Inhibition of Autophagy Promotes the Elimination of Liver Cancer Stem Cells by CD133 Aptamer-Targeted Delivery of Doxorubicin
Wang Yin,
Cuong V. Pham,
Tao Wang,
Hadi Al Shamaileh,
Rocky Chowdhury,
Shweta Patel,
Yong Li,
Lingxue Kong,
Yingchu Hou,
Yimin Zhu,
Sunrui Chen,
Huo Xu,
Lee Jia,
Wei Duan,
Dongxi Xiang
Affiliations
Wang Yin
IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3216, Australia
Cuong V. Pham
IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3216, Australia
Tao Wang
Telethon Kids Institute, University of Western Australia, Perth, WA 6009, Australia
Hadi Al Shamaileh
Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA 6150, Australia
Rocky Chowdhury
IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3216, Australia
Shweta Patel
IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3216, Australia
Yong Li
Cancer Care Centre, St George Hospital, Kogarah, and St George and Sutherland Clinical School, University of New South Wales Kensington, Kogarah, NSW 2217, Australia
Lingxue Kong
Institute for Frontier Materials, Deakin University, Waurn Ponds, VIC 3216, Australia
Yingchu Hou
Laboratory of Tumor Molecular and Cellular Biology College of Life Sciences, Shaanxi Normal University, 620 West Chang’an Avenue, Xi’an 710119, China
Yimin Zhu
CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano–Bionics, Chinese Academy of Sciences, Suzhou 215123, China
Sunrui Chen
Shanghai OneTar Biomedicine, Shanghai 201203, China
Huo Xu
College of Materials and Chemical Engineering, Minjiang University, Fuzhou 350108, China
Lee Jia
College of Materials and Chemical Engineering, Minjiang University, Fuzhou 350108, China
Wei Duan
IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3216, Australia
Dongxi Xiang
State Key Laboratory of Oncogenes and Related Genes, Shanghai 200127, China
Doxorubicin is the most frequently used chemotherapeutic agent for the treatment of hepatocellular carcinoma. However, one major obstacle to the effective management of liver cancer is the drug resistance derived from the cancer stem cells. Herein, we employed a CD133 aptamer for targeted delivery of doxorubicin into liver cancer stem cells to overcome chemoresistance. Furthermore, we explored the efficacy of autophagy inhibition to sensitize liver cancer stem cells to the treatment of CD133 aptamer-doxorubicin conjugates based on the previous observation that doxorubicin contributes to the survival of liver cancer stem cells by activating autophagy. The kinetics and thermodynamics of aptamer-doxorubicin binding, autophagy induction, cell apoptosis, and self-renewal of liver cancer stem cells were studied using isothermal titration calorimetry, Western blot analysis, annexin V assay, and tumorsphere formation assay. The aptamer-cell binding andintracellular accumulation of doxorubicin were quantified via flow cytometry. CD133 aptamer-guided delivery of doxorubicin resulted in a higher doxorubicin concentration in the liver cancer stem cells. The combinatorial treatment strategy of CD133 aptamer-doxorubicin conjugates and an autophagy inhibitor led to an over 10-fold higher elimination of liver cancer stem cells than that of free doxorubicin in vitro. Future exploration of cancer stem cell-targeted delivery of doxorubicin in conjunction with autophagy inhibition in vivo may well lead to improved outcomes in the treatment of hepatocellular carcinoma.
