CD44-Targeted Multifunctional Nanomedicines Based on a SingleComponent Hyaluronic Acid Conjugate with All-Natural Precursors: Construction and Treatment of Metastatic Breast Tumors in Vivo
Huimin Fang, Xiaofei Zhao, Xiaolei Gu, Huanli Sun, Ru Cheng, Zhiyuan Zhong*（钟志远）, and Chao Deng*（邓超）
Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
Biomacromolecules 2020, 21, 104--113
Metastasis is responsible for >90% of the deaths of breast cancer patients in the clinic. Here, we report on cross-linked multifunctional hyaluronic acid nanoparticles carrying docetaxel (DTX-CMHN) for enhanced suppression of highly metastatic 4T1 breast tumors in vivo. DTX-CMHN was formed from a single and all-natural hyaluronic acid-g-polytyrosine-lipoic acid conjugate (HA-g-PTyr-LA; HA, 20 kDa; PTyr, 2.2 kDa), and the size of DTX-CMHN increased from 69 to 78 to 96 nm as the increasing degree of substitution (DS) of PTyr increased from 4 to 11 to 15, respectively. Robust encapsulation of DTX was obtained when DS ≥ 11. DTX-CMHN while steady in a nonreducing environment was destabilized under 10 mM glutathione releasing ∼90% of the DTX within 24 h. It is noteworthy that DTX-CMHN exhibited better antitumor, antimigration, and anti-invasion activity in CD44-overexpressed 4T1-Luc breast cancer cells than free DTX. Interestingly, DTX-CMHN displayed a long elimination half-life of 5.75 h, in contrast to half-lives of 2.11 and 0.75 h for its non-cross-linked counterpart (DTX-MHN) and free DTX, respectively. In vivo therapeutic studies showed significantly better inhibition of primary 4T1-Luc tumor growth and lung metastasis and lower toxicity of DTX-CMHN compared with that of free DTX. These multifunctional nanoformulations based on a single and all-natural hyaluronic acid conjugate emerge as a potential nanoplatform for targeted treatment of CD44-positive metastatic tumors.
链接：https://pubs.acs.org/doi/abs/10.1021/acs.biomac.9b01012
