Novel pH-triggered biocompatible polymeric micelles based on heparin-α-tocopherol conjugate for intracellular delivery of docetaxel in breast cancer.

In the present study, pH-triggered polymeric micelle composed of alpha- tocopherol (TOC) and heparin (HEP) was developed and loaded with docetaxel (DTX). The amphiphilic copolymer was synthesized by grafting TOC onto HEP backbone by a pH-cleavable bond. DTX-loaded micelles were characterized in terms of CMC, particle size, zeta potential, entrapment efficiency (EE), pH-responsive behavior and drug release. In vitro cytotoxicity of the micelles against breast cancer cells was investigated by MTT assay. The cellular uptake of coumarin-loaded micelles was also evaluated. Furthermore, the pharmacokinetics of DTX-loaded micelles was evaluated and compared with that of Taxotere®.HEP-CA-TOC copolymers exhibited low CMC values, high EE. At pH 7.4, the micelles remained stable in size and shape whereas, considerable changes in particle size and morphology were observed at pH 5.5. DTX-loaded micelles exhibited pH-dependent drug release profiles. Coumarin-loaded micelles exhibited higher cellular uptake than free coumarin. Therefore, the DTX-loaded micelles showed more toxicity against breast cancer cells than free DTX. Significant increase in T_1/2 β, AUC_0-∞ and MRT was observed in DTX-loaded micelle treated group compared to group treated with Taxotere^®.The results suggest that the pH-sensitive HEP-modified micelles could be promising for enhanced intracellular drug delivery of DTX for cancer treatment.