zn(ii)-phthalocyanine and Neoplasms

Topics: Antibodies, Neoplasm; Antigens, Tumor-Associated, Carbohydrate; Breast Neoplasms; Female; Humans; Indoles; Isoindoles; Laser Therapy; Neoplasms; Organometallic Compounds; Ovarian Neoplasms; Photochemotherapy; Radiation-Sensitizing Agents; Uterine Cervical Neoplasms; Zinc Compounds

Hypoxia is one of the prominent features of solid tumors. Hypoxia activated prodrugs (HAPs), selectively killing hypoxic cells, possess the potential to transform hypoxia from a nuisance to an advantage in precision therapy. Exhibiting a more significant hypoxic microenvironment, gliomas, as the most frequent and incurable neurological tumors, provide HAPs a more attractive therapeutic prospect. However, the insufficient hypoxia and the obstruction of the blood-brain barrier (BBB) severely limit the activation and bio-availability of HAPs. Herein, a novel nanoparticle iRGD@ZnPc + TPZ was designed and synthesized to achieve gliomas inhibition by encapsulating tirapazamine (TPZ) as a HAP and zinc phthalocyanine (ZnPc) as a photosensitizer to enhance hypoxia. iRGD@ZnPc + TPZ can realize breakthrough BBB, deep penetration, and significant retention in gliomas, which is attributed to the iRGD-mediated receptor targeting and active transport. After being internalized by tumor cells and radiated, ZnPc efficiently consumes intratumoral O

Topics: Antineoplastic Agents; Cell Line, Tumor; Glioma; Humans; Hypoxia; Indoles; Isoindoles; Neoplasms; Organometallic Compounds; Photosensitizing Agents; Prodrugs; Reactive Oxygen Species; Tirapazamine; Tumor Microenvironment; Zinc Compounds

Switchable theranostics are of great interest for accurate tumor imaging and targeted therapy. Here, we develop smart engineering to construct nanostructured phthalocyanines self-assembled by amphiphilic zinc phthalocyanines (ZnPcs) and hydrophobic copper phthalocyanines (CuPcs) (ZnPc(PEG)

Topics: Cell Line, Tumor; Fluorescence; Humans; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Phototherapy; Tumor Microenvironment; Zinc Compounds

Polycyclodextrin (denoted PCD) composed of cyclodextrin monomer units and 1,3-diethoxypropan-2-ol containing many hydroxyl groups with lone pairs of electrons, easily coordinated with transition metals with empty orbitals. The CD unit can also provide host-guest binding sites for functional molecules. This article utilizes this feature of PCD for the first time as a "linker" to combine transition metal nanomaterials with synergistic functional molecules. We synthesized PCD with 50% CD monomer by epichlorohydrin cross-linking method. Utilizing the coordination effect of the hydroxyl group in PCD and the iron ion in photothermal nanoparticles (PB-Yb), the PCD is coated on its surface; simultaneously, CD in PCD can form a host-guest complex with adamantane-modified zinc phthalocyanine (Pc) photosensitizer. Using PCD as a "linker", PB-Yb and Pc (denoted PYPP) were combined to improve the solubility of PB-Yb, reduce the aggregation degree of Pc to increase their activity, and achieve photothermal and photodynamic synergistic tumor therapy.

Topics: Adamantane; Animals; Antineoplastic Agents; Cyclodextrins; Female; Ferrocyanides; HeLa Cells; Humans; Isoindoles; Light; Mice, Inbred BALB C; Nanomedicine; Nanoparticles; Neoplasms; Organometallic Compounds; Photosensitizing Agents; Polymers; Reactive Oxygen Species; Ytterbium; Zinc Compounds

The photodynamic anticancer activity of a photosensitizer can be further increased by co-administration of a flavonoid. However, this requires that both molecules must be effectively accumulated at the tumor site. Hence, in order to enhance the activity of zinc phthalocyanine (ZnPc, photosensitizer), it was co-encapsulated with quercetin (QC, flavonoid) in lipid polymer hybrid nanoparticles (LPNs) developed using biodegradable & biocompatible materials and prepared using a single-step nanoprecipitation technique. High stability and cellular uptake, sustained release, inherent fluorescence, of ZnPC were observed after encapsulation in the LPNs, which also showed a higher cytotoxic effect in breast carcinoma cells (MCF-7) compared to photodynamic therapy (PDT) alone. In vivo studies in tumor-bearing Sprague Dawley rats demonstrated that the LPNs were able to deliver ZnPc and QC to the tumor site with minimal systemic toxicity and increased antitumor effect. Overall, the photodynamic effect of ZnPc was synergized by QC. This strategy could be highly beneficial for cancer management in the future while nullifying the side effects of chemotherapy.

Topics: Animals; Antineoplastic Agents; Biocompatible Materials; Cell Membrane Permeability; Delayed-Action Preparations; Drug Liberation; Humans; Isoindoles; Liposomes; MCF-7 Cells; Molecular Targeted Therapy; Nanoparticles; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Quercetin; Rats, Sprague-Dawley; Reactive Oxygen Species; Zinc Compounds

Cyclodextrins (CDs), as pharmaceutical excipients with excellent biocompatibility, non-immunogenicity, and low toxicity in vivo, are widely used to carry drugs by forming inclusion complexes for improving the solubility and stability of drugs. However, the limited space of CDs' lipophilic central cavity affects the loading of many drugs, especially with larger molecules. In this study, β-CDs were modified by acetonization to improve the affinity for the chemotherapy drug doxorubicin (DOX), and doxorubicin-adsorbing acetalated β-CDs (Ac-CD:DOX) self-assembled to nanoparticles, followed by coating with the amphiphilic zinc phthalocyanine photosensitizer ZnPc-(PEG)

Topics: Animals; Antineoplastic Agents; Apoptosis; beta-Cyclodextrins; Doxorubicin; Drug Carriers; Drug Liberation; Drug Synergism; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Indoles; Isoindoles; Light; Male; Membrane Potential, Mitochondrial; Mice; Mitochondria; Nanoparticles; Neoplasms; Organometallic Compounds; Photosensitizing Agents; Reactive Oxygen Species; Zinc Compounds

Tumor immunotherapy like immune checkpoint blockade (ICB) shows great success nowadays but is severely limited by low response rates and immune-related adverse events (IRAEs). While photodynamic therapy (PDT) could efficiently eradicate tumor cells and further induce immune responses to promote activating of T lymphocytes. Herein a nanodrug hierarchically incorporating photosensitizer and PD-L1 antibody was developed for synergistic tumor immuno-photodynamic therapy. A pH/enzyme dual-sensitive polymeric micelle with sheddable PEG coating was designed for codelivery of PD-L1 antibody and zinc phthalocyanine (ZnPc) in the tumor. The tumor microenvironment featuring low pH and high matrix metallopeptidase 2 (MMP-2) sequentially triggered the shedding of PEG and the release of PD-L1 antibody to exert local ICB in tumor tissue, after which the remaining nanodrug with ZnPc undergoing charge reversal was readily delivered into tumor cells. With light irradiation, the photodynamic therapy effect of sAMPc induced immunogenic cell death of tumor cells and further promoted intratumor recruitment of CD8+ T cells, thus resulting in a synergistic immuno-photodynamic therapy with ICB. Moreover, the PEG-sheddable strategy endowed the nanodrug with stealth properties in blood circulation, making the IRAEs of PD-L1 antibody significantly reduced. This pH/MMP-2 dual-sensitive PEG sheddable nanodrug provids a promising strategy for well-combined ICB therapy and PDT to achieve improved anticancer immuno-photodynamic therapy with reduced adverse effects.

