文献类型：期刊文献

英文题名：Coordinating Biointeraction and Bioreaction of a Nanocarrier Material and an Anticancer Drug to Overcome Membrane Rigidity and Target Mitochondria in Multidrug-Resistant Cancer Cells

作者：Zhang, Rui Xue[1];Li, Lily Yi[1];Li, Jason[1];Xu, Zhensong[2];Abbasi, Azhar Z.[1];Lin, Lucy[1];Amini, Mohammad A.[1];Weng, Wei Yu[3];Sun, Yu[2];Rauth, Andrew M.[4,5];Wu, Xiao Yu[1]

机构：[1]Univ Toronto, Leslie Dan Fac Pharm, Adv Pharmaceut & Drug Delivery Lab, 144 Coll St, Toronto, ON M5S 3M2, Canada;[2]Univ Toronto, Dept Mech & Ind Engn, Adv Micro & Nanosyst Lab, 5 Kings Coll Rd, Toronto, ON M5S 3G8, Canada;[3]East China Univ Sci & Technol, Sch Pharm, 130 Meilong Rd, Shanghai 200237, Peoples R China;[4]Univ Toronto, Dept Med Biophys, Princess Margaret Canc Ctr, 610 Univ Ave, Toronto, ON M5G 2M9, Canada;[5]Univ Toronto, Dept Radiat Oncol, Princess Margaret Canc Ctr, 610 Univ Ave, Toronto, ON M5G 2M9, Canada

年份：2017

卷号：27

期号：39

外文期刊名：ADVANCED FUNCTIONAL MATERIALS

收录：;EI(收录号：20172003670926);WOS:【SCI-EXPANDED(收录号:WOS:000413166400002)】；

基金：R. X. Z. and L. Y. L. contributed equally to this work. The authors gratefully acknowledge the Canadian Breast Cancer Foundation (CBCF)-Ontario Region for funding this project; Natural Sciences and Engineering Research Council of Canada for the equipment grants; University open scholarships to R. X. Z. and J. L.; Canada Research Chair in Micro and Nano Engineering Systems to Y. S.; W. Jun from Department of Mechanical and Industrial Engineering for AFM setup; Dr. Shana O. Kelley for usage of flow cytometer and software FlowJo.

语种：英文

外文关键词：coordinating biointeraction and bioreaction; multidrug-resistant cancer cells; nanocarrier materials; overcoming membrane rigidity; targeting mitochondria

摘要：Multidrug resistance (MDR) is a main cause of chemotherapy failure in cancer treatment. It is associated with complex cellular and molecular mechanisms including overexpression of drug efflux transporters, increased membrane rigidity, and impaired apoptosis. Numerous efforts have been made to overcome efflux transporter-mediated MDR using nanotechnology-based approaches. However, these approaches fail to surmount plasma membrane rigidity that attenuates drug penetration and nanoparticle endocytosis. Here, a "one-two punch" nanoparticle approach is proposed to coordinate intracellular biointeraction and bioreaction of a nanocarrier material docosahexaenoic acid (DHA) and an anticancer prodrug mitomycin C (MMC) to enhance mitochondrion-targeted toxicity. Incorporation of DHA in solid polymer-lipid nanoparticles first reduces the membrane rigidity in live cancer cells thereby increasing nanoparticle cellular uptake and MMC accumulation. Subsequent intracellular MMC bioreduction produces free radicals that in turn react with adjacent DHA inducing significantly elevated mitochondrial lipid peroxidation, leading to irreversible damage to mitochondria. Preferential tumor accumulation of the nanoparticles and the synergistic anticancer cytotoxicity remarkably inhibit tumor growth and prolonged host survival without any systemic toxicity in an orthotopic MDR breast tumor model. This work suggests that combinatorial use of biophysical and biochemical properties of nanocarrier materials with bioreactive prodrugs is a powerful approach to overcoming multifactorial MDR in cancer.