RBC-derived vesicles as a systemic delivery system of doxorubicin for lysosomal-mitochondrial axis-improved cancer therapy

• Main Authors: Shu-Hui Wu, Chia-Chu Hsieh, Szu-Chun Hsu, Ming Yao, Jong-Kai Hsiao, Shih-Wei Wang, Chih-Peng Lin, Dong-Ming Huang
• Format: Article
• Language: English
• Published: Elsevier 2021-05-01
• Series: Journal of Advanced Research
• Subjects: Drug delivery; Doxorubicin; Cancer chemotherapy; Nanoparticle; Lysosome; Mitochondria
• Online Access: http://www.sciencedirect.com/science/article/pii/S2090123220302356
• ISSN: 2090-1232

Introduction: Chemotherapeutic drugs are the main intervention for cancer management, but many drawbacks impede their clinical applications. Nanoparticles as drug delivery systems (DDSs) offer much promise to solve these limitations. Objectives: A novel nanocarrier composed of red blood cell (RBC)-derived vesicles (RDVs) surface-linked with doxorubicin (Dox) using glutaraldehyde (glu) to form Dox-gluRDVs was investigated for improved cancer therapy. Methods: We investigated the in vivo antineoplastic performance of Dox-gluRDVs through intravenous (i.v.) administration in the mouse model bearing subcutaneous (s.c.) B16F10 tumor and examined the in vitro antitumor mechanism and efficacy in a panel of cancer cell lines. Results: Dox-gluRDVs can exert superior anticancer activity than free Dox in vitro and in vivo. Distinct from free Dox that is mainly located in the nucleus, but instead Dox-gluRDVs release and efficiently deliver the majority of their conjugated Dox into lysosomes. In vitro mechanism study reveals the critical role of lysosomal Dox accumulation-mediated mitochondrial ROS overproduction followed by the mitochondrial membrane potential loss and the activation of apoptotic signaling for superior anticancer activity of Dox-gluRDVs. Conclusion: This work demonstrates the great potential of RDVs to serve a biological DDS of Dox for systemic administration to improve conventional cancer chemotherapeutics.