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

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.

SUBMITTER: Zhang S

PROVIDER: S-EPMC9387324 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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

Zhang Shuyue S Jiao Xiuxiu X Heger Michal M Gao Shen S He Mei M Xu Nan N Zhang Jigang J Zhang Mingjian M Yu Yuan Y Ding Baoyue B Ding Xueying X

Drug delivery 20220801 1

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 capac ...[more]

PMID: 35975300

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Project description:Treatment of malignant glioma is a challenge facing cancer therapy. In addition to surgery, and chemotherapy, radiotherapy (RT) is one of the most effective modalities of glioma treatment. However, there are two crucial challenges for RT facing malignant glioma therapy: first, gliomas are known to be resistant to radiation due to their intratumoral hypoxia; second, radiosensitizers may exhibit a lack of target specificity, which may cause a lower concentration of radiosensitizers in tumors and toxic side effects in normal tissues. Thus, novel angiopep-2-lipid-poly-(metronidazoles)n (ALP-(MIs)n) hypoxic radiosensitizer-polyprodrug nanoparticles (NPs) were designed to enhance the radiosensitizing effect on gliomas. Methods: In this study, different degrees and biodegradabilites of hypoxic radiosensitizer MIs-based polyprodrug (P-(MIs)n) were synthesized as a hydrophobic core. P-(MIs)n were mixed with DSPE-PEG2000, angiopep-2-DSPE-PEG2000 and lecithin to self-assemble ALP-(MIs)n through a single-step nanoprecipitation method. The ALP-(MIs)n encapsulate doxorubicin (DOX) (ALP-(MIs)n/DOX) and provoke the release of DOX under hypoxic conditions for glioma chemo- and radiotherapy. In vivo glioma targeting was tested in an orthotopic glioma using live animal fluorescence/bioluminescence imaging. The effect on sensitization to RT of ALP-(MIs)n and the combination of chemotherapy and RT of ALP-(MIs)n/DOX for glioma treatment were also investigated both in vitro and in vivo. Results: ALP-(MIs)n/DOX effectively accumulated in gliomas and could reach the hypoxic glioma site after systemic in vivo administration. These ALP-(MIs)n showed a significant radiosensitizing effect on gliomas and realized combination chemotherapy and RT for glioma treatment both in vitro and in vivo. Conclusions: In summary, we constructed a lipid-poly-(hypoxic radiosensitized polyprodrug) nanoparticles for enhancing the RT sensitivity of gliomas and achieving the combination of radiation and chemotherapy for gliomas.

Dataset Information

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

Publications

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

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