Exploiting sex-dependent brain injury response for nanoparticle therapeutics

利用性别依赖性脑损伤反应进行纳米颗粒治疗

• 批准号: 10320959
• 负责人: Rachael W Sirianni
• 金额: $ 48.88万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10320959
• 关键词: Address; Aging; Americas; Artificial nanoparticles; Bacteriophages; Bioinformatics; Biological; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Injuries; Cancer Model; Cells; Clinical Data; Clinical Pharmacology; Complex; Cytometry; Data; Deposition; Disease; Distributional Activity; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Economic Burden; Encapsulated; Environment; Estrogens; Event; Female; Functional disorder; Goals; Gonadal Steroid Hormones; Histone Deacetylase Inhibitor; Histones; Hormonal; Hormones; Hour; Immune; Inflammation; Inflammatory; Injury; Intervention; Intravenous; Label; Lead; Ligands; Loperamide; Mediating; Memory; Mission; Mus; Nervous System Trauma; Neuraxis; Outcome; Pathologic; Pathology; Patient-Focused Outcomes; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phase III Clinical Trials; Proestrus; Progesterone; Public Health; Publishing; Research; Role; Sex Differences; Shapes; Stroke; Subarachnoid Hemorrhage; System; TBI treatment; Testing; Therapeutic; Tight Junctions; Time; Tissues; Translating; Traumatic Brain Injury; Treatment Efficacy; United States National Institutes of Health; Women' s Health; Work; base; biological sex; blood-brain barrier disruption; blood-brain barrier permeabilization; brain parenchyma; central nervous system injury; controlled cortical impact; design; digital; drug distribution; ethylene glycol; experience; improved; improved outcome; in vivo; inhibitor; injured; injury-related death; innovation; intravital imaging; male; mouse model; nanomedicine; nanoparticle; nanoparticle delivery; nanoparticle drug; neuroinflammation; next generation; next generation sequencing; novel; poly(lactic acid); pre-clinical; response; response to brain injury; response to injury; sex; side effect; targeted treatment; therapeutic nanoparticles; transcriptome sequencing; two photon microscopy; water channel

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.

抽象的 仅在美国，每年就有超过 170 万人遭受创伤性脑损伤 (TBI) 的折磨，导致 每年造成巨大的经济负担。迄今为止，尽管临床前数据有希望，但还没有新的药理学 在 III 期临床试验中，策略已证明可以改善患者的治疗结果。一个重要且经常发生的—— 药理学策略被忽视的陷阱是使用游离药物的全身给药，其中有毒 和/或负面副作用可能会限制组织靶点的治疗阈值。纳米颗粒 (NP) 具有 成为解决此类药物输送障碍的理想方法。我们的长期目标是设计 NP 改善 TBI 治疗效果的输送系统。在这里，我们将重点发展机械理解 病理生理学中的性别依赖性差异导致男性受损大脑的 NP 递送发生改变 与雌性小鼠相比。我们的小组最近证明，TBI 提供了一个独特的窗口来向 这两个 BBB 破坏事件中的实质。我们发现 BBB 存在性别依赖性反应 破坏和随后的 NP 传递曲线，从而使女性的 BBB 保持开放时间更长，并 程度比男性更大。对于性激素如何影响 TBI 诱导的 BBB 的了解有限 长期破坏及其对药物输送的潜在影响。为了解决这一未满足的需求， 我们将直接研究性激素对 TBI 病理生理学和药物输送的影响，并且我们将 制定针对性别依赖性损伤微环境的新策略。我们的研究将解决这两个问题 机制和治疗目标，重点关注由聚乳酸-聚乙二醇（PLA- PEG）并负载组蛋白脱乙酰酶抑制剂 quisinostat，我们已经证明了 小鼠 TBI 后的神经保护作用。我们将利用我们在噬菌体生物淘选方面的现有经验 识别性别靶向配体以增强药物递送到独特的、激素依赖性损伤后 微环境。我们假设雄性和雌性小鼠的 NP 递送差异可归因于 性激素依赖性对 TBI 病理生理学的贡献，我们预测，改善我们的 了解这些性别差异将使我们能够设计更有效的纳米粒子递送系统。我们将 通过以下具体目标探讨这一中心假设：（1）研究激素的贡献 介导的性别依赖性损伤后遗症对 BBB 破坏和炎症的影响，（2）建立关系 激素介导的性依赖性损伤、药物递送和疗效之间的关系，以及 (3) 证明可行性 NP 的性别特异性靶向和 TBI 的药物输送。这些研究的影响包括加深 对 TBI 性别依赖性反应和纳米颗粒药物递送反应的机制理解，如 以及首次探索将性别靶向药物输送到大脑。这将有助于彻底 了解 TBI 的病理生理学以及更广泛地利用固有生物学的潜力 在脑损伤的情况下开发基于 NP 的药物输送策略的复杂性。