hypocrellin-b and Disease-Models--Animal

Photodynamic therapy (PDT) has been successfully implemented as a treatment for wet age-related macular degeneration (AMD), but very few photosensitizers have been developed for clinical use. Herein, we describe a novel formulation of liposomal hypocrellin B (LHB) that was prepared by high-pressure homogenization. The encapsulation efficiency and PDT efficacy in vitro of this new preparation were found to remain nearly constant over 1 year. Moreover, LHB is rapidly cleared from the blood, with a half-life of 2.319 ± 0.462 h and a very low serum concentration at 24 h after injection. Testing in a rat model of choroidal neovascularization (CNV) showed that leakage of blood vessels in CNV lesions was significantly reduced when LHB PDT was given at a dose of 1 mg kg(-1) along with yellow laser irradiation; the damage to the collateral retina and the retinal pigment epithelium was minimal. Skin phototoxicity assays showed that only two of the 200 mice given a 4 mg per kg dose of LHB experienced an inflammatory reaction in the auricle irradiated at 24 h after dosing. These data collectively indicate that LHB may be a safe and effective photosensitizer for vascular-targeted PDT of AMD.

Topics: Animals; Cell Survival; Cells, Cultured; Choroidal Neovascularization; Disease Models, Animal; Drug Evaluation, Preclinical; Ear; Endothelial Cells; Female; Liposomes; Lung; Male; Mice; Microvessels; Organ Size; Perylene; Photochemotherapy; Photosensitizing Agents; Quinones; Rats; Retina; Skin; Wet Macular Degeneration

Hypocrellin B (HB), a monomeric perylenequinone pigment, is a promising second-generation photosensitizer for photodynamic therapy. We have evaluated the efficacy of HB mediated PDT by experimenting with various drug-light intervals, based on the biodistribution analysis in human bladder tumor (MGH cell line) models. Tumor growth rates were assessed at 10-day post treatment followed by morphometric analysis. Biodistribution of HB was evaluated using spectrofluorophotometry analysis (Ex: 480 nm, Em: 620-630 nm). The level of HB peaked at 6 h postinjection in tumor, peritumoral skin and normal muscle followed by a decline over the next 42 h. Concurrently, the ratio of drug in tumor versus skin was relatively low at all times in comparison to tumor to muscle ratio. In serum, concentration of HB peaked at 1 h. Almost 88% of its original uptake level was cleared at 48 h. The level of PDT response revealed a strong dependence on the drug-light intervals (DLI) and light dose. For both high and low fluence/fluence rate, comparable tumor response was observed at 1 h DLI; treated tumors exhibited significant tumor regression compared to 6 and 24 h DLI. The absence of tumor response was observed at 24 h DLI even at high light dose (100 J/cm(2); 100 mW/cm(2)). Tumor response detected at low light dose (12 J/cm(2); 12 mW/cm(2)) at short DLI suggests that the tumor vasculature is a more sensitive target compared to the cellular compartment of the tumor, correlating significantly with the bioavailability of the drug in serum. Therefore, HB mediated PDT effect is characteristics of a predominantly vascular mediated effect. This study confirms that for short drug-light intervals, PDT seems to target tumor vasculature, which contributes to tumor destruction.

Topics: Animals; Cell Line, Tumor; Disease Models, Animal; Humans; Mice; Neoplasm Transplantation; Perylene; Photochemotherapy; Photosensitizing Agents; Quinones; Tissue Distribution; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays