The reversion of anti-cancer drug antagonism of tamoxifen and docetaxel by the hyaluronic acid-decorated polymeric nanoparticles

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Abstract

Docetaxel (DTX) and tamoxifen (TMX) are first-line drugs used to treat breast cancer. However when used in combination, they produce antagonism because of their differential metabolic pathways. In order to prevent this antagonism, an amphiphilic copolymer, cholesterol modified hyaruronic acid (HA-CHOL), was synthesized for investigating the co-delivery of TMX and DTX. In vitro drug release experiment of the Co-encapsulated (encapsulated DTX + TMX) nanoparticles (Co-NPs) revealed that NPs with unique release mechanism can markedly reduce the release of these drugs in the circulatory system. However, when reaching in cell, TMX can release rapidly to prevent DTX from coming into contact with metabolizing enzymes. In vitro cytotoxicity experiment revealed that the Co-NPs exhibited a significant synergistic effect for inhibiting the proliferation of the cancer cell lines A549, MCF7 and S180. NPs carrying Coumarin-6(Cou6) exhibited increased cellular uptake compared with Cou6 solution at similar drug concentrations. As an in vivo treatment of xenograft tumors involving 180 cells, the Co-NPs displayed a clear tumor-inhibiting effect. This led us to conclude that the reversion of drug antagonism by NPs was attributed to the increased stability of the nanoparticles in the blood circulation, the efficient cellular uptake, the hierarchical drug metabolism in the tumor and the good and orderly delivery of the drugs to the tumor tissue.

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