Preparation Of Liposomal Deliveried BCPD-18MA-a Novel Photosensitizer For Cancer Treatment

Background and purpose:Since the discovery of photodynamic therapy, there has been a continuous search for more potent photosensitizers. To that end, we have synthesized a number of novel chlorin photosensitizers BCPDs. Among them, the BCPD-18 easy to synthesize is one of the most potent compounds. In vitro cell culture, it exhibits high phototoxicity and low dark toxicity against human hepatoma BEL-7402 cells. With the aim of further improving its tumoritropic behaviour and hydrophilicity, BCPD-18 presently was hydrolyzed to form its monoacid derivative, so-called BCPD-18-MA chemicallynamed (±)-trans-3,4-dimethoxycarbonyl-4,4a-dihy dro -4a,8,14,19-tetramethyl-18-ethyl-23H,25H-benzo[b]porphine-11,13-dimethoxycarb-onyl-9-propanoicacid. Because of its hydrophobic character, we design to prepare L-BCPD-18MA to improve its hydrophilicity and study its tissue distribution, cellular uptake, subcellular localization and PDT antitumor efficacy in vivo and in vitro, in addition to histological analyses.Experiment approachment:L-BCPD-18MA was prepared according to a modification of the method of Bangham. The rate of BCPD-18MA photo-degradation was determined spectrophotometrically at different times after illustration. The subcellular localization of BCPD-18 was examined by laser confocal microscopy. The PDT cytoxicity of BCPD-18MA on MDA-MB-231 cells was assessed by MTT assay and two aspects of apoptosis such as phosphatidylserine exposure and nuclear fragmentation were investigated. The biodistribution of L-BCPD-18MA in the lewis lung carcinoma (LLC)-bearing mice was followed to evaluate its tumor selectivity and rate of clearance. The in vivo PDT effect of L-BCPD-18MA on LLC-bearing mice was studied. The tumor volume in LLC-bearing mice was measured after PDT. The level of intrinsic toxicity induced by L-BCPD-18 and the efficiency of L-BCPD-18-mediated PDT were also investigated by histological H&E staining.Key resultsThe results showed as follows:Firstly, L-BCPD-18 could be rapidly incorporated into the MDA-MB-231 cells and was localized partially in mitochondria. L-BCPD-18 could induce cells apoptosis by PDT. Secondly, biodistribution of L-BCPD-18MA in LLC-bearing mice clarified its fast rate of clearance and good tumor selectivity related to skin. Thirdly, entrapment of BCPD-18 into liposomes resulted in a dramatic impairment of dark toxicity and a notable improvement of PDT antitumor efficacy in vivo. Moreover, compared with liposomal-delivered BPD-MA, L-BCPD-18MA exhibited lower dark toxicity and higher phototoxicity against MDA-MB-231 cells and the equal photodynamic efficacy on LLC-bearing mice. It was suggested that L-BCPD-18MA could be a potential drug candidate for PDT antitumor。...