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，每年的脑损伤（TBI）每年就会遭受超过170万人的困扰，导致 每年实质性的经济负担。迄今为止，尽管有希望的临床前数据，但没有新的药理学 在III期临床试验中，策略表明患者的结局得到改善。一个重要且经常 - 药理学策略的陷阱被忽视的是使用全身性给予免费药物的使用 和/或负副作用可能会限制组织目标的治疗阈值。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 交付系统以改善TBI的结果。在这里，我们将专注于建立机械理解 性别依赖性的病理生理学差异导致NP递送到男性受伤的大脑的改变 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，可以将NP传递给 这两个BBB中断事件中的实质。我们在BBB中发现了性别依赖性响应 破坏和随后的NP交付概况，因此，女性的BBB持续更长的时间，并且 比男性更大。对性激素如何影响TBI引起的BBB的了解有限 从长远来看，它对药物输送的潜在影响。为了满足这种未满足的需求， 我们将直接研究性激素对TBI病理生理学和药物递送的影响，我们将 制定针对性依赖性损伤微环境的新策略。我们的研究将解决这两个 机械和治疗目标，重点是由聚（乳酸） - 聚乙二醇（乙二醇）（pla-）组成的NP 钉）并带有组蛋白脱乙酰基酶抑制剂quisinostat，我们已经显示为 小鼠TBI后的神经保护作用。我们将利用我们现有的噬菌体生物植物的经验 识别靶向性别的配体，以增强药物输送到独特的激素依赖性后伤害后 微环境。我们假设可以归因于男性和雌性小鼠的NP递送的差异 性激素依赖性对TBI病理生理学的贡献，我们预计改善我们的 了解这些性别差异将使我们能够设计更有效的NP输送系统。我们将 通过以下特定目的探究此中心假设：（1）研究激素的贡献 介导的性别依赖性损伤后遗症在BBB中断和炎症中，（2）建立关系 激素介导的性依赖性损伤，药物输送和功效之间，（3）证明了可行性 针对NP的性别特异性靶向和药物输送到TBI的靶向。这些研究的影响包括加深 对纳米颗粒药物递送的反应对性别依赖性反应的机械理解，如 以及第一次探索以性别为目标的药物向大脑输送。这将有助于彻底 了解TBI的病理生理学，更广泛地利用固有生物学的潜力 在脑损伤的背景下制定基于NP的药物输送策略的复杂性。