Topics: Antineoplastic Agents, Immunological; B7-H1 Antigen; Cell Line, Tumor; Delayed-Action Preparations; Humans; Hydrogen-Ion Concentration; Indoles; Isoindoles; Male; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Polyethylene Glycols; Tumor Microenvironment; Zinc Compounds

The performance of photodynamic therapy (PDT) depends on the solubility, pharmacokinetic behaviors, and photophysical properties of photosensitizers (PSs). However, highly conjugated PSs with strong reactive oxygen species (ROS) generation efficiency tend to have poor solubility and aggregate in aqueous environments, leading to suboptimal PDT performance. Here, we report a new strategy to load highly conjugated but poorly soluble zinc-phthalocyanine (ZnP) PSs in the pores of a Hf

Topics: Animals; Biocompatible Materials; Cell Line, Tumor; Cell Survival; Isoindoles; Lysosomes; Metal-Organic Frameworks; Mice; Mice, Inbred BALB C; Microscopy, Confocal; Nanostructures; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species; Transplantation, Heterologous; Zinc Compounds

Nitric oxide (NO) can play both prosurvival and prodeath roles in photodynamic therapy (PDT). The generation efficiency of peroxynitrite anions (ONOO

Topics: Animals; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Cell Survival; Drug Synergism; Female; Fluorescence; Glutathione; Humans; Indoles; Isoindoles; Mice; Neoplasms; Nitric Oxide; Organometallic Compounds; Peroxynitrous Acid; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species; Superoxides; Tissue Distribution; Xenograft Model Antitumor Assays; Zinc Compounds

The G-quadruplex (G4)-forming sequence within the AS1411 derivatives with alternative nucleobases and backbones can improve the chemical and biological properties of AS1411. Zn(II) phthalocyanine (ZnPc) derivatives have potential as high-affinity G4 ligands because they have similar size and shape to the G-quartets. The interactions of four Zn(II) phthalocyanines with the G4 AS1411 aptamer and its derivatives were determined by biophysical techniques, molecular docking and gel electrophoresis. Cell viability assay was carried out to evaluate the antiproliferative effects of Zn(II) phthalocyanines and complexes. CD experiments showed structural changes after addition of ZnPc 4, consistent with multiple binding modes and conformations shown by NMR and gel electrophoresis. CD melting confirmed that ZnPc 2 and ZnPc 4, both containing eight positive charges, are able to stabilize the AT11 G4 structure (ΔT

Topics: Antineoplastic Agents; Aptamers, Nucleotide; Cell Line; Cell Survival; G-Quadruplexes; HeLa Cells; Humans; Indoles; Isoindoles; Molecular Docking Simulation; Neoplasms; Oligodeoxyribonucleotides; Organometallic Compounds; Zinc Compounds

A novel molecular therapeutic agent was designed and synthesized, which contains three functional components, namely, a zinc(II) phthalocyanine substituted with a 2,4-dinitrobenzenesulfonate (DNBS) group as a glutathione (GSH)-activated photosensitizer, a chemo-prodrug based on combretastatin A-4 (CA4) with a singlet oxygen-cleavable aminoacrylate linker, and a biotin moiety as a tumor-targeting ligand. The conjugate showed preferential uptake toward the biotin-receptor-positive HepG2 cells compared with the low biotin-receptor-expressed HCT-116 cells used as the negative control, resulting in the restoration of the fluorescence emission and singlet oxygen generation upon removal of the DNBS group by intracellular GSH. The singlet oxygen produced not only induced a significant photodynamic effect against HepG2 cells but also triggered the cascaded release of the chemocytotoxic CA4, leading to synergistic cytotoxicity as shown by the less-than-unity combination index.

Topics: Antineoplastic Agents; Benzenesulfonates; Bibenzyls; Drug Delivery Systems; Glutathione; HCT116 Cells; Hep G2 Cells; Humans; Indoles; Isoindoles; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Prodrugs; Zinc Compounds

A tumor redox-activatable micellar nanoplatform based on the naturally occurring biomacromolecule hyaluronic acid (HA) was developed for complementary photodynamic/chemotherapy against CD44-positive tumors. Here HA was first conjugated with l-carnitine (Lc)-modified zinc phthalocyanine (ZnPc) via disulfide linkage and then co-assembled with tirapazamine (TPZ) to afford the physiologically stable micellar nanostructure. The mitochondria-targeted photodynamic activity of ZnPc-Lc could efficiently activate the mitochondrial apoptosis cascade and deplete the oxygen in the tumor intracellular environment to amplify the hypoxia-dependent cytotoxic effect of TPZ.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biopolymers; Carnitine; Cell Line, Tumor; Humans; Hyaluronic Acid; Indoles; Infrared Rays; Isoindoles; Mice; Micelles; Mitochondria; Nanostructures; Neoplasms; Organometallic Compounds; Oxidation-Reduction; Photochemotherapy; Photosensitizing Agents; Tirapazamine; Transplantation, Heterologous; Zinc Compounds

Upconversion nanoparticles (UCNPs) are the preferred choice for deep-tissue photoactivation, owing to their unique capability of converting deep tissue-penetrating near-infrared light to UV/visible light for photoactivation. Programmed photoactivation of multiple molecules is critical for controlling many biological processes. However, syntheses of such UCNPs require epitaxial growth of multiple shells on the core nanocrystals and are highly complex/time-consuming. To overcome this bottleneck, we have modularly assembled two distinct UCNPs which can individually be excited by 980/808 nm light, but not both. These orthogonal photoactivable UCNPs superballs are used for programmed photoactivation of multiple therapeutic processes for enhanced efficacy. These include sequential activation of endosomal escape through photochemical-internalization for enhanced cellular uptake, followed by photocontrolled gene knockdown of superoxide dismutase-1 to increase sensitivity to reactive oxygen species and finally, photodynamic therapy under these favorable conditions. Such programmed activation translated to significantly higher therapeutic efficacy in vitro and in vivo in comparison to conventional, non-programmed activation.

Topics: Animals; Calcium Compounds; Cell Line, Tumor; Cell Membrane Permeability; Drug Carriers; Drug Design; Endosomes; Gene Knockout Techniques; HeLa Cells; Humans; Indoles; Infrared Rays; Isoindoles; Mice; Nanoparticles; Neoplasms; Organometallic Compounds; Photochemical Processes; Photochemotherapy; Photosensitizing Agents; RNA, Small Interfering; Silicates; Superoxide Dismutase-1; Tissue Distribution; Ultraviolet Rays; Zinc Compounds

Controlled drug release systems can enhance the safety and availability but avoid the side effect of drugs. Herein, the concept of DNA complementary base pairing rules in biology is used to design and prepare a photothermal-triggered drug release system. Adenine (A) modified polydopamine nanoparticles (A-PDA, photothermal reagent) can effectively bind with thymine (T) modified Zinc phthalocyanine (T-ZnPc, photosensitizer) forming A-PDA = T-ZnPc (PATP) complex based on A = T complementary base pairing rules. Similar to DNA, whose base pairing in double strands will break by heating, T-ZnPc can be effectively released from A-PDA after near infrared irradiation-triggered light-thermal conversion to obtain satisfactory photodynamic-photothermal synergistic tumor treatment. In addition, PDA can carry abundant Gd

Topics: Adenine; Animals; Base Pairing; Cell Line, Tumor; Combined Modality Therapy; Delayed-Action Preparations; DNA, Complementary; Drug Delivery Systems; Drug Liberation; Drug Synergism; Female; Humans; Hyperthermia, Induced; Indoles; Isoindoles; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Phototherapy; Polymers; Xenograft Model Antitumor Assays; Zinc Compounds

In this study, a novel asymmetric cinnamic acid zinc phthalocyanine (ZnPc, 1) containing three tert-butyl substituents is reported. The asymmetric ZnPc (1) is further linked to amino functionalized magnetic nanoparticles (AMNPs) (1-AMNPs) and to cysteine functionalized silver nanoparticles (cys-AgNPs) (1-cys-AgNPs) through an amide bond. 1-AMNPs and 1-cys-AgNPs improved the triplet and singlet oxygen quantum yields of complex 1, this was also observed with the previously reported 2-AMNPs when compared to 2 while 3-AMNPs yielded an unexpected decrease in triplet quantum yield as compared to 3. The silver nanoparticles (1-cys-AgNPs) had a better effect on improving the singlet oxygen quantum yield of complex 1 than the magnetic nanoparticles (1-AMNPs). The Pcs and conjugates recorded low cell cytotoxicity in the dark and high photocytotoxicity against MCF-7 cells in-vitro. MCF-7 cell viabilities of less than 50% were recorded at 80 μg/mL making the Pcs and conjugates under study potential candidates for use as photosensitizers in cancer therapy.

