Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.
Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
Pharm Dev Technol. 2021 Jan;26(1):21-29. doi: 10.1080/10837450.2020.1832116. Epub 2020 Oct 18.
Multidrug resistance (MDR) is a serious challenge in chemotherapy and also a major threat to breast cancer treatment. As an intracellular energy factory, mitochondria provide energy for drug efflux and are deeply involved in multidrug resistance. Mitochondrial targeted delivery of doxorubicin can overcome multidrug resistance by disrupting mitochondrial function. By incorporating a reactive oxygen species (ROS)-responsive hydrophobic group into the backbone structure of hyaluronic acid - a natural ligand for the highly expressed CD44 receptor on tumor surfaces, a novel ROS-responsive and CD44-targeting nano-carriers was constructed. In this study, mitochondria-targeted triphenylphosphine modified-doxorubicin (TPP-DOX) and amphipathic ROS-responsive hyaluronic acid derivatives (HA-PBPE) were synthesized and confirmed by H NMR. The nanocarriers TPP-DOX @ HA-PBPE was prepared in a regular shape and particle size of approximately 200 nm. Compared to free DOX, its antitumor activity in vitro and tumor passive targeting in vivo has been enhanced. The ROS-responsive TPP-DOX@HA-PBPE nanocarriers system provide a promising strategy for the reverse of MDR and efficient delivery of doxorubicin derivatives into drug-resistant cancer cells.
多药耐药性（MDR）是化疗中的一个严重挑战，也是乳腺癌治疗的主要威胁。作为细胞内的能量工厂，线粒体为药物外排提供能量，并深度参与多药耐药性。通过将阿霉素靶向递送至线粒体，可以通过破坏线粒体功能来克服多药耐药性。通过将活性氧（ROS）响应性疏水性基团整合到透明质酸的骨架结构中，透明质酸是肿瘤表面高度表达的 CD44 受体的天然配体，构建了一种新型的 ROS 响应性和 CD44 靶向纳米载体。在这项研究中，通过 1H NMR 对靶向线粒体的三苯基膦修饰的阿霉素（TPP-DOX）和两亲性 ROS 响应性透明质酸衍生物（HA-PBPE）进行了合成和确认。纳米载体 TPP-DOX@HA-PBPE 呈规则形状，粒径约为 200nm。与游离 DOX 相比，其在体外的抗肿瘤活性和体内肿瘤被动靶向性得到了增强。ROS 响应性 TPP-DOX@HA-PBPE 纳米载体系统为逆转多药耐药性和将阿霉素衍生物高效递送至耐药癌细胞提供了一种有前途的策略。
