OUSD (R&E) CRITICAL TECHNOLOGY AREA(S): Combat Casualty Care OBJECTIVE: To develop and validate a non-aggregating brain-targeted nanoparticle drug delivery platform for traumatic brain injury (TBI) capable of extended/sustained release of neuroprotective drug(s) to mitigate neuroinflammation, oxidative stress, and/or edema that can be safely administered to the injured Warfighter in far-forward and austere prolonged field care settings. DESCRIPTION: TBI is a significant health issue affecting military service members during both wartime and peacetime. To date, there are no FDA-approved pharmacological treatments available for TBI that are clinically effective. Moreover, there is a critical need for point-of-injury therapeutics capable of mitigating the acute neuropathological effects of TBI during future prolonged field care scenarios. On the battlefield, supportive measures prior to medical evacuation usually include hemorrhage control, restoration of blood pressure and tissue oxygenation through resuscitation, or control of intracranial hypertension with hypotonic saline. However, these measures require dedicated medical personnel and secure treatment settings, which are often not available during active combat and don't directly treat the brain injury. Development of evidence-based therapeutic products that can be safely administered by a Combat Medic/Corpsman and have the capability to reduce TBI morbidity and mortality during prolonged field and enroute care is essential to address this key gap in prehospital care for both military and civilian TBI casualties. Nanoparticle (NP) drug delivery platforms utilize precisely engineered nanoscale materials (200 nm or less) capable of bypassing the blood-brain barrier (BBB) and releasing their drug payload to specific neuronal cell types while minimizing potentially adverse systemic drug effects (Bharadwaj et al., 2018; Ribovski et al., 2021). Additionally, NP-mediated drug delivery platforms can provide controlled and sustained release of neuroprotective drug(s) directly to injured brain cell types which may facilitate neuroprotective outcomes during extended prehospital enroute care and prolonged field care which may range from 1 to more than 7 days in future combat scenarios (Natarajan et al., 2014; Bai et al., 2022). The desired end-product would be a stable, non-aggregating, portable, and potentially multi-drug capable NP platform that provides sustained delivery of FDA-approved drug(s) which have shown significant evidence of therapeutic benefit in the preclinical TBI literature. The developed product should target TBI patients presenting with moderate to severe TBI. The system should be designed to facilitate controlled and continuous release of individual or multiple neuroprotective agents, including but not limited to anti-inflammatory drugs to prevent cellular damage, brain swelling, and herniation and antioxidants to reduce oxidative stress and improve mitochondrial function. The release of drugs should be specific to brain cell types (e.g. neurons, astrocytes, oligodendrocytes, or other glial cells). PHASE I: Phase I will demonstrate the feasibility by providing a proof-of-concept of a safe nanoparticle drug delivery platform capable of delivering neuroprotective drug(s) over time in a tissue-specific manner for TBI. The proof-of-concept should explain the prototype development plan and provide in vitro data showing drug release rates of nanoparticle-encapsulated neuroprotective drug(s) to be tested in vivo during Phase II. Additional considerations for the prototype plan may include potential biophysical barriers which may limit biodistribution in the brain such as BBB, drug release kinetics of a range of drug concentrations, nanoparticle toxicity, encapsulation efficiency, and clearance. Animal subjects should not be used during Phase I. PHASE II: Phase II studies shall validate the proposed proof-of-concept plan from Phase I by completing pre-clinical in vivo exploratory studies in established small (i.e., rat) animal models of TBI to (1) demonstrate the safety of the nanoparticle product, (2) evaluate drug pharmacokinetics and pharmacodynamics (PK/PD) with nanoparticle-based drug delivery, and (3) demonstrate effective target engagement and therapeutic efficacy of the nanoparticle-drug(s) system for TBI. PK evaluation shall include drug bioavailability, half-life, stability, and clearance in brain tissue and blood/plasma. Drug candidates of interest include, but are not limited to, dexamethasone, memantine, simvastatin, bumetanide, and candesartan. Evaluation of blood-based TBI biomarkers and neuroimaging for advanced studies would be desirable. Preclinical evaluation is encouraged to include systems that deliver multiple drugs simultaneously. Phase II deliverables: 1. Technical data and results of experiments demonstrating safety, drug PK/PD in serum and drug PK in brain tissue, and therapeutic efficacy of candidate nanoparticle platform + drug formulation(s) in defined non-Good Laboratory Practice (GLP) small (e.g. rodent) animal models of TBI. 2. Plan for securing FDA approval/clearance. PHASE III DUAL USE APPLICATIONS: Phase III shall focus on transitioning the product from pre-clinical research, through FDA-regulated pathways, to operational capability. This period shall include confirmational testing in large animal models of TBI and securing an FDA application for Phase I (safety) clinical testing. The desired end-product should be suitable for use and procurement in austere battlefield/prehospital environments at role of care (ROC) 1 and 2 levels. During this phase, plans to conduct studies under a formally FDA-regulated framework for product safety and toxicity, PK/PD, optimal dosing concentration and administration regimen(s), release, and shelf-life stability should be formalized with appropriate statistical power for measuring therapeutic efficacy. Considerations at this phase should also include manufacturing readiness to support Phase II and III clinical trials, drug packaging and distribution partnerships, and a plan for scaling to GMP certified manufacturing partners if needed. During this phase, early interactions with the Defense Health Agency Advanced Development Program Management Office would ensure product alignment with military-relevant use requirements outlined in the current concepts of operations as well as establishing relations with respective Product Managers to facilitate communications with the TBI Drug Treatment (TBI-DT) Advanced Development Program. Additional funding may be solicited from the Congressional Directed Medical Research Program's (CDMRP) Joint Warfighter Medical Research Program (JWMRP) who support TBI-related military health efforts. TBI affect both military and civilian populations. Realization of dual-use technology applicable for both military and civilian sector stakeholders could be achieved by analysis for commercial viability for use in prehospital settings, to include first responders, paramedics, and ambulance transport, as well as hospital settings. REFERENCES: 1. Bharadwaj VN, Nguyen DT, Kodibagkar VD, Stabenfeldt SE. Nanoparticle-Based Therapeutics for Brain Injury. Adv Healthc Mater. 2018 Jan;7(1):10.1002/adhm.201700668. https://doi.org/10.1002/adhm.201700668 2. Ribovski L, Hamelmann NM, Paulusse JMJ. Polymeric Nanoparticles Properties and Brain Delivery. Pharmaceutics. 2021 Nov 30;13(12):2045. https://doi.org/10.3390/pharmaceutics13122045 3. Natarajan JV, Nugraha C, Ng XW, Venkatraman S. Sustained-release from nanocarriers: a review. J Control Release. 2014 Nov 10;193:122-38 https://doi.org/10.1016/j.jconrel.2014.05.029 4. Bai X, Smith ZL, Wang Y, Butterworth S, Tirella A. Sustained Drug Release from Smart Nanoparticles in Cancer Therapy: A Comprehensive Review. Micromachines (Basel). 2022 Sep 28;13(10):1623. https://doi.org/10.3390/mi13101623 KEYWORDS: Nanoparticles, drug delivery, traumatic brain injury, penetrating brain injury, extended drug release, TBI, skull fracture
