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

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

doi:10.1021/acscentsci.9b01121

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

ACS Cent Sci. 2020 May 27;6(5):715-726. doi: 10.1021/acscentsci.9b01121. Epub 2020 Apr 24.

Authors

Wei Deng¹, Kelly J McKelvey², Anna Guller^{1

3}, Alexey Fayzullin^{1

3}, Jared M Campbell¹, Sandhya Clement¹, Abbas Habibalahi¹, Zofia Wargocka¹, Liuen Liang⁴, Chao Shen⁵, Viive Maarika Howell², Alexander Frank Engel^{6

7}, Ewa M Goldys¹

Affiliations

¹ ARC Centre of Excellence for Nanoscale Biophotonics, Graduate School of Biomedical Engineering, University of New South Wales, Kensington, New South Wales 2052, Australia.
² Bill Walsh Translational Cancer Research Laboratory, The Northern Clinical School, Faculty of Medicine and Health, The University of Sydney and Northern Sydney Local Health District Research (Kolling Institute), St Leonards, New South Wales 2065, Australia.
³ Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia.
⁴ Department of Physics and Astronomy, Faculty of Science and Engineering, Macquarie University, North Ryde, New South Wales 2109, Australia.
⁵ Faculty of Science and Engineering, Macquarie University, North Ryde, New South Wales 2109, Australia.
⁶ Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.
⁷ Department of Colorectal Surgery, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia.

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).