Exploiting sex-dependent brain injury response for nanoparticle therapeutics

摘要 仅在美国，每年就有超过170万人受到创伤性脑损伤(TBI)的困扰，导致 每年都有相当大的经济负担。到目前为止，尽管临床前数据很有希望，但没有新的药理作用 在III期临床试验中，这些策略已经证明改善了患者的结果。一个重要的，而且经常是- 被忽视的药理策略的陷阱是使用系统的免费药物，在那里有毒性 和/或负面副作用可能会限制组织靶点的治疗阈值。纳米粒子(NP)具有 这是一种解决这种药物输送障碍的理想方法。我们的长期目标是设计NP 提供系统，以改善TBI的结果。在这里，我们将重点发展一种机械性的理解 性别相关的病理生理学差异导致男性受损脑内NP递送的改变 对雌性老鼠。我们的团队最近证明，TBI提供了一个独特的窗口来将NP交付给 这两个血脑屏障中断事件中的实质。我们在血脑屏障中发现了一种性别依赖性反应 中断和随后的NP递送情况，从而使女性的血脑屏障保持更长时间的开放和 比男性的程度更大。关于性激素如何影响脑外伤后血脑屏障的认识还很有限。 更长期的干扰及其对药物输送的潜在影响。为了解决这一未得到满足的需求， 我们将直接研究性激素对脑外伤病理生理学和药物释放的影响，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，重点是由聚乳酸-聚乙二醇组分组成的纳米粒子。 Peg)和负载组蛋白去乙酰酶抑制剂quisinostat，我们已经展示了它是 小鼠脑外伤后的神经保护作用。我们将利用我们现有的噬菌体生物筛选经验 确定性靶向配体以加强对独特的激素依赖损伤后的药物输送 微环境。我们假设，雄性和雌性小鼠体内NP传递的差异可以归因于 性激素依赖对脑损伤病理生理学的贡献，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NP递送系统。我们会 通过以下具体目标探讨这一中心假设：(1)调查激素的贡献 介导性依赖损伤后遗症对血脑屏障破坏和炎症的影响，(2)建立关系 激素介导性依赖损伤、药物传递和疗效之间的关系，以及(3)论证了可行性 针对NP的特定性别靶向和对脑外伤的药物输送。这些研究的影响包括深化 从机制上理解脑外伤后性别依赖性反应与纳米粒药物传递的反应，如 这也是首次探索将性靶向药物输送到大脑。这将有助于彻底的 了解颅脑损伤的病理生理学，以及更广泛地挖掘内在生物学的潜力 在脑损伤的背景下开发基于NP的药物传递策略的复杂性。

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.