期刊
PHARMACEUTICAL RESEARCH
卷 37, 期 2, 页码 -出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-019-2750-0
关键词
cancer; mPEG-PLA-S-S-Ce6; PDT; phototoxicity; polymeric micelles
资金
- Department of Science and Technology-Science and Engineering Research Board (DST-SERB) [CRG/2018/001065]
- Deapartment of Science and Technology, Government of India [IF130703]
PurposeIn this study, we developed a polymeric micellar system for glutathione-mediated intracellular delivery of a photosensitizer, chlorin e6 (Ce6) by synthesizing an amphiphilic polymer, methoxy-poly(ethylene glycol)-poly(D,L-lactide)-disulfide-Ce6 (mPEG-PLA-S-S-Ce6), which self-assembled in aqueous environment to form micelles.MethodsThe polymer-drug conjugate was characterized by NMR. The singlet oxygen (O-2(1)) generation and in vitro release of Ce6 micelles were evaluated. Further, glutathione-mediated intracellular drug delivery was assessed in human alveolar adenocarcinoma cells (A549), mouse mammary carcinoma cells (4 T1) and 3D A549 spheroids.ResultsThe micellar system protected Ce6 from aggregation leading to improved O-2(1) generation compared to free Ce6. Due to the availability of glutathione, the disulfide bonds in the micelles were cleaved resulting in rapid release of Ce6 evident from the in vitro study. The Ce6 micelles displayed quicker drug release in presence of glutathione monoester (GSH-OEt) pre-treated A549 and 4 T1 cells compared to without pre-treated cells. In vitro phototoxicity of micelles displayed enhanced toxicity in 10 mM GSH-OEt pre-treated A549 and 4 T1 cells compared to untreated cells. As anticipated, Ce6 micelles showed lower drug release in presence of 0.1 mM of buthionine sulfoximine (BSO) pretreated A549 and 4 T1 cells exhibiting lower phototoxicity. Further, A549 3D spheroids treated with Ce6 micelles showed significant inhibition in growth, enhanced phototoxicity, and cellular apoptosis in comparison to free Ce6.ConclusionThe above results showed that the developed strategy could be effective in improving the PDT efficacy of Ce6, and the developed polymeric micellar system could be utilized as a PDT regimen for cancer.
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