Glioma is a primary intracranial malignant tumor originating from glial cells or progenitor cells, accounting for 25.5% of central nervous system tumors. Clinically, the treatment of glioma mainly depends on surgical resection, supplemented by postoperative chemoradiotherapy. However, gliomas have the characteristics of infiltrative growth, strong invasiveness, and blurred boundary with surrounding tissue, which leads to the failure of surgical resection.
Therefore, chemotherapy has become an important adjuvant therapy for glioma treatment, but chemotherapy still faces great challenges due to the existence of the blood-brain barrier (BBB). At the same time, gliomas promote their own growth, metastasis, and invasion by recruiting microglia and peripheral macrophages and inducing M2 macrophages to polarize, resulting in drug resistance and immunosuppression. Therefore, improving the efficiency of drug delivery and finding new therapeutic targets are the key to the chemotherapy of glioma.
Recently, researchers from Sichuan University published an article entitled “A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization” in the journal Acta Pharmaceutica Sinica B. This study demonstrated the extensive and therapeutic efficacy of SPP-ARV-825 micelles against gliomas, which may provide a new strategy for the treatment of gliomas in the future.
Glioma is a primary aggressive brain tumor with a high recurrence rate. The inefficiency of chemotherapeutic drugs across the BBB is known as one of the major challenges in anti-glioma treatment. In addition, a large number of infiltrating tumor-associated macrophages (TAMs) in gliomas further hinder the efficacy of drugs.
In this study, the proteolysis targeted chimera (PROTAC) ARV-825 that degrades BRD4 was introduced into the compound micelle (SPP) composed of substance P (SP) poly (ethylene glycol)-poly (D, L-lactic acid) copolymer and methoxy poly (ethylene glycol)-poly (D, L-lactic acid) to construct the therapeutic nanosystem (SPP-ARV-825), which can penetrate the blood-brain barrier and target brain tumors.
Subsequently, the released drugs have anti-tumor effects by inhibiting the transcription of IRF4 promoter and the phosphorylation of STAT6, STAT3, and AKT, thereby inhibiting cell proliferation, inducing apoptosis, and inhibiting M2 macrophage polarization.
To sum up, the researchers constructed a brain-targeted BRD4 degrader-loaded micelle and discussed its anti-glioma efficacy and mechanism in this study. The results showed that the SPPARV-825 micelle could achieve an effective anti-tumor effect by inhibiting the proliferation of glioma cells, inducing apoptosis, and reducing the polarization of M2 macrophages.
Overall, this work suggests a potential strategy for targeted therapy of glioma and may have a significant impact on BRD4-targeted cancer therapy.