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

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/cm 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.

Breast Cancer Cell Line Phenotype Affects Sonoporation Efficiency Under Optimal Ultrasound Microbubble Conditions

“…This reflects the higher sensitivity to enhanced sonoporation mediated by USMB exposure for MCF-7/ADR cells than MCF-7 cells, which is consistent with a previous study [31]. The underlying mechanism might involve the enhancement of cell membrane permeability and downregulation of MDR-related genes and proteins [32]. In addition, a reduction in the amount of permeability glycoprotein (P-gp) due to USMB might prevent chemotherapeutic drugs from leaving the tumor cells [33].…”

Recent progress on nanoparticle-based drug delivery systems for cancer therapy

“…It can form cavitation bubbles, heat local tissues, and produce radiation force, which are used to release drugs from nanocomposites, to purify drugs and/or nanoparticles from blood vessels in tumors, and to improve drug penetration to the tumor. Wang et al 52 developed an efficient strategy to overcome multi-drug resistance (MDR) by combining negatively charged nanoparticles with US. In their study, cells are exposed to US with microbubbles prior to treatment with negatively charged Heparin-Folate-Tat-Taxol nanoparticles.…”

Landscape of Cellular Bioeffects Triggered by Ultrasound-Induced Sonoporation

“…Since US can be focused, acoustic waves are easily able to deliver kinetic energy to selected small volumes deep within a human body without damaging other tissues. Therefore, physicians or physical therapists used them to stimulate healing and soften scar tissue, or high-intensity focused US—HIFU—to damage prostate cancer or break down kidney stones [ 10 , 11 , 12 , 13 ]. However, a completely new chapter in US research was opened in 1976 when a strong cytostatic effect of nitrogen mustard was observed in L1210 leukaemia cells treated with sonication without mechanical damage to cells [ 14 ].…”