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J Control Release. 2019 Feb 10;295:164-173. doi: 10.1016/j.jconrel.2018.12.043. Epub 2018 Dec 25.

A nano-complex system to overcome antagonistic photo-chemo combination cancer therapy.

Author information

1
Department of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, 221 Heukseok dong, Dongjak-gu, Seoul 06974, South Korea; Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, 27599, USA.
2
Department of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, 221 Heukseok dong, Dongjak-gu, Seoul 06974, South Korea.
3
Division of Biotechnology, The Catholic University of Korea, Gyeonggi-do, Bucheon 14662, South Korea.
4
Department of Pharmaceutical Sciences, School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea.
5
Department of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, 221 Heukseok dong, Dongjak-gu, Seoul 06974, South Korea. Electronic address: kyungoh@cau.ac.kr.

Abstract

Photo-Chemo combination therapy has been intensively investigated for treatment of cancers, especially multidrug resistance cancer. However, antagonistic interactions between chemo-drugs and photosensitizers are frequently reported, and drugs doses and treatment sequences have been changed to overcome the problems. We observed the antagonistic effect by a decrease in singlet oxygen generation from the photosensitizer when Dox was in close physical proximity. To control the distance between Dox and the photosensitizer, we developed a novel pH-sensitive poly ionomer complex system composed of PEG-PLL(-g-Ce6) [Chlorin e6 grafted poly(ethylene glycol)-poly(l-lysine)] and PEG-PLL(-g-DMA)-PLA [2,3-dimethylmaleic anhydride grafted poly(ethylene glycol)-poly(l-lysine)-poly(lactic acid)] and evaluated this system with regard to singlet oxygen generation and antiproliferative activity against MCF-7/Dox cells. Enhanced singlet oxygen generation and antiproliferative activities were observed in vitro and in vivo for the poly ionomer complex system compared to PEG-PLL(-g-Ce6)-PLA/Dox due to the change in distance between Dox and Ce6 in the PIC system under acidic conditions. Our results highlight the importance of interactions between co-loaded drugs in combination therapy, and provide new insights into design principles for tailor-made nanomedicine platforms.

KEYWORDS:

Chlorin e6; Doxorubicin; MDR; Photo-chemo combination therapy; Synergism; pH sensitive

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