Project Summary Preserving and repairing injured neurons is the primary goal of treatments for brain injuries. Yet, delivering therapeutics specifically to neurons has been a challenge due many factor. Increased glucose uptake and its hypermetabolism, is a hallmark of injury or evolving injury in neurons in many pathological conditions (e.g. seizures, stroke, trauma). Delivering drugs specifically to injured neurons in the area of pathology, would address a significant gap in neuroprotective approaches, opening new treatment avenues for acute CNS disorders. We seek to address this gap by developing novel dendrimers that take advantage of altered glucose transport in injured neurons, without a need for a targeting ligand or antibody. Previously, our group developed hydroxyl polyamidoamine (PAMAM) dendrimers that specifically targeted reactive brain microglia/macrophages and attenuated neuroinflammation and injury in multiple models of brain injury, and now are in early Phase 2 clinical trials. This application aims to develop and validate a novel dendrimer made primarily from glucose that preferentially targets injured neurons. We have designed non- degradable dendrimers made primarily of glucose building blocks, that can facilitate enhanced uptake due to multivalent surface interactions with glucose transporters. We hypothesize that glucose dendrimers will localize primarily into injured neurons, enabling sustained delivery of drugs for neuroprotection and preventing neuronal loss. Importantly, our preliminary data, with a generation-2 glucose dendrimer (GD2) with 24 glucose molecules on the surface, suggests that they specifically localize in injured/active neurons in vitro and four clinically-relevant, diverse in vivo models of acute neuronal injury. Glucose dendrimer-ketamine conjugate (GD2-ket) is more effective than ketamine alone in suppressing clinical seizures in an established rodent epilepsy model. We will test our hypothesis by performing experiments in the following aims: Aim 1: Determine the extent and specific mechanisms of glucose-dendrimers (GD) uptake in neurons. Aim 2: Evaluate in vivo cellular biodistribution and pharmacokinetics (PK) of systemic glucose-dendrimers in a mouse model of acute neuronal injury induced by epilepsy; Aim 3: Determine efficacy of glucose-dendrimer-ketamine conjugates in rodent model of epilepsy. The proposed glucose dendrimer platform can impact treatments for multiple CNS disorders, especially in the acute phase, opening new avenues for nanomaterials. Our team has the combination of dendrimer nanomedicine, neuroscience, epilepsy, and brain injury expertise to carry out the proposed studies and enable translation from the bench to bedside.