Exploiting sex-dependent brain injury response for nanoparticle therapeutics

摘要 创伤性脑损伤（TBI）仅在美国每年就折磨超过170万人， 每年的经济负担。到目前为止，尽管有前景的临床前数据，没有新的药理学 这些策略在III期临床试验中显示出改善的患者结果。一个重要的和经常- 药理学策略的一个被忽视的陷阱是使用游离药物的全身给药， 和/或负面副作用可能限制组织靶点的治疗阈值。纳米颗粒（NPs） 成为解决此类药物递送障碍的理想方法。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，我们将重点放在发展一个机械的理解， 病理生理学中的性别依赖性差异导致NP向男性受损脑的递送改变， 对比雌性小鼠。我们的团队最近证明，TBI提供了一个独特的窗口，将NP输送到 这两种BBB破坏事件中的实质。我们在血脑屏障中发现了一种性别依赖的反应， 破坏和随后的NP递送概况，由此女性的BBB保持开放更长时间， 比男性更严重。性激素如何影响TBI诱导的血脑屏障， 长期中断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创伤性脑损伤病理生理学和药物输送的影响， 开发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）（PLA- PEG）并装载有组蛋白脱乙酰酶抑制剂quisinostat，我们已经证明， 在小鼠TBI后的神经保护作用。我们将利用我们现有的噬菌体生物淘选经验 鉴定性别靶向配体，以增强药物递送至独特的、依赖性的损伤后 微环境我们假设，NP传递到雄性和雌性小鼠的差异可以归因于 性别依赖性对TBI病理生理学的贡献，我们预测，提高我们的 了解这些性别差异将使我们能够设计更有效的NP给药系统。我们将 本研究通过以下几个方面对这一中心假说进行了探讨：（1）研究激素在细胞内的作用 介导的性别依赖性损伤后遗症对血脑屏障破坏和炎症的影响，（2）建立 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 性特异性靶向NP和药物递送至TBI。这些研究的影响包括深化 对TBI的性别依赖性反应与对纳米颗粒药物递送的反应的机制理解， 也是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，更广泛地说， 在脑损伤的背景下开发基于NP的药物递送策略的复杂性。

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.