zn(ii)-phthalocyanine and Breast-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

There has been considerable interest in the development of novel photosensitisers for photodynamic therapy (PDT). The use of liposomes as drug delivery systems containing simultaneously two or more drugs is an attractive idea to create a new platform for PDT application. Therefore, the aim of this study was to evaluate the synergistic effect of diethyldithiocarbamate (DETC) and zinc phthalocyanine (PDT) co-encapsulated in liposomes. The reverse-phase evaporation method resulted in the successful encapsulation of DETC and ZnPc in liposomes, with encapsulation efficiencies above 85 %, mean size of 308 nm, and zeta potential of - 36 mV. The co-encapsulation decreased the cytotoxic effects in mouse embryo fibroblast (NIH3T3) cells and inhibited damage to human erythrocytes compared to free DETC + ZnPc. In addition, both the free drugs and co-encapsulated ones promoted more pronounced phototoxic effects on human breast cancer cells (MDA-MB231) compared to treatment with ZnPc alone. This synergistic effect was determined by DETC-induced decreases in the antioxidant enzyme activity of superoxide dismutase (SOD) and glutathione (GSH).

Topics: Animals; Breast Neoplasms; Ditiocarb; Female; Humans; Indoles; Isoindoles; Liposomes; Mice; NIH 3T3 Cells; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Zinc Compounds

Therapeutic effects of photodynamic therapy (PDT) are limited by the selectivity of photosensitizer (PS). Herein, a novel tumor-targeted drug-PS conjugate (Gan-ZnPc) which integrated with zinc phthalocyanine (ZnPc) and Ganetespib has been developed. ZnPc is a promising PS with remarkable photosensitization ability. Ganetespib is a heat shock protein 90 (Hsp90) inhibitor with preferential tumor selectivity and conjugated to ZnPc as a tumor-targeted ligand. The multifunctional small molecule conjugate, Gan-ZnPc, could be bound to extracellular Hsp90 and then selectively internalized into the tumor cells, followed by the generation of abundant intracellular reactive oxygen species (ROS) upon irradiation. Besides, Gan-ZnPc can arrest cell proliferation and induce apoptosis by the inhibition of Hsp90. Herein, with combination of the inhibition of Hsp90 and the generation of cytotoxic ROS, Gan-ZnPc implements tumor selectivity, concentrated PDT and chemotherapy in a synergistic manner, which results in highly effective anti-tumor activity in vitro and in vivo.

Topics: Animals; Breast Neoplasms; Cell Line; Cell Line, Tumor; Drug Delivery Systems; Drug Synergism; Female; HSP90 Heat-Shock Proteins; Humans; Indoles; Isoindoles; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species; Triazoles; Zinc Compounds

Angiogenesis is a common pathological characteristic of many solid tumors and vulnerable atherosclerotic plaques. Photothermal therapy (PTT) is a promising method to reduce neovascularization. To increase the targeting ability and efficiency of PTT, a novel polymeric nanosystem that encapsulates phthalocyanine zinc (ZnPc) and perfluorohexane (PFH) was developed to target the new blood vessels of breast tumors. After being conjugated to the anti-VEGFR-2 antibody, the polymeric nanoparticles (NPs) targeted vascular endothelial cells efficiently. The photosensitizer (PS) in the NPs could convert laser energy into heat, generating local high temperatures to kill the surrounding cells under laser irradiation. In addition, the liquid-gas phase transition of PFH was induced, and an enhanced ultrasound (US) and photoacoustic (PA) image could be obtained. US/PA imaging enables visualization of the location of NPs, and laser irradiation position can be guided to the optimal location, resulting in fewer side effects than those from traditional treatments with a high targeting ability and an efficient synergistic effect from the PTT.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Proliferation; Cells, Cultured; Female; Fluorocarbons; Humans; Indoles; Isoindoles; Mice; Mice, Nude; Nanoparticles; Optical Imaging; Organometallic Compounds; Particle Size; Photoacoustic Techniques; Photosensitizing Agents; Phototherapy; Polymers; Surface Properties; Ultrasonic Therapy; Vascular Endothelial Growth Factor Receptor-2; Zinc Compounds

