talaporfin and chlorin

The combination of photodynamic therapy (PDT) and chemotherapy is a prospective strategy to improve antitumor efficacy. Herein, a series of novel cytotoxic chlorin-based derivatives as dual photosensitizers (PSs) and histone deacetylase inhibitors (HDACIs) were synthesized and investigated for biological activity. Among them, compound 15e showed definite HDAC2 and 10 inhibitory activities by up-regulating expression of acetyl-H4 and highest phototoxicity and dark-toxicity, which was more phototoxic than Talaporfin as a PS while with stronger dark-toxicity compared to vorinostat (SAHA) as a HDACI. The biological assays demonstrated that 15e was liable to enter A549 cells and localized in mitochondria, lysosomes, golgi and endoplasmic reticulum (ER) etc. multiple organelles, resulting in higher cell apoptosis rate and ROS production compared to Talaporfin. Moreover, it could induce tumor cell autophagy as a dual PS and HDACI. All results suggested that compound 15e could be applied as a potential dual cytotoxic drug for PDT and chemotherapy.

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Molecular Structure; Photochemotherapy; Photosensitizing Agents; Porphyrins; Reactive Oxygen Species; Structure-Activity Relationship; Tumor Cells, Cultured

We previously synthesized a glucose-conjugated chlorin compound e6 (G-chlorin e6), and reported that it has very strong antitumor effects. The aim of the present study was to synthesize acetylated glucose-conjugated chlorin (AcN003HP) and evaluate its antitumor effect and excretion.. To evaluate the antitumor effect of AcN003HP, its IC. AcN003HP showed stronger antitumor effects and accumulation into cancer cells compared to talaporfin sodium, a conventional photosensitizer. AcN003HP was localized in the endoplasmic reticulum. In a xenograft tumor mouse model, AcN003HP showed longer excretion time from the body than G-chlorin e6, and photodynamic therapy using AcN003HP showed very strong antitumor effects.. The safety, improved controllability, and robust antitumor effects suggest AcN003HP as a good next-generation photosensitizer.

Topics: Acetylation; Animals; Apoptosis; Cell Line, Tumor; Endoplasmic Reticulum; Flow Cytometry; Gastrointestinal Neoplasms; Glucose; Humans; Mice; Photochemotherapy; Photosensitizing Agents; Porphyrins; Xenograft Model Antitumor Assays

Photodynamic therapy (PDT) is a Food and Drug Administration authorized method for cancer treatment, which uses photosensitizer and laser photo-irradiation to generate reactive oxygen species to induce cell death in tumors. Photosensitizers have been progressively developed, from first to third generation, with improvements in cell specificity, reduced side effects and toxicity, increased sensitivity for irradiation and reduced persistence of photosensitizer in healthy cells. These improvements have been achieved by basic comparative experiments between current and novel photosensitizers using cell lines; however, photosensitizers should be carefully evaluated because they may have cell type specificity. In the present study, we compared a third-generation photosensitizer, β-mannose-conjugated chlorin (β-M-chlorin), with the second generation, talaporfin sodium (NPe6), using seven different rat and human cell lines and a neuronal/glial primary culture prepared from rat embryos. NPe6 was more effective than β-M-chlorin in human-derived cell lines, and β-M-chlorin was more effective than NPe6 in rat primary cultures and rat-derived cell lines, except for the rat pheochromocytoma cell line, PC12. These differences of phototoxicity in different cell types are not because of differences in photosensitivity between the photosensitizers, but rather are associated with different distribution and accumulation rates in the different cell types. These data suggest that evaluation of photosensitizers for PDT should be carried out using as large a variety of cell types as possible because each photosensitizer may have cell type specificity.

Topics: Animals; Antineoplastic Agents; Cell Line; Cell Line, Tumor; Cell Survival; Cells, Cultured; Humans; Light; Mannose; Neurons; PC12 Cells; Photochemotherapy; Photosensitizing Agents; Porphyrins; Rats; Rats, Wistar

Photodynamic therapy (PDT) is an effective laser treatment for locally treating advanced bile duct carcinoma (BDC). The study's objective was to evaluate the increased cytocidal effect by apoptotic PDT using a novel photosensitizer, glucose-conjugated chlorin, by irradiation of light-emitting diode laser (G-PDT) in comparison with conventional PDT using talaporfin sodium (T-PDT).. The cytocidal effect of G-PDT was compared to that of T-PDT as a control. Tumor viability was determined by an in vitro MTS assay. The percentage of apoptosis-positive cells was examined by triple stain flow cytometry (annexin V, ethidium homodimer III and Hoechst 33342) in the BDC cell line (NOZ cell) in vitro. The change in transplanted tumor volume in vivo (4-week-old male BALB/c mice) was examined 7 days after PDT.. Cell death was induced in a light dose-dependent manner by PDT. The laser power was set at 5 Jules/cm(2) to obtain half maximal inhibitory concentration (IC50) in T-PDT and G-PDT and the concentration of photosensitivity for G-PDT (2.02 μg/ml) was lower than that for T-PDT (4.14 μg/ml). Both T-PDT and G-PDT showed increased induction rates in comparison to the light only or G-chlorin only. Furthermore, the rate of apoptosis in the G-PDT (92.6%) was increased in comparison to that in the T-PDT (38.9%). The increased rates of tumor volume during the 7 days in both the G-PDT and T-PDT groups were significantly lower than that in the non-PDT group (p<0.01). At day 7, the increased rates of tumor volume in the G-PDT group were significantly lower than that in the T-PDT group (p<0.05).. The new G-PDT treatment showed a high prevalence of apoptosis and inhibition of tumor growth in treatment of BDC cells.

Topics: Animals; Apoptosis; Bile Duct Neoplasms; Cell Line, Tumor; Cell Survival; Cholangiocarcinoma; Flow Cytometry; Glucose; Humans; In Situ Nick-End Labeling; Lasers; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Photochemotherapy; Photosensitizing Agents; Porphyrins; Prevalence

The characteristics of two new chlorin photosensitizers were studied in cell culture by determining phototoxicity, subcellular localization, and photophysical properties. Monoaspartyl chlorin e6 (MACE) and diaspartyl chlorin e6 (DACE) are new photosensitizers that show promise for use in photodynamic therapy. These chlorins are pure, monomeric compounds as determined by high-pressure liquid chromatography. Both compounds absorb substantially at a longer wavelength (664 nm) than does dihematoporphyrin ether-ester (DHE). Tumor diagnosis with the use of fluorescence should be facilitated due to the purity of the compounds and the single fluorescence emission peak. Phototoxicity dose-response curves of the sensitizers were completed using a standard clonogenic assay to determine cell viability. The chlorins showed good sensitizing capabilities with light. In addition, subcellular localization of MACE, DACE, and DHE was studied using fluorescence microscopy. Whereas DHE was located throughout the cytoplasm, the primary site of localization of the chlorins appeared to be in the lysosome. The results demonstrate that MACE and DACE are effective photosensitizing agents in vitro and compare favorably to DHE.

Topics: Cell Line; Cell Survival; Dihematoporphyrin Ether; Fluorescence; Hematoporphyrins; Photochemotherapy; Porphyrins; Spectrophotometry