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Implantation of hydrogel-liposome nanoplatform inhibits glioblastoma relapse by inducing ferroptosis.

ABSTRACT: Glioblastoma is acknowledged as the most aggressive cerebral tumor in adults. However, the efficacy of current standard therapy is seriously undermined by drug resistance and suppressive immune microenvironment. Ferroptosis is a recently discovered form of iron-dependent cell death that may have excellent prospect as chemosensitizer. The utilization of ferropotosis inducer Erastin could significantly mediate chemotherapy sensitization of Temozolomide and exert anti-tumor effects in glioblastoma. In this study, a combination of hydrogel-liposome nanoplatform encapsulated with Temozolomide and ferroptosis inducer Erastin was constructed. The αvβ3 integrin-binding peptide cyclic RGD was utilized to modify codelivery system to achieve glioblastoma targeting strategy. As biocompatible drug reservoirs, cross-linked GelMA (gelatin methacrylamide) hydrogel and cRGD-coated liposome realized the sustained release of internal contents. In the modified intracranial tumor resection model, GelMA-liposome system achieved slow release of Temozolomide and Erastin in situ for more than 14 d. The results indicated that nanoplatform (T+E@LPs-cRGD+GelMA) improved glioblastoma sensitivity to chemotherapeutic temozolomide and exerted satisfactory anti-tumor effects. It was demonstrated that the induction of ferroptosis could be utilized as a therapeutic strategy to overcome drug resistance. Furthermore, transcriptome sequencing was conducted to reveal the underlying mechanism that the nanoplatform (T+E@LPs-cRGD+GelMA) implicated in. It is suggested that GelMA-liposome system participated in the immune response and immunomodulation of glioblastoma via interferon/PD-L1 pathway. Collectively, this study proposed a potential combinatory therapeutic strategy for glioblastoma treatment.

SUBMITTER: Wang Z

PROVIDER: S-EPMC10232663 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Implantation of hydrogel-liposome nanoplatform inhibits glioblastoma relapse by inducing ferroptosis.

Wang Zixiao Z Liu Zihao Z Wang Shan S Bing Xin X Ji Xiaoshuai X He Dong D Han Min M Wei Yanbang Y Wang Chanyue C Xia Qian Q Yang Jianqiao J Gao Jiajia J Yin Xianyong X Wang Zhihai Z Shang Zehan Z Xu Jiacan J Xin Tao T Liu Qian Q

Asian journal of pharmaceutical sciences 20230328 3

Glioblastoma is acknowledged as the most aggressive cerebral tumor in adults. However, the efficacy of current standard therapy is seriously undermined by drug resistance and suppressive immune microenvironment. Ferroptosis is a recently discovered form of iron-dependent cell death that may have excellent prospect as chemosensitizer. The utilization of ferropotosis inducer Erastin could significantly mediate chemotherapy sensitization of Temozolomide and exert anti-tumor effects in glioblastoma. ...[more]

PMID: 37274924

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Project description:BackgroundFerroptosis is a novel form of iron-dependent cell death and participates in the malignant progression of glioblastoma (GBM). Although circular RNAs (circRNAs) are found to play key roles in ferroptosis via several mechanisms, including regulating iron metabolism, glutathione metabolism, lipid peroxidation and mitochondrial-related proteins, there are many novel circRNAs regulating ferroptosis need to be found, and they may become a new molecular treatment target in GBM.MethodsThe expression levels of circLRFN5, PRRX2 and GCH1 were detected by qPCR, western blotting, and immunohistochemistry. Lentiviral-based infections were used to overexpress or knockdown these molecules in glioma stem cells (GSCs). The biological functions of these molecules on GSCs were detected by MTS (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium), the 5-ethynyl-20-deoxyuridine (EdU) incorporation assay, transwell, neurosphere formation assays, Extreme Limiting Dilution Analysis (ELDA) and xenograft experiments. The content of ferroptosis levels in GSCs was detected by BODIPY 581/591 C11 assay, glutathione (GSH) assay and malondialdehyde (MDA) assay. The regulating mechanisms among these molecules were studied by RNA immunoprecipitation assay, RNA pull-down assay, ubiquitination assay, dual-luciferase reporter assay and chromatin immunoprecipitation assay.ResultsWe found a novel circRNA circLRFN5 is downregulated in GBM and associated with GBM patients' poor prognosis. CircLRFN5 overexpression inhibits the cell viabilities, proliferation, neurospheres formation, stemness and tumorigenesis of GSCs via inducing ferroptosis. Mechanistically, circLRFN5 binds to PRRX2 protein and promotes its degradation via a ubiquitin-mediated proteasomal pathway. PRRX2 can transcriptionally upregulate GCH1 expression in GSCs, which is a ferroptosis suppressor via generating the antioxidant tetrahydrobiopterin (BH4).ConclusionsOur study found circLRFN5 as a tumor-suppressive circRNA and identified its role in the progression of ferroptosis and GBM. CircLRFN5 can be used as a potential GBM biomarker and become a target for molecular therapies or ferroptosis-dependent therapy in GBM.

Project description:Glioblastoma (GBM) is the most common primary intracranial malignant tumor. Recent literature suggests that induction of programmed death has become a mainstream cancer treatment strategy, with ferroptosis being the most widely studied mode. Complement C5a receptor 1 (C5aR1) is associated with both tumorigenesis and tumor-related immunity. However, knowledge regarding the role of C5aR1 in GBM progression is limited. In the present study, we observed significant upregulation of C5aR1 in glioma tissue. In addition, C5aR1 expression was found to be closely associated with patient prognosis and survival. Subsequent experimental verification demonstrated that C5aR1 promoted the progression of GBM mainly by suppressing ferroptosis induction, inhibiting the accumulation of lipid peroxides, and stabilizing the expression of the core antiferroptotic factor glutathione peroxidase 4 (GPX4). Aberrant N6-methyladenosine (m6A) modification of GPX4 mRNA contributes significantly to epigenetic tumorigenesis, and here, we report that selective methyltransferase-like 3 (METTL3)-dependent m6A methylation of GPX4 plays a key role in C5AR1 knockdown-induced ferroptosis induction. Mechanistically, ERK1/2 signaling pathway activation increases the METTL3 protein abundance in GBM cells. This activation then increases the stability of METTL3-mediated m6A modifications on GPX4, enabling it to fulfill its transcriptional function. More importantly, in an intracranial xenograft mouse model, PMX205, a C5aR1 inhibitor, promoted alterations in ferroptosis in GBM cells and inhibited GBM progression. In conclusion, our findings suggest that C5aR1 inhibits ferroptosis in GBM cells and promotes MettL3-dependent GPX4 expression through ERK1/2, thereby promoting glioma progression. Our study reveals a novel mechanism by which the intracellular complement receptor C5aR1 suppresses ferroptosis induction and promotes GBM progression. These findings may facilitate the identification of a potential therapeutic target for glioma.

Dataset Information

Implantation of hydrogel-liposome nanoplatform inhibits glioblastoma relapse by inducing ferroptosis.

Publications

Implantation of hydrogel-liposome nanoplatform inhibits glioblastoma relapse by inducing ferroptosis.

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