pH-sensitive pluronic micelles combined with oxidative stress amplification for enhancing multidrug resistance breast cancer therapy.

Abstract

Multidrug resistance (MDR) is one of the major obstacles to clinical cancer chemotherapy. Herein, we designed new pH-sensitive pluronic micelles with the synergistic effects of oxidative therapy and MDR reversal. Pluronic (P123) was modified with α-tocopheryl succinate (α-TOS) via an acid-labile ortho ester (OE) linkage to give a pH-sensitive copolymer (POT). Self-assembled POT micelles exhibited desirable size (~80 nm), excellent anti-dilution ability, high drug loading (~85%), acid-triggered degradation and drug release behaviours. In vitro cell experiments verified that POT micelles could significantly reverse MDR through suppressing the function of drug effluxs mediated by P123 and induce more reactive oxygen species (ROS) generation mediated by α-TOS, resulting in enhanced cytotoxicity and apoptosis in MDR cells. In vivo studies further revealed that DOX-loaded POT micelles (POT-DOX) possessed the highest drug accumulation (3.03% ID/g at 24 h) and the strongest tumour growth inhibition (TGI 83.48%). Pathological analysis also indicated that POT-DOX could induce more apoptosis or necrosis at the site of tumour without distinct damage to normal tissues. Overall, these smart POT micelles have great potential as promising nano-carriers for MDR reversal and cancer treatment.

• Authors: Xu Cheng, Xiaoli Zeng, Yan Zheng, Qin Fang, Xin Wang, Jun Wang, Rupei Tang
• Journal: Journal of colloid and interface science (J Colloid Interface Sci) Vol. 565 Pg. 254-269 (Apr 01 2020) ISSN: 1095-7103 [Electronic] United States
• PMID: 31978788 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Micelles
• pluronic block copolymer P123
• Doxorubicin
• Poloxalene

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Doxorubicin (chemistry, pharmacology)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Female
• Humans
• Hydrogen-Ion Concentration
• MCF-7 Cells
• Mammary Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Mice
• Micelles
• Molecular Structure
• Oxidative Stress
• Particle Size
• Poloxalene (chemical synthesis, chemistry, pharmacology)
• Surface Properties
• Tumor Cells, Cultured