Mitochondria-Targeted Photodynamic Cancer Therapy of Nanoscale Liposome-Encapsulating Boron Dipyrromethene Photosensitizers Conjugated with Pyridine Cations
Jie Cao, Yonghe Zhang, Wenjun Shi, Lehan Du, Zhihua Cui, Shujie Liu, Ruibo Zhao, Shibo Wang, Quan Zhang, Xiangdong Kong
Abstract
The development and use of mitochondria-targeted photosensitizers (PSs) hold great promise for enhancing the therapeutic efficacy and minimizing the side effects of photodynamic therapy (PDT). Although many studies have shown that coupling lipophilic cations to PSs facilitates their targeting to mitochondria, this process leads to a nonspecific distribution of PSs in the body and undesired systemic toxicity. Herein, three boron dipyrromethene (BODIPY) PSs conjugated with pyridine cations (1Py-BDP, 2Py-BDP, and 3Py-BDP) were synthesized to systematically evaluate the effects of the cationic pyridine number on the cytotoxicity and mitochondria-targeting property of the PSs for precise cancer PDT. To increase their stability in biological systems, these BODIPY PSs were encapsulated with an amphiphilic polymer (DSPE-mPEG2000) to afford PS-loaded liposomal nanoparticles designated 1Py-BDP@Lipos, 2Py-BDP@Lipos, and 3Py-BDP@Lipos. The results demonstrated that 2Py-BDP@Lipos showed higher efficiency for targeted delivery of the PSs to mitochondria compared with 1Py-BDP@Lipos and 3Py-BDP@Lipos. Moreover, the cytotoxicity of these BODIPY PSs was enhanced with the increase in the number of pyridine cations. In vivo results confirmed that liposomal encapsulation enhanced the tumor accumulation and retention of 2Py-BDP, which could effectively inhibit tumor growth under 660 nm laser irradiation. This study demonstrates that the conjugation of two pyridine cations with BODIPY PSs leads to improved targeting to mitochondria while maintaining low toxicity, thus facilitating the design of mitochondria-targeted PSs for in vivo PDT applications.