In this work, the photodynamic therapy (PDT) activities (using human carcinoma adherent MCF-7 cells) of zinc phthalocyanine derivatives: complexes 1 (Zn mono cinnamic acid phthalocyanine) and 2 (zinc mono carboxyphenoxy phthalocyanine) when covalently linked to folic acid (FA) and amine functionalized magnetic nanoparticles (AMNPs) are reported. The covalent linkage of asymmetric zinc cinnamic acid Pc (1) to FA (1-FA) through an amide bond is reported for the first time. Complex 1 is insoluble in water, but upon linkage to FA, (to form 1-FA) the molecule become water soluble, hence the UV-Vis spectrum and singlet oxygen quantum yield for 1-FA were also done in water since water solubility is essential for biological applications. The reported 2-FA is also water soluble. Linking complexes 1 and 2 to FA and AMNPs decreased the dark toxicity of 1 and 2 on MCF-7 cells. Pc-FA (1-FA and 2-FA) conjugates had better singlet oxygen quantum yields (Φ

Topics: Breast Neoplasms; Cell Survival; Dimethyl Sulfoxide; Female; Folic Acid; Humans; Indoles; Isoindoles; Magnetite Nanoparticles; MCF-7 Cells; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Singlet Oxygen; Solubility; Spectroscopy, Fourier Transform Infrared; Water; Zinc Compounds

Regarding post-complication of convenient therapies against breast cancer, the emergence of effective approaches is essential. Photodynamic therapy is touted as a novel invasive therapeutic approach by the application of a photosensitizer promoted by laser irradiation. This study aimed to investigate the combined regime of low-level laser irradiation with zinc phthalocyanine in human breast cancer ZR-75-1 cell line. Cells were treated with 0.01 and 5 μg/ml of ZnPc for 24 h and exposed to radiation (70 mW) for 60 s. Cell viability was evaluated by MTT and flow cytometry. Cell migration capacity was monitored by scratch test, Transwell migration insert, and gelatin zymography. The function of MDR in treated cells was examined by Rhodamine 123 exclusion test. The level of GALNT11 was measured by ELISA. The expression of Bax and Bcl-2 genes was evaluated by real-time PCR. Laser irradiation and zinc phthalocyanine induced cell cytotoxicity in a dose-dependent manner. Flow cytometry analysis showed the induction of apoptotic and necrotic changes in treated cells. We found a reduction in migration rate and MMP-9 activity in cells undergoing the experimental procedure (p < 0.05). Immunofluorescence imaging revealed the intracellular accumulation of Rhodamine 123 coincided with a reduction in the level of GALNT11 in treated cells, showing the reduction of MDR activity and tumor cell resistance. Similar to flow cytometry assay, the reduction of Bcl-2 (approximately twofold) and upregulation of Bax genes were found in treated cells. Photodynamic therapy could be as an effective and alternative method for the treatment of breast cancer in a human.

Topics: Apoptosis; ATP Binding Cassette Transporter, Subfamily B; bcl-2-Associated X Protein; Breast Neoplasms; Cell Count; Cell Line, Tumor; Cell Movement; Cell Survival; Drug Resistance, Neoplasm; Female; Humans; Indoles; Isoindoles; Light; Matrix Metalloproteinase 9; N-Acetylgalactosaminyltransferases; Necrosis; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Rhodamine 123; Zinc Compounds

Cancer is a non-communicable disease that occurs following a mutation in the genes which control cell growth. Breast cancer is the most diagnosed cancer among South African women and a major cause of cancer-related deaths worldwide. Photodynamic therapy (PDT) is an alternative cancer therapy that uses photochemotherapeutic agents, known as photosensitizers. Drug-delivery nanoparticles are commonly used in nanomedicine to enhance drug-therapeutic efficiency. This study evaluated the photodynamic effects following treatment with 0.3 μM multiple particles delivery complex (MPDC) and irradiated with a laser fluence of 10 J/cm. Cell damage was assessed by inverted light microscopy for cell morphology; the Apoptox-Glo triple assay was used for cell viability, caspase activity and identification of cytodamage markers; flow cytometric analysis for cell death pathways and mitochondrial membrane potential; the enzyme linked immunosorbent assay (ELISA) for cytochrome C release; and real-time reverse transcriptase polymerase chain reaction (RT-PCR) array for gene expression.. Laser activated-MPDC induced a significant change in morphology of PDT-treated cells, with the appearance of apoptotic like morphological features. An increase in cytotoxicity, caspase activity, cell depolarization and cytochrome C release were identified in PDT-treated cells. Finally, the upregulation of BAX, BCL-2, CASP-2 and ULK-1 genes was observed.. The MPDC yielded a successful and stable hybrid agent with potent photodynamic abilities.