Topics: Cinnamates; Humans; Indoles; Isoindoles; MCF-7 Cells; Metal Nanoparticles; Neoplasms; Organometallic Compounds; Photochemotherapy; Zinc Compounds

Herein, we report a ligand-reversible-shielding strategy based on the mutual shielding of dual ligands tethered to the surface of nanoparticles. To exemplify this concept, phenylboronic acid-functionalized poly(ethylene glycol)- b-poly(ε-caprolactone) (PBA-PEG-PCL) and galactose-functionalized diblock polymer (Gal-PEG-PCL) were mixed to form dual-ligand micelles (PBA/Gal). PBA and Gal residues could form a complex at pH 7.4 and mutually shield their targeting function. At pH 6.8, the binding affinity between PBA and Gal weakened, and PBA preferred to bind with the sialic acid residues on the tumor cell surface rather than to Gal on the micellar surface; furthermore, the unbound Gal recovered its targeting ability toward the asialoglycoprotein receptor. When the pH decreased from 7.4 to 6.8, enzyme-linked immunosorbent assays exhibited that the percentage of exposed Gal on the micellar surface increased 1.9-fold, and flow cytometry showed that HepG2 cellular uptake increased 4.3-fold. More importantly, this process was reversible, confirming the reversible shielding and deshielding of dual ligands. With the encapsulation of a photosensitizer, zinc phthalocyanine (ZnPc), the reversible-shielding micelles showed a 48% improvement in the half-life ( t

Topics: Boronic Acids; Drug Carriers; Ethylene Glycols; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Indoles; Isoindoles; Lactones; Ligands; Micelles; Nanoparticles; Neoplasms; Organometallic Compounds; Polyesters; Polyethylene Glycols; Polymers; Zinc Compounds

Topics: Animals; Cell Survival; Drug Carriers; Humans; Hydrophobic and Hydrophilic Interactions; Indoles; Isoindoles; MCF-7 Cells; Microscopy, Confocal; Nanoparticles; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Polyethylene Glycols; Polymers; Rats; Rats, Sprague-Dawley; Singlet Oxygen; Theranostic Nanomedicine; Transplantation, Heterologous; Zinc Compounds

Multifunctional nanodots represent an emerging platform for overcoming the delivery challenges of poorly water-soluble drugs for use in the diagnosis and treatment of cancer. The authors describe the preparation of nanocrystallites composed of the water-insoluble photosensitizer zinc(II)-phthalocyanine in the form of nanodots by applying a cryodesiccation-driven crystallization approach. Modification of the surface of the nanodots with Pluronic F127 and folic acid endows them with excellent water solubility and stealth properties in blood. Under near-infrared (NIR) photoexcitation at 808 nm, the nanodots are shown to produce singlet oxygen, which is widely used in photodynamic therapy of cancer. The nanodots exhibit strong NIR absorbance at 808 nm and can be used as a non-toxic contrast agent for photoacoustic imaging of tissue. Graphical abstract Schematic presentation of the preparation of ZnPcNDs by droplet-confined/cryodesiccation-driven crystallization.

Topics: Animals; Cell Line, Tumor; Contrast Media; Crystallization; Drug Carriers; Folic Acid; Humans; Indoles; Infrared Rays; Isoindoles; Mice, Inbred BALB C; Neoplasms; Organometallic Compounds; Photoacoustic Techniques; Photochemotherapy; Photosensitizing Agents; Poloxamer; Quantum Dots; Singlet Oxygen; Zinc Compounds

The spectral and the photophysical properties of phthalocyanines have made these dyes attractive for applications in photodynamic therapy of cancer. One important known issue of these compounds is their tendency to aggregate in aqueous media, which decreases their fluorescence, triplet, and singlet oxygen quantum yields. We report on the use of apomyoglobin as a carrier for zinc phthalocyanine (ZnPc) to overcome solubility limitations of the dye. We show that the protein is able to bind ZnPc in monomeric form, preserving its photophysics. Confocal fluorescence imaging of PC3 and HeLa cells, treated with the complex between ZnPc and apomyoglobin, demonstrates that the photosensitizer is uptaken quickly by cells. Illumination of treated cells strongly decreases viability, as demonstrated by live/dead fluorescence assay.

Topics: Apoproteins; Cell Survival; Drug Carriers; HeLa Cells; Humans; Hydrophobic and Hydrophilic Interactions; Indoles; Isoindoles; Myoglobin; Neoplasms; Optical Imaging; Organometallic Compounds; Particle Size; PC-3 Cells; Photochemotherapy; Photosensitizing Agents; Surface Properties; Tumor Cells, Cultured; Zinc Compounds

Two cationic zinc phthalocyanines have been tested for their interactions with several DNA secondary structures. Despite different aggregation properties, both phthalocyanines bind to DNA in monomeric forms. The strong photodynamic activity of phthalocyanines was demonstrated by in vitro experiments and correlate well with high singlet oxygen yields determined experimentally with 1,3-diphenylisobenzofurane. Both phthalocyanines accumulate in the cell cytoplasm prior to radiation; however, only the octacationic photosensitizer was observed in the cell nuclei after irradiation.

Topics: Cell Communication; Circular Dichroism; Cytoplasm; DNA; Humans; Indoles; Isoindoles; MCF-7 Cells; Microscopy, Confocal; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Singlet Oxygen; Zinc Compounds

This work was intended to develop novel doxorubicin (DOX)/zinc (II) phthalocyanine (ZnPc) co-loaded mesoporous silica (MSNs)@ calcium phosphate (CaP)@PEGylated liposome nanoparticles (NPs) that could efficiently achieve collaborative anticancer therapy by the combination of photodynamic therapy (PDT) and chemotherapy. The interlayer of CaP could be utilized to achieve pH-triggered controllable drug release, promote the cellular uptake, and induce cell apoptosis to further enhance the anticancer effects.. MSNs were first synthesized as core particles in which the pores were diffusion-filled with DOX, then the cores were coated by CaP followed by the liposome encapsulation with ZnPc to form the final DOX/ZnPc co-loaded MSNs@CaP@PEGylated liposome.. A core-interlayer-shell MSNs@CaP@PEGylated liposomes was developed as a multifunctional theranostic nanoplatform. In vitro experiment indicated that CaP could not only achieve pH-triggered controllable drug release, promote the cellular uptake of the NPs, but also generate high osmotic pressure in the endo/lysosomes to induce cell apoptosis. Besides, the chemotherapy using DOX and PDT effect was achieved by the photosensitizer ZnPc. Furthermore, the MSNs@CaP@PEGylated liposomes showed outstanding tumor-targeting ability by enhanced permeability and retention (EPR) effect.. The novel prepared MSNs@CaP@PEGylated liposomes could serve as a promising multifunctional theranostic nanoplatform in anticancer treatment by synergic chemo-PDT and superior tumor-targeting ability.

