Issue 17, 2024

A convenient protonated strategy for constructing nanodrugs from hydrophobic drug-inhibitor conjugates to reverse tumor multidrug resistance

Abstract

Combination therapy has proven effective in counteracting tumor multidrug resistance (MDR). However, the pharmacokinetic differences among various drugs and inherent water insolubility for most small molecule agents greatly hinder their synergistic effects, which makes the delivery of drugs for combination therapy in vivo a key problem. Herein, we propose a protonated strategy to transform a water-insoluble small molecule drug-inhibitor conjugate into an amphiphilic one, which then self-assembles into nanoparticles for co-delivery in vivo to overcome tumor MDR. Specifically, paclitaxel (PTX) is first coupled with a third-generation P-glycoprotein (P-gp) inhibitor zosuquidar (Zos) through a glutathione (GSH)-responsive disulfide bond to produce a hydrophobic drug-inhibitor conjugate (PTX-ss-Zos). Subsequently treated with hydrochloric acid ethanol solution (HCl/EtOH), PTX-ss-Zos is transformed into the amphiphilic protonated precursor and then forms nanoparticles (PTX-ss-Zos@HCl NPs) in water by molecular self-assembly. PTX-ss-Zos@HCl NPs can be administered intravenously and accumulated specifically at tumor sites. Once internalized by cancer cells, PTX-ss-Zos@HCl NPs can be degraded under the overexpressed GSH to release PTX and Zos simultaneously, which synergistically reverse tumor MDR and inhibit tumor growth. This offers a promising strategy to develop small molecule self-assembled nanoagents to reverse tumor MDR in combination therapy.

Graphical abstract: A convenient protonated strategy for constructing nanodrugs from hydrophobic drug-inhibitor conjugates to reverse tumor multidrug resistance

Supplementary files

Article information

Article type
Paper
Submitted
10 dec 2023
Accepted
01 apr 2024
First published
02 apr 2024

Nanoscale, 2024,16, 8434-8446

A convenient protonated strategy for constructing nanodrugs from hydrophobic drug-inhibitor conjugates to reverse tumor multidrug resistance

P. Wang, Y. Wang, X. Xia, J. Wu, J. Lin, W. Huang and D. Yan, Nanoscale, 2024, 16, 8434 DOI: 10.1039/D3NR06293G

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