Co-Delivery of Paclitaxel by a Capsaicin Prodrug Micelle Facilitating for Combination Therapy on Breast Cancer.

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-CAP₂) polymeric prodrug micellar carrier was developed and further encapsulated with PTX for antitumor combination treatment. The PEG-Fmoc-CAP₂ 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-CAP₂-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-OA₂ micelles, Taxol, and PEG-Fmoc-CAP₂ micelle-treated mice, respectively). Thus, the dual-functional PEG-Fmoc-CAP₂ polymeric prodrug micelles are a promising co-delivery nanosystem for achieving synergistic antitumor efficacy of PTX and CAP.