment

The normoxic and hypoxic microenvironments in solid tumors cause cancer cells to show different sensitivities to various treatments. Therefore, it is essential to develop different therapeutic modalities based on the tumor microenvironment. In this study, we designed size-switchable nanoparticles with self-destruction and tumor penetration characteristics for site-specific phototherapy of cancer. This was achieved by photodynamic therapy in the perivascular normoxic microenvironment due to high local oxygen concentrations and photothermal therapy (PTT) in the hypoxic microenvironment, which are not in proximity to blood vessels due to a lack of effective approaches for heat transfer. In brief, a poly(amidoamine) dendrimer with photothermal agent indocyanine green (PAMAM-ICG) was conjugated to the amphiphilic polymer through a singlet oxygen-responsive thioketal linker and then loaded with photosensitizer chlorin e6 (Ce6) to construct a nanotherapy platform (denoted as SNP

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Humans; Indocyanine Green; Mice; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Polyamines; Porphyrins; Singlet Oxygen

Hypoxia of solid tumor compromises the therapeutic outcome of photodynamic therapy (PDT) that relies on localized O

Topics: Animals; Apoptosis; Biocompatible Materials; Catalase; Cell Line, Tumor; Chlorophyllides; HEK293 Cells; HeLa Cells; Humans; Hydrogen Peroxide; Mice; Nanoparticles; Nanotechnology; Neoplasms; Photochemotherapy; Photosensitizing Agents; Polymers; Porphyrins; Reactive Oxygen Species; Singlet Oxygen; Tumor Hypoxia; Tumor Microenvironment

Protein-based nanobubbles such as halophilic archaeabacterial gas vesicles (GVs) represent a new class of stable, homogeneous nanoparticles with acoustic properties that allow them to be visualized by ultrasound (US) waves. To design GVs as theranostic agents, we modified them to respond to light, with a view to locally generate reactive oxygen species that can kill cancer cells. Specifically, up to 60,000 photoreactive chlorin e6 (Ce6) molecules were chemically attached to lysine ε-amino groups present on the surface of each purified Halobacterium sp. NRC-1 GV. The resulting fluorescent NRC-1 Ce6-GVs have dimensions comparable to that of native GVs and were efficiently taken up by human breast [MCF-7] and human hypopharyngeal [FaDu-GFP] cancer cells as monitored by confocal microscopy and flow cytometry. When exposed to light, internalized Ce6-GVs were 200-fold more effective on a molar basis than free Ce6 at killing cells. These results demonstrate the potential of Ce6-GVs as novel and promising nanomaterials for image-guided photodynamic therapy.

Topics: Chlorophyllides; Humans; MCF-7 Cells; Nanoparticles; Neoplasms; Photochemotherapy; Porphyrins; Radiation-Sensitizing Agents; Reactive Oxygen Species; Theranostic Nanomedicine

As one of the most promising noninvasive therapeutic modalities, sonodynamic therapy (SDT) can focus the ultrasound energy on tumor sites located in deep tissue and locally activate the preloaded sonosensitizer to kill tumor cells. However, exploring sonosensitizers with high SDT efficacy and desirable biosafety is still a significant challenge. Herein, we utilized the hydrophilic-hydrophobic self-assembly technology to assemble the hydrophobic organic dye Ce6 and broad spectral anti-cancer agent Paclitaxel with hydrophilic organic dye IR783 to generate a nanoscale sonosensitizer, Ce6-PTX@IR783, without the introduction of extra nanomaterials into the fabrication to guarantee high therapeutic biosafety and further potential clinical translation. The constructed nanodrug was endowed with an external ultrasound-activatable chemo-sonodynamic effect and photoacoustic imaging performance via integrating multiple moieties into one nanosystem. Ce6 could enhance the sonodynamic effect, while PTX exerted a chemotherapeutic effect, and IR783 was applied to increase tumor-specific accumulation and assist in fulfilling photoacoustic imaging. In particular, the small particle size (70 nm) of Ce6-PTX@IR783 contributed to the increased tumor accumulation via the enhanced permeability and retention effect. The high synergistically chemo-sonodynamic therapeutic efficacy has been successfully demonstrated in vitro and in vivo, in addition to the demonstrated high biodegradability, biocompatibility and biosafety. This facile self-assembly procedure provides an intriguing strategy for highly efficient utilization of hydrophobic drugs and is liable to realize large-scale production and further clinical translation.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Survival; Chlorophyllides; Drug Carriers; Endocytosis; Female; Fluorescent Dyes; Humans; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasms; Paclitaxel; Porphyrins; Radiation-Sensitizing Agents; Singlet Oxygen; Theranostic Nanomedicine; Tissue Distribution; Transplantation, Heterologous

Photodynamic therapy (PDT) is commonly employed in clinics to treat the cancer, but because of the hypoxic tumor microenvironment prevalent inside tumors, PDT therapeutic efficiency is not adequate hence limiting the effectiveness of PDT. Therefore, we designed a nanocomposite consisting of reduced nanographene oxide (rGO) modified with polyethylene glycol (PEG), manganese dioxide (MnO

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chlorophyllides; Female; Fluorides; Gadolinium; Graphite; Humans; Infrared Rays; Manganese Compounds; Mice; Nanocomposites; Nanoparticles; Neoplasms; Oxides; Oxygen; Photochemotherapy; Photosensitizing Agents; Polyethylene Glycols; Porphyrins; Tumor Microenvironment; Xenograft Model Antitumor Assays

Abnormally increased reactive oxygen species (ROS) are intimately related to the development and metastasis of cancer. Since hydrogen peroxide (H

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Drug Design; Humans; Hydrogen Peroxide; Luminol; Mice; Mice, Nude; Nanoparticles; Neoplasms; Optical Imaging; Photochemotherapy; Photosensitizing Agents; Polyethylene Glycols; Porphyrins; Quantum Theory; Singlet Oxygen; Transplantation, Homologous

Although tremendous efforts have been made to construct gene vectors incorporating multiple functionalities and moieties, designing gene vectors integrating innovative features to successfully negotiate biological impediments, which hamper efficacious responses in gene-based therapy, is still very urgent. Herein, a light-induced virus-inspired mimic, in which a modular envelope was utilized to mask polyethylenimine/DNA (PD) polyplexes, was developed based on two pH-responsive polymers. The virus-inspired envelope, which was capable of achieving multitargeting and dual-pH-responsiveness in endo/lysosomal compartments, was composed of an internalizing arginylglycylaspartic acid-modified module and a citraconic anhydride-modified nuclear localized signal-functionalized module. The envelope conjugated with chlorin e6 (Ce6) was shielded on the surface of PD polyplexes. Dual-pH-responsive deshielding of the virus-inspired mimic in endo/lysosomes allowed generation of a nonfatal amount of reactive oxygen species (ROS) under short-time photoirradiation, leading to photochemical internalization and much more substantial enhancement in light-induced gene expression without DNA damage caused by ROS. Confocal images revealed that the virus-inspired mimic achieved successful nuclear translocation of Ce6, resulting in nucleus-targeting photodynamic therapy (PDT). Furthermore, pTRAIL-mediated gene therapy, accompanied by a fatal amount of ROS under long-time photoirradiation, additionally consolidated

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Biomimetics; Cell Line, Tumor; Cell Nucleus; Chlorophyllides; DNA; Gene Transfer Techniques; Hydrogen-Ion Concentration; Light; Lysosomes; Mice; Neoplasms; Photosensitizing Agents; Polyethyleneimine; Polysaccharides; Porphyrins; Reactive Oxygen Species; TNF-Related Apoptosis-Inducing Ligand

The development of intelligent and precise cancer therapy systems that enable accurate diagnosis and specific elimination of cancer cells while protecting normal cells to improve the safety and effectiveness of the treatment is still a challenge. Herein, we report a novel activatable nanodevice for precise cancer therapy. The nanodevice is constructed by adsorbing a DNA duplex probe onto MnO2 nanosheets. After cellular uptake, the DNA duplex probe undergoes telomerase-triggered conformation switching, resulting in a Ce6 "turn-on" signal for the identification of cancer cells. Furthermore, Deoxyribozyme (DNAzyme) is activated to catalyse the cleavage of survivin mRNA, actualizing a precise synergistic therapy in cancer cells involving photodynamic therapy and gene-silencing. The MnO2 nanosheets provide Mn2+ for the DNAzyme and relieve hypoxia to improve the efficiency of the photodynamic therapy. Live cell studies reveal that this nanodevice can diagnose cancer cells and specifically eliminate them without harming normal cells, so making the treatment safer and more effective. The developed DNA-MnO2 nanodevice provides a valuable and general platform for precise cancer therapy.

Topics: Catechin; Cell Line, Tumor; Cell Survival; Chlorophyllides; DNA; DNA, Catalytic; Gene Silencing; Humans; Light; Manganese Compounds; Nanostructures; Neoplasms; Oxides; Photochemotherapy; Photosensitizing Agents; Porphyrins; RNA, Messenger; Survivin; Telomerase

Recent cancer immunotherapy has attracted much attention due to high specificity and recurrence prevention of tumor. Nevertheless, its therapeutic effects are still challenging in solid cancer. To establish superior antitumor immunity, chlorin e6 (Ce6)-loaded pH sensitive carbon dots were investigated (Ce6@IDCDs). At tumoral pH 6.5, Ce6 was released four times compared with the release at physiological pH 7.4 due to an imbalance between hydrophilic and hydrophobic forces via protonation of imidazole groups in Ce6@IDCDs. This result led to the superior singlet oxygen generating activity of Ce6@IDCDs without Ce6 quenching. The maturation effects of dendritic cells after co-incubation with supernatant media obtained from Ce6@IDCDs with laser-treated cells at pH 6.5 were much higher than at physiological pH. Furthermore, Ce6@IDCDs following a laser at pH 6.5 significantly promoted calreticulin exposure and high-mobility group box 1 release, as major immunogenic cell death markers. In bilateral CT-26-bearing mice model, the Ce6@IDCDs elicited significant antitumoral effects at laser treated-primary tumor regions via therapeutic reactive oxygen species. Furthermore, Ce6@IDCDs upon laser irradiation induced a large amount of activated CD8

Topics: Animals; Calreticulin; Carbon; Cell Death; Cell Line, Tumor; Chlorophyllides; Dendritic Cells; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Imidazoles; Immunotherapy; Lasers; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Electron, Transmission; Nanoparticles; Neoplasms; Particle Size; Photochemotherapy; Porphyrins; Radiation-Sensitizing Agents; Reactive Oxygen Species; Spectroscopy, Fourier Transform Infrared; Tumor Microenvironment; Xenograft Model Antitumor Assays

Multifunctional intelligent theranostics agents are promising for next-generation oncotherapy. We fabricated a tumor-microenvironment (TME)-responsive carbon nanotube (CNT)-based nanoplatform for T1 weighted magnetic resonance imaging (MRI)-guided synergistic photodynamic and photothermal therapy (PDT and PTT). CNTs convert near infrared (NIR) radiation into hyperthermia for PTT, and can effectively deliver their cargo into cells due to their unique 1D nanostructure. The CNT@MnO2-PEG@Ce6 nanomedicine was internalized into tumor cells, and rapidly released the photosensitizer (Ce6) in response to the low pH and high glutathione (GSH) levels characteristic of the TME. The degradation of the MnO2 layer under the same conditions released Mn2+ for T1-MRI. Furthermore, catalytic decomposition of the excess H2O2 into oxygen by MnO2 enhanced the efficacy of PDT, relieved hypoxia, and increased consumption of superfluous GSH to mitigate the effects of excessive reactive oxygen species (ROS) generation during PDT. MRI-guided PDT and PTT synergistically inhibited tumor cell growth in vitro, and ablated tumors in vivo. The side effects were negligible due to specific tumor cell targeting via surface modification with folic-PEG, and enhanced permeability and retention. Taken together, CNT@MnO2-PEG is a fully TME-responsive theranostics nanoplatform for targeted tumor ablation and real-time disease tracking.

Topics: Animals; Catalysis; Chlorophyllides; Female; Glutathione; HeLa Cells; Humans; Hydrogen Peroxide; Infrared Rays; Magnetic Resonance Imaging; Manganese Compounds; Mice, Inbred BALB C; Nanotubes, Carbon; Neoplasms; Oxides; Photochemotherapy; Photosensitizing Agents; Photothermal Therapy; Polyethylene Glycols; Porphyrins; Theranostic Nanomedicine; Tumor Microenvironment

Controlled release of CRISPR-Cas9 ribonucleoprotein (RNP) and codelivery with other drugs remain a challenge. We demonstrate controlled release of CRISPR-Cas9 RNP and codelivery with antitumor photosensitizer chlorin e6 (Ce6) using near-infrared (NIR)- and reducing agent-responsive nanoparticles in a mouse tumor model. Nitrilotriacetic acid-decorated micelles can bind His-tagged Cas9 RNP. Lysosomal escape of nanoparticles was triggered by NIR-induced reactive oxygen species (ROS) generation by Ce6 in tumor cells. Cytoplasmic release of Cas9/single-guide RNA (sgRNA) was achieved by reduction of disulfide bond. Cas9/sgRNA targeted the antioxidant regulator

Topics: Animals; Cell Line, Tumor; Chlorophyllides; CRISPR-Cas Systems; Delayed-Action Preparations; Gene Editing; Mice; Nanoparticles; Neoplasms; NF-E2-Related Factor 2; Reactive Oxygen Species; Ribonucleoproteins; RNA, Guide, Kinetoplastida

The major limitations of photodynamic therapy (PDT) are the poor tissue penetration of excitation light and the neutralization of reactive oxygen species (ROS) generated by overexpressed glutathione (GSH) in cancer cells. Despite tremendous efforts to design nanoplatforms, PDT still suffers from unsatisfactory effects. Furthermore, the residual of nanomaterials in the body has restricted their clinical application. To address these issues, Janus nanocomposites containing an Yb/Er codoped NaYF4 upconverting nanocrystal head and a disulfide-bridged mesoporous organosilicon body (UCN/MON) with loaded chlorin e6 (Ce6) were designed. On one hand, the upconverting nanocrystal head can convert near-infrared (NIR) light into visible light to activate Ce6 to release ROS. On the other hand, the silica body can be degraded though a redox reaction with GSH, to not only improve the tumor selectivity of the photosensitizer by redox- and pH-triggered Ce6 release, but also diminish the concentration of GSH in cancer cells to reduce the depletion of ROS. Thereby, an enhanced PDT triggered by NIR irradiation was achieved. Furthermore, UCN/MONs showed a higher clearance rate after therapeutic actions than nonbiodegradable UCN/MSNs due to their biocompatibility. Taken together, this work revealed the potential of UCN/MONs for highly efficient and NIR-induced PDT, highlighting the prospects of UCN/MONs in the clinic.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chlorophyllides; Erbium; Female; Fluorides; Glutathione; Humans; Infrared Rays; Mice, Inbred BALB C; Nanocomposites; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Silicon Dioxide; Singlet Oxygen; Ytterbium; Yttrium

The common existence of hypoxia within the tumor microenvironment severely restricts the efficacy of photodynamic therapy (PDT), which is attributed to the fact that the PDT process is strongly oxygen (O2) dependent. Here, a multifunctional composite (named CPCG), which combines polyethylene glycol (PEG) functionalized cerium oxide nanoparticles (CeO2) with photosensitizer chlorin e6 (Ce6) and glucose oxidase (GOx), is reported for generating O2 within the tumor microenvironment by the dual-path hydrogen peroxide (H2O2)-modulated ways to ameliorate hypoxia, thereby enhancing the PDT efficiency. This process is realized based on the dual enzyme-like activity of CeO2. The first modulated way is to transform the superoxide anion (O2˙-) into H2O2 by the superoxide dismutase-like activity of CeO2. The second modulated way is to decompose glucose into H2O2 through the catalysis of GOx. Subsequently, H2O2 generated from the above dual modulated ways can further produce O2via the catalase-like activity of CeO2. Additionally, the depletion of glucose could impede the nutrient supply to obtain starvation therapy. Both in vitro and in vivo experiments indicate that the CPCG composite could enhance the efficacy of photodynamic/starvation synergistic therapy. Therefore, this strategy offers great potential to modulate the O2 level in the tumor microenvironment for better therapeutic outcomes, and can act as a promising candidate in photodynamic/starvation synergistic therapy.

