School of Chemistry, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China.
Department of Chemistry, School of Science, College of Science and Technology, University of Rwanda, Kigali, 3900 Kigali, Rwanda.
Bioconjug Chem. 2023 Feb 15;34(2):377-391. doi: 10.1021/acs.bioconjchem.2c00559. Epub 2023 Jan 30.
The multi-drug resistance (MDR) of cancers is one of the main barriers for the success of diverse chemotherapeutic methods and is 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 is recognized as an effective strategy to reverse the MDR of cancers due to the relatively weak DNA-repairing capability in the mitochondria. Herein, we report on a polyprodrug that can sequentially target cancer cells and mitochondria using 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), which 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 the 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 the mitochondria. TF@CNM + DOX shows great potential 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 the intracellular oxidative level and ROS-responsive drug release.
癌症的多药耐药性（MDR）是多种化疗方法成功的主要障碍之一，也是大多数癌症死亡的原因。开发有效的方法来克服 MDR 仍然是癌症高效化疗的迫切需要。由于线粒体中的 DNA 修复能力相对较弱，因此将能够与线粒体 DNA 相互作用的靶向抗癌药物递送到线粒体被认为是逆转癌症 MDR 的有效策略。在此，我们报告了一种多前药，它可以分别使用叶酸（FA）和四苯膦（TPP）靶向部分来顺序靶向癌细胞和线粒体。它们分别连接到由聚[聚（乙二醇）甲基醚甲基丙烯酸酯]（POEGMA）和含有肉桂醛（CNM）和阿霉素（DOX）的共聚单体组成的两亲嵌段共聚物前药的末端基团上。自组装成合适尺寸（约 30nm）的胶束后，将其命名为 TF@CNM+DOX，并在静脉给药后，胶束可以在肿瘤组织中积累。在 FA 介导的内吞作用后，内体酸度（约 pH 5）可以触发 CNM 从 TF@CNM+DOX 胶束中释放，随后通过 TPP 靶向增强进入线粒体的积累。这促进了活性氧（ROS）的过度产生，随后可以增强细胞内氧化应激并触发 ROS 响应性将 DOX 释放到线粒体中。TF@CNM+DOX 具有抑制 DOX 耐药 MCF-7 ADR 肿瘤生长而无明显副作用的巨大潜力。因此，肿瘤和线粒体双重靶向多前药设计代表了通过提高细胞内氧化水平和 ROS 响应性药物释放来治疗 MDR 肿瘤的理想策略。
