A hypoxia-dissociable siRNA nanoplatform for synergistically enhanced chemo-radiotherapy of glioblastoma. (31st October 2022)

• Record Type: Journal Article
• Authors: Xie, Yandong; Lu, Xueying; Wang, Zhen; Liu, Mingxi; Liu, Liang; Wang, Ran; Yang, Kun; Xiao, Hong; Li, Jianyong; Tang, Xianglong; Liu, Hongyi
• Is Part Of: Biomaterials science. Volume 10:Number 23(2022)
• Page Start: 6791
• Page End: 6803
• Publication Date: 2022-10-31
• Subjects: Biomedical materials -- Periodicals; 610.28
• DOI: 10.1039/d2bm01145j
• Languages: English
• ISSNs: 2047-4830

Abstract

Abstract : Due to the unique chemical properties of metronidazoles under hypoxic conditions, RDPP(Met) liposomes were found to promote the release of TMZ and siMGMT in hypoxic cells and have strong radiosensitivity for GBM. Abstract : Glioblastoma (GBM), as the most aggressive adult brain tumor, seriously threatened people's lives with a low survival time. Standard postoperative treatment, chemotherapy combined with radiotherapy (RT), was the major therapeutic strategy for GBM. However, this therapeutic efficacy was hindered by chemoradiotherapy resistance of GBM. Herein, to sensitize temozolomide (TMZ)-based chemotherapy and RT, a hypoxia-radiosensitive nanoparticle for co-delivering TMZ and siMGMT (RDPP(Met)/TMZ/siMGMT) was synthesized in this study. Our nanoparticle could effectively release the encapsulated alkylating agent (TMZ) and small interfering O6-methylguanine-DNA-methyltransferase RNA (siMGMT) in the hypoxic GBM. DNA-damage repair was effectively inhibited by down-regulating MGMT expression and activating cell apoptosis, which obviously enhanced the sensitivity of TMZ as well as RT. In vitro and in vivo experiments showed that RDPP(Met)/TMZ/siMGMT could efficiently penetrate the blood–brain barrier (BBB), accurately target GBM cells and effectively inhibit GBM proliferation. Compared with traditional TMZ combined with RT, RDPP(Met)/TMZ/siMGMT remarkably improved the survival time of orthotopic GBM-bearing mice, which demonstrated that our nanoplatform was an efficient combinatorial GBM therapy.