Reversal of lung cancer multidrug resistance by pH-responsive micelleplexes mediating co-delivery of siRNA and paclitaxel

Haijun Yu; Zhiai Xu; Xianzhi Chen; Leilei Xu; Qi Yin; Zhiwen Zhang; Yaping Li

doi:10.1002/mabi.201300282

Reversal of lung cancer multidrug resistance by pH-responsive micelleplexes mediating co-delivery of siRNA and paclitaxel

Macromol Biosci. 2014 Jan;14(1):100-9. doi: 10.1002/mabi.201300282. Epub 2013 Aug 21.

Authors

Haijun Yu¹, Zhiai Xu, Xianzhi Chen, Leilei Xu, Qi Yin, Zhiwen Zhang, Yaping Li

Affiliation

¹ Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, P. R. China.

PMID: 23966347
DOI: 10.1002/mabi.201300282

Abstract

The recent advances in RNA interference (RNAi) technology provided novel and promising solutions for human cancer treatment. In this study, the application of dual pH-responsive cationic micellar nanoparticles for small interfering RNA (siRNA) and paclitaxel (PTX) co-delivery to overcome cancer multidrug resistance (MDR) is reported. The in vitro siRNA transfection shows that siRNA-luciferase (Luc) loaded micelleplexes efficiently silences Luc expression in various carcinoma cell lines. The Luc knockdown ability of the micelleplexes can be enhanced by choloquine (CQ) co-incubation. However, is abolished by bafilomycin-A1 (Baf-A1) treatment. The micelleplexes are further exploited for co-delivery of siRNA-Bcl-2 and PTX to Bcl-2 overexpressing A549 lung cancer cells (A549-Bcl-2). The experimental results show that the micelleplexes could sensitize A549-Bcl-2 cells to PTX via down-regulation of anti-apoptosis gene of Bcl-2, suggesting that PDMA-b-PDPA micelleplexes are promising nanovectors for siRNA and anti-cancer drug co-delivery to overcome cancer MDR.

Keywords: Paclitaxel; lung cancer; micelleplexes; multidrug resistance; pH-responsive; siRNA.

Publication types

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

MeSH terms

Antineoplastic Agents, Phytogenic / administration & dosage
Antineoplastic Agents, Phytogenic / pharmacology
Apoptosis / drug effects
Apoptosis / genetics
Cell Line, Tumor
Chloroquine / pharmacology
Drug Carriers
Drug Resistance, Multiple / drug effects
Drug Resistance, Multiple / genetics
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics*
Gene Knockdown Techniques
Humans
Hydrogen-Ion Concentration
Luciferases / genetics
Lung Neoplasms / drug therapy*
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Macrolides / pharmacology
Micelles
Nanoparticles / administration & dosage
Nanoparticles / chemistry
Paclitaxel / administration & dosage
Paclitaxel / pharmacology*
Polymethacrylic Acids
Proto-Oncogene Proteins c-bcl-2 / genetics
RNA, Small Interfering / administration & dosage*
RNA, Small Interfering / genetics
Transfection

Substances

Antineoplastic Agents, Phytogenic
Drug Carriers
Macrolides
Micelles
Polymethacrylic Acids
Proto-Oncogene Proteins c-bcl-2
RNA, Small Interfering
poly(2-(dimethylamino)ethyl methacrylate)-block-poly(2-(diisopropylamino)ethyl methacrylate)
Chloroquine
bafilomycin A1
Luciferases
Paclitaxel