Synthesis and biological evaluation of paclitaxel and vorinostat co-prodrugs for overcoming drug resistance in cancer therapy in vitro

Bioorganic & Medicinal Chemistry
Shuangxi LiuWei Lu

Abstract

Paclitaxel (PTX) is the first-line treatment drug for breast cancer. However, drug resistance after a course of treatment and low selectivity restricted its clinical utility sometimes. In this study, we successfully bound PTX and vorinostat (SAHA) to form co-prodrugs based on the synergistic anticancer effects. The PTX-SAHA co-prodrugs were conjugated by glycine (1a) and succinic acid (1b) respectively and the former has shown better activity in cytotoxicity, cell cycle arrest and western-blot experiments. Therefore, 1a was further prepared to nanomicelles with mPEG2000-PLA1750 as the carrier by using thin film method. PTX-SAHA co-prodrug nanomicelles were spherical with a particle size of 20-100 nm. In vitro drug release test showed 1a nanomicelles had sustained release effect, which could reduce the resistance of PTX. In vitro cytotoxicity was evaluated by SRB assay in HCT-116 cells, MCF-7 cells and drug-resistant MCF-7/ADR cells. The results showed 1a nanomicelles had comparable or even better cytotoxicity than PTX especially in the MCF-7/ADR cells. All the results suggested that PTX-SAHA co-prodrug nanomicelles were promising treatment for PTX resistance cancer.

Citations

Feb 23, 2020·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Sabrina DallavalleRoberta Fruttero
Sep 23, 2020·European Journal of Medicinal Chemistry·Xiaopeng PengJianjun Chen
Jul 15, 2021·ChemMedChem·Kathrin S TroelsenStuart J Conway
Dec 7, 2021·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Bowen JiangZhigang Xie
Aug 11, 2021·Current Medicinal Chemistry·Erva Ozkan, Filiz Bakar-Ates

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