Original articles
Minglu Zhou, Lijia Li, Lian Li, Xi Lin, Fengling Wang, Qiuyi Li, Yuan Huang. Overcoming chemotherapy resistance via simultaneous drug-efflux circumvention and mitochondrial targeting[J]. Acta Pharmaceutica Sinica B, 2019, 9(3): 615-625

Overcoming chemotherapy resistance via simultaneous drug-efflux circumvention and mitochondrial targeting
Minglu Zhoua, Lijia Lia, Lian Lib, Xi Lina, Fengling Wanga, Qiuyi Lia, Yuan Huanga
a Key Laboratory of Drug Targeting and Drug Delivery System(Ministry of Education), West China School of Pharmacy, Sichuan University, Chengdu 610041, China;
b Department of Pharmaceutics and Pharmaceutical Chemistry/Center for Controlled Chemical Delivery, University of Utah, Salt Lake City, UT 84112, USA
Abstract:
Multidrug resistance (MDR) has been considered as a huge challenge to the effective chemotherapy. Therefore, it is necessary to develop new strategies to effectively overcome MDR. Here, based on the previous research of N-(2-hydroxypropyl)methacrylamide (HPMA) polymer-drug conjugates, we designed an effective system that combined drug-efflux circumvention and mitochondria targeting of anticancer drug doxorubicin (Dox). Briefly, Dox was modified with mitochondrial membrane penetrating peptide (MPP) and then attached to (HPMA) copolymers (P-M-Dox). Our study showed that macromolecular HPMA copolymers successfully bypassed drug efflux pumps and escorted Dox into resistant MCF-7/ADR cells via endocytic pathway. Subsequently, the mitochondria accumulation of drugs was significantly enhanced with 11.6-fold increase by MPP modification. The excellent mitochondria targeting then resulted in significant enhancement of reactive oxygen species (ROS) as well as reduction of adenosine triphosphate (ATP) production, which could further inhibit drug efflux and resistant cancer cell growth. By reversing Dox resistance, P-M-Dox achieved much better suppression in the growth of 3D MCF-7/ADR tumor spheroids compared with free Dox. Hence, our study provides a promising approach to treat drug-resistant cancer through simultaneous drug efflux circumvention and direct mitochondria delivery.
Key words:    Drug resistance    P-gp pumps    Mitochondrial targeting    HPMA copolymer    Drug delivery    Doxorubicin   
Received: 2018-07-15     Revised:
DOI: 10.1016/j.apsb.2018.11.005
Funds: The authors gratefully acknowledge the financial support from the National Natural Science Foundation for Distinguished Young Scholars (81625023, China), the National Natural Science Foundation of China (81473167) and Sichuan Youth Science and Technology Innovation Research Team Funding (2016TD0001, China).
Corresponding author: Yuan Huang     Email:huangyuan0@163.com
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Minglu Zhou
Lijia Li
Lian Li
Xi Lin
Fengling Wang
Qiuyi Li
Yuan Huang

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