Topics: Antibiotics, Antineoplastic; Apoptosis; Calcium Phosphates; Combined Modality Therapy; Delayed-Action Preparations; Doxorubicin; Drug Compounding; Drug Liberation; Drug Screening Assays, Antitumor; Drug Synergism; HeLa Cells; Humans; Hydrogen-Ion Concentration; Indoles; Isoindoles; Liposomes; Nanoparticles; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Polyethylene Glycols; Silicates; Theranostic Nanomedicine; Zinc Compounds

A series of polymeric micelles encapsulating different ratios of doxorubicin (DOX) and zinc(II) phthalocyanine (ZnPc) have been prepared for dual chemotherapy and photodynamic therapy (PDT). The amphiphilic block copolymers consist of methoxypolyethylene glycol (PEG) and poly(β-benzyl-l-aspartate) (PBLA), in which DOX and ZnPc were conjugated to the aspartate side chain through an acid-labile hydrazone linker and a redox-responsive disulfide linker, respectively. The polymers were self-assembled into spherical polymeric micelles with diameters of about 160-180 nm and their surface charges were found to be nearly neutral due to the outermost PEG layer. These polymeric micelles exhibited excellent stability and silenced fluorescence in aqueous media. The controlled release of DOX and ZnPc was studied in phosphate solution under acidic and reducing environments, respectively. In vitro study demonstrated that these polymeric micelles could be internalized into HepG2 human hepatocellular carcinoma cells, showing the fluorescence of DOX in the nucleus and fluorescence of ZnPc in the cytoplasm. This observation suggested that the acidic and reducing intracellular environments could trigger the release of DOX and ZnPc by cleaving the corresponding linkers. These micelles exhibited different degree of dark- and photo-cytotoxicity on the HepG2 cells due to the chemocytotoxic DOX and the singlet oxygen generated upon irradiation of the ZnPc. With a certain ratio of DOX and ZnPc, they caused a synergistic cytotoxicity as calculated by combination index. The DOX-ZnPc-micelles-2, which has a DOX/ZnPc molar ratio of 3.8, could induce cell death mainly through apoptosis and exhibit preferential tumor retention in tumor-bearing mice via the enhanced permeability and retention effect. The results suggest that these polymeric micelles are promising nanoplatforms for the delivery of anticancer drugs and photosensitizers for dual therapy.

Topics: Animals; Antibiotics, Antineoplastic; Cell Death; Delayed-Action Preparations; Doxorubicin; Drug Liberation; Female; Glutathione; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Indoles; Isoindoles; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Organometallic Compounds; Peptides; Photochemotherapy; Photosensitizing Agents; Polyethylene Glycols; Zinc Compounds

For the purpose of precision theranostic of tumor, multifunctional drug delivery systems are always receiving great attentions. Here, we developed a zinc phthalocyanine-soybean phospholipid (ZnPc-SPC) complex based drug delivery system with doxorubicin (Dox) as loading cargo to achieve additional chemotherapy while the carrier itself could serve as multifunctional and switchable theranostic agent. In the early phase, the ZnPc-SPC complex assembled to nanostructure displaying photothermal therapy (PTT) and photoacoustic (PA) properties while in the late phase, the prepared NPs dis-assembled into ZnPc-SPC complex again performing photodynamic therapy (PDT) and low-background fluorescence (FL) image. With the decoration of folate receptors α (FRα) targeted MTX, Dox-loaded, MTX-decorated self-assembled ZnPc-SPC complex NPs (DZSM) was formed. In vitro and in vivo evaluations both indicated that DZSM presented high selectivity for FRα over-expressed tumor cells, excellent switchable PA/FL image, significant multiphase PTT/PDT effect, as well as great synergetic therapy potential, leading to notable inhibition of tumor growth.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Doxorubicin; Drug Carriers; Glycine max; Humans; Hyperthermia, Induced; Indoles; Isoindoles; Methotrexate; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Optical Imaging; Organometallic Compounds; Phospholipids; Photoacoustic Techniques; Photochemotherapy; Theranostic Nanomedicine; Zinc Compounds

Development of a photosensitizer that can achieve tumor specificity, improve therapeutic efficacy, and reduce side effects remains a challenge for photodynamic therapy (PDT). In this work, a pH-sensitive activatable nanophotosensitizer (SMSN-ZnPc1) has been elaborately designed, which could be readily prepared by using a functionalized zinc(ii) phthalocyanine (ZnPc) to conjugate with stellate mesoporous silica nanoparticles (SMSNs) through an acid-sensitive hydrazone bond. Meanwhile, a non-activatable analogue SMSN-ZnPc2 has also been prepared as a negative control. The fluorescence emission and singlet oxygen generation of the photosensitizer are essentially quenched in the intact nanophotosensitizer. However, these properties of SMSN-ZnPc1 can be restored greatly both in acidic solutions and at the cellular level. More importantly, after intravenous administration, SMSN-ZnPc1 can also be selectively activated at the tumor site and exhibit efficient tumor growth inhibition in S180 rat ascitic tumor-bearing KM mice with negligible systemic toxicity. It thus may serve as a promising nanoplatform for cancer diagnosis and targeted PDT.

Topics: Animals; Delayed-Action Preparations; Female; HeLa Cells; Humans; Hydrogen-Ion Concentration; Indoles; Isoindoles; Mice; Nanoconjugates; Neoplasms; Optical Imaging; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Porosity; Rats; Silicon Dioxide; Zinc Compounds

Zinc phthalocyanine (ZnPc) has been applied widely in photodynamic therapy (PDT) with high ROS-production capacity and intense absorption in the near-infrared region. However, weak tumor targeting and the aggregation tendency of ZnPc seriously affect the therapeutic effect of PDT. Therefore, overcoming the aggregation of ZnPc and enhancing its antitumor effect were the purpose of this study.. In this study, we first found that the aggregation behaviors of the photosensitizer ZnPc(TAP). We found that NP-ZnPc(TAP). NP-ZnPc(TAP)

Topics: Albumins; Amines; Animals; Cell Line, Tumor; Drug Delivery Systems; Drug Liberation; Humans; Hydrogen-Ion Concentration; Indoles; Isoindoles; Male; Mice; Nanoparticles; Neoplasms; Organometallic Compounds; Paclitaxel; Reactive Oxygen Species; Solutions; Time Factors; Treatment Outcome; Zinc Compounds

C-Phycocyanin (CPC) as a tumour-associated macrophage (TAM)-targeted photosensitiser has been first proved, and used as a vehicle of zinc phthalocyanine (ZnPc) to fabricate a ZnPc-CPC conjugate, which exhibits an efficient in vitro photodynamic activity, and selectively accumulates in tumour sites probably due to the affinity to TAM.

Topics: Animals; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Hep G2 Cells; Humans; Indoles; Injections, Intravenous; Isoindoles; Macrophages; Mice; Mice, Inbred Strains; Neoplasms; Optical Imaging; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Phycocyanin; Structure-Activity Relationship; Zinc Compounds

Similar to many other anticancer therapies, photodynamic therapy (PDT) also suffers from the intrinsic cancer resistance mediated by cell survival pathways. These survival pathways are regulated by various proteins, among which anti-apoptotic protein Bcl-2 plays an important role in regulation of programmed cell death and has been proved to involve in protecting against oxidative stimuli. Confronted by this challenge, we propose and validate here a novel upconversion photosensitizing nanoplatform which enables significant reduction of cancer resistance and improve PDT efficacy. The upconversion nanophotosensitizer contains the photosensitizing molecules - Zinc phthalocyanine (ZnPc) and Bcl-2 inhibitor - ABT737 small molecules, denoted as ABT737@ZnPc-UCNPs. ABT737 molecules were encapsulated, in a pH sensitive way, into the nanoplatform through Poly (ethylene glycol)-Poly (l-histidine) diblock copolymers (PEG-b-PHis). This nanosystem exhibits the superiority of sensitizing tumor cells for PDT through adjuvant intervention strategy. Upon reaching to lysosomes, the acidic environment changes the solubility of PEG-b-PHis, resulting in the burst-release of ABT737 molecules which deplete the Bcl-2 level in tumor cells and leave the tumor cells out from the protection of anti-apoptotic survival pathway in advance. Owing to the sensitization effect of ABT737@ZnPc-UCNPs, the PDT therapeutic efficiency of cancer cells can be significantly potentiated in vitro and in vivo.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Delayed-Action Preparations; Histidine; Humans; Hydrogen-Ion Concentration; Indoles; Isoindoles; Mice, Inbred C57BL; Mitochondrial Dynamics; Nanoparticles; Neoplasms; Organometallic Compounds; Photosensitizing Agents; Polyethylene Glycols; Proto-Oncogene Proteins c-bcl-2; Zinc Compounds

