Tumor mitochondria-targeted photodynamic therapy using TSPO as a molecular target

Objectives Photodynamic therapy (PDT) has been proven to be a non-invasive and effective therapeutic strategy for cancer treatment. Mitochondrion is an attractive target for developing novel PDT agents, as it produces ATP and regulates apoptosis. Current strategy of mitochondria targeting is mainly focused on adapting cationic photosensitizers that bind to the negatively charged mitochondria membrane. However, such an approach is lack of selectivity of tumor cells. To minimize the damage on healthy tissues, an alternative targeting strategy with high tumor specificity is in critical need. Herein, we report a novel tumor mitochondria-specific PDT approach by targeting translocator protein (TSPO), an 18kDa mitochondrial protein up-regulated in multiple types of cancers including breast, prostate, and brain cancer.

Methods We developed a novel TSPO-targeted photosensitizer, IR700DX-C₆DAA1106, by conjugating a phthalocyanine dye IR700DX to a functional TSPO-targeted molecule C₆DAA1106. The phototherapeutic effect of IR700DX-C₆DAA1106 was evaluated both in cells and in tumor-bearing mice.

Results In vitro study indicated that IR700DX-C₆DAA1106 phototherapy induced photo damage in TSPO positive breast cancer cells (MDA-MB-231) but not TSPO negative breast cancer cells (MCF-7). The treatment resulted in an apoptosis-like cell death, typically seen in mitochondria mediated cell death. Remarkably, in vivo phototherapy study suggested that, IR700DX-C₆DAA1106-mediated phototherapy significantly inhibited the growth of MDA-MB-231 tumors.

Conclusions In conclusion, we developed a novel mitochondria TSPO targeted photosensitizer IR700DX-C₆DAA1106. This photosensitizer effectively induced apoptosis-like cell death in TSPO positive cancer cells. In addition, IR700DX-C₆DAA1106 significantly inhibited tumor growth in TSPO positive tumor bearing mice. These combined data suggest that this new mitochondria TSPO-targeted photosensitizer has great potential for cancer treatment using PDT.