Topics: Animals; Cerium; Chlorophyllides; Female; Glucose Oxidase; HeLa Cells; Humans; Hydrogen Peroxide; Mice, Inbred BALB C; Nanoparticles; Neoplasms; Photosensitizing Agents; Porphyrins; Tumor Hypoxia; Tumor Microenvironment

The current trend of cancer therapy has changed from monotherapy to synergistic or combination therapies. Among the treatment strategies, photodynamic therapy (PDT) and starvation therapy are widely employed together. However, the therapeutic effect of these treatments could lead to strong resistance and poor prognosis due to tumor hypoxia. Therefore, a smart nanoplatform (MONs-GOx@MnO2-Ce6) has been constructed herein by the assembly of glucose oxidase (GOx)-coated mesoporous organosilica nanoparticles (MONs) and MnO2 nanosheets-chlorin e6 (Ce6), which form a nanosystem. Once MONs-GOx@MnO2-Ce6 enter tumor cells, it catalyzes the oxidation of glucose using oxygen (O2) and generates hydrogen peroxide (H2O2) and gluconic acid, the former of which may accelerate the decomposition of MnO2 nanosheets. The released MnO2 nanosheets would regenerate O2 in the presence of H2O2. In this case, MnO2 nanosheets serve as (i) a nanocarrier and fluorescence quencher for the photosensitizer Ce6, (ii) a degradable material that is activated by the tumor microenvironment (TME) for fluorescence recovery, and (iii) an O2-producing carrier that reacts with H2O2 for relieving hypoxia in the tumor, which contributes to the combined starvation/photodynamic cancer therapy since these treatment strategies need O2. MONs-GOx@MnO2-Ce6 could not only realize cancer cell imaging, but also reduce intracellular glucose uptake and Glut1 expression, inhibiting the metabolism of cancer cells. This strategy shows great potential for clinical applications.

Topics: Chlorophyllides; Glucose Oxidase; HeLa Cells; Humans; Manganese Compounds; Microscopy, Confocal; Nanoparticles; Nanostructures; Neoplasms; Organosilicon Compounds; Oxides; Oxygen; Photosensitizing Agents; Porphyrins; Tumor Hypoxia

For reactive oxygen species (ROS)-sensitive and CD44 receptor-mediated delivery of photosensitizers, chlorin e6 (ce6) tetramer was synthesized using tetra acid (TA) via selenocystamine linkages and then conjugated with hyaluronic acid (HA) (abbreviated as HAseseCe6TA). HAseseCe6TA nanophotosensitizers were fabricated by dialysis procedure. HAseseCe6TA nanophotosensitizers showed spherical morphology with small particle sizes less than 100 nm and monomodal pattern. When H

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Hyaluronan Receptors; Hyaluronic Acid; Hydrogen Peroxide; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Oxidation-Reduction; Particle Size; Photochemotherapy; Photosensitizing Agents; Porphyrins; Reactive Oxygen Species

Cancer photodynamic therapy (PDT) represents an attractive local treatment in combination with immunotherapy. Successful cancer PDT relies on image guidance to ensure the treatment accuracy. However, existing nanotechnology for co-delivery of photosensitizers and image contrast agents slows the clearance of PDT agents from the body and causes a disparity between the release profiles of the imaging and PDT agents. We have found that the photosensitizer Chlorin e6 (Ce6) is inherently bound to immunoglobulin G (IgG) in a nanomolarity range of affinity. Ce6 and IgG self-assemble to form the nanocomplexes termed Chloringlobulin (

Topics: Animals; B7-H1 Antigen; Cell Line, Tumor; Chlorophyllides; CTLA-4 Antigen; Female; Fluorescence; Immunoglobulin G; Immunotherapy; Intraoperative Care; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasms; Photochemotherapy; Porphyrins; Rats; Tissue Distribution

The combination of chemotherapy and photodynamic therapy (PDT) is considered a valuable strategy for increasing therapeutic response in cancer treatment, and the re-formulation of pharmaceuticals in biocompatible nanoparticles (NPs) is particularly appealing for the possibility of co-loading drugs exerting cytotoxicity by different mechanisms, with the aim to produce synergic effects. We report the in-water synthesis of a novel keratin-based nanoformulation for the co-delivery of the antimitotic Docetaxel (DTX) and the photosensitizer Chlorin e6 (Ce6). The drug-induced aggregation method allowed the formation of monodisperse NPs (DTX/Ce6-KNPs) with an average diameter of 133 nm and loaded with a drug ratio of 1:1.8 of Ce6 vs DTX. The efficacy of DTX/Ce6-KNPs was investigated in vitro in monolayers and spheroids of DTX-sensitive HeLa (HeLa-P) and DTX-resistant HeLa (HeLa-R) cells. In monolayers, the cytotoxic effects of DTX/Ce6-KNPs toward HeLa-P cells were comparable to those induced by free DTX + Ce6, while in HeLa-R cells the drug co-loading in KNPs produced synergic interaction between chemotherapy and PDT. Moreover, as respect to monotherapies, DTX/Ce6-KNPs induced stronger cytotoxicity to both HeLa-P and HeLa-R multicellular spheroids and reduced their volumes up to 50%. Overall, the results suggest that KNPs are very promising systems for the co-delivery of chemotherapeutics and PSs, favoring synergic interactions between PDT and chemotherapy.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biocompatible Materials; Cell Membrane Permeability; Cell Survival; Chlorophyllides; Docetaxel; Drug Carriers; Drug Compounding; Drug Liberation; Drug Synergism; HeLa Cells; Humans; Keratins; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Spheroids, Cellular

Photodynamic therapy (PDT), as an essential tumor treatment method, has received great attention; however, there are still some challenges such as hydrophobicity of most of the photosensitizers, safety of in vivo transport, and characteristics of oxygen consumption. Herein, we used albumin as the nanocarrier for the loading of Chlorin e6 (Ce6) photosensitizer. In the meantime, tirapazaming (TPZ) was co-loaded onto the nanocomposite, which could be activated by hypoxia caused by PDT for enhanced therapy. Considering the over irradiation problem, a strategy for measuring PDT degree by ratio fluorescence was utilized. The PDT monitoring design relies on ratio emissions of C6 (Coumarin 6) and Ce6 molecules since the red emission of Ce6 is dependent on the PDT capability. Based on the characterization of the albumin nanocomposites, we further explored the combined therapy effect at both the in vitro and in vivo levels and attained the corresponding results.

Topics: Animals; Cattle; Cell Line, Tumor; Cell Survival; Chlorophyllides; Coumarins; Humans; Light; Liver; Mice; Microscopy, Confocal; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Serum Albumin, Bovine; Thiazoles; Tirapazamine; Transplantation, Homologous

Photodynamic therapy (PDT) is a noninvasive powerful tool for tumor treatment. However, phototoxicity seriously limits the clinical application of PDT, and activated PDT specifically response to tumor cell antigen is rarely reported. Herein, a tumor cell specific "switch-on" PDT nanoplatform, which employs a well-designed hairpin structure mucl protein (MUC1) aptamer (Apt) as specific linker to conjugate gold nanorod and Chlorin e6 (Ce6) (GNR/Apt-Ce6) is prepared, and "switch on" via conformational changes of aptamer-induced fluorescence resonance energy transfer missing between GNR and Ce6 for selective tumor therapy. In the absence of tumor cells, MUC1 Apt keeps a hairpin structure, leading to Ce6 closely adhered to the surface of GNR, PDT is in an "off" state even under the irradiations. On the contrary, in the presence of tumor cells with overexpressed MUC1, Apt specifically recognizes and binds to MUC1, resulting in conformational changes of Apt from regular hairpin to extended chain structure. Thus with an enlarged distance between Ce6 and GNR, PDT is switched-on. GNR/Apt-Ce6 shows excellent PDT efficacy in tumor-bearing mice (55.1% vs 1.3%, tumor apoptosis rate of GNR/Apt-Ce6 vs GNR/random sequence-Ce6) due to its high tumor-targeting and "switch-on" properties. The strategy of tumor antigen activated PDT is expected to provide a new perspective for clinical application.

Topics: Animals; Antigens, Neoplasm; Cell Line, Tumor; Cell Survival; Chlorophyllides; Female; Humans; Hydrogen-Ion Concentration; Hypoxia; Lipid Peroxides; Male; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mucin-1; Nanomedicine; Nanotubes; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Protein Binding; Protein Conformation; Reactive Oxygen Species; Treatment Outcome

The therapeutic efficacy of photodynamic therapy (PDT) in cancer treatment is attributed to the conversion of tumor oxygen into reactive singlet oxygen (

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Chlorophyllides; Humans; Light; Mice; Molecular Targeted Therapy; Nanoparticles; Neoplasms; Oligopeptides; Photosensitizing Agents; Porphyrins

Immunogenic cell death (ICD) provides momentous theoretical principle for modern cancer immunotherapy. However, the currently available ICD inducers are still very limited and photosensitizer-based ones can hardly induce sufficient ICD to achieve satisfactory cancer immunotherapy by themselves. Herein, an organic photosensitizer (named TPE-DPA-TCyP) with a twisted molecular structure, strong aggregation-induced emission activity, and specific ability is reported for effectively inducing focused mitochondrial oxidative stress of cancer cells, which can serve as a much superior ICD inducer to the popularly used ones, including chlorin e6 (Ce6), pheophorbide A, and oxaliplatin. Furthermore, more effective in vivo ICD immunogenicity of TPE-DPA-TCyP than Ce6 is also demonstrated using a prophylactic tumor vaccination model. The underlying mechanism of the effectiveness and robustness of TPE-DPA-TCyP in inducing antitumor immunity and immune-memory effect in vivo is verified by immune cell analyses. This study thus reveals that inducing focused mitochondrial oxidative stress is a highly effective strategy to evoke abundant and large-scale ICD.

Topics: Animals; Cell Line, Tumor; Cell Survival; Chlorophyllides; Density Functional Theory; Female; Humans; Immunogenic Cell Death; Mice; Mice, Inbred BALB C; Mitochondria; Nanoparticles; Neoplasms; Oxidative Stress; Photosensitizing Agents; Porphyrins; Reactive Oxygen Species; Survival Rate; X-Rays

Based on the Pt nanozyme modified mesoporous polydopamine in situ, a multi-functional nanoplatform was established, which could overcome tumour hypoxia by catalyzing overexpressed H2O2 in tumour cells to enhance photodynamic therapy. In vivo results confirmed that the tumour growth was inhibited efficiently by synergetic therapy.

Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Chlorophyllides; Doxorubicin; Humans; Hydrogen Peroxide; Indoles; Lasers; Metal Nanoparticles; Mice; Neoplasms; Photochemotherapy; Platinum; Polymers; Porosity; Porphyrins; Serum Albumin, Bovine

Cytotoxic and photoinduced activity of chlorine e6 (Ce6) in phospholipid nanoparticles with specific tumor targeting and cell-penetrating peptides was studied in vitro using human fibrosarcoma cells HT-1080. It was shown, that the binding of cell-penetrating peptide R7 - alone or combined with the peptide containing specific targeting motif NGR (Asn-Gly-Arg) - resulted in 3-fold decrease of Ce6 photoinduced activity as compared with that in nanoparticles without peptides (IC50 values were 0.7 μg/ml and 2.1 μg/ml, respectively). The NGR influence was unexpectedly low - less than 20% (IC50 1.7 μg/ml). This suggests the more importance of Ce6 cell penetration in this case, than of NGR-mediated targeting. The effect of inclusion of both peptides on the total cytotoxicity of Ce6 was minimal (10-16 times less than on the specific photoinduced activity). The obtained results - together with earlier shown effects on improvement of the pharmacokinetics of Ce6 in vivo after its embedding into phospholipid nanoparticles - indicate the prospects of using the obtained phospholipid nanoparticles system for photodynamic therapy.. V sisteme in vitro na kul'ture kletok fibrosarkomy cheloveka NT-1080 izuchena tsitotoksicheskaia i fotoindutsirovannaia aktivnost' khlorina e6 (Se6) v fosfolipidnykh nanochastitsakh (NCh), soderzhashchikh spetsificheskiĭ adresnyĭ i kletochno-pronikaiushchiĭ peptidy. Pokazano, chto dobavlenie kletochno-pronikaiushchego peptida R7 (geptaarginina) – odnogo ili v sochetanii s peptidom, soderzhashchim spetsificheskiĭ vektornyĭ fragment NGR (Asn-Gly-Arg), – privodit k 3-kh kratnomu povysheniiu spetsificheskoĭ fotoidutsirovannoĭ aktivnosti Se6 po sravneniiu s takovoĭ v NCh bez peptidov (velichiny IK50 sostavliali 0,7 mkg/ml i 2,1 mkg/ml sootvetstvenno). Slaboe vliianie odnogo NGR – menee 20% (IK50 1,7 mkg/ml) i otsutstvie ego éffekta pri dopolnenii k R7 (IK50 0,7 mkg/ml) – ukazyvaet na bol'shuiu znachimost' v dannom sluchae proniknoveniia Se6 v kletku, chem obespechivaemoĭ NGR adresnoĭ napravlennosti. Vliianie vkliucheniia peptidov na obshchuiu tsitotoksichnost' Se6 okazalos' minimal'nym (v 10-16 raz men'she, chem na spetsificheskuiu fotoindutsiruemuiu aktivnost'). Poluchennye rezul'taty v sochetanii s pokazannym nami ranee uluchsheniem farmakokinetiki Se6 pri ego vkliuchenii v fosfolipidnye NCh v sisteme in vivo ukazyvaiut na perspektivnost' ispol'zovaniia poluchennoĭ sistemy fosfolipidnykh NCh dlia fotodinamicheskoĭ terapii.

