Lipid Armor Loaded with Doxylamine and Gemfibrozil for Glioblastoma Therapy: Particle Engineering and...

Glioblastoma multiforme (GBM) is an aggressive and highly treatment-resistant brain tumor with a poor prognosis and limited therapeutic options. Temozolomide (TMZ), the current standard chemotherapeutic agent, often fails due to acquired resistance and its high systemic toxicity at therapeutic doses. In our recent study, we repurposed two FDA-approved drugs, Doxylamine and Gemfibrozil, as potential alternatives to TMZ for GBM treatment. Both agents demonstrated superior efficacy in vitro, with lower IC₅₀ values (∼750 μM for Doxylamine and ∼300 μM for Gemfibrozil) compared to TMZ (∼1.25 mM). However, at these concentrations, the free drugs still exhibited off-target toxicity to noncancerous cells. To address this, in this study, we developed solid lipid nanoparticle (SLN) formulations of Doxylamine and Gemfibrozil to prevent off-target distribution and enhance their therapeutic index. Compared to the free drugs, the SLN formulations reduced IC₅₀ values (1.5 to 1.66-fold) in GBM cells, indicating enhanced potency. Furthermore, nanoencapsulation enhanced cellular uptake, minimized cytotoxic effects on healthy cells, and enabled effective drug action at significantly lower concentrations. Mechanistic studies carried out in 2D and 3D cultures of U87 cells revealed that both free and nanoformulation-encapsulated drugs inhibited autophagy flux and triggered apoptotic pathways in GBM cells, with the nanoformulations exhibiting greater selectivity and efficiency. These results underscore the advantages of SLN-based Doxylamine and Gemfibrozil delivery over their free forms, highlighting their promise as safer and more effective treatment options for GBM.