Original Articles
Lu Zhong, Lu Xu, Yanying Liu, Qingsong Li, Dongyang Zhao, Zhenbao Li, Huicong Zhang, Haotian Zhang, Qiming Kan, Yongjun Wang, Jin Sun, Zhonggui He. Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapy[J]. Acta Pharmaceutica Sinica B, 2019, 9(2): 397-409

Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapy
Lu Zhonga, Lu Xua, Yanying Liua, Qingsong Lia, Dongyang Zhaoa, Zhenbao Lia, Huicong Zhanga, Haotian Zhangb, Qiming Kanb, Yongjun Wanga, Jin Suna, Zhonggui Hea
a Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China;
b Department of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China
Hyaluronic acid (HA) is a natural ligand of tumor-targeted drug delivery systems (DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors (HARE and LYVE-1) are also overexpressing in the reticuloendothelial system (RES). Therefore, polyethylene glycol (PEG) modification of HA-based DDS is necessary to reduce RES capture. Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement, significantly compromising the in vitro antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform (Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage. The in vitro and in vitro investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and in vitro nonspecific biodistribution.
Key words:    Hyaluronic acid    Benzoic imine linkage    Active-targeting    Cancer therapy    Natural ligand    Supramolecular nanoplatform    Transformative nanoparticles    PEG dilemma   
Received: 2018-07-23     Revised: 2018-10-02
DOI: 10.1016/j.apsb.2018.11.006
Funds: This work was supported by the National Basic Research Program of China (No.81573371) and the Key Projects of Liaoning Province Department of Education (No.2017LZD03,China).
Corresponding author: Jin Sun, Zhonggui He     Email:sunjin@syphu.edu.cn;hezhgui_student@aliyun.com
Author description:
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Lu Zhong
Lu Xu
Yanying Liu
Qingsong Li
Dongyang Zhao
Zhenbao Li
Huicong Zhang
Haotian Zhang
Qiming Kan
Yongjun Wang
Jin Sun
Zhonggui He

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