Topics: Apoptosis; Breast Neoplasms; Dendrimers; Female; Gold; Humans; Indoles; Isoindoles; MCF-7 Cells; Membrane Potential, Mitochondrial; Nanoparticles; Organometallic Compounds; Photochemotherapy; Zinc Compounds

A near IR absorbing phthalocyanine bearing four binaphtyl group has been synthesized in order to investigate its cytotoxicity and intracellular uptake of sensitizer on MCF-7 (human breast cancer), MDAH (ovarian cancer), HeLa (human epitheloid cervix carcinoma), EMT-6 (mouse breast cancer) and WI-38 (human fibroblast lung) cell lines. ZnPc showed four time higher intracellular uptake in carcinoma cells (MCF-7) than normal (WI-38) cell lines. With the aim of studying in detail the biodistribution feature and tumor nuclear imaging capacity, ZnPc was also labeled with I-131. The efficiency of radiolabeled compound was 95±4.6%. In addition, ZnPc reveals to be very efficient singlet oxygen generators (ΦΔ=0.612 in DMSO) and promising PS for PDT application. In vitro fluorescence imaging study with MCF-7 cells showed that ZnPc localized in cytoplasm of the cells. This results showed that synthesized ZnPc is promising candidate for dual fluorescence/nuclear imaging breast cancer and shows potential PS for PDT application.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cytoplasm; Female; Humans; Indoles; Iodine Radioisotopes; Isoindoles; MCF-7 Cells; Mice; Optical Imaging; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Singlet Oxygen; Tissue Distribution; Zinc Compounds

The functionalisation of therapeutic nanoparticle constructs with cancer-specific biomolecules can enable selective tumour accumulation and targeted treatment. Water soluble gold nanoparticles (ca. 4 nm) stabilised by a mixed monolayer of a hydrophobic zinc phthalocyanine photosensitiser (C11Pc) and hydrophilic polyethylene glycol (PEG) have been prepared. The C11Pc-PEG gold nanoparticle constructs were further functionalised with jacalin, a lectin specific for the cancer-associated Thomsen-Friedenreich (T) carbohydrate antigen, or with monoclonal antibodies specific for the human epidermal growth factor receptor-2 (HER-2). The two biofunctionalised nanoparticle conjugates produced similar levels of singlet oxygen upon irradiation at 633 nm. Importantly, both nanoparticle conjugates demonstrated extensive, yet comparable, phototoxicity in HT-29 colorectal adenocarcinoma cells (80-90%) and in SK-BR-3 breast adenocarcinoma cells (>99%). Non-conjugated C11Pc-PEG gold nanoparticles were only minimally phototoxic. Lysosomal colocalisation studies performed with the HT-29 colon cancer cells and the SK-BR-3 breast cancer cells revealed that both nanoparticle conjugates were partially localised within acidic organelles, which is typical of receptor-mediated endocytosis. The similarity of the targeted PDT efficacy of the two biofunctionalised C11Pc-PEG gold nanoparticles is discussed with respect to targeting ligand binding affinity and cell surface antigen density as key determinants of targeting efficiency. This study highlights how targeting small cell-surface molecules, such as the T antigen, can mediate a selective photodynamic treatment response which is similar to that achieved when targeting overexpressed protein receptors, such as HER-2. The high prevalence of the T antigen present on the cellular surface of primary tumours emphasises the broad potential applications for lectin-targeted therapies.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Gold Compounds; Humans; Hydrophobic and Hydrophilic Interactions; Indoles; Isoindoles; Lectins; Lysosomes; Metal Nanoparticles; Molecular Targeted Therapy; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Polyethylene Glycols; Receptor, ErbB-2; Singlet Oxygen; Zinc Compounds

Although photodynamic therapy (PDT) yields very good outcomes in numerous types of superficial solid cancers, some tumors respond suboptimally to PDT. Novel treatment strategies are therefore needed to enhance the efficacy in these therapy-resistant tumors. One of these strategies is to combine PDT with inhibitors of PDT-induced survival pathways. In this respect, the transcription factor nuclear factor κB (NF-κB) has been identified as a potential pharmacological target, albeit inhibition of NF-κB may concurrently dampen the subsequent anti-tumor immune response required for complete tumor eradication and abscopal effects. In contrast to these postulations, this study demonstrated that siRNA knockdown of NF-κB in murine breast carcinoma (EMT-6) cells increased survival signaling in these cells and exacerbated the inflammatory response in murine RAW 264.7 macrophages. These results suggest a pro-death and immunosuppressive role of NF-κB in PDT-treated cells that concurs with a hyperstimulated immune response in innate immune cells.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Culture Media, Conditioned; Cytokines; Drug Resistance, Neoplasm; Female; Gene Knockdown Techniques; Indoles; Isoindoles; Macrophages; Mice; NF-kappa B; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; RNA, Small Interfering; Zinc Compounds

