Abstract Traumatic brain injury (TBI) afflicts over 1.7 million persons per year in the U.S. alone, resulting in substantial economic burden annually. To date, despite promising pre-clinical data, no new pharmacological strategies have demonstrated improved patient outcomes in a phase III clinical trial. One significant and often- overlooked pitfall of pharmacological strategies is the use of systemic administration of free drug, where toxic and/or negative side effects may limit the therapeutic threshold at tissue targets. Nanoparticles (NPs) have emerged as an ideal approach to address such drug delivery obstacles. Our long-term goal is to engineer NP delivery systems to improve outcomes in TBI. Here, we will focus on developing a mechanistic understanding of sex-dependent differences in pathophysiology that lead to altered NP delivery to the injured brain of male versus female mice. Our group recently demonstrated that a TBI provides a unique window to deliver NPs to the parenchyma within both of these BBB disruption events. We discovered a sex-dependent response in BBB disruption and subsequent NP delivery profiles, whereby the BBB of females remained open for longer and to a greater extent than males. There is limited understanding of how sex hormones influence TBI induced BBB disruption over the longer term and the potential impact it has on drug delivery. To address this unmet need, we will directly examine the influence of sex hormones on TBI pathophysiology and drug delivery, and we will develop new strategies for targeting sex-dependent injury microenvironments. Our studies will address both mechanistic and therapeutic goals, focusing on NPs composed of poly(lactic acid)-poly(ethylene glycol) (PLA- PEG) and loaded with the histone deacetylase inhibitor quisinostat, which we have already shown are neuroprotective following TBI in mice. We will leverage our existing experience with bacteriophage biopanning to identify sex-targeting ligands to enhance drug delivery to unique, hormone-dependent post injury microenvironments. We hypothesize that differences in NP delivery to male and female mice can be attributed to sex hormone-dependent contributions to TBI pathophysiology, and we predict that improving our understanding of these sex differences will enable us to design more effective NP delivery systems. We will probe this central hypothesis through the following specific aims: (1) Investigate the contribution of hormone mediated sex-dependent injury sequelae on BBB disruption and inflammation, (2) Establish the relationship between hormone mediated sex-dependent injury, drug delivery, and efficacy, and (3) Demonstrate feasibility of sex-specific targeting for NP and drug delivery to TBI. Impact from these studies includes deepened mechanistic understanding of sex-dependent responses to TBI with response to nanoparticle drug delivery, as well as the first exploration of sex-targeted drug delivery to the brain. This will contribute to a thorough understanding of the pathophysiology of TBI and more broadly the potential to exploit inherent biological complexities for developing NP-based drug delivery strategies in context of brain injury.

Project Narrative The proposed research is relevant to public health because it probes differential pathological response to traumatic brain injury based on sex and subsequent implications for neurotherapeutic interventions. This project is relevant to NIH’s mission as it focuses on biological considerations for improving treatment of traumatic brain injury, the leading cause of injury related death in America.