Optimized mucus adhesion and penetration of lipid-polymer nanoparticles enables effective nose-to-brain delivery of perillyl alcohol for glioblastoma therapy

Abstract

The delivery of drugs directly from the nose to the brain has been explored for the treatment of neurological diseases, such as glioblastoma, by overcoming the blood–brain barrier. Nanocarriers have demonstrated outstanding ability to enhance drug bioavailability in the brain, following intranasal administration. However, the performance of these nanosystems may be hindered by inadequate interactions with the nasal mucosa, limiting their effectiveness in reaching the olfactory region, and consequently, the translocation of particles to the brain. Here, we designed hybrid lipid-polymer nanoparticles (LPNP), containing the cationic lipid DOTAP and the triblock copolymer Pluronic® F127 to combine the mucoadhesiveness and mucus-penetrating properties. Perillyl alcohol (POH), a molecule currently under clinical trials against glioblastoma, via intranasal route, was entrapped in the nanoparticles. LPNP-POH exhibited a balanced profile of mucus adhesion and penetration, suggesting that the formulation may enhance mucosal retention while maintaining effective mucus diffusivity. In vivo evaluations displayed higher translocation of LPNP-POH from the nasal cavity to the brain. LPNP-POH resulted in a 2.5-fold increase in the concentration of perillyl acid (a primary metabolite of POH) in the cerebral tissue compared to the free drug. In vitro assays demonstrated that LPNP-POH increased the cytotoxicity and reduced the tumor growth of U87MG glioma cells. These results highlighted that the engineered formulation, with optimized mucoadhesiveness and mucus penetration properties, improved nose-to-brain delivery of POH, offering a promising potential for glioblastoma therapy.