Topics: Cell Line, Tumor; Chlorophyllides; Humans; Nanoparticles; Neoplasms; Peptides; Photochemotherapy; Photosensitizing Agents; Porphyrins

Minimizing drug leakage at off-target sites and triggering sufficient drug release in tumor tissue are major objectives for effective nanoparticle (NP)-based cancer therapy. The current covalent and cleavable drug-NP conjugation strategy is promising but lacks high controllability to realize tumor-specific release. As a proof-of-concept, the reactive oxygen species (ROS)-activatable thioketal (TK) bond was explored as the linkage between doxorubicin (DOX) and polyphosphoester (PPE-TK-DOX). The Ce6@PPE-TK-DOX NPs constructed by co-self-coassembly of PPE-TK-DOX and the photosensitizer Ce6 efficiently prevented premature drug leakage in the off-target tissue and cells because of the high stability of the TK bond under physiological conditions. Once circulating into the tumor site, the 660-nm red light was precisely employed to irradiate the tumor area under the guidance of fluorescence/magnetic resonance (MR) dual-model imaging, which can induce localized ROS generation, resulting in rapid cleavage of the TK bond. Consequently, the DOX prodrug was locoregionally released and activated, achieving tumor-specific drug delivery with high controllability by light. Such phototriggered prodrug release and activation at the desired site significantly enhanced the therapeutic efficacy and minimized the side effect, providing new avenues to develop drug delivery systems for remote on-demand drug delivery in vivo.

Topics: Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Chlorophyllides; Delayed-Action Preparations; Doxorubicin; Drug Delivery Systems; Drug Liberation; Female; Light; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasms; Photosensitizing Agents; Porphyrins; Reactive Oxygen Species

Photo-Chemo combination therapy has been intensively investigated for treatment of cancers, especially multidrug resistance cancer. However, antagonistic interactions between chemo-drugs and photosensitizers are frequently reported, and drugs doses and treatment sequences have been changed to overcome the problems. We observed the antagonistic effect by a decrease in singlet oxygen generation from the photosensitizer when Dox was in close physical proximity. To control the distance between Dox and the photosensitizer, we developed a novel pH-sensitive poly ionomer complex system composed of PEG-PLL(-g-Ce6) [Chlorin e6 grafted poly(ethylene glycol)-poly(l-lysine)] and PEG-PLL(-g-DMA)-PLA [2,3-dimethylmaleic anhydride grafted poly(ethylene glycol)-poly(l-lysine)-poly(lactic acid)] and evaluated this system with regard to singlet oxygen generation and antiproliferative activity against MCF-7/Dox cells. Enhanced singlet oxygen generation and antiproliferative activities were observed in vitro and in vivo for the poly ionomer complex system compared to PEG-PLL(-g-Ce6)-PLA/Dox due to the change in distance between Dox and Ce6 in the PIC system under acidic conditions. Our results highlight the importance of interactions between co-loaded drugs in combination therapy, and provide new insights into design principles for tailor-made nanomedicine platforms.

Topics: Animals; Antibiotics, Antineoplastic; Cell Proliferation; Chlorophyllides; Delayed-Action Preparations; Doxorubicin; Drug Resistance, Multiple; Female; Humans; MCF-7 Cells; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Photosensitizing Agents; Polyesters; Polyethylene Glycols; Polylysine; Porphyrins

Topics: Animals; Carbon; Cell Line, Tumor; Cell Survival; Chlorophyllides; Combined Modality Therapy; Female; Humans; Hypothermia, Induced; Infrared Rays; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Confocal; Neoplasms; Photochemotherapy; Photosensitizing Agents; Phototherapy; Porphyrins; Quantum Dots; Transplantation, Heterologous

Topics: Animals; Cell Line, Tumor; Cell Survival; Chlorophyllides; Disulfides; Humans; Hyaluronic Acid; Mice; Microscopy, Confocal; Molybdenum; Multimodal Imaging; Nanocomposites; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Phototherapy; Porphyrins; Quantum Dots; Silicon Dioxide; Singlet Oxygen; Transplantation, Heterologous

Taking advantage of the mesoporous structure of bismuth sulfide nanostars (Bi

Topics: Animals; Antibiotics, Antineoplastic; Bismuth; Cell Line, Tumor; Chlorophyllides; Delayed-Action Preparations; Doxorubicin; Hyperthermia, Induced; Mice; Nanoparticles; Neoplasms; Optical Imaging; Photochemotherapy; Photosensitizing Agents; Polyethylene Glycols; Porosity; Porphyrins; Sulfides; Theranostic Nanomedicine; Tomography, X-Ray Computed

Nanoparticles have been extensively used for inflammation imaging and photodynamic therapy of cancer. However, the major translational barriers to most nanoparticle-based imaging and therapy applications are the limited depth of tissue penetration, inevitable requirement of external irradiation, and poor biocompatibility of the nanoparticles. To overcome these critical limitations, we synthesized a sensitive, specific, biodegradable luminescent nanoparticle that is self-assembled from an amphiphilic polymeric conjugate with a luminescent donor (luminol) and a fluorescent acceptor [chlorin e6 (Ce6)] for in vivo luminescence imaging and photodynamic therapy in deep tissues. Mechanistically, reactive oxygen species (ROS) and myeloperoxidase generated in inflammatory sites or the tumor microenvironment trigger bioluminescence resonance energy transfer and the production of singlet oxygen (

Topics: A549 Cells; Animals; Antineoplastic Agents; Chlorophyllides; Humans; Inflammation; Luminescence; Luminescent Agents; Luminol; Male; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Nanoparticles; Neoplasms; Photochemotherapy; Polymers; Porphyrins; RAW 264.7 Cells; Reactive Oxygen Species; Theranostic Nanomedicine; Xenograft Model Antitumor Assays

Precision diagnosis and effective treatment are the cores of early cancer therapy. Here, for the first time, we report a hybridization chain reaction-based nanoprobe for selective and sensitive cancer cell recognition and amplified photodynamic therapy.

Topics: Adsorption; Cell Survival; Chlorophyllides; DNA; Drug Delivery Systems; Graphite; HEK293 Cells; HeLa Cells; Humans; Neoplasms; Nucleic Acid Hybridization; Photochemotherapy; Photosensitizing Agents; Porphyrins

Photodynamic therapy (PDT) is an approved modality for the treatment of various types of maligancies and diseased states. However, most of the available photosensitizers (PS) are highly hydrophobic, which limits their solubility and dispersion in biological fluids and can lead to self-quenching and sub-optimal therapeutic efficacy. In this study, chlorin e6 (Ce6)-coated superparamagnetic iron oxide nanoparticle (SPION) nanoclusters (Ce6-SCs) were prepared via an oil-in-water emulsion. The physical-chemical properties of the Ce6-SCs were systematically evaluated. Dual-mode imaging and PDT was subsequently performed in tumor-bearing mice. Chlorin e6 is capable of solubilizing hydrophobic SPION into stable, water-soluble nanoclusters without the use of any additional amphiphiles or carriers. The method is reproducible and the Ce6-SCs are highly stable under physiological conditions. The Ce6-SCs have an average diameter of 92 nm and low polydispersity (average PDI < 0.2). Encapsulation efficiency of both Ce6 and SPION is ≈100%, and the total Ce6 payload can be as high as 56% of the total weight (Ce6 + Fe). The Ce6-SCs localize within tumors via enhanced permeability and retention and are detectable by magnetic resonance (MR) and optical imaging. With PDT, Ce6-SCs demonstrate high singlet oxygen generation and produce a significant delay in tumor growth in mice.

Topics: Animals; Cell Death; Cell Line, Tumor; Chlorophyllides; Dextrans; Diagnostic Imaging; Disease Models, Animal; Human Umbilical Vein Endothelial Cells; Humans; Magnetic Resonance Imaging; Magnetite Nanoparticles; Mice, Nude; Neoplasms; Optical Imaging; Photochemotherapy; Porphyrins; Singlet Oxygen; Theranostic Nanomedicine; Tumor Burden

In this work, novel amphiphilic diblock copolymers of polyethylene glycol and polyphosphoester with pendant thioether groups, denoted as mPEG- b-PMSPEP, were synthesized through the ring-opening polymerization of functionalized cyclic phosphoester monomer using methoxy poly(ethylene glycol) and Sn(Oct)

Topics: Cell Line, Tumor; Chlorophyllides; Delayed-Action Preparations; Drug Carriers; Humans; Hydrogen Peroxide; Nanoparticles; Neoplasms; Paclitaxel; Polyethylene Glycols; Porphyrins

Nanosized self-assemblies built from inorganic nanoparticles and polymer ligands have the potential to generate personalized theranostics systems for diagnostic imaging and cancer therapy. However, most of the theranostics systems suffer from poor targeting activity, insensitive diagnosis and drug leakage, leading to poor treatment results. In this study, a hierarchical tumor acidity-responsive magnetic nanobomb (termed HTAMN) was developed for photodynamic therapy and diagnostic imaging. The HTAMNs were formed through the self-assembly of chlorin e6 (Ce6)-functionalized polypeptide ligand, methoxy poly (ethyleneglycol)-block-poly (dopamine-ethylenediamine-2,3-dimethylmaleic anhydride)-L-glutamate-Ce6 [mPEG-b-P (Dopa-Ethy-DMMA)LG-Ce6] and superparamagnetic iron oxide nanoparticles (SPIONs). Negatively charged HTAMNs circulate in the blood for prolonged periods and promote tumor retention by passive targeting to the tumor. Once the HTAMNs arrive at the tumor location, the acidic extracellular tumor environment reverses the surface charge of the HTAMNs, resulting in tumor accumulation and cellular uptake. Moreover, in response to the more acidic environment inside cells, the photosensitizers are activated resulted in enhanced diagnostic imaging and cancer treatment. The in vitro and in vivo results indicate the effective tumor accumulation, internalization, diagnostic sensitivity and superior photodynamic therapy effect of the HTAMNs. Therefore, designing smart HTAMNs can promote the rapid development of cancer theranostics for clinical implementation.

Topics: Animals; Cell Survival; Chlorophyllides; Diagnostic Imaging; Ferric Compounds; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Magnetic Phenomena; Mice, Nude; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Polymers; Porphyrins; Theranostic Nanomedicine

We demonstrate a MnO2-based nanoreactor to achieve continuous oxygen generation and efficient conversion from glucose to singlet oxygen for combined photodynamic-starvation therapy.

Topics: Animals; Cell Line, Tumor; Cell Membrane; Chlorophyllides; Enzymes, Immobilized; Female; Glucose; Glucose Oxidase; Hydrogen Peroxide; Manganese Compounds; Mice, Inbred BALB C; Nanoparticles; Neoplasms; Oxides; Photochemotherapy; Photosensitizing Agents; Porphyrins; Singlet Oxygen; Tumor Hypoxia

Multifunctional nanodrugs with the integration of precise diagnostic and effective therapeutic functions have shown great promise in improving the efficacy of cancer therapy. We report herein a simple and effective approach to directly assemble an anticancer drug (curcumin), a photodynamic agent (Ce6) and tumor environment-sensitive molecules into cross-linked polyphosphazene and coat on superparamagnetic Fe3O4 nanoclusters to form discrete nanoparticles (termed as FHCPCe NPs). FHCPCe NPs have high physiological stability and good biocompatibility, and can enhance accumulation in tumor tissue via the enhanced permeability and retention effect. Meanwhile, the FHCPCe NPs exhibit an effective performance of dual-modality magnetic resonance imaging (MRI) due to the Fe3O4 cores and fluorescence imaging (FL) in the xenografted HeLa tumor because of the fluorescence of Ce6. Importantly, under the conditions of supernormal glutathione levels and acidic microenvironment in tumor tissue, curcumin and Ce6 can be effectively released by the degradation of FHCPCe NPs. Therefore, excellent anti-tumor effects both in vitro and in vivo have been achieved by synergistic chemotherapy/photodynamic therapy (CT/PDT) using multifunctional NPs. Our study highlights the promise of developing multifunctional nanomaterials for accurate multimodal imaging-guided highly sensitive therapy of cancer.

Topics: Animals; Chlorophyllides; Curcumin; Drug Carriers; Ferrosoferric Oxide; HeLa Cells; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Imaging; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasms; Organophosphorus Compounds; Oxidation-Reduction; Photochemotherapy; Photosensitizing Agents; Polymers; Porphyrins; Reactive Oxygen Species; Transplantation, Heterologous; Whole Body Imaging

Hypoxia is the trickiest barrier for oncotherapy, which can cause the resistance of various tumor treatments, even promote cancer progression and metastasis, especially in the treatment of photodynamic therapy (PDT). Therefore, alleviating tumor hypoxia would be a favorable modality to improve PDT treatment. In this study, we designed an innovative biological oxygen-evolving material, autotrophic light-triggered green affording‑oxygen engine (ALGAE), which could perform an on-off switchable and inexhaustible oxygen generation triggered by the same irradiation of PDT with good biocompatibility and degradability. And the hypoxia-resistant PDT induced by ALGAE could successfully eradicate tumors and avoid tumor metastasis. The ALGAE system could be standby in a long period for efficient oxygen-affording around tumors, which not only dramatically alleviated tumor hypoxia but also achieved a high-efficiency and repetitive PDT treatments. Furthermore, the innovative biological oxygen-affording engine described in the study presents a new class of oxygen-generating material for hypoxia-resistant cancer therapy.

Topics: Animals; Cell Line, Tumor; Chlorella; Chlorophyllides; Female; Light; Mice, Inbred BALB C; Neoplasms; Oxygen; Photochemotherapy; Porphyrins; Radiation-Sensitizing Agents; Reactive Oxygen Species; Tumor Hypoxia; Wound Healing

Covalently self-assembled polymer nanocapsules (NCs) based on cucurbit[6]uril have been previously prepared and their applications in payload delivery and bioimaging have been demonstrated, showing significant potentials. However, the preparation of these NCs often requires laborious and tedious multistep reactions, including a low-yield conversion of perhydroxycucurbit[6]uril to perallyloxycucurbit[6]uril, subsequent photopolymerization of perallyloxycucurbit[6]uril with dithiol linkers, and two additional steps of treatment to remove disulfide loops and create cationic sulfoniums. Herein, we report a novel, facile approach leading to cucurbit[6]uril-based polymer NCs via direct alkylation of perhydroxycucurbit[6]uril with a ditopic linker, thereby saving significant time and efforts, which may lead to significant expansion in investigations of these unique materials in various applications, particularly biomedical sciences. As a proof of concept, we have further demonstrated that a photosensitive therapeutic payload, such as chlorin e6, may get encapsulated inside the NCs for improved, targeted photodynamic therapy against cancer cells.

Topics: Alkylation; Bridged-Ring Compounds; Chlorophyllides; Humans; Imidazoles; Nanocapsules; Neoplasms; Photochemotherapy; Polymers; Porphyrins

This paper describes the fabrication and evaluation of phase-change material (PCM) nanoparticles containing chlorin e6 (Ce6) and nanodiamonds (NDs) for photodynamic and photothermal approaches for tumor therapy, respectively. The temperature of the PCM nanoparticles containing NDs (ND/PCM, 0.5mg/mL in water) is increased to 45°C during laser exposure for 5min. The singlet oxygen generation intensity of PCM nanoparticles containing Ce6 and NDs (Ce6/ND/PCM) is gradually increased with respect to the laser exposure time. Also, the release of Ce6 from Ce6/ND/PCM can be controlled in an on-and-off manner using laser. Cell ablation tests reveal that Ce6/ND/PCM greatly ablates KB cells upon laser exposure, which is attributed to both the temperature increase in the media and singlet oxygen generation by the released Ce6. In an animal model, tumor volume is notably reduced over time after the intratumoral injection of Ce6/ND/PCM and subsequent laser exposure with a higher efficiency compared to ND/PCM. The Ce6/ND/PCM can be a promising nanomedicine for tumor therapy.

