Dual Agent Loaded PLGA Nanoparticles Enhanced Antitumor Activity in a Multidrug-Resistant Breast Tumor Xenograft Model

Yan Chen,Hui-Li Li,Ke Ren,Xiang-Rong Song,Dai-Long Fang,Xue-Lian Zheng,Bei Xu,Jin-Kun Zhang,Yi Lei,Yang Yang

doi:10.3390/ijms15022761

Abstract

Multidrug-resistant breast cancers have limited and ineffective clinical treatment options. This study aimed to develop PLGA nanoparticles containing a synergistic combination of vincristine and verapamil to achieve less toxicity and enhanced efficacy on multidrug-resistant breast cancers. The 1:250 molar ratio of VCR/VRP showed strong synergism with the reversal index of approximately 130 in the multidrug-resistant MCF-7/ADR cells compared to drug-sensitive MCF-7 cells. The lyophilized nanoparticles could get dispersed quickly with the similar size distribution, zeta potential and encapsulation efficiency to the pre-lyophilized nanoparticles suspension, and maintain the synergistic in vitro release ratio of drugs. The co-encapsulated nanoparticle formulation had lower toxicity than free vincristine/verapamil combinations according to the acute-toxicity test. Furthermore, the most effective tumor growth inhibition in the MCF-7/ADR human breast tumor xenograft was observed in the co-delivery nanoparticle formulation group in comparison with saline control, free vincristine, free vincristine/verapamil combinations and single-drug nanoparticle combinations. All the data demonstrated that PLGANPs simultaneously loaded with chemotherapeutic drug and chemosensitizer might be one of the most potential formulations in the treatment of multidrug-resistant breast cancer in clinic.

Highlights

Breast cancer is the most common cancer in women, with more than 1,300,000 cases and450,000 deaths each year worldwide [1]
The first generation of ATP binding cassette (ABC) blockers such as verapamil, cyclosporine A and quinidine are the most widely investigated probably because they are drugs already approved by the regulatory agencies for other uses [7] and easy to be clinically evaluated as ABC inhibitors for new intended uses
The in vitro cytotoxicity studies were first conducted with VCR/VRP combinations on MCF-7/ADR cells to determine whether VRP could reverse the drug resistance and what was the optimum dose for VRP to achieve strong synergism with VCR

Summary

Introduction

Breast cancer is the most common cancer in women, with more than 1,300,000 cases and450,000 deaths each year worldwide [1]. Despite considerable advances in early detection as well as therapeutic strategies with surgery, radiotherapy, and chemotherapy, the mortality rates in breast cancer patients have remained relatively unaffected over the span of three decades [2]. The MDR proteins are responsible for energy dependent efflux of drugs, resulting in less likeliness to accumulate therapeutically relevant doses of chemotherapeutics in cancer cells. Among these proteins, P-glycoprotein (Pgp), encoded by the MDR1 (ABCB1) gene is the first ever identified ABC and the most well studied [4]. Several Pgp inhibitors have been explored over the last four decades to overcome MDR in cancer [5,6]. The first generation of ABC blockers such as verapamil, cyclosporine A and quinidine are the most widely investigated probably because they are drugs already approved by the regulatory agencies for other uses [7] and easy to be clinically evaluated as ABC inhibitors for new intended uses

Objectives

Results

Conclusion