Redox-sensitive hyaluronic acid-cholesterol nanovehicles potentiate efficient Transmembrane internalization and controlled release for penetrated "full-line" inhibition of pre-metastatic initiation.
Redox-sensitive hyaluronic acid-cholesterol nanovehicles potentiate efficient Transmembrane internalization and controlled release for penetrated "full-line" inhibition of pre-metastatic initiation.
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DOI：
10.1016/j.jconrel.2021.06.013
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发表时间：
2021-06
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通讯作者：
Meirong Huo;Honglan Wang;Lingchao Li;Yuqing Tong;Chengxia Hu;Yongwei Gu;Jiyong Liu;Tingjie Yin-Ting
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作者：
Meirong Huo;Honglan Wang;Lingchao Li;Yuqing Tong;Chengxia Hu;Yongwei Gu;Jiyong Liu;Tingjie Yin-Ting
转移性乳腺癌是全球癌症相关死亡率的主要原因。肿瘤特异性穿透和引发的药物释放对转移前启动的“全线”抑制在改善死亡率方面至关重要。在此，构建了交联的氧化还原敏感性两亲性缀合物（cHLC），其具有以下特征的组合，包括透明质酸（HA）介导的肿瘤活性靶向、基于硫辛酸（LA）核交联的生物稳定性和还原性、以及通过胆固醇（CHO）修饰的脂筏锚定促进的HA介导的内吞作用，用于紫杉醇（PTX）和多靶向抗转移剂的渗透共递送，水飞蓟宾（SB）。结果表明，cHLC/（PTX + SB）纳米药物在体内外的4 T1模型中均表现出增强的肿瘤细胞质选择性快速给药。释放的SB有效地使细胞对PTX治疗敏感，并抑制转移前启动的整个过程，包括上皮向间质转化（EMT）、局部和血管侵袭。该给药系统的精致设计为提高多靶点药物的聚焦可及性提供了深刻的见解，以有效抑制肿瘤转移。
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.