Developing multifunctional phototheranostics with nanoplatforms offers promising potential for effective eradication of malignant solid tumors. In this study, we develop a multifunctional phototheranostic by combining photothermal therapy (PTT) and photoacoustic therapy (PAT) based on a tumor-targeting nanoagent (DBCO-ZnPc-LP). The nanoagent DBCO-ZnPc-LP was facilely prepared by self-assembling of a single lipophilic near-infrared (NIR) dye zinc(II)-phthalocyanine (ZnPc) with a lipid-poly(ethylene glycol) (LP) and following modified further with dibenzyl cyclootyne (DBCO) for introducing the two-step chemical tumor-targeting strategy based on metabolic glycoengineering and click chemistry. The as-prepared DBCO-ZnPc-LP could not only convert NIR light into heat for effective thermal ablation but also induce a thermal-enhanced ultrasound shockwave boost to trigger substantially localized mechanical damage, achieving synergistic antitumor effect both in vitro and in vivo. Moreover, DBCO-ZnPc-LP can be efficiently delivered into tumor cells and solid tumors after being injected intravenously via the two-step tumor-targeting strategy. By integrating the targeting strategy, photoacoustic imaging, and the synergistic interaction between PTT and PAT, a solid tumor could be accurately positioned and thoroughly eradicated in vivo. Therefore, this multifunctional phototheranostic is believed to play an important role in future oncotherapy by the enhanced synergistic effect of PTT and PAT under the guidance of photoacoustic imaging.

Topics: A549 Cells; Alkynes; Animals; Benzyl Compounds; Click Chemistry; Combined Modality Therapy; Female; Humans; Hyperthermia, Induced; Indoles; Isoindoles; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Organometallic Compounds; Photoacoustic Techniques; Polyethylene Glycols; Theranostic Nanomedicine; Zinc Compounds

The efficacy of photodynamic therapy (PDT) in some solid tumors is limited by the poor biodistributive properties of conventional photosensitizers and a natural predisposition of tumor cells to survive hypoxia and oxidative stress. This study investigated the therapeutic potential of a third-generation photosensitizer, liposomal zinc phthalocyanine (ZnPC), in combination with the hypoxic cytotoxin tirapazamine (TPZ). TPZ induces DNA double strand breaks (DSBs) under hypoxic conditions and subsequent apoptosis via p53 signaling. Experiments were performed in tumor cells with functional p53 (Sk-Cha1) and dysfunctional p53 (A431). The combination therapy of TPZ and PDT induced DNA DSBs and cell cycle stalling and enhanced the cytotoxicity of PDT by exacerbating apopotic and non-apoptotic tumor cell death. These phenomena occurred regardless of oxygen tension and the mechanism of cell death differed per cell line. Liposomes containing both ZnPC and TPZ exhibited no dark toxicity but were more lethal to both cell types after PDT compared to ZnPC-liposomes lacking TPZ—an effect that was more pronounced under hypoxic conditions. In conclusion, TPZ is a suitable pharmaceutical compound to increase PDT efficacy by exploiting the post-PDT tumor hypoxia. The inclusion of TPZ and ZnPC into a single liposomal delivery system was feasible. The PDT strategy described in this study may be valuable for the treatment of PDT-recalcitrant tumors.

Topics: Antineoplastic Agents; Cell Death; Cell Line, Tumor; Cell Survival; DNA Damage; Humans; Indoles; Isoindoles; Liposomes; Neoplasms; Organometallic Compounds; Oxidative Stress; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species; Tirapazamine; Triazines; Zinc Compounds

In this experimental study, cancer and normal cells behavior during an in vitro photodynamic therapy (PDT) under exposure of continuous wave (CW) and fractionated mode of laser with different irradiation power and time intervals was compared and investigated. At the first, human fibroblast cancer cell line (SW 872) and human dermal normal (HFFF2) cell line were incubated with different concentrations of zinc phthalocyanine (ZnPc), as a PDT drug. The cells, then, were irradiated with a 675nm diode laser and the cell viability was evaluated using MTT assay. Under optimized conditions, the viability of the cancer cells was eventually reduced to 3.23% and 13.17%, and that of normal cells was decreased to 20.83% and 36.23% using CW and fractionated diode lasers, respectively. In general, the ratio of ZnPc LD50 values for the normal cells to the cancer cells with CW laser was much higher than that of the fractionated laser. Subsequently, cancer cells in comparison with normal ones were found to be more sensitive toward the photodynamic damage induced by ZnPc. In addition, treatment with CW laser was found to be more effective against the cancer cells with a lower toxicity to the normal cells compared with the fractionated diode laser.

Topics: Apoptosis; Cell Line; Cell Survival; Fibroblasts; Humans; Indoles; Isoindoles; Lasers, Semiconductor; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Zinc Compounds

Photodynamic therapy (PDT) has been successfully used to treat various solid tumors. However, some cancer types respond poorly to PDT, including urothelial carcinomas, nasopharyngeal carcinomas, and extrahepatic cholangiocarcinomas. The therapeutic recalcitrance is in part due to the use of photosensitizers with suboptimal optical/ photochemical properties and unfavorable pharmacokinetics.. To circumvent these drawbacks, a second-generation photosensitizer with improved optical/photochemical properties, zinc phthalocyanine (ZnPC), was encapsulated in interstitially targeted, polyethylene glycol-coated liposomes (ITLs) intended for systemic administration. The ZnPC-ITLs were examined for reactive oxygen species (ROS) generation and oxidation capacity and validated for tumoricidal efficacy in human extrahepatic cholangiocarcinoma (Sk-Cha1) cells. ZnPC-ITL uptake and the mechanism and mode of PDT-induced cell death were studied.. The ITL formulation was optimized on the basis of fluorescence spectroscopy and photon correlation spectroscopy. The extent of ROS generation, protein oxidation, and membrane oxidation were determined by the 2',7'-dichlorodihydrofluorescein, tryptophan oxidation, and calcein leakage assays, respectively. PDT efficacy was evaluated by measuring mitochondrial activity and apoptosis-/necrosis-specific staining in combination with flow cytometry. The uptake of fluorescently labeled ITLs was assayed by confocal microscopy, flow cytometry, and fluorescence spectroscopy.. ZnPC-ITLs exhibited maximum ROS-generating and oxidation potential at a ZnPC:lipid molar ratio of 0.003. PDT of Sk-Cha1 cells incubated with ZnPC-ITLs induced cell death in a lipid concentration- dependent manner. The mode of PDT-induced cell death comprised both apoptosis and necrosis, with necrotic cell death predominating. Post-PDT cell death was attributable to pre-PDT ZnPC-ITL uptake by cancer cells, which was more efficient at smaller ITL diameters and a more positive surface charge.. ZnPC-ITLs constitute a nanoparticulate photosensitizer delivery system capable of inducing apoptosis and necrosis in cultured extrahepatic cholangiocarcinoma cells by PDT-mediated oxidative processes. PDT-induced cell death is dependent on the extent of ITL uptake, which in turn relies on ITL size and zeta potential.

