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

Abstract

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).

• Authors: Wei Deng, Kelly J McKelvey, Anna Guller, Alexey Fayzullin, Jared M Campbell, Sandhya Clement, Abbas Habibalahi, Zofia Wargocka, Liuen Liang, Chao Shen, Viive Maarika Howell, Alexander Frank Engel, Ewa M Goldys
• Journal: ACS central science (ACS Cent Sci) Vol. 6 Issue 5 Pg. 715-726 (May 27 2020) ISSN: 2374-7943 [Print] United States
• PMID: 32490188 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 American Chemical Society.