Dexamethasone nanotherapeutics for traumatic brain injury

Traumatic brain injury (TBI) poses a significant healthcare risk to military service members, both because of blast impacts experienced during active deployment and a wide range of training-related and accidental injuries. TBI initiates a complex secondary injury pathophysiology of neuroinflammation that results in acute cell death and axonal degeneration that can have long-term impacts on neurological and psychosocial health, reducing quality of life and incurring substantial healthcare costs. Dexamethasone (DX) and other glucocorticoids have been known for decades to possess anti-inflammatory properties and hold therapeutic potential for TBI and other forms of neurotrauma. However, clinical translation has been hindered by challenges in regulating the dose and duration of administration, resulting in a wide range of systemic side effects. The goal of this project is to develop a nanotherapeutic delivery system that can be administered intranasally and provide sustained, local DX delivery to the injured brain. Our approach is based on a novel amphiphilic graft copolymer, poly (lactide-co-glycolide)-graft-polyethylenimine (PLGA-graft-PEI or PgP, US Patent 10,232,050 B1). PgP spontaneously assembles into nanoparticles composed of a hydrophobic PLGA core and hydrophilic, cationic outer PEI shell in aqueous solution.  In previous, related work, we have investigated PgP as a carrier for the phosphodiesterase IV inhibitor rolipram (Rm-PgP) for treatment of both spinal cord injury (SCI) and TBI. As a novel nanocarrier, PgP offers several important benefits, including: incorporation of hydrophobic drugs with the PLGA core at concentrations exceeding their normal solubility and eliminating the need for formulation with organic solvents; prolonged residence in the spinal cord and brain after intraparenchymal or intrathecal injection; and improvements in histological and functional outcomes in both SCI and TBI preclinical injury models. Here, we propose to develop DX-loaded PgP (DX-PgP) as a new therapeutic treatment for TBI. Our technical objectives will be to 1) measure physico-chemical properties (size, charge, drug-loading) of DX-PgP, measure DX release, and DX-PgP stability during storage at ambient temperature; 2) to evaluate cellular uptake and cytotoxicity in cultured neurons, macrophages, and microglia and brain tissue slices, and 3) to evaluate anti-inflammatory efficacy of DX-PgP by measuring changes in inflammation-related cytokine expression in cultured cells and brain slices after exposure to lipopolysaccharide (LPS) These proof-of-concept studies will enable phase II testing of intranasal DX-PgP administration in a rodent preclinical controlled cortical impact (CCI) TBI model to evaluate DX pharmacokinetics and biodistribution; toxicology; and therapeutic efficacy for reducing neuroinflammation, increasing tissue preservation, and improving recovery of cognitive and motor function.