Hyaluronic acid-decorated redox-sensitive chitosan micelles for tumor-specific intracellular delivery of gambogic acid

Abstract

Introduction:

Herein, a hyaluronic acid (HA)-coated redox-sensitive chitosan-based nanoparticle, HA(HECS-ss-OA)/GA, was successfully developed for tumor-specific intracellular rapid delivery of gambogic acid (GA).

Materials and methods:

The redox-sensitive polymer, HECS-ss-OA, was prepared through a well-controlled synthesis procedure with a satisfactory reproducibility and stable resulted surface properties of the assembled cationic micelles. GA was solubilized into the inner core of HECS-ss-OA micelles, while HA was employed to coat outside HECS-ss-OA/GA for CD44-mediated active targeting along with protection from cation-associated in vivo defects. The desirable redox-sensitivity of HA(HECS-ss-OA)/GA was demonstrated by morphology and particle size changes alongside in vitro drug release of nanoparticles in different simulated reducing environments.

Results:

The results of flow cytometry and confocal microscopy confirmed the HA-receptor mediated cellular uptake and burst drug release in highly reducing cytosol of HA(HECS-ss-OA)/GA. Consequently, HA(HECS-ss-OA)/GA showed the highest apoptosis induction and cytotoxicity over the non-sensitive (HA(HECS-cc-OA)/GA) and HA un-coated (HECS-ss-OA/GA) controls against A549 NSCLC model both in vitro and in vivo. Furthermore, a diminished systemic cytotoxicity was observed in HA(HECS-ss-OA)/GA treated mice compared with those treated by HA un-coated cationic ones and GA solution.

Keywords:

• gambogic acid
• nanoparticles
• redox-sensitive
• intracellular drug delivery
• tumor

Acknowledgments

This work was supported by the project of the National Natural Science Foundation of China (Nos. 81872424, 81703442, 81503261, 81573613), the Natural Science Foundation of Shandong Province (ZR2013HQ011), the Natural Science Foundation of Jiangsu Province (BK20130655), Primary Research & Development Plan of Shandong Province (2017GSF218016), Qing Lan Project of Jiangsu Province (No. 02432009), the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. JKPZ2013004), and the Open Fund of State Key Laboratory of Natural Medicines (SKLNMKF201612), Double First-rate construction project of China Pharmaceuticla University: Advanced Technology in New Drug Discovery and its Inversion and Application (CPU2018GY26).

Disclosure

The authors report no conflicts of interest in this work.

Supplementary material

The ¹HNMR and HR-MS spectrum of OA-ss-COOH and OA-cc-COOH.