Targeted manipulation of injured glia through nanomedicines: towards treatments for neuroinflammation and CNS disorders
Neuroinflammation, mediated by activated microglia and astrocytes, plays a key role in the pathogenesis of cerebral palsy (CP), autism, and most other debilitating central nervous system (CNS) disorders. 'Appropriate', targeted manipulation of neuroinflammation can bring novel approaches for treated diseases, increasing the drug efficacy and decreasing the side effects (a major issue with many CNS therapeutics). However, targeted delivery of drugs to specific cells in the CNS is a challenge. To address this, we take advantage of the unique, intrinsic, pathology-dependent, brain uptake of dendrimers (with no targeting moieties) in disease models of CNS and retinal disorders. Upon systemic administration, hydroxyl-terminal poly(amidoamine) dendrimers localize selectively in activated microglia and astrocytes in animals with CP. Such selective localization has been broadly validated in pre-clinical models of brain and retinal injuries in more than 25 small and large animal models, including primates. The potential mechanism for such selective uptake will be discussed. Building on these findings, we have designed and synthesized dendrimer-drug conjugates which have shown significant promise for many brain and ocular disorders. Two examples of this approach of targeted, systemic therapy for neuroinflammation, one for pediatric brain injury and one for age-related macular degeneration, representing two opposite ends of the age spectrum, will be presented. 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, neuronal growth/myelination, along with decrease in neuroinflammation and oxidative injury by 5 days of age.1 This improvement is sustained till adulthood, and has been validated in multiple etiologies of CP, paving way for new approaches to treat pediatric/neonatal brain injuries. Delivering drugs to injured glia cells also allows us to understand their role in repair and recovery following brain injury, with broad implications in developing novel therapies for CNS disorders, a growing health problem worldwide, and yet an unmet need. These dendrimer-drug conjugates are undergoing commercialization and clinical translation.
Reference: 1. Kannan S, Dai H, Navath RS, et al. Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model. Sci Transl Med. 2012;4(130):130ra46. PMID: 22517883