Topics: Animals; Cell Line; Cell Survival; Chlorophyllides; Humans; Lasers; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Phototherapy; Porphyrins; Radiation-Sensitizing Agents; Singlet Oxygen

The use of polymeric carriers to deliver hydrophobic photosensitizers has been widely discussed as a way to improve both fluorescence diagnostic and photodynamic therapy (PDT) of cancers; however, the photophysical and pharmacokinetic parameters, as well as the PDT activity, of such modifications have, until now, only been poorly investigated. The purpose of the present study was to explore the efficacy of PDT with the formulation of the photosensitizer chlorin e6 (Ce6) in combination with polyvinyl alcohol (PVA) in comparison with Ce6 alone and with the clinical drug, Photodithazine in a mouse tumor model. We also investigated the photoactivity of the Ce6-PVA in a model reaction of tryptophan oxidation, analyzed the polymer-Ce6 interaction using fluorescence spectroscopy and atomic-force microscopy, and tested the phototoxicity in vitro. Using fluorescence imaging in vivo we found that injection to mice of Ce6 in a formulation with PVA resulted in a higher tumor-to-normal ratio and greater photobleaching when compared with either the use of Ce6 alone, or with the effects of Photodithazine. Tumor growth study and histological examination of CT26 tumors revealed fast, reproducible tumor regression and more advanced necrosis after PDT with Ce6-PVA. The higher photoactivity of the Ce6-PVA complex was confirmed in a model reaction of tryptophan oxidation and in cultured cells. Therefore, encapsulation of Ce6 in PVA represents a promising strategy for further increasing the selectivity and efficacy of PDT.

Topics: Animals; Cell Line, Tumor; Cell Survival; Chlorophyllides; Disease Models, Animal; Mice; Mice, Inbred BALB C; Microscopy, Atomic Force; Microscopy, Confocal; Neoplasms; Oxidation-Reduction; Photochemotherapy; Photosensitizing Agents; Polyvinyl Alcohol; Porphyrins; Reactive Oxygen Species; Spectrometry, Fluorescence; Transplantation, Homologous; Tryptophan; Whole Body Imaging

The protein corona is inevitably formed on nanoparticles (NPs) when they are introduced in vivo and has been associated with a reduction in targeting yield, immune recognition and rapid blood clearance, leading to poor tumor accumulation. We have recently shown that it is possible to exploit the protein corona for drug delivery by exploiting it for loading and triggering the release of a photosensitizer Chlorin e6 (Ce6) for simultaneous photodynamic (PDT) and photothermal therapy (PTT) in vitro. Here, we extended our previous in vitro studies to evaluate its effectiveness in vivo. Specifically, we pre-formed the protein corona from mouse serum (MS) around gold nanorods (NRs) and loaded it with Ce6 to form NR-MS-Ce6. The intravenous delivery of NR-MS-Ce6 at a dose of 10 mg kg

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Drug Delivery Systems; Female; Gold; Humans; Mice; Mice, Nude; Nanotubes; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Protein Corona; Xenograft Model Antitumor Assays

The development of activatable nanoplatforms to simultaneously improve diagnostic and therapeutic performances while reducing side effects is highly attractive for precision cancer medicine. Herein, we develop a one-pot, dopamine-mediated biomineralization method using a gas diffusion procedure to prepare calcium carbonate-polydopamine (CaCO

Topics: Animals; Calcium Carbonate; Cell Line, Tumor; Chlorophyllides; Delayed-Action Preparations; Female; Hydrogen-Ion Concentration; Indoles; Magnetic Resonance Imaging; Mice; Mice, Inbred BALB C; Multimodal Imaging; Nanoparticles; Neoplasms; Optical Imaging; Photochemotherapy; Photosensitizing Agents; Polymers; Porphyrins; Theranostic Nanomedicine

The photosensitizer Chlorin e6 (Ce6) has been frequently employed for photodynamic therapy (PDT) of cancer; however, its nonspecific toxicity has limited its clinical applications. In this study, we prepared chitosan nanoparticles (CNPs), with a mean diameter of approximately 130 nm, by a nonsolvent-aided counterion complexation method in an aqueous solution, into which Ce6 could be physically entrapped during the preparation process. These CNPs and Ce6-loaded CNPs (CNPs-Ce6) were fully characterized by UV-vis, photoluminescence, and Fourier transform infrared spectroscopic analysis, as well as dynamic light scattering and transmission electron microscopy measurements. More importantly, the biocompatibility of the otherwise toxic Ce6 was significantly improved upon its loading into the CNPs, as demonstrated by both confocal laser scanning microscopy analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Furthermore, the PDT efficiency of Ce6-loaded CNPs was dramatically enhanced, in comparison with that of the free Ce6, as shown by both MTT and flow cytometry assays. This discovery provides a novel strategy for improving the biocompatibility and therapeutic efficacy of PDT agents by using a natural, biocompatible polysaccharide carrier.

Topics: Chitosan; Chlorophyllides; Humans; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins

The cytotoxicity and unique tumor-tropic properties of cytokine-induced killer (CIK) cells render them promising in the field of cancer immunotherapy and delivery systems. Here, we report a novel and facile approach to assemble gold nanoclusters (GNCs) into stable and monodispersed nanoparticles (NPs) using Chlorin e6 (Ce6) molecules. Notably, the fluorescence intensity of the GNCs-Ce6 NPs was about 4.5 folds stronger than the GNCs counterparts. The as-prepared GNCs-Ce6 NPs were conjugated with CD3 antibody (Ab) and further employed to label CIK cells to create a CIK cell-based drug delivery system (Ce6-GNCs-Ab-CIK). The Ce6-GNCs-Ab-CIK exhibited high tumor-targeting efficiency and excellent therapeutic efficacy toward MGC-803 tumor-bearing mice. Benefiting from the synergistic therapeutic effect between GNCs-Ce6-Ab NPs and CIK cells, the GNCs-Ce6-Ab-CIK strategy may present an ideal cancer theranostic platform for tumor targeted imaging and combination therapy.

Topics: Animals; Antibodies; Cell Line, Tumor; Chlorophyllides; Cytokine-Induced Killer Cells; Cytokines; Drug Delivery Systems; Endocytosis; Gold; Humans; Immunotherapy; Metal Nanoparticles; Mice, Inbred C57BL; Mice, Nude; Neoplasms; Phenotype; Photochemotherapy; Porphyrins

Topics: Chlorophyllides; Doxorubicin; Humans; Hydrogen Peroxide; MCF-7 Cells; Nanoparticles; Neoplasms; Photochemotherapy; Polycarboxylate Cement; Porphyrins

Cancer cells in hypoxic tumors are remarkably resistant to photodynamic therapy. Here, we hypothesize that an oxygen and Pt(II) self-generating multifunctional nanocomposite could reverse the hypoxia-triggered PDT resistance. The nanocomposite contains Pt(IV) and chlorin e6, in which upconversion nanoparticles are loaded to convert 980 nm near-infrared light into 365 nm and 660 nm emissions. Upon accumulation at the tumor site, a 980 nm laser is used to trigger the nanocomposite to generate O

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Female; Humans; Hypoxia; Male; Mice; Mice, Nude; Nanoparticles; Neoplasms; Oxygen; Photochemotherapy; Photosensitizing Agents; Platinum; Porphyrins; Prodrugs; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

To overcome the limitations of single therapy, chemotherapy has been studied to be combined with photodynamic therapy. However, nanomedicine combining anticancer drug and photosensitizer still cannot address the insufficiency of drug delivery and the off-targeting effect. To address drug delivery issue, we have developed a doxorubicin encapsulating human serum albumin nanoparticles/chlorin e6 encapsulating microbubbles (DOX-NPs/Ce6-MBs) complex system. Microbubbles enable ultrasound-triggered local delivery via sonoporation for maximizing the drug delivery to a target site. In both in vitro and in vivo experiments, the developed DOX-NPs/Ce6-MBs drug delivery complex could be confirmed to transfer drugs deeply and effectively into cancerous tumors through the following three steps; (1) the local release of nanoparticles due to the cavitation of DOX-NPs/Ce6-MBs; (2) the enhanced extravasation of DOX-NPs and Ce6-liposome/micelle due to the sonoporation phenomenon; (3) the improved penetration of extravasated nanomedicines into the deep tumor region due to the mechanical energy of ultrasound. As a result, the developed DOX-NPs/Ce6-MBs complex with ultrasound irradiation showed increased therapeutic effects compared to the case where no ultrasound irradiation was applied. The DOX-NPs/Ce6-MBs was concluded from this study to be the optimal drug delivery system for external-stimuli local combination (chemotherapy + PDT) therapy.

Topics: Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Chlorophyllides; Doxorubicin; Humans; Male; Mice, Inbred BALB C; Microbubbles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Radiation-Sensitizing Agents; Tumor Burden; Ultrasonic Waves

Photodynamic therapy (PDT) is commonly restricted by inefficient tumor selectivity during clinical study. Hence, a mitochondria-targeting multifunctional nanocarrier "theranosome (TNS)" was developed for near-infrared fluorescent (NIRF) imaging and photoacoustic (PA) imaging. What's more, the TNS can also enhance PDT efficacy. In this work, chlorin e6 (Ce6) undertakes reactive oxygen generation and fluorescence emission. Ce6 was quenched when being encapsulated into TNS together with IR780 iodide. When exposed under 808 nm NIR light, IR780 from the TNS can be photobleached; thus, the phototoxicity of Ce6 can be activated. The IR780 induced hyperthermia damaged tumor cells to perform photothermal therapy (PTT) effect. Then lysosomes disruption under PTT facilitated PDT effect induced by Ce6 through enhanced cytoplasmic delivery. Moreover, in vitro subcellular uptake experiments showed that triphenylphosphonium (TPP) group attached to the IR780/Ce6 TNS (ICT) could promote mitochondria targeting capacity. It can lead to PDT induced oxidizing damage to the mitochondria by mitochondrial membrane potential decreasing and cell apoptosis eventually. In in vivo antitumor studies, the TPP/IR780/Ce6 TNS (TICT) substantially repressed tumor growth in nude mice. Besides, we did not find any obvious side effects to normal tissues and organs. The results suggested the TICT conjugate provided a dual NIRF/PA tumor imaging modalities with spatial resolution and superior imaging contrast. This study offered an improved phototherapy for potential theranostic application.

Topics: Animals; Apoptosis; Chlorophyllides; Drug Carriers; Drug Compounding; Female; Fluorescence; HeLa Cells; Humans; Hyperthermia, Induced; Indoles; Infrared Rays; Intravital Microscopy; Lysosomes; Membrane Potential, Mitochondrial; Mice; Mice, Nude; Mitochondria; Nanoparticles; Neoplasms; Optical Imaging; Organophosphorus Compounds; Photochemotherapy; Porphyrins; Theranostic Nanomedicine; Xenograft Model Antitumor Assays

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Delayed-Action Preparations; Fatty Acids; Female; Light; Lipid Peroxidation; Mice; Mice, Inbred BALB C; Micelles; Neoplasms; Photosensitizing Agents; Porphyrins; Singlet Oxygen

Supramolecular photosensitizer nanodrugs that combine the flexibility of supramolecular self-assembly and the advantage of spatiotemporal, controlled drug delivery are promising for dedicated, precise, noninvasive tumor therapy. However, integrating robust blood circulation and targeted burst release in a single photosensitizer nanodrug platform that can simultaneously improve the therapeutic performance and reduce side effects is challenging. Herein, we demonstrate a multicomponent coordination self-assembly strategy that is versatile and potent for the development of photodynamic nanodrugs. Inspired by the multicomponent self-organization of polypeptides, pigments, and metal ions in metalloproteins, smart metallo-nanodrugs are constructed based on the combination and cooperation of multiple coordination, hydrophobic, and electrostatic noncovalent interactions among short peptides, photosensitizers, and metal ions. The resulting metallo-nanodrugs have uniform sizes, well-defined nanosphere structures, and high loading capacities. Most importantly, multicomponent assembled nanodrugs have robust colloidal stability and ultrasensitive responses to pH and redox stimuli. These properties prolong blood circulation, increase tumor accumulation, and enhance the photodynamic tumor therapeutic efficacy. This study offers a new strategy to harness robust, smart metallo-nanodrugs with integrated flexibility and multifunction to enhance tumor-specific delivery and therapeutic effects, highlighting opportunities to develop next-generation, smart photosensitizing nanomedicines.

Topics: Animals; Chlorophyllides; Coordination Complexes; Dipeptides; Drug Carriers; Female; Histidine; Humans; Light; MCF-7 Cells; Metal Nanoparticles; Mice, Inbred BALB C; Neoplasms; Particle Size; Photochemotherapy; Photosensitizing Agents; Porphyrins; Zinc

In this paper, we introduce a new drug delivery system (DDS) called magneto low-density nanoemulsion (MLDE), which can carry maghemite nanoparticles and Chlorin e6 as an active photosensitizer drug. This design can enhance tumor damage after minor heat dissipation and/or minimum visible light photosensitization doses by classical magnetic hyperthermia (MHT) and photodynamic therapy (PDT), respectively. We establish protocols to prepare the MLDE and to load the drug combination onto it. The MLDE prepared herein is nanometric (<200 nm), has high encapsulation efficiency, and is stable for at least 12 months in water dispersions. Flow cytometry results demonstrated that MLDE presents targeted selectivity toward the MCF-7 breast cancer cell line but not in NHI-3T3 mouse fibroblast cell lines, because the MCF-7 cancer cell surface contains overexpressed low density lipoprotein (LDL) receptors. Despite this targeted effect, MHT or PDT alone does not prompt significant antiproliferative outcomes. On the other hand, MHT and PDT in combination induce a strong and synergic action on MCF-7 cells and reduce the cell viability. In conclusion, the developed MLDE deserves further investigation because it is biocompatible, displays good encapsulation efficiency, and is highly stable. Moreover, it is selectively taken up by cancer cell surfaces with receptor recognition based on LDL receptor overexpression, which potentiates the action of combined MHT and PDT.

Topics: Animals; Cell Survival; Chlorophyllides; Drug Carriers; Humans; Hyperthermia, Induced; Light; Magnetics; MCF-7 Cells; Mice; Nanostructures; Neoplasms; NIH 3T3 Cells; Particle Size; Photochemotherapy; Photosensitizing Agents; Porphyrins

Hypoxia tumor microenvironment is a major challenge for photodynamical therapy (PDT), and hypoxia-activated chemotherapy combined PDT could be promising for enhanced anticancer therapy. In this study, we report an innovative 2-nitroimidazole derivative conjugated polyethylene glycol (PEG) amphoteric polymer theranostic liposome encapsulated a photosensitizer Chlorin e6 (Ce6), hypoxia-activated prodrug Tirapazamine (TPZ) and gene probe for synergistic photodynamic-chemotherapy. Ce6-mediated PDT upon irradiation with a laser induces hypoxia, which leads to the disassembly of the liposome and activates the antitumor activity of TPZ for improved cancer cell-killing. The released co-delivered gene probe could effectively detect the oncogenic intracellular biomarker for diagnosis. Both in vitro and in vivo studies demonstrated the greatly improved anti-cancer activity compared to conventional PDT. This work contributes to the design of hypoxia-responsive multifunctional liposome for tumor diagnosis and hypoxia-activated chemotherapy combined PDT for synergetic therapy, which holds great promise for future cancer therapy.

