Co-delivery of paclitaxel by a capsaicin prodrug micelle facilitating for combination therapy on breast cancer.
MOLECULAR PHARMACEUTICS(2019)
摘要
Poor anticancer ability, serious adverse reaction, and drug resistance against paclitaxel (PTX) have limited its clinical applications. When a mouse breast carcinoma cell line (4T1) was treated with both PTX and capsaicin (CAP), there was a synergistic anti-proliferative effect demonstrated with a combination index of 0.28. Therefore, a novel polyethylene glycol-derivatized CAP (PEG-Fmoc-CAP(2)) polymeric prodrug micellar carrier was developed and further encapsulated with PTX for antitumor combination treatment. The PEG-Fmoc-CAP(2) polymeric micelles co-delivered with PTX achieved a 62.3% fraction of apoptotic cells in comparison to 45.4% fraction of apoptotic cells to that upon treatment with PTX alone. Comparable CAP amounts were found in the cell lysate treatment with PEG-Fmoc-CAP(2)-conjugated micelles to that of free CAP-treated 4T1 cells after 12 h treatment. Pharmacokinetic and biodistribution studies showed that the micelles possessed much longer circulation time in blood and preferential tumor tissue accumulation compared to the Taxol solution. Importantly, PTX/CAP-loaded micelles exhibited superior in vivo antitumor activity on the inhibition rate of tumor growth than other treatments (70.5% tumor growth reduction in PTX/CAP micelle-treated mice vs 57.8, 43.3, and 23.8% of tumor growth inhibition rate in PTX/PEG-Fmoc-OA(2) micelles, Taxol, and PEG-Fmoc-CAP(2) micelle-treated mice, respectively). Thus, the dual-functional PEG-Fmoc-CAP(2) polymeric prodrug micelles are a promising co-delivery nanosystem for achieving synergistic antitumor efficacy of PTX and CAP.
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关键词
PTX,CAP,PEG-Fmoc-CAP(2) prodrug micelles,breast cancer,combination chemotherapy
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