Redox-sensitive hyaluronic acid-cholesterol nanovehicles potentiate efficient transmembrane internalization and controlled release for penetrated “full-line” inhibition of pre-metastatic initiation

• Published in: Journal of controlled release Vol. 336; pp. 89 - 104
• Main Authors: Huo, Meirong, Wang, Honglan, Li, Lingchao, Tong, Yuqing, Hu, Chengxia, Gu, Yongwei, Liu, Jiyong, Yin, Tingjie
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 10.08.2021
• Subjects: Cholesterol; Efficient transmembrane; Penetrated multitarget therapy; Pre-metastatic initiation; Promoted CD44-mediated endocytosis; Penetrated multitarget therapy; Promoted CD44-mediated endocytosis; Efficient transmembrane; Pre-metastatic initiation; Cholesterol
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2021.06.013

Metastatic breast cancer is a major cause of cancer-related mortality worldwide. The tumor-specific penetration and triggered drug release for “full-line” inhibition of pre-metastatic initiation are of essential importance in improving mortality rates. Here, a crosslinked, redox-sensitive amphiphilic conjugate (cHLC) was constructed with a combination of features, including hyaluronic acid (HA)-mediated tumor active targeting, lipoic acid (LA) core-crosslinking based bio-stability and reducibility, and lipid raft anchoring-promoted HA-mediated endocytosis through cholesterol (CHO) modification for the penetrated co-delivery of paclitaxel (PTX) and the multi-targeted anti-metastatic agent, silibinin (SB). Resultantly, the nanodrug (cHLC/(PTX + SB)) demonstrated enhanced tumor cytoplasm-selective rapid drug delivery in a 4T1 model both in vitro and in vivo. The released SB efficiently sensitized cells to PTX treatment and inhibited the whole process of pre-metastatic initiation including epithelial-to-mesenchymal transition (EMT), local and blood vessel invasion. The exquisite design of this delivery system provides a deep insight into enhancing focus accessibility of multi-targeted drugs for an efficient inhibition of tumor metastasis. [Display omitted]