Hybrid Nanoparticles Modified by Hyaluronic Acid Loading an HSP90 Inhibitor as a Novel Delivery System for Subcutaneous and Orthotopic Colon Cancer Therapy

Chenwei Pan,1,* Tiaotiao Zhang,2,3,* Shaoxun Li,1,3,* Zhihua Xu,2,3 Binhui Pan,2,3 Sheng Xu,2,3 Shuanghong Jin,1,3 Guangrong Lu,2 Shouxing Yang,2 Zhanxiong Xue,2 Ping Chen,4 Xian Shen,5 Fangyan Wang,6 Changlong Xu2,7 1Department of Infectious Disease, Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 2Department of Gastroenterology, Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 3Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 4Department of Infectious Disease, Shulan Hospital, Hangzhou, Zhejiang, 310012, People’s Republic of China; 5Department of Gastrointestinal Surgery, Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 6Department of Pathophysiology, School of Basic Medicine Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 7Center for Diagnostics and Therapeutics, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30302, USA*These authors contributed equally to this workCorrespondence: Fangyan Wang; Changlong Xu Email wzyxywfy@126.com; xchlong@163.comBackground: As a therapeutic target for cancer treatment, HSP90 has been explored extensively. However, the significant side effects of the HSP90 inhibitor 17AAG have limited its clinical use.Methods: In this study, we used hyaluronic acid (HA)–decorated DOTAP–PLGA hybrid nanoparticles (HA-DOTAP-PLGA NPs) as 17AAG-delivery carriers for targeted colon cancer therapy.Results: Different methods were used to characterize the successful fabrication of these hybrid PLGA NPs. Our results demonstrated that internalization of HA-NPs in colon cancer cells was governed by CD44receptor–mediated endocytosis. Annexin V–propidium iodide staining experiments revealed that cell apoptosis induced by HA-NPs-17AAG in colon cancer cells was more efficient than free 17AAG. In two animal models used to screen anticancer efficacy (Luc-HT29 subcutaneous xenograft and AOM/DSS-induced orthotopic tumor model), HA-NPs-17AAG significantly inhibited xenograft and orthotopic tumor growth, demonstrating HA-NPs-17AAG had much better therapeutic efficiency than free 17AAG. It is worth noting that great biocompatibility of HA-DOTAP-PLGA NPs was observed both in vitro and in vivo.Conclusion: Our research offers a preclinical proof of concept for colon cancer therapy with DOTAP-PLGA NPs as a creative drug-delivery system.Keywords: cationic hybrid nanoparticles, hyaluronic acid, HA, HSP90 inhibitor, colon cancer, targeted delivery system