IP: 191.101.55.189 On: Thu, 09 Aug 2018 17:58:22 Copyright: American Scientific Publishers Delivered by Ingenta Copyright © 2018 American Scientific Publishers All rights reserved Printed in the United States of America Article Journal of Biomedical Nanotechnology Vol. 14, 1705–1718, 2018 www.aspbs.com/jbn Folate-Targeted Redox-Responsive Polymersomes Loaded with Chemotherapeutic Drugs and Tariquidar to Overcome Drug Resistance Yu Qin 1 , Zhiming Zhang 1 , Chenlu Huang 1 , Fan Fan 1 , Lanxia Liu 1 , Li Lu 1 , Hai Wang 1 , Zhipeng Liu 1 , Jun Yang 1 , Chun Wang 2 , Hu Yang 3 , Hongfan Sun 1 , Xigang Leng 1 , Deling Kong 4 , Linhua Zhang 1 ∗ , and Dunwan Zhu 1 ∗ 1 Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin Key Laboratory of Biomedical Materials, Tianjin 300192, People’s Republic of China 2 Department of Biomedical Engineering, University of Minnesota, 7-116 Hasselmo Hall, Minneapolis, MN 55455, USA 3 Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA 23219, USA 4 State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Science, Nankai University, Tianjin, 300071, People’s Republic of China Tumor multidrug resistance (MDR) is a fatal obstacle to cancer chemotherapy. The combination of P-glycoprotein (P-gp) inhibitor and chemotherapeutic drugs is one of the effective strategies to reverse tumor MDR. Herein, a folate-decorated PCL-ss-PEG-ss-PCL based redox-responsive polymersome (FA-TQR-Co-PS) was constructed, which was loaded with P-gp inhibitor tariquidar (TQR), anticancer drugs doxorubicin (DOX) and paclitaxel (PTX). The results suggested that the FA-TQR-Co-PS with an apparent bilayered lamellar structure displayed good monodispersity, high drug loading capacity, superior stability and redox-stimulated drug release peculiarity. In vitro cellular uptake study demonstrated that FA-TQR-Co-PS increased drug accumulation into MCF-7/ADR cells via the TQR-induced P-gp efflux inhibition, and further improved targeting to tumor cells due to folate receptor-mediated endocytosis. Furthermore, the DOX and PTX cytotoxi- city and proapoptotic activity against MCF-7/ADR was enhanced dramatically along with the administration of TQR, and the cell cycle was profoundly blocked in G2/M phase. The folate-targeted redox-responsive polymersomes loaded with chemotherapeutic drugs and P-gp inhibitor demonstrated noticeable synergistic effect against human MDR MCF-7 cells and successfully reversed drug resistance, which displayed high potential in overcoming tumor MDR as a novel drug delivery system. KEYWORDS: Polymersome, Redox-Responsive, Tariquidar, Drug Resistance, Combination Therapy. INTRODUCTION Multidrug resistance (MDR) is a major cause of cancer chemotherapy failure. 1–3 Aadenosine triphosphate (ATP)- binding cassette transporters (ABC transporters) play a significant role in brining about MDR. 4 Among them, the P-glycoprotein (P-gp) is the most comon form. 5 6 Many anticancer drugs such as doxorubicin become ther- apeutically ineffective because they are P-gp’s substrates. 7 Therefore, blocking the effects of P-gp efflux is a ∗ Authors to whom correspondence should be addressed. Emails: zhanglinhua@bme.pumc.edu.cn, zhudunwan@bme.pumc.edu.cn Received: 11 April 2018 Accepted: 23 May 2018 viable approach to overcome drug resistance. Small molecule drugs that have been shown to inhibit the drug efflux activity of P-gp include curcumin, vera- pamil, (-)-Epigallocatechin-3-O-gallate, tariquidar (TQR) and laniquidar, and so on. 8–12 TQR is a third-generation of MDR reversing reagent. It is a potent P-gp inhibitor in that it exhibits high affinity with P-gp and exerts the noncompetitive inhibitive effect. 13 Besides, its inhibitory effect on BCRP (breast cancer resistance protein) has been reported. 14 Nonetheless, the systemic toxicity of TQR shall be reduced because the non-specific binding of TQR to P-gp may interfere with normal cells, causing the pharma- cokinetic disturbance of co-delivered anticancer drugs. 15–17 J. Biomed. Nanotechnol. 2018, Vol. 14, No. 10 1550-7033/2018/14/1705/014 doi:10.1166/jbn.2018.2623 1705