UC San Diego

Many traumatic brain injury (TBI) survivors suffer cognitive impairments after injury, yet there are currently no FDA approved therapeutics that address long-term patient brain health. Development of vascularly delivered TBI therapeutics is challenging due to their poor pharmacokinetics, which reduces their accumulation and retention in the brain. Nanoparticles are promising technologies that can improve the vascular delivery of TBI therapeutics by protecting the drug payload in circulation, increasing blood half-life, and passively accumulating in injured brain tissue across the transiently permeable blood-brain barrier (BBB). Nanoparticle surfaces can be modified to change their physicochemical properties and implement targeting strategies, thereby tuning their pharmacokinetics to improve delivery. Thus, vascular delivery of nanoparticle-based TBI therapeutics can be improved by engineering the surface properties of nanoparticles.To engineer nanoparticles that accumulate in the injured brain, we modified the surfaces of diverse nanoparticle platforms to tune their physicochemical properties and implement active targeting. First, we engineered the steric forces and hydrophobicity of lipid nanoparticles (LNP) by modifying their polyethylene glycol (PEG) layer with short and long anchor PEG-lipids. We found that vascularly delivered LNPs formulated with long anchored PEG-lipids had longer blood half-lives and extended activity in the injured brain. Next, we engineered the charge and hydrophobicity of model polystyrene nanoparticles via surface modification with peptides. We found that peptide physicochemical properties affected nanoparticle pharmacokinetics, with neutral, zwitterionic, and negatively charged nanoparticles demonstrating greater passive accumulation in the injured brain than positively charged nanoparticles. Finally, we applied these ideas to a porous silicon nanoparticle (pSiNP) drug delivery system for brain derived neurotrophic factor (BDNF) surface modified with PEG and a peptide that targets the injured brain (CAQK). After intravenous administration of pSiNP-BDNF, we observed a ~24% reduction in brain lesion volumes compared to both free BDNF and untreated controls. Understanding how engineered nanoparticle surface properties affect their pharmacokinetics in TBI models informs the design of nanoparticle-based TBI therapeutics and is broadly applicable to the design of vascularly delivered therapeutic nanoparticles.