Topics: Animals; Antineoplastic Agents; Chlorophyllides; Delayed-Action Preparations; Humans; Light; Liposomes; MCF-7 Cells; Mice; Neoplasms; Nitroimidazoles; Optical Imaging; Photosensitizing Agents; Polyethylene Glycols; Porphyrins; Theranostic Nanomedicine; Tirapazamine; Tumor Hypoxia

Hypoxia in solid tumors may be a hindrance to effective treatments of tumors in achieving their therapeutic potential, especially for photodynamic therapy (PDT) which requires oxygen as the supplement substrate. Oxygen delivery using perfluorocarbon emulsions or lipid oxygen microbubbles has been developed as the agents to supply endogenous oxygen to fuel singlet oxygen generation in PDT. However, such methods suffer from premature oxygen release and storage issues. To address these limitations, we designed lipid-polymer bilaminar oxygen nanobubbles with chlorin e6 (Ce6) conjugated to the polymer shell as a novel oxygen self-supplement agent for PDT. The resultant nanobubbles possessed excellent stability to reduce the risk of premature oxygen release and were stored as freeze-dried powders to avoid shelf storage issues. In vitro and in vivo experimental results demonstrated that the nanobubbles exhibited much higher cellular uptake rates and tumor targeting efficiency compared to free Ce6. Using the oxygen nanobubbles for PDT, a significant enhancement of therapeutic efficacy and survival rates was achieved on a C6 glioma-bearing mice model with no noticeable side effects, owing to the greatly enhanced singlet oxygen generation powered by oxygen encapsulated nanobubbles.

Topics: Animals; Cell Line, Tumor; Cell Survival; Chlorophyllides; Hypoxia; Lipids; Mice; Mice, Nude; Microbubbles; Nanoparticles; Nanotechnology; Neoplasm Transplantation; Neoplasms; Oxygen; Photochemotherapy; Photosensitizing Agents; Polymers; Porphyrins

Despite great progress in photodynamic therapy (PDT), the therapeutic effect is still limited by some points, such as tumor hypoxia, the short lifetime and the limited action region of 1O2. Herein, a special kind of three-dimensional dendritic mesoporous silica nanosphere (3D-dendritic MSN) was synthesized and used as a robust nanocarrier to deliver abundant hydrophobic photosensitizer chlorin e6 (Ce6) to the A549 lung cancer cells. To address the tumor hypoxia issue, the nanozyme Pt nanoparticles (Pt NPs) were immobilized onto the channels of 3D-dendritic MSNs to catalyze the conversion of intracellular H2O2 to oxygen. Moreover, due to the in situ reduction process, the uniform Pt NPs distributed well on the surface of 3D-dendritic MSNs with high homogeneous dispersity. Additionally, a mitochondria-targeting ligand, triphenylphosphine (TPP), was conjugated to the Pt-decorated 3D-dendritic MSN composites to form a mitochondria targeted system for the PDT. In a combination of the peroxidase-like Pt NPs with mitochondria-targeting ability of TPP, a reactive oxygen species (ROS) burst in the mitochondria was achieved and resulted in the cell apoptosis. This well-designed system shows an enhanced PDT effect of killing A549 cells, and promotes a new H2O2-activatable strategy to overcome hypoxia for tumor PDT.

Topics: A549 Cells; Chlorophyllides; Drug Delivery Systems; Humans; Metal Nanoparticles; Mitochondria; Nanospheres; Neoplasms; Photochemotherapy; Platinum; Porosity; Porphyrins; Silicon Dioxide; Tumor Hypoxia

Multifunctional theranostics have offered some interesting new opportunities for cancer therapy and diagnosis in the last decade. Herein, magnetic mesoporous silica nanoparticles (M-MSNs) were designed and synthesized, then the photosensitizer chlorin e6 (Ce6) and antitumor drug doxorubicin (Dox) were adsorbed onto the M-MSNs. Biocompatible alginate/chitosan polyelectrolyte multilayers (PEM) were assembled on the M-MSNs to achieve a pH-responsive drug delivery system and adsorb P-gp shRNA for reversing the multidrug resistance. The obtained M-MSN(Dox/Ce6)/PEM/P-gp shRNA nanocomposites were characterized using TEM, SEM, X-ray diffraction, BET, FTIR and electrophoresis. The nanocomposites with average diameter of 280 nm exhibited a pH-responsive drug release profile, and more singlet oxygen generation in cancer cells after laser illumination. CCK-8 assay and calcein-AM/PI co-staining showed that the multifunctional nanocomplexes significantly increased cell apoptosis in vitro. With tumor-bearing Balb/c mice employed as the animal model, combined photodynamic therapy and chemotherapy was carried out, also achieving synergistic anti-tumor effects in vivo. The cores of bifunctional Fe

Topics: Alginates; Animals; Antineoplastic Agents; Cell Line, Tumor; Chitosan; Chlorophyllides; Delayed-Action Preparations; Doxorubicin; Drug Delivery Systems; Female; Genetic Therapy; Glucuronic Acid; Hexuronic Acids; Hydrogen-Ion Concentration; Magnetic Resonance Imaging; Mice, Inbred BALB C; Nanocomposites; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Silicon Dioxide; Theranostic Nanomedicine

Topics: Acids; Antineoplastic Agents; Cell Line, Tumor; Chlorophyllides; Gadolinium; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Imaging; Nanoparticles; Neoplasms; Optical Imaging; Photochemotherapy; Porphyrins

Photodynamic therapy (PDT) efficacy is limited by the very short half-life and limited diffusion radius of singlet oxygen (

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Drug Carriers; Drug Liberation; Female; Imidazoles; Light; Mice, Inbred BALB C; Micelles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Singlet Oxygen

Therapeutic effects of photodynamic therapy (PDT) are limited by cancer hypoxia because the PDT process is dependent on O

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Ferric Compounds; Humans; Hypoxia; Manganese Compounds; Mice; Nanoparticles; Neoplasms; Oxygen; Photochemotherapy; Photosensitizing Agents; Porphyrins; Silicon Dioxide

In this study, we report the synthesis of the tumor acidity-activatable amorphous porous manganese phosphate nanoparticles and their application for a photoactivable synergistic nanosystem that imparts reactive oxygen species (ROS) induced cytotoxicity in synchrony with hypoxia-inducible factor 1α/vascular endothelial growth factor (HIF-1α/VEGF) inhibitor that suppresses tumor growth and treatment escape signalling pathway. Besides, upon the stimulus of the tumor acid microenvironment, the manganese phosphate nanoparticles finally disintegrate and release Mn

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Contrast Media; Delayed-Action Preparations; Humans; Magnetic Resonance Imaging; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Organometallic Compounds; Photochemotherapy; Porphyrins; Xenograft Model Antitumor Assays

A polyelectrolyte nanoparticle composed of PEG-PLL(-

Topics: Animals; Chlorophyllides; Drug Carriers; Female; Humans; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; KB Cells; Maleic Anhydrides; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Polyesters; Polyethylene Glycols; Polylysine; Porphyrins

The polysaccharide chitosan has abundant cationic amine groups, and can form ion-complexes with anionic molecules such as the strong photosensitizer chlorin e6 (Ce6). In this study, water-soluble chitosan (WSC) was used to fabricate Ce6-incorporated nanophotosensitizers (Abbreviated as ChitoCe6 nanophotosensitizer) via a self-assembling process. This was accomplished by dissolving WSC in pure water and then directly mixing the solution with solid Ce6 causing ion complex formation between WSC and Ce6. The resulting nanophotosensitizer was spherical in shape and had a particle size of less than 300nm. The photodynamic effect of ChitoCe6 nanophotosensitizer was evaluated using gastrointestinal (GI) cancer cells. At in vitro study using SNU478 cholangiocarcinoma cells, ChitoCe6 nanophotosensitizer showed improved Ce6 uptake by tumor cells, reactive oxygen species production, and cellular phototoxicity. An in vivo study using SNU478-bearing nude mice showed that the ChitoCe6 nanophotosensitizer efficiently accumulated in the tumor tissue and inhibited tumor growth more than treatment with Ce6 alone. Furthermore, ChitoCe6 nanophotosensitizer was also efficiently absorbed through tissue layers in an ex vivo study using porcine bile duct explants. ChitoCe6 nanophotosensitizer showed enhanced photosensitivity and photodynamic effects against cancer cells in vitro and in vivo. We present ChitoCe6 nanophotosensitizer as a promising candidate for photodynamic therapy of GI cancer.

Topics: Animals; Cell Line, Tumor; Cell Survival; Chitosan; Chlorophyllides; Humans; Light; Male; Mice, Nude; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Reactive Oxygen Species; Solubility; Tumor Burden; Water

Photothermal/photodynamic therapies (PTT/PDT) have been widely accepted as non-invasive therapeutic modalities to erase tumours. However, both therapies face the problem of precisely locating tumours and reducing their side effects. Herein, chlorin e6 conjugated gold nanorod, (Ce6-PEG-AuNR), a type of gold nanorod-photosensitizer conjugate, is designed as a kind of nano-therapeutic agent to simultaneously realize combined PTT/PDT. Compared to free Ce6, the fluorescence of Ce6 adhered to the conjugate is effectively quenched by the longitudinal surface plasmon resonance (LSPR) of in the Ce6-PEG-AuNR. However, the specific fluorescence of Ce6 can be recovered in tumour tissue when Ce6 is separated from the conjugate owing to the cleavage of hydrazone bond between Ce6 and PEG caused by intracellular acidic conditions in tumour tissue. Based on this effect, we can precisely locate tumours and further kill cancer cells by combined PTT/PDT. In addition, the combined therapy (PTT/PDT) function is more efficient in cancer treatment than that of PTT or PDT alone. Therefore, Ce6-PEG-AuNR can serve as a promising dual-modal phototherapeutic agent as well as a tumour-sensitive fluorescent probe to diagnose and treat cancer.

Topics: Animals; Cell Survival; Chlorophyllides; Female; Fluorescence; Gold; HeLa Cells; Humans; Hydrogen-Ion Concentration; Mice, Inbred BALB C; Mice, Nude; Microscopy, Electron, Transmission; Nanotubes; Neoplasms; Photochemotherapy; Porphyrins; Radiation-Sensitizing Agents; Reactive Oxygen Species; Tissue Distribution; Xenograft Model Antitumor Assays

Recent researches in photodynamic therapy have focused on novel techniques to enhance tumour targeting of anticancer drugs and photosensitizers. Coupling a photosensitizer with folic acid could allow more effective targeting of folate receptors which are over-expressed on the surface of many tumour cells. In this study, different folic acid-OEG-conjugated photosensitizers were synthesized, characterized and their photophysical properties were evaluated. The introduction of an OEG does not significantly improve the hydrophilicity of the FA-porphyrin. All the FA-targeted photosensitizers present good to very good photophysical properties. The best one appears to be Ce6. Molar extinction coefficient, fluorescence and singlet oxygen quantum yields were determined and were compared to the corresponding photosensitizer alone.

Topics: Chemistry Techniques, Synthetic; Chlorophyllides; Diethylamines; Folic Acid; Humans; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins

Topics: Animals; Antineoplastic Agents, Phytogenic; Catalase; Cell Line, Tumor; Chlorophyllides; Combined Modality Therapy; Female; Hydrogen Peroxide; Hypoxia; Mice, Nude; Nanoparticles; Neoplasms; Paclitaxel; Porphyrins; Radiation-Sensitizing Agents; Serum Albumin; Theranostic Nanomedicine; Tumor Microenvironment

Nanoengineering of hydrophobic photosensitizers (PSs) is a promising approach for improved tumor delivery and enhanced photodynamic therapy (PDT) efficiency. A variety of delivery carriers have been developed for tumor delivery of PSs through the enhanced permeation and retention (EPR) effect. However, a high-performance PS delivery system with minimum use of carrier materials with excellent biocompatibility is highly appreciated. In this work, we utilized the spatiotemporal interfacial adhesion and assembly of supramolecular coordination to achieve the nanoengineering of water-insoluble photosensitizer Chlorin e6 (Ce6). The hydrophobic Ce6 nanoparticles are well stabilized in a aqueous medium by the interfacially-assembled film due to the coordination polymerization of tannic acid (TA) and ferric iron (Fe(III)). The resulting Ce6@TA-Fe(III) complex nanoparticles (referenced as Ce6@TA-Fe(III) NPs) significantly improves the drug loading content (~65%) and have an average size of 60 nm. The Ce6@TA-Fe(III) NPs are almost non-emissive as the aggregated states, but they can light up after intracellular internalization, which thus realizes low dark toxicity and excellent phototoxicity under laser irradiation. The Ce6@TA-Fe(III) NPs prolong blood circulation, promote tumor-selective accumulation of PSs, and enhanced antitumor efficacy in comparison to the free-carrier Ce6 in vivo evaluation.

Topics: Animals; Cell Survival; Chlorophyllides; Drug Carriers; Female; Ferric Compounds; Humans; Lasers; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Confocal; Nanoparticles; Neoplasms; Particle Size; Photochemotherapy; Photosensitizing Agents; Porphyrins; Tannins; Water

Current photodynamic therapy (PDT) is suffering from limited efficacy towards hypoxia tumors and severe post-treatment photo-toxicity such as light-induced skin damages. To make PDT more effective in cancer treatment while being patient-comfortable, herein, a hexylamine conjugated chlorin e6 (hCe6) as the photosensitizer together with a lipophilic near-infrared (NIR) dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) are co-encapsulated into polyethylene glycol (PEG) shelled liposomes. In the obtained DiR-hCe6-liposome, the photosensitizing effect of hCe6 is quenched by DiR via fluorescence resonance energy transfer (FRET). Interestingly, upon irradiation with a 785-nm NIR laser to photobleach DiR, both fluorescence and photodynamic effect of hCe6 in DiR-hCe6-liposome would be activated. Meanwhile, such NIR irradiation applied on tumors of mice with intravenous injection of DiR-hCe6-liposome could result in mild photothermal heating, which in turn would promote intra-tumor blood flow and relieve tumor hypoxia, contributing to the enhanced photodynamic tumor treatment. Importantly, compared to hCe6-loaded liposomes, DiR-hCe6-liposome without being activated by the 785-nm laser shows much lower skin photo-toxicity, demonstrating its great skin protection effect. This work demonstrates a promising yet simple strategy to prepare NIR-light-activatable photodynamic theranostics for synergistic cancer phototherapy, which is featured high specificity/efficacy in tumor treatment with minimal photo-toxicity towards the skin.

Topics: Animals; Cell Death; Cell Line, Tumor; Chlorophyllides; Endocytosis; Female; Infrared Rays; Liposomes; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Phototherapy; Porphyrins; Skin; Spectrophotometry, Ultraviolet

DNA-driven hierarchical core-satellite nanostructures with plasmonic gold nanorod dimers and upconversion nanoparticles are fabricated. Once the core-satellite structure is activated, combined photothermal therapy and photodynamic therapy are carried out under the guidance of upconversion luminesce, T1 -weighted magnetic resonance, photoacoustics, and computed tomography imaging of tumors in vivo, which exhibit the multifunctional biological applications of the DNA-based self-assemblies.

