Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with blast TBI (bTBI) particularly affecting military personnel and individuals exposed to explosive environments, yet there are no available curative treatments to date. While adrenergic receptor antagonists have shown promise in reducing neuroinflammation and improving TBI mortality rates, systemic administration of these drugs can have deleterious effects including bradycardia and hypotension. Here, we introduce a polymeric nanoparticle system for the delivery of adrenergic receptor antagonists, which allows for size-based targeting of the injured blood–brain barrier (BBB). These nanoparticles consist of chitosan-coated polylactic co-glycolic acid encapsulating the β-adrenergic receptor antagonist propranolol and/or the α-adrenergic receptor antagonist phenoxybenzamine. Particles designed with a 200 nm hydrodynamic diameter showed a 20–24% increase in permeability on an in vitro contact co-culture BBB model exposed to a 23 or 35 PSI acoustic blast when compared to uninjured controls, whereas 100 nm particles show no difference, suggesting blast injury induces BBB damage that enables the accumulation of larger particles. Treatment of blast-injured human brain microvascular cells with our nanoformulation reduced extracellular inflammatory cytokine levels and reduced the expression of pro-inflammatory markers in microglia. Moreover, these particles mitigated the upregulation of extracellular TNFα induced by free phenoxybenzamine in injured and uninjured microglia, suggesting nanoparticle drug encapsulation can reduce adverse drug reactions in the brain. Together, these findings provide proof-of-concept for size-based targeting and the potential anti-inflammatory effects of CS-PLGA nanoparticles containing adrenergic receptor antagonists for treatment of TBI and bTBI.
Schmitt et al. (Mon,) studied this question.