A tumor microenvironment-responsive micelle co-delivered radiosensitizer Dbait and doxorubicin for the collaborative chemo-radiotherapy of glioblastoma

Drug Deliv. 2022 Aug 8;29(1):2658-2670. doi: 10.1080/10717544.2022.2108937.

Abstract

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.

Keywords: Glioblastoma; chemo-radiotherapy; mic-roenvironment-responsive; radiosensitization; targeted nanotherapeutics.

MeSH terms

  • Animals
  • Brain Neoplasms* / drug therapy
  • Brain Neoplasms* / radiotherapy
  • Cell Line, Tumor
  • Chemoradiotherapy / methods
  • Doxorubicin
  • Glioblastoma* / drug therapy
  • Glioblastoma* / radiotherapy
  • Humans
  • Mice
  • Micelles
  • Radiation-Sensitizing Agents* / pharmacology
  • Tumor Microenvironment

Substances

  • Micelles
  • Radiation-Sensitizing Agents
  • Doxorubicin

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 81472349, No. 81872220, China); Shanghai Pujiang Program (No. 18PJD063, China); Key Science and Technology Program of Songjiang District (No. 18sjkjgg33, China); Tumor nanotargeting and TCM technology innovation team (Key Science and Technology Innovation Team of Jiaxing 2018, China). Michal Heger was supported by grants from the Dutch Cancer Foundation (KWF project # 10666), a Zhejiang Provincial Foreign Expert Program Grant, Zhejiang Provincial Key Natural Science Foundation of China (#Z20H160031), and a grant for the establishment of the Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics.