The effect of dual-functional hyaluronic acid-vitamin E succinate micelles on targeting delivery of doxorubicin

Jinling Wang,1 Wenzhuan Ma,1,2 Qiang Guo,1,2 Ying Li,1,2 Zhongdong Hu,1 Zhixiang Zhu,1 Xiaohui Wang,1 Yunfang Zhao,1 Xingyun Chai,1 Pengfei Tu1 1Modern Research Center for Traditional Chinese Medicine, 2School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China Abstract: Tumor-targeted delivery system has been developed as an attractive strategy for effective tumor therapy. In this study, in order to enhance the antitumor effects of doxorubicin (DOX), amphiphilic hyaluronic acid (HA)-conjugated vitamin E succinate (VES) copolymers (HA-VES) with different degrees of substitution (DS) were prepared with synergistic antitumor effects and active targeting activities, and utilized as nanocarriers for the efficient delivery of DOX. DOX-loaded HA-VES polymeric micelles (HA-VES/DOX) self-assembled from dual-functional HA-VES copolymer and exhibited excellent loading efficiency and superior colloidal stability. In vitro, HA-VES/DOX displayed enhanced cytotoxicity with synergistic anticancer effects of HA-VES copolymer, high apoptosis-inducing activities of tumor cells, and reversal effects of DOX on multidrug resistance, in comparison with DOX. Also, in vitro cellular uptake and subcellular localization studies revealed that HA-VES/DOX could more efficiently internalize into cancer cells and selectively release DOX within lysosomes, thereby enhancing the distribution of DOX in nuclei and facilitating its interactions with DNA. Specifically, HA-VES/DOX decreased the activity of CD44 mRNA and improved the targeting efficiency on MCF-7 cells, based on the active recognition between HA and CD44 receptor. More importantly, HA-VES/DOX displayed better tumor accumulation and targeting, and enhanced antitumor efficacy with reduced systemic toxicity in 4T1 tumor-bearing mice. In summary, the developed HA-VES–based drug delivery system, which increased drug targeting on the tumor site and exhibited preferable anticancer activity, could hold great potential as an effective and promising strategy for efficient tumor therapy. Keywords: hyaluronic acid, self-assembled micelles, tumor targeting, doxorubicin, vitamin E succinate