title: 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/cm2and 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.
authors: 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.
authors: Dongxiao
authors: D
authors: Wang
authors: Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors: Wanxian
authors: W
authors: Luo
authors: Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors: Ge
authors: G
authors: Wen
authors: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors: Li
authors: L
authors: Yang
authors: Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors: Shaofu
authors: S
authors: Hong
authors: Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors: Shiyu
authors: S
authors: Zhang
authors: Molecular Biology Laboratory, College of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
authors: Jianxin
authors: J
authors: Diao
authors: Guangdong Provincial Key Laboratory of Cancer Immunotherapy, Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou, China.
authors: Jianguo
authors: J
authors: Wang
authors: Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors: Hongqin
authors: H
authors: Wei
authors: Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: lyjia@smu.edu.cn.
authors: Yingjia
authors: Y
authors: Li
authors: 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.
authors: Ying
authors: Y
authors: Wang
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004705:Endocytosis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D053758:Nanoparticles; D010641:Phenotype; D000069453:Ultrasonic Waves
chemical_list: D057846:Cell-Penetrating Peptides
keywords: Multidrug resistance; Negative-charged nanoparticles; Synergistic effects; Ultrasound