Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options due to tumor heterogeneity and the blood-brain tumor barrier (BBTB). Proteolysis-targeting chimeras (PROTACs) offer a novel therapeutic strategy by degrading target proteins. ARV-825, a BET degrader PROTAC, has shown promise against GBM, but faces challenges such as poor solubility, limited BBTB permeability, and potential off-target toxicity. To address these limitations, we developed a pH-sensitive nanomedicine encapsulating ARV-825 for enhanced delivery and efficacy against GBM.

We formulated ARV-825 into nanomedicines using PEG-PBLA polymers and pH-sensitive linker via self-assembly and cross-link. The nanomedicine was characterized for size, stability, and drug encapsulation efficiency. In vitro cytotoxicity was assessed in GL-261 glioblastoma cells by measuring the IC-50. In vivo efficacy was evaluated in orthotopic GL-261-luc glioblastoma models in C57BL/6 mice. We monitored tumor growth using in vivo imaging and assessed treatment efficacy by analyzing survival rates.

pH-sensitive ARV-825-loaded nanomedicines exhibited enhanced drug potency with an in vitro IC-50 of 0.013 µM compared to 0.1 µM for free ARV-825. In vivo imaging revealed significant tumor growth inhibition in mice treated with ARV-825 nanomedicines. Furthermore, the nanomedicine significantly prolonged survival time and improved survival rates compared to controls.

This study demonstrates that PROTAC-based nanomedicine represents a promising approach for treating glioblastoma. Our ARV-825-loaded pH-sensitive PBLA-PEG micelles enhanced drug potency, improved tumor targeting, and extended survival in preclinical GBM models. This nanomedicine approach warrants further investigation for clinical translation. Future research should focus on detailed mechanistic studies, safety evaluations, and strategies to further enhance tumor-specific delivery and minimize off-target effects.