A tumor microenvironment-responsive micelle co-delivered radiosensitizer Dbait and doxorubicin for the collaborative chemo-radiotherapy of glioblastoma
Shuyue Zhang,
Xiuxiu Jiao,
Michal Heger,
Shen Gao,
Mei He,
Nan Xu,
Jigang Zhang,
Mingjian Zhang,
Yuan Yu,
Baoyue Ding,
Xueying Ding
Affiliations
Shuyue Zhang
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Xiuxiu Jiao
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Michal Heger
Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China
Shen Gao
Department of Pharmaceutical Science, School of Pharmacy, Naval Medical University, Shanghai, China
Mei He
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Nan Xu
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Jigang Zhang
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Mingjian Zhang
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yuan Yu
Department of Pharmaceutical Science, School of Pharmacy, Naval Medical University, Shanghai, China
Baoyue Ding
Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China
Xueying Ding
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Glioblastoma is rather recalcitrant to existing therapies and effective interventions are needed. Here we report a novel microenvironment-responsive micellar system (ch-K5(s-s)R8-An) for the co-delivery of the radiosensitizer Dbait and the chemotherapeutic doxorubicin (DOX) to glioblastoma. Accordingly, the ch-K5(s-s)R8-An/(Dbait-DOX) micelles plus radiotherapy (RT) treatment resulted in a high degree of apoptosis and DNA damage, which significantly reduced cell viability and proliferation capacity of U251 cells to 64.0% and 16.3%, respectively. The angiopep-2-modified micelles exhibited substantial accumulation in brain-localized U251 glioblastoma xenografts in mice compared to angiopep-2-lacking micelles. The ch-K5(s-s)R8-An/(Dbait-DOX) + RT treatment group exhibited the smallest tumor size and most profound tumor tissue injury in orthotopic U251 tumors, leading to an increase in median survival time of U251 tumor-bearing mice from 26 days to 56 days. The ch-K5(s-s)R8-An/(Dbait-DOX) micelles can be targeted to brain-localized U251 tumor xenografts and sensitize the tumor to chemotherapy and radiotherapy, thereby overcoming the inherent therapeutic challenges associated with malignant glioblastoma.