Topics: Acrylates; Animals; Cell Survival; Chlorophyllides; Exoribonucleases; Gold; HeLa Cells; Humans; Infrared Rays; Mice; Mice, Nude; Nanoparticles; Nanotubes; Neoplasms; Phototherapy; Polystyrenes; Porphyrins; Radiation-Sensitizing Agents; Tomography, X-Ray Computed; Transplantation, Heterologous

Smart delivery system of photosensitizer chlorin e6 (Ce6) has been developed for targeted photodynamic therapy (PDT). Simple self-assemblies of the mixtures comprising soybean lecithin derived phosphatidylcholine (PC), phosphatidylethanolamine-poly(L-histidine)40 (PE-p(His)40), and folic acid (FA) conjugated phosphatidylethanolamine-poly(N-isopropylacrylamide)40 (PE-p(NIPAM)40-FA) in different ratios yield smart nanospheres characterized by (i) stable and uniform particle size (∼100 nm), (ii) positive surface charge, (iii) high hydrophobic drug (Ce6) loading efficiency up to 45%, (iv) covalently linked targeting moiety, (v) low cytotoxicity, and (vi) smartness showing p(His) block oriented pH and p(NIPAM) oriented temperature responsiveness. The Ce6-encapsulated vesicular nanospheres (Ce6@VNS) were used to confirm the efficiency of cellular uptake, intracellular distribution, and phototoxicity against KB tumor cells compared to free Ce6 at different temperature and pH conditions. The Ce6@VNS system showed significant photodynamic therapeutic efficiency on KB cells than free Ce6. A receptor-mediated inhibition study proved the site-specific delivery of Ce6 in targeted tumor cells.

Topics: Acrylamides; Cell Line, Tumor; Chlorophyllides; Histidine; Humans; KB Cells; Nanospheres; Neoplasms; Photochemotherapy; Photosensitizing Agents; Polymers; Porphyrins

A unique matrix metalloproteinase 2-targeted photosensitizer delivery platform was developed in this study for tumor-targeting imaging and photodynamic therapy. The model photosensitizer therapeutic agent chlorin e6 (Ce6) was first covalently conjugated with matrix metalloproteinase 2-cleavable polypeptide and then modified with polyethylene glycol via a redox-responsive cleavable disulfide linker. The resultant matrix metalloproteinase 2-cleavable polypeptide modified PEGylated Ce6 (PEG-SS-Ce6-MMP2) nanoparticles, which formed via self-assembly, were observed to be monodisperse and significantly stable in aqueous solution. In addition, owing to their cellular redox-responsiveness at the cleavable disulfide linker, the PEG-SS-Ce6-MMP2 nanoparticles were able to release Ce6 rapidly. Despite displaying enhanced intracellular internalization, the synthesized PEG-SS-Ce6-MMP2 nanoparticles did not compromise their phototoxic effects toward A549 cancer cells when compared with free Ce6 and PEGylated Ce6 nanoparticles. In vivo experiments further revealed that, in contrast with the free Ce6 or with the PEGylated Ce6 nanoparticles, the PEG-SS-Ce6-MMP2 nanoparticles showed a remarkable increase in tumor-targeting ability and a significantly improved photodynamic therapeutic efficiency in A549 tumor-bearing mice. These results suggest that the PEG-SS-Ce6-MMP2 nanoparticles hold great potential for tumor-targeting imaging and photodynamic therapy.

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Diagnostic Imaging; Humans; Matrix Metalloproteinase 2; Mice; Nanoparticles; Neoplasms; Oxidation-Reduction; Photochemotherapy; Polyethylene Glycols; Porphyrins

Radiotherapy, a common cancer treatment, often adversely affects the surrounding healthy tissue and/or cells. Some tumor tissue-focused radiation therapies have been developed to lower radiation-induced lesion formation; however, achieving tumor cell-targeted radiotherapy (i.e., precisely focusing the radiation efficacy to tumor cells) remains a challenge. In the present study, we developed a novel tumor cell-targeted radiotherapy, named targeted sensitization-enhanced radiotherapy (TSER), that exploits tumor-specific folic acid-conjugated carboxymethyl lauryl chitosan/superparamagnetic iron oxide (FA-CLC/SPIO) micelles to effectively deliver chlorin e6 (Ce6, a sonosensitizer) to mitochondria of HeLa cells under magnetic guidance. For the in vitro tests, the sensitization of Ce6 induced by ultrasound, that could weaken the radiation resistant ability of tumor cells, occurred only in Ce6-internalizing tumor cells. Therefore, low-dose X-ray irradiation, that was not harmful to normal cells, could exert high tumor cell-specific killing ability. The ratio of viable normal cells to tumor cells was increased considerably, from 7.8 (at 24h) to 97.1 (at 72h), after they had received TSER treatment. Our data suggest that TSER treatment significantly weakens tumor cells, resulting in decreased viability in vitro as well as decreased in vivo subcutaneous tumor growth in nude mice, while the adverse effects were minimal. Taken together, TSER treatment appears to be an effective, clinically feasible tumor cell-targeted radiotherapy that can solve the problems of traditional radiotherapy and photodynamic therapy.

Topics: Animals; Chitosan; Chlorophyllides; Drug Delivery Systems; Female; Ferric Compounds; Folic Acid; HeLa Cells; Humans; Magnets; Mice, Nude; Micelles; Neoplasms; Porphyrins; Radiation-Sensitizing Agents

The therapeutic effectiveness of photodynamic therapy (PDT) was hampered by the poor water solubility and instability in physiological conditions of the photosensitizers. Here, we designed folate conjugated thermosensitive liposomes (TSL) as the nanocarrier to improve the solubility, stability and biocompatibility of photosensitizer Chlorin e6 (Ce6). Based on the photothermal effect, we combined copper sulfide (CuS) as the photothermal agent to realize heat-triggered Ce6 release as well as synergistic effect of photothermal and photodynamic therapy. In vitro MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay showed that Ce6-CuS-TSL had low dark toxicity, while performed excellent phototoxicity under the combined 660 and 808 nm laser irradiation compared to any single laser irradiation alone. Moreover, in vivo combination therapy study revealed that Ce6-CuS-TSL inhibited tumor growth to a great extent without evident side effect under the laser irradiation. All detailed evidence demonstrated a considerable potential of Ce6-CuS-TSL for synergistic cancer treatment.

Topics: Animals; Cell Survival; Chlorophyllides; Copper; Drug Stability; Female; Folic Acid; HeLa Cells; Humans; Light; Liposomes; Mice, Inbred BALB C; Mice, Nude; Microscopy, Electron, Transmission; Nanoparticles; Neoplasms; Photochemotherapy; Porphyrins; Reactive Oxygen Species; Solubility

Photodynamic therapy (PDT) is a noninvasive and effective approach for cancer treatment. The main bottlenecks of clinical PDT are poor selectivity of photosensitizer and inadequate oxygen supply resulting in serious side effects and low therapeutic efficiency. Herein, a thermal-modulated reactive oxygen species (ROS) strategy using activatable human serum albumin-chlorin e6 nanoassemblies (HSA-Ce6 NAs) for promoting PDT against cancer is developed. Through intermolecular disulfide bond crosslinking and hydrophobic interaction, Ce6 photosensitizer is effectively loaded into the HSA NAs, and the obtained HSA-Ce6 NAs exhibit excellent reduction response, as well as enhanced tumor accumulation and retention. By the precision control of the overall body temperature instead of local tumor temperature increasing from 37 °C to 43 °C, the photosensitization reaction rate of HSA-Ce6 NAs increases 20%, and the oxygen saturation of tumor tissue raise 52%, significantly enhancing the generation of ROS for promoting PDT. Meanwhile, the intrinsic fluorescence and photoacoustic properties, and the chelating characteristic of porphyrin ring can endow the HSA-Ce6 NAs with fluorescence, photoacoustic and magnetic resonance triple-modal imaging functions. Upon irradiation of low-energy near-infrared laser, the tumors are completely suppressed without tumor recurrence and therapy-induced side effects. The robust thermal-modulated ROS strategy combined with albumin-based activatable nanophotosensitizer is highly potential for multi-modal imaging-guided PDT and clinical translation.

Topics: Albumins; Animals; Cell Line, Tumor; Chlorophyllides; Endocytosis; Humans; Magnetic Resonance Imaging; Mice, Inbred BALB C; Mice, Nude; Multimodal Imaging; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Reactive Oxygen Species; Temperature

Tumor-responsive nanocarriers are highly valuable and demanded for smart drug delivery particularly in the field of photodynamic therapy (PDT), where a quick release of photosensitizers in tumors is preferred. Herein, it is demonstrated that protein-based nanospheres, prepared by the electrostatic assembly of proteins and polypeptides with intermolecular disulfide cross-linking and surface polyethylene glycol coupling, can be used as versatile tumor-responsive drug delivery vehicles for effective PDT. These nanospheres are capable of encapsulation of various photosensitizers including Chlorin e6 (Ce6), protoporphyrin IX, and verteporfin. The Chlorin e6-encapsulated nanospheres (Ce6-Ns) are responsive to changes in pH, redox potential, and proteinase concentration, resulting in multitriggered rapid release of Ce6 in an environment mimicking tumor tissues. In vivo fluorescence imaging results indicate that Ce6-Ns selectively accumulate near tumors and the quick release of Ce6 from Ce6-Ns can be triggered by tumors. In tumors the fluorescence of released Ce6 from Ce6-Ns is observed at 0.5 h postinjection, while in normal tissues the fluorescence appeared at 12 h postinjection. Tumor ablation is demonstrated by in vivo PDT using Ce6-Ns and the biocompatibility of Ce6-Ns is evident from the histopathology imaging, confirming the enhanced in vivo PDT efficacy and the biocompatibility of the assembled drug delivery vehicles.

Topics: Animals; Cell Survival; Chlorophyllides; Drug Delivery Systems; Female; HeLa Cells; Humans; MCF-7 Cells; Mice, Inbred BALB C; Nanospheres; Neoplasms; Particle Size; Peptides; Photochemotherapy; Porphyrins; Protoporphyrins; Serum Albumin; Tissue Distribution; Verteporfin

A new method to image drug release from drug-nanoparticle composites in living cells was established. The composites of silica coated gold nanorods (AuNR@SiO2) and chlorine e6 (Ce6) photosensitizers (AuNR@SiO2-Ce6) were formed by electrostatic force with a Ce6 loading efficiency of 80%. The strong resonance absorptions of AuNR@SiO2-Ce6 in the near-infrared (NIR) region enabled the effective release of Ce6 from AuNR@SiO2-Ce6 by 780 nm CW laser irradiation. The 780 nm laser beam was applied to not only control the releasing amount of Ce6 from cellular AuNR@SiO2-Ce6 by adjusting the irradiation dose (time), but also to spatially confine the Ce6 release in cells by focusing the laser beam on the target sites. Furthermore, the fluorescence lifetime of Ce6 was found to change drastically from 0.9 ns in the AuNR@SiO2-Ce6 complex to 6 ns after release, and therefore fluorescence lifetime imaging microscopy (FLIM) was introduced to image the photo-induced Ce6 release in living cells. Finally, the controllable killing effect of photodynamic cancer therapy (PDT) using AuNR@SiO2-Ce6 was demonstrated by changing the released amount of Ce6, which indicates that AuNR@SiO2-Ce6 is promising for targeted tumour PDT.

Topics: Chlorophyllides; Drug Delivery Systems; Equipment Design; Gold; HeLa Cells; Humans; Lasers; Metal Nanoparticles; Microscopy, Fluorescence; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porosity; Porphyrins; Silicon Dioxide; Singlet Oxygen; Skin; Spectroscopy, Near-Infrared; Static Electricity; Temperature

Stable water-soluble complexes of Cd-free ZnSe/ZnS quantum dots (QDs) and chlorin e6 complexes have been prepared. These complexes have shown approximately 50% intracomplex fluorescence resonance energy transfer from QDs to chlorin e6. The photodynamic therapy (PDT) test of the complexes against the Erlich acsite carcinoma cell culture demonstrated a two-fold enhancement of the cancer cell photodynamic destruction as compared to that of free chlorin e6 molecules. It was shown that the PDT effect was significantly increased due to two factors: the efficient QD-chlorin e6 photoexcitation energy transfer and the improvement of cellular uptake of the photosensitizer in the presence of ZnSe/ZnS QDs.

Topics: Animals; Chlorophyllides; Female; Fluorescence Resonance Energy Transfer; Male; Mice; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Quantum Dots; Tumor Cells, Cultured

The phototoxicity of Chlorin e6 (Ce6) for photodynamic therapy (PDT) was found to be effectively suppressed by indocyanine green (ICG), a near infrared (NIR) dye. Upon NIR laser irradiation at 808 nm, ICG in the liposomes containing ICG and Ce6 could be degraded, while the phototoxicity of Ce6 could be recovered. In addition, we demonstrate that this newly developed liposomal component can be successfully used for activatable PDT to destroy cancer cells in vitro.

Topics: Cell Survival; Chlorophyllides; Coloring Agents; Indocyanine Green; Infrared Rays; Liposomes; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins

Optical energy can trigger a variety of photochemical processes useful for therapies. Owing to the shallow penetration of light in tissues, however, the clinical applications of light-activated therapies have been limited. Bioluminescence resonant energy transfer (BRET) may provide a new way of inducing photochemical activation. Here, we show that efficient bioluminescence energy-induced photodynamic therapy (PDT) of macroscopic tumors and metastases in deep tissue. For monolayer cell culture in vitro incubated with Chlorin e6, BRET energy of about 1 nJ per cell generated as strong cytotoxicity as red laser light irradiation at 2.2 mW/cm(2) for 180 s. Regional delivery of bioluminescence agents via draining lymphatic vessels killed tumor cells spread to the sentinel and secondary lymph nodes, reduced distant metastases in the lung and improved animal survival. Our results show the promising potential of novel bioluminescence-activated PDT.

Topics: Animals; Chlorophyllides; Disease Models, Animal; Humans; Lasers; Luminescence; Mice, Inbred C57BL; Neoplasms; Photochemotherapy; Porphyrins; Radiation-Sensitizing Agents

We report on the application of pristine graphene as a drug carrier for phototherapy (PT). The loading of a photosensitizer, chlorin e6 (Ce6), was achieved simply by sonication of Ce6 and graphite in an aqueous solution. During the loading process, graphite was gradually exfoliated to graphene to give its composite with Ce6 (G-Ce6). This one-step approach is considered to be superior to the graphene oxide (GO)-based composites, which required pretreatment of graphite by strong oxidation. Additionally, the directly exfoliated graphene ensured a high drug loading capacity, 160 wt %, which is about 10 times larger than that of the functionalized GO. Furthermore, the Ce6 concentration for killing cells by G-Ce6 is 6-75 times less than that of the other Ce6 composites including GO-Ce6.