To date, the application of photodynamic therapy in deep tissue has been severely restricted by the limited penetration depth of excitation light, such as UV light and visible light. In this work, a protocol of upconverting crystal/dextran-g-DOPE nanocomplex (UCN/dextran-g-DOPE) was developed. The nanocomplex was assembled from the hydrophobic upconverting nanoparticle (UCN) core and hydrophilic lipid shell. The photosensitizer zinc phthalocyanine (ZnPc) loaded UCN/dextran-g-DOPE offers possibilities to overcome the problem mentioned above. The UCN core works as a transducer to convert deeply penetrating near-infrared light to visible light to activate ZnPc for photodynamic therapy. The dextran-g-DOPE lipid shell is used for loading ZnPc and protecting the whole system from nonspecific absorbance or corrosion during the transportation. The experiment results show that the nanocomplex is an individual sphere with an average size of 30 nm. The ZnPc was activated to produce singlet oxygen successfully by the upconverting fluorescence emitted from UCN. The nanocomplex has high fluorescence stability in alkaline or neutral buffer solutions. Importantly, the ZnPc loaded UCN/dextran-g-DOPE nanocomplex showed a significant inhibitory effect on tumor cells after NIR exposure. Our data suggest that a ZnPc loaded UCN/dextran-g-DOPE nanocomplex may be a useful nanoplatform for future PDT treatment in deep-cancer therapy based on the upconverting mechanism.

Topics: Breast; Breast Neoplasms; Cell Line, Tumor; Dextrans; Drug Carriers; Female; Fluorescent Dyes; Humans; Indoles; Isoindoles; Organometallic Compounds; Phosphatidylethanolamines; Photochemotherapy; Photosensitizing Agents; Zinc Compounds

Zinc phthalocyanine (ZnPcSmix) was used as the photosensitizer (PS) in this study to investigate the cell death patterns as a result of photodynamic therapy (PDT) in a breast cancer cell line (MCF-7) in vitro using a 680 nm diode laser at a fluence of 5 J/cm(2).. PDT is a noninvasive form of cancer therapy, successfully applied for the treatment of various cancer types.. Flow cytometry using Annexin V-fluorescein isothiocyanate (FITC), a cell death immunosorbent assay (ELISA), and gene expression analysis following ZnPcSmix mediated PDT were performed to determine the induced cell death pathways.. The apoptotic cells abounded after the treatment, nuclear fragmentation was seen as oligonucleosomal degradation and increased expression of the B-cell lymphoma 2 (Bcl-2), DNA fragmentation factor alpha (DFFA1), and caspase 2 (CASP2) genes, indicated that apoptosis is the main induced mode of cell death.. ZnPcSmix mediated PDT led to an apoptotic cell death pathway and the PS used showed its ability to stimulate and initiate programmed cell death.

Topics: Apoptosis; Breast Neoplasms; Cell Death; Cells, Cultured; Female; Humans; Indoles; Isoindoles; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Zinc Compounds

A therapeutic technology that combines the phototoxic and immune-stimulating ability of photodynamic therapy (PDT) with the widespread effectiveness of the immune system can be very promising to treat metastatic breast cancer. We speculated that the knowledge of molecular mechanisms of existing multi-component therapies could provide clues to aid the discovery of new combinations of an immunostimulant with a photosensitizer (PS) using a nanoparticle (NP) delivery platform. Therapeutic challenges when administering therapeutic combinations include the choice of dosages to reduce side effects, the definitive delivery of the correct drug ratio, and exposure to the targets of interest. These factors are very difficult to achieve when drugs are individually administered. By combining controlled release polymer-based NP drug delivery approaches, we were able to differentially deliver zinc phthalocyanine (ZnPc) based PS to metastatic breast cancer cells along with CpG-ODN, a single-stranded DNA that is a known immunostimulant to manage the distant tumors in a temporally regulated manner. We encapsulated ZnPc which is a long-wavelength absorbing PS within a polymeric NP core made up of poly(d,l-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG). After coating the outside of the polymeric core with gold NPs (AuNPs), we further modified the AuNP surface with CpG-ODN. In vitro cytotoxicity using 4T1 metastatic mouse breast carcinoma cells shows significant photocytotoxicity of the hybrid NPs containing both ZnPc and CpG-ODN after irradiation with a 660 nm LASER light and this activity was remarkably better than either treatment alone. Treatment of mouse bone marrow derived dendritic cells with the PDT-killed 4T1 cell lysate shows that the combination of PDT with a synergistic immunostimulant in a single NP system results in significant immune response, which can be used for the treatment of metastatic cancer.

