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Gemcitabine and rapamycin-loaded mixed polymeric thermogel for metastatic pancreatic cancer therapyopen access

Authors
Kim, S.Y.Jo, M.J.Yoon, M.S.Jin, C.E.Shin, Y.B.Lee, J.M.Shin, H.J.Oh, J.G.Cho, J.M.Kim, H.Park, H.Choi, Y.-W.Park, C.-W.Kim, J.-S.Shin, D.H.
Issue Date
Aug-2023
Publisher
Elsevier B.V.
Keywords
Combination therapy; Gemcitabine; Intraperitoneal injection; Pancreatic cancer therapy; Rapamycin; Thermosensitive hydrogel
Citation
Journal of Controlled Release, v.360, pp 796 - 809
Pages
14
Journal Title
Journal of Controlled Release
Volume
360
Start Page
796
End Page
809
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/151689
DOI
10.1016/j.jconrel.2023.07.010
ISSN
0168-3659
1873-4995
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. © 2023 The Author(s)
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