title: Reversal of multidrug resistance phenotype in human breast cancer cells using doxorubicin-liposome-microbubble complexes assisted by ultrasound.
abstract: The circumvention of multidrug resistance (MDR) plays a critically important role in the success of chemotherapy. The aim of this work is to investigate the effectiveness and possible mechanisms of the reversal of MDR phenotype in human breast cancer cells by using doxorubicin-liposome-microbubble complexes (DLMC) assisted by ultrasound (US). DLMC is fabricated through conjugating doxorubicin (DOX)-liposome (DL) to the surface of microbubbles (MBs) via the biotin-avidin linkage. The resulting drug-loaded complexes are then characterized and incubated with MCF-7/ADR human breast cancer cells and followed by US exposure. Our results show the more rapid cellular uptake, evident enhancement of nuclear accumulation and less drug efflux in the resistant cells treated by DLMC+US than those treated by DL, DL+verapamil under the same US treatment or DLMC without US. The enhanced drug delivery and cellular uptake also associated with the increase of cytotoxicity against MCF-7/ADR cells, lower MCF-7/ADR cell viability and higher apoptotic cells. Mechanism investigations further disclose a significant increase of reactive oxygen species (ROS) level, enhanced DNA damage and obvious reduction of P-glycoprotein expression in the resistant cells treated with DLMC+US compared with the control cases of cells treated by DLMC, DL+US or DL+verapamil+US. In conclusion, our study demonstrates that DLMC in combination with US may provide an effective delivery of drug to sensitize cells to circumvent MDR and to enhance the therapeutic index of the chemotherapy.
authors.affiliation: Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Zhiting
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. Electronic address: fei.yan@siat.ac.cn.
authors.forename: Fei
authors.initials: F
authors.lastname: Yan
authors.affiliation: Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Qiaofeng
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Physics, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Junru
authors.initials: J
authors.lastname: Wu
authors.affiliation: Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. Electronic address: hr.zheng@siat.ac.cn.
authors.forename: Hairong
authors.initials: H
authors.lastname: Zheng
mesh_terms: D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D045423:Microbubbles; D011092:Polyethylene Glycols / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism; D014465:Ultrasonics
chemical_list: C468783:H2AX protein, human; D006657:Histones; D017382:Reactive Oxygen Species; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Doxorubicin; Doxorubicin-liposome–microbubble complexes; Drug delivery; Multidrug resistance; Ultrasound