Optimization of cationic functionalized nanoparticles for brain targeting: in vivo evaluation

Brain disorders affect millions of people worldwide, and their treatments often cause serious side effects and have difficult to bypass the blood-brain barrier (BBB). Intranasal drug administration may be a non-invasive route to bypass the BBB. Combined with this proposal, nanoparticles have been used to improve this route, such as polymeric nanoparticles (PNPs). These systems can be surface modified with cationic peptides, such as Low Molecular Weight Protamine (LMWP), to enhance epithelial mucus penetration. In this context, this work was to optimize the size of LMWP-functionalized pegylated polycaprolactone nanoparticles as a potential system for intranasal drug delivery to the brain. First, Plackett-Burmann Design (PBD) verified statistically significant factors to be evaluated. These factors were then optimized using a central composite design (CCD) to predict the optimum preparation conditions. These optimized conditions were used to synthesize pegylated and functionalized PNPs. The resulting systems ranged in size from 139.0 to 479.6 nm with a Zeta Potential of -21.9 to 3.5 mV. IVIS spectroscopy in k18-hACE2 mice (female) demonstrated efficient nose-to-brain delivery, even at a minimum functionalization ratio. Experimental design proved to be a powerful tool for nanoparticle synthesis for potential drug delivery, even in complex regions such as the brain.