Topics: Cell Line, Tumor; Drug Delivery Systems; Humans; Indoles; Isoindoles; Liposomes; Neoplasms; Organometallic Compounds; Oxidation-Reduction; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species; Zinc Compounds

A 1,4-disubstituted zinc(II) phthalocyanine conjugated with a cyclic Arg-Gly-Asp-D-Phe-Lys (cRGDfK) moiety through a triazole linker was prepared and characterized by UV/Vis spectroscopy and high-resolution ESI-MS. The conjugate showed a relatively weak fluorescence emission in N,N-dimethylformamide (ΦF =0.08), but it was a very efficient singlet oxygen generator (ΦΔ=0.80) as a result of the di-α-substituted structure. Owing to the presence of the cyclic peptide sequence cRGDfK, which is a well-known αvβ3 -integrin antagonist, this conjugate exhibited significantly higher cellular uptake toward the αvβ3(+) U87-MG cells compared with the αvβ3(-) MCF-7 cells, as determined by flow cytometry and fluorescence microscopy. The photocytotoxicity of this compound against these two cell lines, however, was comparable owing to the similar efficiency of intracellular reactive oxygen species generation. Confocal microscopic studies also revealed that this conjugate localized preferentially in the lysosomes, but not in the nucleus, endoplasmic reticulum, and mitochondria of the U87-MG cells.

Topics: Apoptosis; Cell Line, Tumor; Coordination Complexes; Humans; Indoles; Integrins; Isoindoles; MCF-7 Cells; Microscopy, Fluorescence; Neoplasms; Oligopeptides; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species; Spectrophotometry, Ultraviolet; Zinc Compounds

Photodynamic therapy (PDT) is a clinically approved therapeutic modality for the treatment of diseases characterized by uncontrolled cell proliferation, mainly cancer. It involves the selective uptake of a photosensitizer (PS) by neoplastic tissue, which is able to produce reactive oxygen species upon irradiation with light, leading to tumor regression. Here a synergistic cell photoinactivation is reported based on the simultaneous administration of two PSs, zinc(II)-phthalocyanine (ZnPc) and the cationic porphyrin meso-tetrakis(4-N-methylpyridyl)porphine (TMPyP) in three cell lines (HeLa, HaCaT and MCF-7), using very low doses of PDT. We detected changes from predominant apoptosis (without cell detachment) to predominant necrosis, depending on the light dose used (2.4 and 3.6 J/cm(2), respectively). Analysis of changes in cytoskeleton components (microtubules and F-actin), FAK protein, as well as time-lapse video microscopy evidenced that HeLa cells were induced to undergo apoptosis, without losing adhesion to the substrate. Moreover, 24 h after intravenous injection into tumor-bearing mice, ZnPc and TMPyP were preferentially accumulated in the tumor area. PDT with combined treatment produced significant retardation of tumor growth. We believe that this combined and highly efficient strategy (two PSs) may provide synergistic curative rates regarding conventional photodynamic treatments (with one PS alone).

Topics: Actins; Animals; Apoptosis; Dose-Response Relationship, Radiation; Drug Synergism; Female; Focal Adhesion Kinase 1; HeLa Cells; Humans; Indoles; Injections, Intravenous; Isoindoles; MCF-7 Cells; Mice; Mice, Inbred C57BL; Microscopy, Video; Microtubules; Necrosis; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Porphyrins; Time Factors; Time-Lapse Imaging; Tumor Burden; Xenograft Model Antitumor Assays; Zinc Compounds

Subcellular localization of photosensitizers (PSs) determines the therapeutic efficacy in the photodynamic therapy. However, among the subcellular compartments, there has been little effort to deliver the PSs selectively into the plasma membrane and examine the phototherapeutic efficacy of membrane-localized PSs. Here, we developed a liposomal delivery system to localize the hydrophobic PSs selectively into the plasma membrane. The membrane fusogenic liposomes (MFLs), the membrane of which is engineered to fuse with the plasma membrane, was prepared for the membrane localization of PSs. The phototherapeutic efficacy of cells treated with ZnPc-loaded MFLs was superior over that of cells treated with ZnPc-loaded non-fusogenic liposomes, which is the conventional liposomal formulation that delivers the PSs into the intracellular compartments via endocytosis. The membrane localization of ZnPc molecules led to rapid membrane disruption upon irradiation and subsequent necrosis-like cell death. The membrane-localized generation of reactive oxygen species in the cells treated with ZnPc-loaded MFLs was likely to account for the effective disruption of plasma membrane. Thus, this work provides a novel delivery method to localize the PSs selectively into the plasma membrane with the enhanced phototherapeutic efficacy.

Topics: Animals; Cell Line, Tumor; Cell Membrane; Cell Survival; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Humans; Hydrophobic and Hydrophilic Interactions; Indoles; Isoindoles; Lipids; Liposomes; Membrane Fusion; Mice; Necrosis; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species; Technology, Pharmaceutical; Zinc Compounds

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

A targeted photosensitizer used in photodynamic therapy (PDT) was fabricated by incorporation of zinc phthalocyanine (ZnPc) and folic acid (FA) into polyvinylpyrrolidone (PVP) micelles, which exhibits excellent anticancer performance revealed by both in vitro studies and in vivo tests.

Topics: Animals; Drug Carriers; Folic Acid; Hep G2 Cells; Humans; Indoles; Isoindoles; Male; Mice, Inbred BALB C; Micelles; Neoplasms; Optical Imaging; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Povidone; Singlet Oxygen; Sunlight; Zinc Compounds

Electronic structures, energies and splitting of the Qx and Qy bands for positional isomers of zinc mono-, di-, tri-, and tetra pyridinoporphyrazines as well as parent zinc phthalocyanine were investigated using density functional theory (DFT) and time-dependent (TD) DFT approaches. The influence of the Hartree-Fock exchange on excited state energies and Qx and Qy bands splitting were studied using GGA BP86 and hybrid B3LYP and PBE1PBE exchange-correlation functionals. Solvent effects were estimated using the polarized continuum model (PCM) approach and cyclohexane, toluene, or DMSO as solvents. It was found that general trends in the Qx and Qy band energies and splitting correlate very well with the available experimental data on pyridinoporphyrazines and follow the trends in HOMO-LUMO and HOMO-LUMO+1 energy gaps as well as LUMO-LUMO+1 splitting. TDDFT trends allow estimation of the Qx and Qy band energies and splitting in unknown tripyridinoporphyrazines and in individual positional isomers of tetrapyridinoporphyrazines.

Topics: Cyclohexanes; Dimethyl Sulfoxide; Drug Discovery; Indoles; Isoindoles; Isomerism; Metalloporphyrins; Models, Molecular; Neoplasms; Organometallic Compounds; Quantum Theory; Solvents; Spectrophotometry, Ultraviolet; Spectrum Analysis; Toluene; Zinc Compounds

One of the limitations for clinical applications of dendritic cell (DC)-based cancer immunotherapy is the low potency in generating tumor antigen specific T cell responses. We examined the immunotherapeutic potential of a mitochondria-targeted nanoparticle (NP) based on a biodegradable polymer and zinc phthalocyanine (ZnPc) photosensitizer (T-ZnPc-NPs). Here, we report that tumor antigens generated from treatment of breast cancer cells with T-ZnPc-NPs upon light stimulation activate DCs to produce high levels of interferon-gamma, an important cytokine considered as a product of T and natural killer cells. The remarkable ex vivo DC stimulation ability of this tumor cell supernatant is a result of an interleukin (IL)-12/IL-18 autocrine effect. These findings contribute to the understanding of how in situ light activation amplifies the host immune responses when NPs deliver the photosensitizer to the mitochondria and open up the possibility of using mitochondria-targeted-NP-treated, light-activated cancer cell supernatants as possible vaccines.