Topics: Chlorophyllides; Drug Delivery Systems; Graphite; Humans; Neoplasms; Oxidation-Reduction; Oxides; Photosensitizing Agents; Phototherapy; Porphyrins

A multifunctional theranostic platform based on photosensitizer (chlorin e6, Ce6)-loaded branched polyethylenimine-PEGylated ceria nanoparticles (PPCNPs-Ce6) was created for the development of effective cancer treatments involving the use of imaging-guided synchronous photochemotherapy. PPCNPs-Ce6 with high Ce6 photosensitizer loading (Ce6: cerium ∼40 wt %) significantly enhanced the delivery of Ce6 into cells and its accumulation in lysosomes, remarkably improving photodynamic therapeutic (PDT) efficacy levels compared to those in the administration of free Ce6 at ultralow drug doses (∼200 nM). Interestingly, PPCNPs-Ce6 efficiently induced HeLa cell death even at low concentrations (∼10 μM) without the use of laser irradiation and exhibit chemocytotoxicity. Inductively coupled plasma mass spectrometry (ICP-MS) and biology transmission electron microscopy (Bio-TEM) analyses demonstrated that ceria nanoparticles enter cells abundantly and accumulate in lysosomes or large vesicles. We then evaluated the effects of the different materials on lysosomal integrity and function, which revealed that PPCNPs-Ce6 catastrophically impaired lysosomal function compared to results with PPCNPs and Ce6. Studies of apoptosis revealed greater induction of apoptosis by PPCNPs-Ce6 treatment. This multifunctional nanocarrier also exhibited a high degree of solubility and stability in aqueous solutions, suggesting its applicability for extensive biomedical application.

Topics: Antineoplastic Agents; Apoptosis; Biocompatible Materials; Cell Line, Tumor; Cell Survival; Cerium; Chlorophyllides; Green Fluorescent Proteins; HeLa Cells; Humans; Lasers; Lysosomes; Microscopy, Confocal; Microscopy, Electron, Transmission; Nanoparticles; Nanotechnology; Neoplasms; Photochemotherapy; Photosensitizing Agents; Polyethylene Glycols; Polyethyleneimine; Porphyrins; Solubility; Spectrophotometry, Ultraviolet

There is currently great interest in the development of efficient and specific carrier delivery platforms for systemic photodynamic therapy. Therefore, we aimed to develop covalent conjugates between the photosensitizer chlorin e6 (Ce6) and PAMAM G4.5 dendrimers. Singlet oxygen generation (SOG) efficiency and fluorescence emission were moderately affected by the covalent binding of the Ce6 to the dendrimer. Compared to free Ce6, PAMAM anchored Ce6 displays a much higher photodynamic effect, which is ascribable to better internalization in a tumor cell model. Intracellular fate and internalization pathway of our different compounds were investigated using specific inhibition conditions and confocal fluorescence microscopy. Free Ce6 was shown to enter the cells by a simple diffusion mechanism, while G4.5-Ce6-PEG internalization was dependent on the caveolae pathway, whereas G4.5-Ce6 was subjected to the clathrin-mediated endocytosis pathway. Subcellular localization of PAMAM anchored Ce6, PEGylated or not, was very similar suggesting that the nanoparticles behave similarly in the cells. As a conclusion, we have demonstrated that PEGylated G4.5 PAMAM-Ce6 dendrimers may offer effective biocompatible nanoparticles for improved photodynamic treatment in a preclinical tumor model.

Topics: Cell Line, Tumor; Cell Survival; Chlorophyllides; Dendrimers; Humans; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Singlet Oxygen

To synthesize and to study for photodynamic activity a composite photosensitizer consisting of chlorin e6 and human serum albumin nanoparticles (HSA NPs).. Starting from sorption-purified HSA, the albumin nanoparticles with a different degree of lysine residues cross-linking (10; 20; 40, and 100%) were obtained by the coacervation method. The HSA NPs were used for synthesis of nanocomposites with chlorin e6 and fluorescein isothiocyanate (FITC)-labeled preparations. Malignant lymphocytes of the MT-4 (human T-cell leukemia) line and normal lymphocytes of healthy donors served as cell targets. For photodynamic treatment, a semiconductor laser was exploited as a light source, and cell viability was assessed by MTT or trypan blue dye exclusion tests. For cell imaging and HSA NPs visualization, the fluorescence microscopy and transmission electron microscopy were applied, respectively. C57Bl/6 mice were used in animal experiments.. The absorption and fluorescence spectra of chlorin e6-HSA NPs composites were characterized, and by the electron microscopy investigation the size of NPs (nanospheres) was estimated: 100-120 nm. FITC-labeled albumin preparations allowed to establish that HSA NPs have much higher exposition and concentration dependent affinity to malignant cell surface than initial HSA. In experiments with MT-4 cells on PDT activity of chlorin e6-HSA NPs, the nanocomposite effectiveness elevated along with increasing percentage of cross-linked amino acid residues, and for the nanocomposite with 100% of albumin cross-linking it exceeded the activity of free chlorin e6. In contrast to malignant cells, the complexation of chlorin e6 with HSA NPs decreased its photodynamic effect on normal human lymphocytes. Intravenous introduction of the chlorin e6-HSA NPs composite to mice showed prolonged circulation of the nanocomposite in blood in comparison with free PS.. Promising results obtained with chlorin e6-HSA NPs composites warrant conduction of full-fledged PDT studies in vivo using the nanocomposites as photosensitizers.

Topics: Albumins; Animals; Biocompatible Materials; Cell Line, Tumor; Chlorophyllides; Humans; Mice; Mice, Inbred C57BL; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins

Multimeric grain-marked micelles consisting of an inner core micelle (for Fe3O4 encapsulation) and outer multi-grain micelles (for chlorin e6 (Ce6, a model drug) encapsulation) were fabricated using a micelle-to-micelle conjugation method. Grain micelles (mono-thiol functionalized micelles) were chemically linked to the surface of the core micelle (multi-maleimide functionalized micelle). These micelles enable discrete compartments for Ce6 and iron oxide (Fe3O4) that enable a significantly increased in vivo photodynamic tumor inhibition while preserving high contrast magnetic resonance (MR) imaging of the tumor in vivo.

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Drug Carriers; Drug Liberation; Female; Humans; Magnetic Resonance Imaging; Magnetite Nanoparticles; Mice, Nude; Micelles; Neoplasms; Photochemotherapy; Porphyrins; Radiation-Sensitizing Agents; Surface Properties; Xenograft Model Antitumor Assays

Photoacoustic imaging is a novel hybrid imaging modality combining the high spatial resolution of optical imaging with the high penetration depth of ultrasound imaging. Here, for the first time, we evaluate the efficacy of various photosensitizers that are widely used as photodynamic therapeutic (PDT) agents as photoacoustic contrast agents. Photoacoustic imaging of photosensitizers exhibits advantages over fluorescence imaging, which is prone to photobleaching and autofluorescence interference. In this work, we examined the photoacoustic activity of 5 photosensitizers: zinc phthalocyanine, protoporphyrin IX, 2,4-bis [4-(N,N-dibenzylamino)-2,6-dihydroxyphenyl] squaraine, chlorin e6 and methylene blue in phantoms, among which zinc phthalocyanine showed the highest photoacoustic activity. Subsequently, we evaluated its tumor localization efficiency and biodistribution at multiple time points in a murine model using photoacoustic imaging. We observed that the probe localized at the tumor within 10 minutes post injection, reaching peak accumulation around 1 hour and was cleared within 24 hours, thus, demonstrating the potential of photosensitizers as photoacoustic imaging contrast agents in vivo. This means that the known advantages of photosensitizers such as preferential tumor uptake and PDT efficacy can be combined with photoacoustic imaging capabilities to achieve longitudinal monitoring of cancer progression and therapy in vivo.

Topics: Cell Line, Tumor; Chlorophyllides; Contrast Media; Cyclobutanes; Diagnostic Imaging; Humans; Indoles; Isoindoles; MCF-7 Cells; Methylene Blue; Neoplasms; Organometallic Compounds; Phenols; Photoacoustic Techniques; Photochemotherapy; Photosensitizing Agents; Porphyrins; Protoporphyrins; Tissue Distribution; Treatment Outcome; Xenograft Model Antitumor Assays; Zinc Compounds

Upconversion nanoparticles (UCNPs) have drawn much attention in cancer imaging and therapy in recent years. Herein, we for the first time report the use of UCNPs with carefully engineered surface chemistry for combined photodynamic therapy (PDT) and gene therapy of cancer. In our system, positively charged NaGdF4:Yb,Er UCNPs with multilayered polymer coatings are synthesized via a layer by layer strategy, and then loaded simultaneously with Chlorin e6 (Ce6), a photosensitizing molecule, and small interfering RNA (siRNA), which targets the Plk1 oncogene. On the one hand, under excitation by a near-infrared (NIR) light at 980 nm, which shows greatly improved tissue penetration compared with visible light, cytotoxic singlet oxygen can be generated via resonance energy transfer from UCNPs to photosensitizer Ce6, while the residual upconversion luminescence is utilized for imaging. On the other hand, the silencing of Plk1 induced by siRNA delivered with UCNPs could induce significant cancer cell apoptosis. As the result of such combined photodynamic and gene therapy, a remarkably enhanced cancer cell killing effect is realized. Our work thus highlights the promise of UCNPs for imaging guided combination therapy of cancer.

Topics: Cell Line, Tumor; Chlorophyllides; Genetic Therapy; HeLa Cells; Humans; Infrared Rays; Microscopy, Confocal; Microscopy, Electron, Transmission; Nanoparticles; Nanotechnology; Neoplasms; Oncogenes; Oxygen; Photochemotherapy; Photosensitizing Agents; Polymers; Porphyrins; RNA, Small Interfering; Surface Properties

Multifunctional theranostics have recently been intensively explored to optimize the efficacy and safety of therapeutic regimens. In this work, a photo-theranostic agent based on chlorin e6 (Ce6) photosensitizer-conjugated silica-coated gold nanoclusters (AuNCs@SiO2-Ce6) is strategically designed and prepared for fluorescence imaging-guided photodynamic therapy (PDT). The AuNCs@SiO2-Ce6 shows the following features: i) high Ce6 photosensitizer loading; ii) no non-specific release of Ce6 during its circulation; iii) significantly enhanced cellular uptake efficiency of Ce6, offering a remarkably improved photodynamic therapeutic efficacy compared to free Ce6; iv) subcellular characterization of the nanoformula via both the fluorescence of Ce6 and plasmon luminescence of AuNCs; v) fluorescence imaging-guided photodynamic therapy (PDT). This photo-theranostics owns good stability, high water dispersibility and solubility, non-cytotoxicity, and good biocompatibility, thus facilitating its biomedical applications, particularly for multi-modal optical, CT and photoacoustic (PA) imaging-guided PDT or sonodynamic therapy.

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Female; Gold; Humans; Mice; Mice, Nude; Nanostructures; Neoplasms; Optical Imaging; Photochemotherapy; Photosensitizing Agents; Porphyrins; Silicon Dioxide

Gold nanorods (AuNRs) were conjugated with chlorin e6 (Ce6), a commonly used photosensitizer, to form AuNRs-Ce6 by electrostatic binding. Due to the strong surface plasmon resonance coupling, the fluorescence of conjugated Ce6 was enhanced 3-fold and the production of singlet oxygen was increased 1.4-fold. AuNRs-Ce6 were taken up by the HeLa and KB cell lines more easily than free Ce6, enhancing the intracellular delivery of Ce6. The increased cellular amount of Ce6 leads to a 3-fold more efficient photodynamic killing of these two cell lines. This demonstrates the potential of this approach to improve photodynamic detection and therapy of cancers.

Topics: Apoptosis; Cell Line, Tumor; Chlorophyllides; Gold; HeLa Cells; Humans; Microscopy, Confocal; Nanotubes; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Singlet Oxygen; Static Electricity

A dual-function nano-system for synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) was constructed. Gold nanorods (GNRs) as a PTT agent and chlorin e6 (Ce6) as a photosensitizer (PS) for PDT were loaded into a chitosan-functionalized, Pluronic-based nanogel that was proven to be an efficient delivery vehicle to the tumor site in vivo. Previously reported combined therapy systems relied on quenching and de-quenching of PS for PDT upon thermo-impact of PTT, thus only PTT followed by PDT procedure was possible. In contrast, the present dual-acting system has no quenching between PS and GNRs by preventing direct contact and self-aggregation of photo-sensitizers, allowing independent PDT or PTT procedure. In both in vitro cell culture and in vivo tumor-bearing mice experiments, a remarkably enhanced tumor ablation compared to the treatment of PDT or PTT only was observed by the treatment of PDT followed by PTT, but not significantly by the treatment of PTT followed by PDT. Thus, the present study demonstrated the synergistic effect of PDT and PTT in a sequence-dependent manner, and our system is a promising dual function nano system to achieve the enhanced phototherapy in vivo.

Topics: Animals; Chitosan; Chlorophyllides; Gels; Gold; Male; Mice; Mice, Nude; Nanotubes; Neoplasms; Photosensitizing Agents; Phototherapy; Poloxamer; Porphyrins; Tumor Burden

Here, we report the safety, tumor accumulation and potential of polyethylene glycol-grafted graphene oxide (pGO) as a multimodal nanocarrier of photosensitizers and synergistic anticancer agents. First, both graphene oxide (GO) and pGO were synthesized, and their in vitro and in vivo toxicities were tested. When 80 mg/kg was injected intravenously into mice, there was 100% fatality in the GO-treated group, but 100% survival among mice treated with pGO nanosheets. Treatment of cells with a photosensitizer chlorin e6 (Ce6) in pGO nanophysisorplexes significantly enhanced cellular delivery compared to that seen with Ce6 alone. The combination and dose reduction indexes revealed that combining doxorubicin (Dox) with Ce6 with at a molar ratio of 1:2 provided the highest synergism. The Ce6- and Dox-loaded pGO nanophysisorplexes (Ce6/Dox/pGO) were 148.0 ± 18.0 nm in size. Molecular imaging of mice showed that Ce6/Dox/pGO could accumulate in tumor tissues over 3 days. Moreover, in SCC tumor-bearing mice, the photodynamic anticancer effects of Ce6/Dox/pGO were higher than those of Ce6/pGO or Dox/pGO. Moreover, tumor sections from illuminated mice treated with Ce6/Dox/pGO showed substantial disruption of tumor nuclei, whereas the other groups did not. Our results suggest that pGO nanosheets have superior in vivo safety relative to GO, and that it is possible to enhance the tumor tissue distribution and photodynamic anticancer effects of systemically administered Ce6 by forming multimodal nanophysisorplexes with pGO and synergistic anticancer chemotherapeutics such as Dox.

