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J. Control. Release, Vol 360, Aug 2023, Pages 796-809 | https://doi.org/10.1016/j.jconrel.2023.07.010 Gemcitabine and rapamycin-loaded mixed polymeric thermogel for metastatic pancreatic cancer therapy

Seo Yeon Kim ^a,1, Min Jeong Jo ^a,1, Moon Sup Yoon ^a,1, Chae Eun Jin ^a, Yu Been Shin ^a, Jae Min Lee ^a, Hee Ji Shin ^a, Joon Gyo Oh ^b, Jae Min Cho ^b, Hyunjun Kim ^b, Hyunjin Park ^b, Yong-Won Choi ^b, Chun-Woong Park ^a, Jin-Seok Kim ^c, Dae Hwan Shin ^a

^aCollege of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea
^bR&D Center, Huons Co., Ltd., Ansan, 15588, Republic of Korea
^cDrug Information Research Institute (DIRI), College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea

¹These authors contributed equally as cofirst authors.
Corresponding author : Dae Hwan Shin

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer–related death and has a poor 5–year overall survival. The superior therapeutic benefits of combination or co–administration of drugs as intraperitoneal chemotherapy have increased interest in developing strategies to deliver chemotherapeutic agents to patients safely. In this study, we prepared a gel comprising the thermosensitive poly(lactide–co–glycolide)–b–poly(ethylene glycol)–b–poly(lactide–co–glycolide) (PLGA–PEG–PLGA) polymer and gemcitabine (GEM), which is currently used as the primary chemotherapy for PDAC and rapamycin (RAPA), a mammalian TOR (mTOR) inhibitor, to deliver the drug through intraperitoneal injection. We performed in vitro cytotoxicity experiments to verify the synergistic effects of the two drugs at different molar ratios and characterized the physicochemical properties of the GEM, RAPA, and GEM/RAPA–loaded thermosensitive PLGA–PEG–PLGA gels, hereafter referred to as (g(G), g(R), and g(GR)), respectively. The g(GR) comprising PLGA–PEG–PLGA polymer (25% w/v) and GEM and RAPA at a molar ratio of 11:1 showed synergism and was optimized. An in vitro cytotoxicity assay was performed by treating Panc–1–luc2 tumor spheroids with g(G), g(R), or g(GR). The g(GR) treatment group showed a 2.75–fold higher inhibition rate than the non–treated (NT) and vehicle–treated groups. Furthermore, in vivo drug release assay in mice by intraperitoneal injection of g(G), g(R), or g(GR) showed a more rapid release rate of GEM than RAPA, similar to the in vitro release pattern. The drugs in the gel were released faster in vivo than in vitro and degraded in 48 h. In addition, g(GR) showed the highest anti–tumor efficacy with no toxicity to mice. These results provide evidence for the safety and efficacy of g(GR) for intraperitoneal drug delivery. This study will assist in developing and clinically administering topical anti–cancer formulations.

논문정보

형식Research article
게재일2023년 08월 (BRIC 등록일 2023-07-28)
연구진국내 연구진
분야 의약학 > 약학

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