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
基本信息
- 批准号:10532166
- 负责人:
- 金额:$ 49.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAgingArtificial nanoparticlesBacteriophagesBioinformaticsBiologicalBlood - brain barrier anatomyBlood VesselsBrainBrain InjuriesCancer ModelCellsCentral Nervous SystemClinical PharmacologyComplexCytometryDataDepositionDiseaseDrug Delivery SystemsDrug KineticsDrug TargetingEconomic BurdenEncapsulatedEnvironmentEstrogensEventFemaleFunctional disorderGoalsGonadal Steroid HormonesHistone Deacetylase InhibitorHistonesHormonalHormonesHourImmuneInflammationInflammatoryInjuryInterventionLabelLigandsLoperamideMediatingMemoryMissionMusNervous System TraumaOutcomePathologicPathologyPatient-Focused OutcomesPersonsPharmaceutical PreparationsPhasePhase III Clinical TrialsProestrusProgesteronePublic HealthPublishingResearchRoleSex DifferencesShapesStrokeSubarachnoid HemorrhageSystemTBI treatmentTestingTherapeuticTight JunctionsTimeTissuesTranslatingTraumatic Brain InjuryTreatment EfficacyUnited States National Institutes of HealthWomen&aposs HealthWorkbiological sexblood-brain barrier disruptionblood-brain barrier permeabilizationbrain parenchymacandidate validationcentral nervous system injurycontrolled cortical impactdesigndigitaldrug distributionethylene glycolexperienceimprovedimproved outcomein vivoinhibitorinjuredinjury-related deathinnovationintravenous administrationintravital imagingmalemouse modelnanomedicinenanoparticlenanoparticle deliverynanoparticle drugneuroinflammationneuroprotectionnext generationnext generation sequencingnovelpharmacologicpoly(lactic acid)pre-clinicalresponseresponse to brain injuryresponse to injurysexside effecttargeted treatmenttherapeutic nanoparticlestranscriptome sequencingtwo photon microscopywater channel
项目摘要
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.
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输送系统。我们将
通过以下具体目标来探讨这一中心假设:(1)调查激素的贡献
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。
项目成果
期刊论文数量(0)
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Rachael W Sirianni其他文献
Rachael W Sirianni的其他文献
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{{ truncateString('Rachael W Sirianni', 18)}}的其他基金
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 - 财政年份:2021
- 资助金额:
$ 49.92万 - 项目类别:
Intrathecal delivery of radiation sensitizing nanoparticles in pediatric neuro-oncology
放射增敏纳米颗粒在儿科神经肿瘤学中的鞘内递送
- 批准号:
9811126 - 财政年份:2019
- 资助金额:
$ 49.92万 - 项目类别:
Targeting leptomeningeal metastasis in medulloblastoma
靶向髓母细胞瘤的软脑膜转移
- 批准号:
9917838 - 财政年份:2019
- 资助金额:
$ 49.92万 - 项目类别:
Intrathecal delivery of radiation sensitizing nanoparticles in pediatric neuro-oncology
放射增敏纳米颗粒在儿科神经肿瘤学中的鞘内递送
- 批准号:
10653853 - 财政年份:2019
- 资助金额:
$ 49.92万 - 项目类别:
Intrathecal delivery of radiation sensitizing nanoparticles in pediatric neuro-oncology
放射增敏纳米颗粒在儿科神经肿瘤学中的鞘内递送
- 批准号:
10200874 - 财政年份:2019
- 资助金额:
$ 49.92万 - 项目类别:
Targeting Leptomeningeal Metastasis in Medulloblastoma
靶向髓母细胞瘤的软脑膜转移
- 批准号:
10829143 - 财政年份:2019
- 资助金额:
$ 49.92万 - 项目类别:
Intrathecal delivery of radiation sensitizing nanoparticles in pediatric neuro-oncology
放射增敏纳米颗粒在儿科神经肿瘤学中的鞘内递送
- 批准号:
10755398 - 财政年份:2019
- 资助金额:
$ 49.92万 - 项目类别:
Targeting leptomeningeal metastasis in medulloblastoma
靶向髓母细胞瘤的软脑膜转移
- 批准号:
10595323 - 财政年份:2019
- 资助金额:
$ 49.92万 - 项目类别:
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