Topics: Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Chlorophyllides; Doxorubicin; Drug Delivery Systems; Drug Synergism; Endocytosis; Female; Graphite; Mice; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Polyethylene Glycols; Porphyrins; Tissue Distribution

Tumor-targeted imaging and therapy have been the challenging issue in the clinical field. Herein, we report tumor-targeting hyaluronic acid nanoparticles (HANPs) as the carrier of the hydrophobic photosensitizer, chlorin e6 (Ce6) for simultaneous photodynamic imaging and therapy. First, self-assembled HANPs were synthesized by chemical conjugation of aminated 5β-cholanic acid, polyethylene glycol (PEG), and black hole quencher3 (BHQ3) to the HA polymers. Second, Ce6 was readily loaded into the HANPs by a simple dialysis method resulting in Ce6-loaded hyaluronic acid nanoparticles (Ce6-HANPs), wherein in the loading efficiency of Ce6 was higher than 80%. The resulting Ce6-HANPs showed stable nano-structure in aqueous condition and rapid uptake into tumor cells. In particular Ce6-HANPs were rapidly degraded by hyaluronidases abundant in cytosol of tumor cells, which may enable intracellular release of Ce6 at the tumor tissue. After an intravenous injection into the tumor-bearing mice, Ce6-HANPs could efficiently reach the tumor tissue via the passive targeting mechanism and specifically enter tumor cells through the receptor-mediated endocytosis based on the interactions between HA of nanoparticles and CD44, the HA receptor on the surface of tumor cells. Upon laser irradiation, Ce6 which was released from the nanoparticles could generate fluorescence and singlet oxygen inside tumor cells, resulting in effective suppression of tumor growth. Overall, it was demonstrated that Ce6-HANPs could be successfully applied to in vivo photodynamic tumor imaging and therapy simultaneously.

Topics: Animals; Cell Survival; Chlorophyllides; Diagnostic Imaging; Fluorescence; HT29 Cells; Humans; Hyaluronic Acid; Hyaluronoglucosaminidase; Intracellular Space; Mice; Mice, Nude; Nanoparticles; Neoplasms; NIH 3T3 Cells; Photochemotherapy; Porphyrins; Singlet Oxygen; Spectroscopy, Near-Infrared

Poly (lactide-co-glycolide) (PLGA) coupled with methoxy poly (ethylene glycol) (mPEG) or chlorin e6 (Ce6) was synthesized using the Steglich esterification method. PLGA-linked mPEG (PLGA-mPEG), PLGA-linked Ce6 (PLGA-Ce6), and Fe(3)O(4) were utilized to constitute multifunctional PLGA nanoparticles (∼160 nm) via the multi-emulsion W(1)/O/W(2) (water-in-oil-in-water) method. The photo-sensitizing properties of Ce6 molecules anchored to PLGA nanoparticles enabled in vivo luminescence imaging and photodynamic therapy for the tumor site. The encapsulation of Fe(3)O(4) allowed high contrast magnetic resonance (MR) imaging of the tumor in vivo. Overall, PLGA nanoparticles resulted in a significant tumor volume regression for the light-illuminated KB tumor in vivo and enhanced the contrast at the tumor region, compared to that of Feridex(®) (commercial contrast agent).

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Dextrans; Female; Ferric Compounds; Humans; KB Cells; Lactic Acid; Luminescent Measurements; Magnetic Resonance Imaging; Magnetite Nanoparticles; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Polyesters; Polyethylene Glycols; Polyglactin 910; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Porphyrins

Dual-modal in vivo tumor imaging and photodynamic therapy using hexagonal NaYF(4):Yb,Er/NaGdF(4) core-shell upconverting nanoparticles combined with a photosensitizer, chlorin e6, is reported. Tumors can be clearly observed not only in the upconversion luminescence image but also in the magnetic resonance image. In vivo photodynamic therapy by systemic administration is demonstrated under 980 nm irradiation.

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Humans; Infrared Rays; Lanthanoid Series Elements; Luminescent Measurements; Magnetic Resonance Imaging; Metal Nanoparticles; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Transplantation, Heterologous

Topics: Animals; Anthracenes; Chlorophyllides; HeLa Cells; Humans; Hydrogen-Ion Concentration; Mice; Mice, Nude; Microscopy, Fluorescence; Neoplasms; Photochemotherapy; Photosensitizing Agents; Polyethylene Glycols; Polysaccharides; Porphyrins; Spectrometry, Fluorescence; Transplantation, Heterologous

Topics: Animals; Aptamers, Nucleotide; Base Sequence; Biological Transport; Cell Line, Tumor; Chlorocebus aethiops; Chlorophyllides; COS Cells; HeLa Cells; Humans; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Ribonuclease, Pancreatic

Here we report the tumor ablation effects of the negatively charged photosensitizer chlorin e6 (Ce6) in nanocomplexes. Ce6 was complexed to cationic 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine-based liposomes, forming cationic nanolipoplexes. The loading efficiency of Ce6 to cationic nanolipoplexes was greater than 90%. The degree of enhancement of cellular uptake of Ce6 by treatment in cationic nanolipoplexes increased with the concentration of Ce6, showing 18.3-fold higher uptake than free Ce6 at 15 µM. Molecular imaging revealed the preferential distribution and retention of Ce6 in SCC7 tumor tissues after intravenous administration of Ce6 in cationic nanolipoplexes. Moreover, localized illumination of mice receiving Ce6 in cationic nanolipoplexes resulted in the formation of thick scabs over tumor regions, and complete ablation of tumors after scab detachment. In contrast, continuous growth of tumors was observed in the group treated with free Ce6. Our results suggest that the cationic nanolipoplexes of Ce6 improve the therapeutic effects of photodynamic cancer therapy as compared to free Ce6.

Topics: Ablation Techniques; Animals; Antineoplastic Agents; Cations; Cell Line, Tumor; Chlorophyllides; Liposomes; Mice; Nanotechnology; Neoplasms; Oleic Acids; Phosphatidylcholines; Photochemotherapy; Photons; Porphyrins; Treatment Outcome

Cancer cells can be killed by photosensitizing agents that induce toxic effects when exposed to nonhazardous light, but this also causes significant damage to surrounding healthy cells. The specificity of photodynamic therapy can be increased by conjugating photosensitizing agents to antibodies and antibody fragments that bind specifically to tumor cell antigens. However, standard conjugation reactions produce heterogeneous products whose targeting specificity and spectroscopic properties can be compromised. In this study, we used an antibody fragment (scFv-425) that binds to the epidermal growth factor receptor (EGFR) as a model to investigate the use of SNAP-tag fusions as an improved conjugation strategy. The scFv-425-SNAP-tag fusion protein allowed the specific conjugation of a chlorin e6 photosensitizer modified with O(6)-benzylguanine, generating a homogeneous product that was delivered specifically to EGFR(+) cancer cells and resulted in significant, tumor cell-specific cytotoxicity. The impact of our results on the development of photodynamic therapy is discussed.

Topics: Cell Line, Tumor; Chlorophyllides; Drug Delivery Systems; ErbB Receptors; Gene Expression; Guanine; Humans; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Recombinant Fusion Proteins; Single-Chain Antibodies

The aim of our study was to determine if electroporation could improve the efficacy of photodynamic tumor therapy. A disadvantage of photodynamic therapy is a slow and in some cases insufficient accumulation of photosensitizer in tumor tissue, which could restrict the achievement of an efficient dose. Under the action of electric pulses, cells undergo membrane electroporation, which results in an increased permeability to various exogenous molecules. In this study, murine hepatoma MH22A cells were exposed to light in vitro in the presence of a photosensitizer, either chlorin e6 or aluminum phthalocyanine tetrasulfonate, following electroporation. Accumulation of the photosensitizers was registered by fluorescence microscopy. Cell viability was determined by the MTT assay. Our results demonstrate that electroporation improves an access of chlorin e6 and aluminum phthalocyanine tetrasulfonate to MH22A cells. Electroporation in combination with photosensitization significantly reduces viability of the treated cells even at low doses of photosensitizers.

Topics: Animals; Cell Line, Tumor; Chlorophyllides; Electrochemotherapy; Electroporation; Humans; Indoles; Microscopy, Fluorescence; Neoplasms; Organometallic Compounds; Photochemotherapy; Porphyrins; Radiation-Sensitizing Agents

It is recognized that chlorin e6-polyvinylpyrrolidone (Ce6-PVP) formulations are characterized by a high efficacy in photodynamic therapy of malignant tumors. Currently, a commercially available formulation of this type is Photolon (Fotolon) with Ce6:PVP=1:1 (w/w) and the weight-average molecular weight of PVP is 1.2x10(4). To gain a better understanding of the role played by PVP in Ce6-PVP formulations, we carry out experiments on IR and UV-VIS absorption, steady-state and time-resolved fluorescence, time-resolved triplet-triplet absorption, octanol-water partitioning, and solubility of chlorin e6 in buffer solutions at pH 6.3, 7.4, and 8.5 in presence of PVP with Ce6:PVP ratios ranging from 1:0 to 1:1000 (w/w) for PVP samples with weight-average molecular weights of 8x10(3), 1.2x10(4), and 4.2x10(4). We show that Ce6 interacts with PVP by forming molecular complexes via hydrophobic interactions and determine the Ce6-PVP binding constant, as well as the mean number of PVP monomers per binding site. We find that complexation of Ce6 with PVP prevents Ce6 aggregation in aqueous media and leads to an enhancement of Ce6 fluorescence quantum yield, while keeping the quantum yield of the intersystem crossing essentially unchanged. Possible scenarios of how the presence of PVP can favorably affect the PDT efficacy of chlorin e6 in Ce6-PVP formulations are discussed.

Topics: Chlorophyllides; Humans; Hydrogen-Ion Concentration; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Povidone; Protoporphyrins; Spectrometry, Fluorescence; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet

Photolon is a photosensitiser with demonstrated potential as an anti-tumour agent. In this study, an in vitro investigation was performed to determine the mechanism of Photolon-induced cell death. Cell killing was observed in a light-dependent manner and light-activated Photolon resulted in a significant production of reactive oxygen species (ROS), which could be blocked by type I ROS scavengers. Inhibition of ROS production using Trolox prevented Photolon-induced cell death. Light-activated Photolon caused no increase in caspase-3/7 activity, but a rapid increase in lactate dehydrogenase (LDH) release suggesting a loss of membrane integrity and subsequent cell death by necrosis. We conclude that the mechanism of Photolon-induced cell death involves the induction of ROS via a type I mechanism, which is ultimately responsible for cell killing by necrosis.

Topics: Cell Death; Cell Proliferation; Cell Survival; Chlorophyllides; Drug Evaluation, Preclinical; Humans; Light; Necrosis; Neoplasms; Photochemotherapy; Porphyrins; Povidone; Protoporphyrins; Radiation-Sensitizing Agents; Reactive Oxygen Species; Tumor Cells, Cultured

An improved formulation of the photosensitizer chlorin e6 (Ce6) in combination with the hydrophilic polymer polyvinylpyrrolidone (PVP) was investigated for its potential clinical applications in fluorescence diagnosis and photodynamic therapy (PDT) of cancer. This study reports the comparative preclinical biodistribution and efficacy of Ce6 delivered with or without PVP versus dimethyl sulfoxide (DMSO). The safety and fluorescence pharmacokinetics of Ce6-PVP in humans was also accessed. Biodistribution results showed that Ce6-PVP had higher tumor to normal tissue ratio compared to the other formulations. The sensitivity and specificity derived from the area under the receiver operating characteristics curves showed that the formulations were able to discriminate tumor from peritumoral muscle in the following order: Ce6-PVP > Ce6 > Ce6-DMSO. In vitro PDT results showed that Ce6-PVP was found to induce selective phototoxicity in leukemic cells compared to peripheral mononuclear blood cells. In addition, in vivo light irradiation at 1h after Ce6-PVP was found to induce greater tumor necrosis without causing animal toxicity. In patients, preferential accumulation of Ce6-PVP was observed in angiosarcoma lesions compared to normal skin following intravenous administration. In conclusion, PVP significantly enhanced the Ce6 concentration in tumors compared with Ce6 alone and increased the therapeutic index of PDT without any side effects in animal model. No serious adverse events were observed in human as well.

Topics: Animals; Cell Line, Tumor; Cell Survival; Chemistry, Pharmaceutical; Chlorophyllides; Hemangiosarcoma; Humans; Image Processing, Computer-Assisted; Male; Mice; Mice, Inbred BALB C; Microscopy, Fluorescence; Middle Aged; Neoplasms; Nonlinear Dynamics; Photochemotherapy; Photosensitizing Agents; Porphyrins; Povidone; Regression Analysis; ROC Curve; Spectrometry, Fluorescence; Tissue Distribution; Xenograft Model Antitumor Assays

Under the influence of electric pulses cells undergo membrane electroporation (EP), which results in increased permeability of the membrane to exogenous compounds. EP is applied in oncology as a method to enhance delivery of anticancer drugs. For that reason it was essential to combine photodynamic tumor therapy (PDT)--the cancer treatment method based on the use of photosensitizers that localize selectively in malignant tumors and become cytotoxic when exposed to light, and EP, with the aim to enhance the delivery of photosensitizers into the tumor and therefore to increase the efficacy of PDT. Thus, the aim of study was to evaluate the cytotoxic effect of PDT in combination with EP. A Chinese hamster lung fibroblast cell line (DC-3F) was used. The cells were affected by photosensitizers chlorin e(6) (C e(6)) at the dose of 10 mug/ml and aluminium phthalocyanine tetrasulfonate (AlPcS4) at the dose of 50 microg/ml. Immediately after adding of photosensitizers the cells were electroporated with 8 electric pulses at 1200 V/cm intensity, 0.1 ms duration, 1 Hz frequency. Then, after 20 min of incubation the cells were irradiated using a light source--a visible light passing through a filter (KC 14, emitted light from 660 nm). The fluence rate at the level of the cells was 3 mW/m(2). Cytotoxic effect on cells viability was evaluated using MTT assay. Our in vitro data showed that the cytotoxicity of PDT in combination with EP increases fourfold on the average. Based on the results we suggest that EP could enhance the effect of PDT.

Topics: Animals; Cell Line; Cell Survival; Chlorophyllides; Cricetinae; Electroporation; Indoles; Neoplasms; Photochemotherapy; Porphyrins

The specific light-induced, non-enzymatic photolysis of mOGG1 by porphyrin-conjugated or rose bengal-conjugated streptavidin and porphyrin-conjugated or rose bengal-conjugated first specific or secondary anti-IgG antibodies is reported. The porphyrin chlorin e6 and rose bengal were conjugated to either streptavidin, rabbit anti-mOGG1 primary specific antibody fractions or goat anti-rabbit IgG secondary antibody fractions. Under our experimental conditions, visible light of wavelengths greater than 600 nm induced the non-enzymatic degradation of mOGG1 when this DNA repair enzyme either directly formed a complex with chlorin e6-conjugated anti-mOGG1 primary specific antibodies or indirectly formed complexes with either streptavidin-chlorin e6 conjugates and biotinylated first specific anti-mOGG1 antibodies or first specific anti-mOGG1 antibodies and chlorin e6-conjugated anti-rabbit IgG secondary antibodies. Similar results were obtained when rose bengal was used as photosensitizer instead of chlorin e6. The rate of the photochemical reaction of mOGG1 site-directed by all three chlorin e6 antibody complexes was not affected by the presence of the singlet oxygen scavenger sodium azide. Site-directed photoactivatable probes having the capacity to generate reactive oxygen species (ROS) while destroying the DNA repair system in malignant cells and tumors may represent a powerful strategy to boost selectivity, penetration and efficacy of current photodynamic (PDT) therapy methodologies.

Topics: Animals; Chlorophyllides; DNA Glycosylases; Humans; Light; Models, Animal; Neoplasms; Photochemotherapy; Photolysis; Porphyrins; Rabbits; Radiation-Sensitizing Agents; Rose Bengal