Topics: Adjuvants, Immunologic; Animals; Breast Neoplasms; Cell Line, Tumor; Combined Modality Therapy; Female; Indoles; Isoindoles; Mice; Mice, Inbred BALB C; Nanocapsules; Oligodeoxyribonucleotides; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Treatment Outcome; Zinc Compounds

The development of curative techniques which are selective for neoplasms is one of the main focal areas in cancer research. The mechanism of cell damage due to Zinc phthalocyanine (ZnPcSmix)-mediated photodynamic therapy (PDT) in a breast cancer cell line (MCF-7) was assessed by inverted light microscopy for morphology, the Trypan blue exclusion assay and adenosine triphosphate (ATP) luminescence assay for cell viability, alamarBlue for proliferation, Lactate Dehydrogenase (LHD) membrane integrity for cytotoxicity and fluorescent microscopy for ZnPcSmix localization. Fluorescent microscopy revealed that ZnPcSmix was localized in both mitochondria and lysosomes, and PDT treated cells showed damaging structural changes and decreased cell viability and proliferation. The light-dependent ZnPcSmix displayed appreciable photosensitivity and the intensity of damage was directly related to its concentration.

Topics: Biological Transport; Breast Neoplasms; Cell Death; Cell Proliferation; Cell Survival; Humans; Indoles; Intracellular Space; Isoindoles; Laser Therapy; MCF-7 Cells; Organometallic Compounds; Photosensitizing Agents; Sulfonic Acids; Zinc Compounds

Steady state fluorescence spectroscopy is used to study the binding characteristics of zinc phthalocyanine (ZnPc) to MCF-7 human breast cancer cells solubilized in a liposomal vesicle prepared with L-alpha-phosphatidic acid, dipalmitoyl. The observed apparent binding constant, K', of 1.14 x 10(7) together with the free energy of binding, deltaG, of -40.38 kJ/mole suggests a very strong affinity and spontaneous binding between the breast cancer cells and ZnPc. The wavelength of excitation of ZnPc in the liposomal vesicle (611 nm) is favorable to cytotoxic reactive singlet oxygen (1O2*) production necessary for photooxygenation reaction with the cancerous cells and is within the energy threshold that has good penetration to normal tissues without undue skin necrosis.

Topics: Breast Neoplasms; Female; Humans; Indoles; Isoindoles; Liposomes; Organometallic Compounds; Oxygen; Photosensitizing Agents; Solubility; Spectrometry, Fluorescence; Tumor Cells, Cultured; Zinc; Zinc Compounds

The photodynamic therapy is a technique by which the tumor cells are selectively sensitized to destruction by light of an appropriate wavelength. The aim of this work is to analyze the biological effectiveness of photochemical reactions induced by laser light in tumor cells exposed to photosensitizers.. The toxicity of the 2 photosensitizers zinc phthalocyanine (ZnPC) and meso-tetrahydroxyphenylchlorine (m-THPC) as well as the biological effect of the combination of sensitizers with laser light were tested in vitro by means of a colony forming assay. In addition, the influence on the photodynamic reaction of a previous exposure of the tumor cells to ionizing radiation has been tested.. For both sensitizers doses of 5 micrograms per milliliter of culture medium showed low toxicity, i.e. the survival of the treated cells exceeded 90%. For laser treatments the dose permitting 90% survival was determined to be around 10 J/cm2. With these doses, the combined application of photosensitizers and laser light proved to be very effective and resulted in a nearly complete reduction of survival. As expected, irradiation of the cells with doses of 1 and 2 Gy of X-rays reduced the survival to 66 and 47%, respectively, compared to untreated controls. Cells surviving such treatment showed no changes either in the response to treatments with photosensitizers or to combined applications of photosensitizers and laser light.. The effects of photodynamic treatment by ionizing radiation seem to be additive and independent of each other. So, our preliminary results are quite encouraging and point out the need of further detailed studies in view of the intended clinical application of this new kind of a local treatment.

Topics: Breast Neoplasms; Carcinoma; Combined Modality Therapy; Drug Evaluation, Preclinical; Female; Humans; Indoles; Isoindoles; Laser Therapy; Liposomes; Mesoporphyrins; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Tumor Cells, Cultured; Zinc Compounds