Topics: Animals; Antigens, Neoplasm; Apoptosis; Biocompatible Materials; Cancer Vaccines; Cell Line, Tumor; Dendritic Cells; HeLa Cells; Humans; Immunotherapy; Indoles; Interferon-gamma; Isoindoles; MCF-7 Cells; Mice; Mice, Inbred C57BL; Mitochondria; Nanoparticles; Necrosis; Neoplasms; Organometallic Compounds; Photosensitizing Agents; Polymers; Zinc Compounds

In this study, two phthalocyanine-erlotinib conjugates linked by an oligoethylene glycol chain have been synthesised and fully characterised. Having erlotinib as the targeting moiety, the two conjugates exhibited high specific affinity to HepG2 cancer cells and tumour tissues, therefore leading to high photodynamic activity.

Topics: Antineoplastic Agents; Drug Delivery Systems; Erlotinib Hydrochloride; Ethylene Glycol; Hep G2 Cells; Humans; Indoles; Isoindoles; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Quinazolines; Zinc Compounds

Newly synthesized zinc phthalocyanine bearing sixteen quaternized imidazolyl moieties on the periphery displays high water-solubility, lack of aggregation and high singlet oxygen quantum yield in water (ΦΔ > 0.33). The in vitro tests indicated excellent anticancer photodynamic activity (EC50 = 36.7 nM) and low dark toxicity to non-cancerous cells (TC50 = 395 μM).

Topics: 3T3 Cells; Animals; Cell Survival; Crystallography, X-Ray; HeLa Cells; Humans; Indoles; Isoindoles; Mice; Molecular Conformation; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Quantum Theory; Singlet Oxygen; Solubility; Water; Zinc Compounds

Photodynamic therapy (PDT) is a promising therapeutic modality which uses a photosensitizer to capture visible light resulting in phototoxicity in the irradiated region. PDT has been used in a number of pathological indications, including tumor. A key desirable feature of the photosensitizer is the high phototoxicity on tumor cells but not on normal cells. In this study, we conjugate a gonadotropin-releasing hormone (GnRH) to a photosensitizer, Zinc phthalocyanine (ZnPc), in order to enhance its specificity to breast cancer, which over-expresses GnRH receptor. ZnPc has unique advantages over other photosensitizers, but is difficult to derivatize and purify as a single isomer. We previously developed a straight-forward way to synthesize mono-substituted β-carboxy-phthalocyanine zinc (ZnPc-COOH). Photophysical and photochemical parameters of this ZnPc-GnRH conjugate including fluorescence quantum yield (Ф(f)), fluorescence decay time (τ(s)) and singlet oxygen quantum yield (Ф(Δ)) were evaluated and found comparable with that of ZnPc, indicating that addition of a GnRH peptide does not significantly alter the generation of singlet oxygen from ZnPc. Cellular uptakes and phototoxicities of this conjugate were tested and found significantly enhanced on human breast cancer cell lines overexpressing GnRH receptors (MDA-MB-231 and MCF-7 cells) compared to cells with low levels of GnRH receptors, such as human embryonic lung fibroblast (HELF) and human liver carcinoma (HepG2) cells. In addition, the cellular uptake of this conjugate toward MCF-7 cells were found clearly alleviated by a GnRH receptor blocker Cetrorelix, suggesting that the cellular uptake of this conjugate was GnRH receptor-mediated. Put together, these findings revealed that coupling ZnPc with GnRH analogue was an effective way to improve the selectivity of ZnPc towards tumors with over-expressed GnRH receptors.

Topics: Antineoplastic Agents; Biological Transport; Cell Line, Tumor; Cell Proliferation; Chemical Phenomena; Darkness; Gonadotropin-Releasing Hormone; Humans; Indoles; Isoindoles; Molecular Targeted Therapy; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Receptors, LHRH; Zinc Compounds

The photodynamic effect of upconversion nanoparticles loaded with a photosensitizer was studied on murine bladder cancer cells (MB49). Mesoporous silica was coated onto sodium yttrium fluoride upconversion nanocrystals to form a core-shell structure and then loaded with the photosensitizer zinc (II)-phthalocyanine into the porous silica. The nanoparticles displayed a uniform spherical shape with an average diameter of about 50 nm and showed good dispersibility in water. Intracellular uptake study in MB49 cells revealed a time- and concentration-dependent accumulation of these nanoparticles. Upon irradiation with 980-nm near-infrared light, their efficiency in activating the loaded zinc (II)-phthalocyanine to generate singlet oxygen molecules was confirmed in live cells. The cytotoxic effect of the released singlet oxygen from the nanoplatform was proven by cell viability assay, confocal microscopy, DNA agarose gel electrophoresis, cytochrome c-releasing assay, and prostate-specific antigen-enzyme-linked immunosorbent assay, all of which showed a strong photodynamic effect of the nanoparticles on MB49 cells. This suggests the efficacy of sodium yttrium fluoride upconversion nanoparticles as a carrier for photosensitizers and their use in photodynamic therapy of cancer and some other diseases.. In this study, the photodynamic effect of upconversion nanoparticles loaded with a photosensitizer was investigated on murine bladder cancer cells, with strongly positive results, which may pave its way to future clinical use in malignant tumors and potentially other diseases.

Topics: Apoptosis; Cell Line, Tumor; Cell Nucleus; Cell Nucleus Shape; Cell Survival; Cytochromes c; DNA Fragmentation; Drug Carriers; Fluorides; Humans; Indoles; Intracellular Space; Isoindoles; Male; Nanomedicine; Nanoparticles; Neoplasms; Organometallic Compounds; Oxidative Stress; Photochemotherapy; Photosensitizing Agents; Porosity; Prostate-Specific Antigen; Silicon Dioxide; Singlet Oxygen; Spectrometry, Fluorescence; Yttrium; Zinc Compounds

Unsymmetrical phthalocyanine derivatives have been widely studied as photosensitizers for photodynamic therapy (PDT), targeting various tumor types. However, the preparation of unsymmetrical phthalocyanines is always a challenge due to the presence of many possible structural isomers. Herein we report a new unsymmetrical zinc phthalocyanine, pentalysine beta-carbonylphthalocyanine zinc (ZnPc-(Lys)(5)), that was prepared in large quantity and high purity. This is a water-soluble cationic photosensitizer and maintains a high quantum yield of singlet oxygen generation similar to that of unsubstituted zinc phthalocyanine (ZnPc). Compared with anionic ZnPc counterparts, ZnPc-(Lys)(5) shows a higher level cellular uptake and 20-fold higher phototoxicity toward tumor cells. Pharmacokinetics and PDT studies of ZnPc-(Lys)(5) in S180 tumor-bearing mice showed a high ratio of tumor versus skin retention and significant tumor inhibition. This new molecular framework will allow synthetic diversity in the number of lysine residues incorporated and will facilitate future QSAR studies.

Topics: Animals; Antineoplastic Agents; Cell Line; Humans; Indoles; Isoindoles; K562 Cells; Mice; Neoplasms; Oligopeptides; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Singlet Oxygen; Zinc Compounds

Multifunctionalization of carbon nanotubules is easily achieved by attaching functional molecules that provide specific advantages for microscopic applications. We fabricated a double photodynamic therapy (PDT) and photohyperthermia (PHT) cancer phototherapy system that uses a single laser. Zinc phthalocyanine (ZnPc) was loaded onto single-wall carbon nanohorns with holes opened (SWNHox), and the protein bovine serum albumin (BSA) was attached to the carboxyl groups of SWNHox. In this system, ZnPc was the PDT agent, SWNHox was the PHT agent, and BSA enhanced biocompatibility. The double phototherapy effect was confirmed in vitro and in vivo. When ZnPc-SWNHox-BSA was injected into tumors that were subcutaneously transplanted into mice, the tumors almost disappeared upon 670-nm laser irradiation. In contrast, the tumors continued to grow when only ZnPc or SWNHox-BSA was injected. We conclude that carbon nanotubules may be a valuable new tool for use in cancer phototherapy.

