Zero Hunger (SDG 2), Good Health & Well-being (SDG 3)
Mitochondria-Targeting Polyprodrugs to overcome drug resistance of cancer cells by self-amplified Oxidation-Triggered drug release Jean Felix Mukerabigwi* a,b,† , Rui Tang d,† , Yufei Cao a , Fathelrahman Mohammed c , Qinghao Zhou ,a,c , Min Zhou d and Zhishen Ge a a School of Chemistry, Xi’an Jiaotong University, Xi’an, China. b Department of Chemistry, School of Science, College of Science and Technology, University of Rwanda, Kigali, Rwanda c CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, China d Neurocritical Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
Multi-drug resistance (MDR) of cancers is one of the main barriers for the success of diverse chemotherapeutic methods and responsible for most cancer deaths. Developing efficient approaches to overcome MDR is still highly desirable for efficient chemotherapy of cancers. The delivery of targeted anticancer drugs that can interact with mitochondrial DNA are recognized as the effective strategy to reverse MDR of cancers due to the relatively weak DNA repairing capability in mitochondria. Herein, we report a polyprodrug that can sequentially target cancer cells and mitochondria by folic acid (FA) and tetraphenylphosphonium (TPP) targeting moieties, respectively. They were conjugated to the terminal groups of the amphiphilic block copolymer prodrugs composed of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) and copolymerized monomers containing cinnamaldehyde (CNM) and doxorubicin (DOX). After self-assembly into micelles with the suitable size (~ 30 nm) that were termed as TF@CNM+DOX and upon intravenous administration, the micelles can accumulate in tumor tissues. After FA-mediated endocytosis, the endosomal acidity (~ pH 5) can trigger the release of CNM from TF@ CNM+DOX micelles, followed by enhanced accumulation into the mitochondria via TPP target. This promotes the overproduction of reactive oxygen species (ROS) which can subsequently enhance the intracellular oxidative stress and trigger ROS-responsive release of DOX into mitochondria. TF@ CNM+DOX show great potentials to inhibit the growth of DOX-resistant MCF-7 ADR tumors without observable side effects. Therefore, the tumor and mitochondria dual-targeting polyprodrug design represents an ideal strategy to treat MDR tumors through improvement of intracellular oxidative level and ROS-responsive drug release. Keywords: drug resistance, cancer therapy, oxidative stress, mitochondria, dual-targeting
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© The Author(s), 2023
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