Synergistic effects of negative-charged nanoparticles assisted by ultrasound on the reversal multidrug resistance phenotype in breast cancer cells

Dongxiao Wang; Wanxian Luo; Ge Wen; Li Yang; Shaofu Hong; Shiyu Zhang; Jianxin Diao; Jianguo Wang; Hongqin Wei; Yingjia Li; Ying Wang

doi:10.1016/j.ultsonch.2016.06.012

Synergistic effects of negative-charged nanoparticles assisted by ultrasound on the reversal multidrug resistance phenotype in breast cancer cells

Ultrason Sonochem. 2017 Jan:34:448-457. doi: 10.1016/j.ultsonch.2016.06.012. Epub 2016 Jun 11.

Authors

Dongxiao Wang¹, Wanxian Luo², Ge Wen³, Li Yang⁴, Shaofu Hong², Shiyu Zhang², Jianxin Diao⁵, Jianguo Wang⁶, Hongqin Wei², Yingjia Li⁷, Ying Wang⁸

Affiliations

¹ Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Cancer Immunotherapy, Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou, China.
² Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
³ Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁴ Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁵ Molecular Biology Laboratory, College of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
⁶ Guangdong Provincial Key Laboratory of Cancer Immunotherapy, Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou, China.
⁷ Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: lyjia@smu.edu.cn.
⁸ Guangdong Provincial Key Laboratory of Cancer Immunotherapy, Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou, China. Electronic address: ningmengquan@gmail.com.

PMID: 27773267
DOI: 10.1016/j.ultsonch.2016.06.012

Abstract

We have fabricated a negative-charged nanoparticle (Heparin-Folate-Tat-Taxol NP, H-F-Tat-T NP) with dual ligands, tumor targeting ligand folate and cell-penetrating peptide Tat, to deliver taxol presenting great anticancer activity for sensitive cancer cells, while it fails to overcome multidrug resistance (MDR) in MCF-7/T cells (taxol-resistant breast cancer cells). Ultrasound (US) can increase the sensitivity of positive-charged NPs thereby making it possible to reverse MDR through inducing NPs' drug release. However, compared with the negative-charged NPs, positive-charged NPs may cause higher toxic effect. Hence, the combination of negative-charged NPs and US may be an efficient strategy for overcoming MDR. The conventional procedure to treat with NPs followed by US exposure possibly destruct multifunctional NPs resulting in its bioactivity inhibition. Herein, we have further improved the operating approach to eliminate US mechanical damage and keep the integrity of negative-charged NPs: cells are exposed to US with microbubbles (MBs) prior to the treatment of H-F-Tat-T NPs. Superior to the conventional method, US sonoporation affects the physiological property of cancer cells while preventing direct promotion of drug release from NPs. The results of the present study displayed that US in condition (1MHz, 10% duty cycle, duration of 80s, US intensity of 0.6W/cm² and volume ratio of medium to MBs 20:1) combined with H-F-T-Tat-T NPs can achieve optimal reversal MDR effect in MCF-7/T cells. Mechanism study further disclosed that the individual effect of US was responsible for the enhancement of cell membrane permeability, inhibition of cell proliferation rate and down-regulation of MDR-related genes and proteins. Simultaneously, US sonoporation on resistant cancer cells indirectly increased the accumulation of NPs by inducing endosomal escape of negative-charged NPs. Taken together, the overcoming MDR ability for the combined strategy was achieved by the synergistic effect from individual function of NPs, physiological changes of resistant cancer cells and behavior changes of NPs caused by US.

Keywords: Multidrug resistance; Negative-charged nanoparticles; Synergistic effects; Ultrasound.

Publication types

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

MeSH terms

Breast Neoplasms / pathology*
Cell Proliferation / drug effects
Cell-Penetrating Peptides / chemistry
Cell-Penetrating Peptides / metabolism
Cell-Penetrating Peptides / pharmacology
Drug Resistance, Neoplasm*
Endocytosis
Gene Expression Regulation, Neoplastic / drug effects
Humans
MCF-7 Cells
Nanoparticles*
Phenotype*
Ultrasonic Waves*

Substances

Cell-Penetrating Peptides