Topics: Animals; Cell Line, Tumor; Humans; Hyperthermia, Induced; Indoles; Isoindoles; Lasers; Materials Testing; Mice; Mice, Inbred Strains; Nanotubes, Carbon; Neoplasm Transplantation; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Proteins; Serum Albumin, Bovine; Zinc Compounds

The aim of the present study was to evaluate the photodynamic efficacy of a novel phthalocyanine derivate 2,3,9,10,16,17,23,24-octakis[(N,N-dimethylamino) ethylsulfanyl]phthalocyaninatozinc(II) (referred here as S1) using MCF-7c3 human breast cancer cells and the LM2 adenocarcinoma subcutaneously implanted in Balb/c mice as experimental models. The S1-l-alpha-dimyristoyl-phosphatidylcholine liposome was selected as the best delivery system because it showed greater internalization into cells (35 nmol/10(6) cells), relative to other liposomes. After 3 h incubation S1 was partially localized in lysosomes, the compartment that represented its primary photodamage site. The S1 treated cultures also revealed a degree of mitochondrial morphology alteration. Indeed, S1 leads to photokilling of the cells with different efficacies indicating that cell photoinactivation was dependent on both the phthalocyanine concentration and the light dose applied. Analyses of morphology and nuclear condensation level indicated that some of the cells exposed to photodynamic therapy were undergoing apoptosis within 8h after treatment. To assess the in vivo effectiveness of S1, animals bearing tumors were treated with 0.2mg/kg S1 followed 24h later by 108 J cm(-2) light at 600-800 nm and 60 mW cm(-2),while other animals served as controls (no treatment, light alone, or S1 alone). All S1 treated tumors and none of the controls exhibited complete or partial responses, and these responses continued for the entire observation period of 12 days. Evaluation of tumor size showed that the treatment effectively delayed tumor growth. Light microscopy investigations of irradiated tumor specimens showed that S1 causes an early direct damage of malignant cells, largely via processes leading to random necrotic pathways.

Topics: Animals; Cell Death; Cell Line, Tumor; Cell Survival; Culture Media; Darkness; Female; Humans; Indoles; Intracellular Space; Isoindoles; Mice; Mice, Inbred BALB C; Neoplasms; Organometallic Compounds; Photochemotherapy; Solutions; Spectrometry, Fluorescence; Treatment Outcome; Xenograft Model Antitumor Assays; Zinc Compounds

Phthalocyanine-nanoparticle conjugates have been designed and synthesised for the delivery of hydrophobic photosensitizers for photodynamic therapy (PDT) of cancer. The phthalocyanine photosensitizer stabilized gold nanoparticles have an average diameter of 2-4 nm. The synthetic strategy interdigitates a phase transfer reagent between phthalocyanine molecules on the particle surface that solubilises the hydrophobic photosensitizer in polar solvents enabling delivery of the nanoparticle conjugates to cells. The phthalocyanine is present in the monomeric form on the nanoparticle surface, absorbs radiation maximally at 695 nm and catalytically produces the cytotoxic species singlet oxygen with high efficiency. These properties suggest that the phthalocyanine-nanoparticle conjugates are ideally suited for PDT. In a process that can be considered as cancer therapy using a 'Trojan horse', when the nanoparticle conjugates are incubated with HeLa cells (a cervical cancer cell line), they are taken up thus delivering the phthalocyanine photosensitizer directly into the cell interior. Irradiation of the nanoparticle conjugates within the HeLa cells induced substantial cell mortality through the photodynamic production of singlet oxygen. The PDT efficiency of the nanoparticle conjugates, determined using colorimetric assay, was twice that obtained using the free phthalocyanine derivative. Following PDT with the nanoparticle conjugates, morphological changes to the HeLa cellular structure were indicative of cell mortality via apoptosis. Further evidence of apoptosis was provided through the bioluminescent assay detection of caspase 3/7. Our results suggest that gold nanoparticle conjugates are an excellent vehicle for the delivery of surface bound hydrophobic photosensitizers for efficacious photodynamic therapy of cultured tumour cells.

Topics: Apoptosis; Drug Screening Assays, Antitumor; Gold; HeLa Cells; Humans; Hydrophobic and Hydrophilic Interactions; Indoles; Isoindoles; Light; Molecular Structure; Nanoparticles; Neoplasms; Organometallic Compounds; Oxygen; Photochemotherapy; Photosensitizing Agents; Structure-Activity Relationship; Surface Properties; Zinc Compounds

In this study we evaluated the photophysical, photochemical properties of the zinc phthalocyanine/ magnetic fluid (ZnPC/MF) complex in liposomal medium. As a result of the present investigation we propose the liposome-encapsulated ZnPC/MF complex as a very promising nanostructured device for cancer treatment. The spectroscopy characterization and the in vitro dark toxicity of both ZnPC and ZnPC/MF complex in Hank's and in liposomal medium are reported. Our findings revealed that the spectroscopic properties of the ZnPC associated or not with MF presented little differences and are very close to what one expects from an ideal photosensitizer compound. Indeed, the ZnPC/MF complex in liposomal medium presented lower dark toxicity compared to the ZnPC/MF complex in Hank's, strongly supporting the use of the former for cancer treatment.

Topics: Animals; Drug Carriers; Drug Delivery Systems; Humans; Indoles; Isoindoles; Liposomes; Magnetics; Mice; Nanotechnology; Neoplasms; Organometallic Compounds; Oxygen; Photochemotherapy; Spectrometry, Fluorescence; Zinc Compounds

The synthesis, characterization and electronic spectra of a series of nine 1,4,8,11,15,18,22,25-octa-alkyl zinc phthalocyanines (ZnPc), potential photosensitizers for the photodynamic therapy of cancer, are described. The substituents on the phthalocyanine (Pc) macrocycle "red-shift" the absorbance maximum, in cyclohexane, of all nine members of this series to a value of 703 +/- 2 nm, with a corrected fluorescence emission maximum for the octadecyl derivative of 715 nm. The solubilities and degree of aggregation of six examples in cyclohexane have been measured. The highest homologue, the octadecyl derivative, remains essentially unaggregated to a concentration of 1.5 x 10(-4) mol dm-3. the photostability of this Pc has been examined and the compound shown to be sensitive to photooxidation processes which lead to its decomposition to 3,6-bis-decylphthalimide. Known singlet oxygen quenchers inhibit the photodecomposition. In a comparative study, the octadecyl ZnPc underwent a more rapid photodecomposition than the corresponding metal-free derivative.

Topics: Indoles; Isoindoles; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Structure-Activity Relationship; Zinc; Zinc Compounds

Zn-phthalocyanine (Zn-Pc) incorporated into liposomes of different phospholipids has been incubated in vitro with human serum and administered i.v. to rabbits. In both cases, chromatographic and density gradient ultracentrifugation studies indicate that Zn-Pc is almost exclusively bound by the 3 major lipoprotein components of the plasma (VLDL, LDL and HDL). The amounts of Zn-Pc recovered from the different lipoprotein fractions reflect their relative concentration in the serum. The presence of 20% moles of cholesterol in liposomes of dipalmitoyl phosphatidylcholine (DPPC) optimizes the release of Zn-Pc to LDL. This fact is important for enhancing the selectivity of drug delivery to tumors since LDL display a preferential interaction with neoplastic cells.

Topics: Animals; Blood Proteins; Cholesterol; Drug Carriers; Female; Humans; Indoles; Isoindoles; Lipoproteins; Liposomes; Male; Neoplasms; Organometallic Compounds; Photochemotherapy; Rabbits; Zinc Compounds