Application of Mitochondrially Targeted Nanoconstructs to Neoadjuvant X‑ray-Induced Photodynamic Therapy for Rectal Cancer

• Published in: ACS central science Vol. 6; no. 5; pp. 715 - 726
• Main Authors: Deng, Wei, McKelvey, Kelly J, Guller, Anna, Fayzullin, Alexey, Campbell, Jared M, Clement, Sandhya, Habibalahi, Abbas, Wargocka, Zofia, Liang, Liuen, Shen, Chao, Howell, Viive Maarika, Engel, Alexander Frank, Goldys, Ewa M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 27.05.2020
• ISSN: 2374-7943; 2374-7951
• DOI: 10.1021/acscentsci.9b01121

In this work, we brought together two existing clinical techniques used in cancer treatmentX-ray radiation and photodynamic therapy (PDT), whose combination termed X-PDT uniquely allows PDT to be therapeutically effective in deep tissue. To this end, we developed mitochondrially targeted biodegradable polymer poly­(lactic-co-glycolic acid) nanocarriers incorporating a photosensitizer verteporfin, ultrasmall (2–5 nm) gold nanoparticles as radiation enhancers, and triphenylphosphonium acting as the mitochondrial targeting moiety. The average size of the nanocarriers was about 160 nm. Upon X-ray radiation our nanocarriers generated cytotoxic amounts of singlet oxygen within the mitochondria, triggering the loss of membrane potential and mitochondria-related apoptosis of cancer cells. Our X-PDT strategy effectively controlled tumor growth with only a fraction of radiotherapy dose (4 Gy) and improved the survival rate of a mouse model bearing colorectal cancer cells. In vivo data indicate that our X-PDT treatment is cytoreductive, antiproliferative, and profibrotic. The nanocarriers induce radiosensitization effectively, which makes it possible to amplify the effects of radiation. A radiation dose of 4 Gy combined with our nanocarriers allows equivalent control of tumor growth as 12 Gy of radiation, but with greatly reduced radiation side effects (significant weight loss and resultant death).