Folate-Targeted polymeric micelles enhance the anti-glioma efficacy of pterostilbene in an orthotopic rat model

Abstract

The clinical translation of Pterostilbene, a neuroactive stilbene with broad therapeutic potential, is hampered by its poor aqueous solubility and insufficient brain accumulation. To address these limitations, we developed a folate receptor-targeted polymeric micelle system (F–Pt/M) using poly (ethylene glycol)-block-poly (ε-caprolactone) copolymers. The optimized F–Pt/M exhibited a small hydrodynamic diameter (∼133 nm), high drug loading, and increased the apparent solubility of pterostilbene by 25-fold. In folate receptor-expressing U251 and RG-2 glioma cells, F–Pt/M significantly enhanced cellular uptake via folate-mediated endocytosis and showed superior cytotoxicity compared to non-targeted micelles. In an orthotopic RG-2 glioma model, intravenous administration of F–Pt/M improved brain accumulation and prolonged median survival by 76.5% relative to free drug. Mechanistically, the enhanced anti-glioma efficacy was associated with induction of apoptosis and inhibition of the STAT3 signaling pathway. These findings establish folate-targeted micelles as a robust and versatile nanoplatform for delivering poorly soluble bioactive compounds to the brain, with pterostilbene representing a promising candidate for further neuro-oncological development.