Resveratrol–Temozolomide Cocrystal Induced Antiglioblastoma Effects via Enhanced Dissolution Behavior and Mitochondrial Apoptosis

Glioblastoma is a highly aggressive brain tumor with a poor prognosis and limited treatment options. Resveratrol (RES) and temozolomide (TMZ) both showed significant antitumor activity in GBM therapy. However, they are limited by poor solubility and stability, respectively. This study reports the first successful development of a resveratrol–temozolomide (RES–TMZ) cocrystal. The cocrystal significantly improved the solubility of RES and stability of TMZ, while it exhibited enhanced oral bioavailability in rats. In vitro cytotoxicity assays revealed that the RES–TMZ cocrystal showed superior inhibitory effects on U87 glioma cell proliferation and induced a higher apoptosis rate compared to that of monotherapy or physical mixtures. Mechanistic studies further demonstrated that the cocrystal exerts its effects through the mitochondrial-dependent apoptotic pathway, characterized by the upregulation of the proapoptotic protein Bax, downregulation of the antiapoptotic protein Bcl-2, activation of the caspase-3 pathway, and collapse of mitochondrial membrane potential coupled with a burst of intracellular reactive oxygen species. This work establishes pharmaceutical cocrystallization as a viable strategy to develop improved combination therapies for glioblastoma by overcoming drug limitations while potentiating therapeutic effects.