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

Shuangxi Liu; Kaili Zhang; Qiwen Zhu; Qianqian Shen; Qiumeng Zhang; Jiahui Yu; Yi Chen; Wei Lu

doi:10.1016/j.bmc.2019.02.046

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

Bioorg Med Chem. 2019 Apr 1;27(7):1405-1413. doi: 10.1016/j.bmc.2019.02.046. Epub 2019 Feb 21.

Authors

Shuangxi Liu¹, Kaili Zhang², Qiwen Zhu¹, Qianqian Shen³, Qiumeng Zhang¹, Jiahui Yu¹, Yi Chen⁴, Wei Lu⁵

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China.
² Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; University of Chinese Academy of Sciences, NO. 19A Yuquan Road, Beijing 100049, PR China.
³ Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
⁴ Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: ychen@simm.ac.cn.
⁵ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China. Electronic address: wlu@chem.ecnu.edu.cn.

PMID: 30819618
DOI: 10.1016/j.bmc.2019.02.046

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.

Keywords: Co-prodrug; Nanomicelles; PTX; SAHA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm / drug effects*
Drug Screening Assays, Antitumor
HCT116 Cells
Humans
MCF-7 Cells
Molecular Structure
Paclitaxel / chemistry
Paclitaxel / pharmacology*
Prodrugs / chemical synthesis*
Prodrugs / chemistry
Prodrugs / pharmacology*
Structure-Activity Relationship
Vorinostat / chemistry
Vorinostat / pharmacology*

Substances

Antineoplastic Agents
Prodrugs
Vorinostat
Paclitaxel