Tumor-targeted docetaxel-loaded hyaluronic acid-quercetin polymeric micelles with p-gp inhibitory property for hepatic cancer therapy
2016
Xu, Chenfeng | Ding, Yu | Ni, Jiang | Yin, Lifang | Zhou, Jianping | Yao, Jing
Docetaxel (DTX) has profound effects on several hepatic cancer (HC) cells, but shows unsatisfactory clinical efficacy due to the lack of tumor specificity and p-gp mediated drug efflux. Herein, a novel targeted drug delivery nanosystem based on hyaluronic acid (HA) and quercetin (QU) was designed to improve the in vivo therapeutic efficacy of DTX on HC through HA-CD44 mediated targeting and QU-based p-gp efflux inhibition. DTX-loaded HA–QU polymeric micelles (DTX/HA–QU PMs) displayed a mean particle size of 176.8 ± 3.4 nm with a low polydispersity index (<0.2). The drug loading and entrapment efficiency were 23.6 ± 1.3% and 86.8 ± 1.8%, respectively. Not only did the nanosystem facilitate cellular uptake via HA-CD44 mediated endocytosis, but it also preferentially accumulated at the tumor site via the EPR effect. Moreover, DTX/HA–QU PMs showed prolonged circulation time and high stability in the bloodstream, and achieved AUC₀–∞ and t₁/₂ values that were 3.0-fold and 5.51-fold higher than those of Taxotere®, respectively. In addition, an in vitro cytotoxicity study showed that DTX/HA–QU PMs were 13.6-fold more effective than Taxotere®, judging by the IC₅₀. Importantly, DTX/HA–QU PMs presented the highest antitumor efficacy in a xenograft tumor-bearing mice model and the tumor inhibition ratio was 73.91%. Meanwhile, DTX/HA–QU PMs could down-regulate p-gp expression in tumor cells. These results suggested that the targeting moiety and p-gp efflux inhibitory property help DTX to accumulate at the tumor site and improve its antitumor efficacy in vivo.
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