Tumor microenvironment dual-responsive core–shell nanoparticles with hyaluronic acid-shield for efficient co-delivery of doxorubicin and plasmid DNA

International Journal of Nanomedicine

关键词: Co-delivery;    core-shell nanoparticles;    hyaluronic acid;    CD44 targeted;    pH sensitive;   

DOI  :  

来源: DOAJ

【 摘 要 】

Tianqi Wang, Xiaoyue Yu, Leiqiang Han, Tingxian Liu, Yongjun Liu, Na ZhangDepartment of Pharmaceutics, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong Province, People’s Republic of ChinaAbstract: As the tumor microenvironment (TME) develops, it is critical to take the alterations of pH value, reduction and various enzymes of the TME into consideration when constructing the desirable co-delivery systems. Herein, TME pH and enzyme dual-responsive core–shell nanoparticles were prepared for the efficient co-delivery of chemotherapy drug and plasmid DNA (pDNA). A novel pH-responsive, positively charged drug loading material, doxorubicin (DOX)-4-hydrazinobenzoic acid (HBA)-polyethyleneimine (PEI) conjugate (DOX-HBA-PEI, DHP), was synthesized to fabricate positively charged polyion complex inner core DHP/DNA nanoparticles (DDN). Hyaluronic acid (HA) was an enzyme-responsive shell which could protect the core and enhance the co-delivery efficiency through CD44-mediated endocytosis. The HA-shielded pH and enzyme dual-responsive nanoparticles (HDDN) were spherical with narrow distribution. The particle size of HDDN was 148.3±3.88 nm and the zeta potential was changed to negative (-18.1±2.03 mV), which led to decreased cytotoxicity. The cumulative release of DOX from DHP at pH 5.0 (66.4%) was higher than that at pH 7.4 (30.1%), which indicated the pH sensitivity of DHP. The transfection efficiency of HDDN in 10% serum was equal to that in the absence of serum, while the transfection of DDN was significantly decreased in the presence of 10% serum. Furthermore, cellular uptake studies and co-localization assay showed that HDDN were internalized effectively through CD44-mediated endocytosis in the tumor cells. The efficient co-delivery of DOX and pEGFP was confirmed by fluorescent image taken by laser confocal microscope. It can be concluded that TME dual-responsive HA-shielded core–shell nanoparticles could be considered as a promising platform for the co-delivery of chemotherapy drug and pDNA.Keywords: co-delivery, core–shell nanoparticles, hyaluronic acid, CD44 targeted, pH sensitive

【 授权许可】

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