1Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA
Neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of cerebral palsy (CP), retinal degeneration, and other debilitating neurodegenerative disorders. Engineering and reprogramming the microglial response, to achieve targeted attenuation of neuroinflammation, can be a potent therapeutic strategy. However, drug delivery to the central nervous system is strongly restricted for most drugs by the blood-brain-barrier, making treatment of diffuse neuroinflammation a challenge. We take advantage of the unique, intrinsic, pathology-dependent, biodistribution patterns of dendrimers in diseases models of neurodegeneration. For example, dendrimers are transported to the periventricular region of the brain of newborn rabbit kits with cerebral palsy (CP), whereas little brain uptake is seen in healthy animals. Interestingly, they further localize selectively in activated microglia and astrocytes in animals with CP. Building on these findings, we have designed and synthesized dendrimer-N-acetyl cysteine (NAC) nanodevices, taking advantage of their rich surface functionality using appropriate linking chemistry. They can deliver and release the drug in the targeted tissue in a tailored and sustained manner. We show that a single intravenous dose of dendrimer-drug conjugate, administered after birth to rabbit kits with CP, results in significant improvement in motor function along with decrease in neuroinflammation and oxidative/neuronal injury, followed by improved myelination, by 5 days of age.1 These studies suggest that attenuation of ongoing neuroinflammation, achieving by appropriate engineering of the glial response, can have significant positive consequences in these and other debilitating neurodegenerative diseases.