Colloidal stability as a determinant of nanoparticle behavior in the brain

Drug delivery to the brain is challenging due to a highly regulated blood-brain barrier (BBB) and a complex brain microenvironment. Nanoparticles, due to their tailorability, provide promising platforms to enhance therapeutic delivery and achieve controlled release and disease-specific localization in the brain. However, we have yet to fully understand the complex interactions between nanoparticles and the biological environments in which they operate. It is important to perform a systematic study to characterize nanoparticle behavior as a function of ion composition, concentration, and pH in cerebrospinal fluid (CSF). These could alter nanoparticle biological identity and influence diffusive capability and cellular uptake. In this study, poly(ethylene glycol) (PEG)-coated and carboxyl-coated polystyrene (PS-PEG and PS-COOH respectively) nanoparticles (NPs) were used to evaluate the aggregation kinetics, colloidal stability, and diffusive capability of nanoparticles in conditions relevant to the brain microenvironment. Size, surface charge, and surface coating were varied in a range of CSF ion concentrations and compositions, pH conditions, and temperatures. Small changes in calcium concentration and pH destabilize nanoparticles in CSF. However, PS-PEG NPs remain stable over a wider variety of conditions than PS-COOH NPs, and have higher diffusion capabilities in both agarose gels, an in vitro model of the brain microenvironment, and an organotypic brain tissue slice model. These results demonstrate the need for steric stabilization to maintain nanoparticle colloidal stability in a wide range of conditions. Importantly, colloidal stabilization allows for increased diffusive capability and can be used to predict diffusive behavior in the brain microenvironment.