机构：[1]Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People’s Republic of China[2]Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, People’s Republic of China
Protein drugs with intracellular targets like Granzyme B (GrB) have demonstrated great proliferative inhibition activity in cancer cells. Their clinical translation, however, relies on the development of safe, efficient, and selective protein-delivery vehicles. Here, we report that epidermal growth factor receptor (EGFR) and CD44 dual-targeted multifunctional hyaluronic acid nanogels (EGFR/CD44-NGs) boost protein delivery to ovarian and breast cancers in vitro and in vivo. EGFR/CD44-NGs obtained via nanoprecipitation and photoclick chemistry from hyaluronic acid derivatives with tetrazole, GE11 peptide/tetrazole, and cystamine methacrylate groups had nearly quantitative loading of therapeutic proteins like cytochrome C (CC) and GrB, a small size of ca. 165 nm, excellent stability in serum, and fast protein release under a reductive condition. Flow cytometry assays showed that EGFR/CD44-NGs exhibited over 6-fold better uptake in CD44 and EGFR-positive SKOV-3 ovarian cancer cells than CD44-NGs. In accordance, GrB-loaded EGFR/CD44-NGs (GrB-EGFR/CD44-NGs) displayed enhanced caspase activity and growth inhibition in SKOV-3 cells as compared to GrB-loaded CD44-NGs (GrB-CD44-NGs) control. Intriguingly, the therapeutic studies in SKOV-3 human ovarian carcinoma and MDA-MB-231 human breast tumor xenografted in nude mice revealed that GrB-EGFR/CD44-NGs at a low dose of 3.85 nmol GrB equiv/kg induced nearly complete growth suppression of both tumors, which was obviously more effective than GrB-CD44-NGs, without causing any adverse effects. EGFR and CD44 dual-targeted multifunctional hyaluronic acid nanogels have appeared as a safe and efficacious platform for cancer protein therapy.
基金：
This work was supported by the National Natural Science
Foundation of China (NSFC 51473110, 51403147, and
51633005) and a Project funded by the Priority Academic
Program Development of Jiangsu Higher Education Institutions.
第一作者机构：[1]Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People’s Republic of China
通讯作者：
通讯机构：[1]Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People’s Republic of China
推荐引用方式(GB/T 7714)：
Jing Chen ,Jia Ouyang ,Qijun Chen ,et al.EGFR and CD44 Dual-Targeted Multifunctional Hyaluronic Acid Nanogels Boost Protein Delivery to Ovarian and Breast Cancers In Vitro and In Vivo[J].ACS APPLIED MATERIALS & INTERFACES.2017,9(28):24140-24147.doi:10.1021/acsami.7b06879.
APA：
Jing Chen,,Jia Ouyang,,Qijun Chen,,Chao Deng,,Fenghua Meng,...&Zhiyuan Zhong.(2017).EGFR and CD44 Dual-Targeted Multifunctional Hyaluronic Acid Nanogels Boost Protein Delivery to Ovarian and Breast Cancers In Vitro and In Vivo.ACS APPLIED MATERIALS & INTERFACES,9,(28)
MLA：
Jing Chen,,et al."EGFR and CD44 Dual-Targeted Multifunctional Hyaluronic Acid Nanogels Boost Protein Delivery to Ovarian and Breast Cancers In Vitro and In Vivo".ACS APPLIED MATERIALS & INTERFACES 9..28(2017):24140-24147
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