The development of a multifunctional nanoenzyme for AD treatment
用于AD治疗的多功能纳米酶的开发
基本信息
- 批准号:10611675
- 负责人:
- 金额:$ 29.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-30 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3xTg-AD mouseAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease therapeuticAlzheimer&aposs disease therapyAmyloid beta-ProteinAnimal ModelAntiinflammatory EffectAntioxidantsArea Under CurveAttenuatedBiological AssayBlood - brain barrier anatomyBrainCause of DeathClinical TrialsCyclic GMPDataDepositionDevelopmentDiseaseDoseDrug KineticsEngineeringExhibitsGlycolic-Lactic Acid PolyesterHalf-LifeHealthcareHumanIn VitroIndividualInductively Coupled Plasma Mass SpectrometryInflammationInflammatory ResponseInjectionsInvestigational DrugsInvestigational New Drug ApplicationLearningLigandsLinkMaintenanceMaximum Tolerated DoseMeasuresMemoryMetalsMicrogliaMissionMolecular TargetMusMutationNamesNeurofibrillary TanglesPathologicPharmaceutical PreparationsPhasePilot ProjectsPlayProcessPropertyReactive Oxygen SpeciesResearchRoleSafetySenile PlaquesSmall Business Technology Transfer ResearchSolubilitySuperoxide DismutaseSurveysSystemTechnologyTestingTherapeuticToxic effectToxicologyTransgenesUnited StatesUnited States National Institutes of Healthblood-brain barrier penetrationcatalasecatalystcerium oxide nanoparticleclinical applicationcostdesigndrug candidateefficacy studyimprovedinhibitormacromoleculemacrophagemorris water mazemouse modelnanoparticlenanoparticle deliveryneuroinflammationnovel therapeuticsoverexpressionoxidative damagepresenilin-1preventreceptor for advanced glycation endproductsreduce symptomssafety testingsmall moleculesuccesssystemic toxicitytargeted deliverytau Proteinstherapeutic evaluationtherapy developmenttoolβ-amyloid burden
项目摘要
Summary. The development of Alzheimer’s disease (AD) is the collective consequence of the toxicities induced
by β-amyloid (Aβ) plaques, tau protein-formed neurofibrillary tangles, and malfunction of microglia due to
inflammation and oxidative damage. Most AD therapeutics only target one of these key factors; the failed clinical
trials proved the insufficiency of these individual approaches. In addition, although many inhibitors of key
molecular targets in AD either exist or could be easily designed, 98% of small molecules and almost all
macromolecules cannot effectively pass through the blood-brain barrier (BBB). Thus, drugs capable of curing or
stably alleviating the symptoms of AD are still not available. Cerium oxide nanoparticles (CeNPs) act as a metal
catalyst, exhibiting both superoxide dismutase (SOD) and catalase (CAT) mimicking activities, which scavenges
noxious intracellular reactive oxygen species (ROS). Our preliminary study revealed that CeNPs show
outstanding antioxidant and anti-inflammatory effects. However, the clinical application of CeNPs is hindered by
its poor solubility and inability to cross the BBB. During neuroinflammation, the receptor for advanced glycation
endproducts (RAGE) is overexpressed on the BBB. Thus, the objective of this study is to develop an AD brain
targeted CeNP by utilizing the RAGE overexpression on the BBB and the bioactivities of CeNP. We developed
a CeNP-embedded Poly(lactide-co-glycolide) (PLGA) nanoparticle to overcome the pharmacokinetic limitation
of free CeNP and equipped it with a targeting ligand for the RAGE receptor to facilitate BBB penetration. Our
preliminary data demonstrates that this AD brain targeted-CeNP (T-CeNP) can effectively cross the BBB, quench
the elevated ROS, attenuate the activation of microglia, and reduce Aβ burden in the brain in an AD mouse
model. In this STTR Phase I proof-of-concept study, we will validate our hypothesis that our proprietary T-CeNP
can be developed as a novel therapy for AD through two specific aims. SA1: Evaluate the toxicity and
pharmacokinetic properties of T-CeNP in mice. The maximum tolerated dose (MTD) of T-CeNP will be first
determined in C57BL/6J mice; and then the pharmacokinetic properties of T-CeNP will be examined in the mice.
SA2: Test the therapeutic efficiency of the T-CeNP and evaluate its systemic toxicity in AD mouse models. Our
preliminary study showed efficacy of T-CeNP in a 5xFAD AD mouse model. To further validate if T-CeNP could
be used for AD treatment, we will evaluate the anti-inflammatory effects of the T-CeNP in a 3xTg-AD mouse
model, which displays all three pathological hallmarks of AD, assess the effect of T-CeNP in protecting learning
and memory of the mice using Morris water maze test and nest construction assay, and measure the systemic
toxicity. Upon completion of this Phase I project, we will start an IND-enabling STTR Phase II project to complete
more advanced toxicology and efficacy studies using large animal models of AD in a GLP setting and carry out
cGMP manufacturing of T-CeNP for human use. Our proprietary AD brain-targeted delivery technology can also
be used for the delivery of other agents that do not cross BBB but may be otherwise effective for AD treatment.
摘要阿尔茨海默病(AD)的发展是由其毒性引起的集体后果
β-淀粉样蛋白(Aβ)斑块,tau蛋白形成的神经元缠结,以及由于
炎症和氧化损伤。大多数AD治疗剂仅针对这些关键因素之一;失败的临床
试验证明了这些单独方法的不足。此外,尽管许多关键抑制剂
AD中的分子靶点要么存在,要么可以很容易地设计,98%的小分子和几乎所有
大分子不能有效地通过血脑屏障(BBB)。因此,能够治愈或
稳定缓解AD症状的药物仍然不存在。氧化铈纳米颗粒(CeNPs)作为金属
催化剂,表现出超氧化物歧化酶(SOD)和过氧化氢酶(CAT)模拟活性,其清除
有害的细胞内活性氧(ROS)。我们的初步研究表明,CeNPs显示,
具有显著的抗氧化和抗炎作用。然而,CeNPs的临床应用受到以下因素的阻碍:
其溶解性差且不能穿过BBB。在神经炎症过程中,晚期糖基化受体
终产物(endproducts,EDP)在BBB上过表达。因此,本研究的目的是开发AD脑
目的:利用CeNP在血脑屏障上的过表达和CeNP的生物学活性,我们开发
CeNP-embedded Poly(lactide-co-glycolide)(PLGA)nanoparticles to overcome the pharmacokinetic limitation
的游离CeNP,并为其配备了针对C3 H4受体的靶向配体以促进BBB穿透。我们
初步数据表明,这种AD脑靶向-CeNP(T-CeNP)可以有效地穿过BBB,淬灭
升高的ROS,减弱小胶质细胞的活化,并减少AD小鼠脑中的Aβ负荷
模型在这项STTR第一阶段概念验证研究中,我们将验证我们的假设,即我们专有的T-CeNP
可以通过两个特定的目的开发为AD的新疗法。SA 1:评价毒性和
图10示出了T-CeNP在小鼠中的药代动力学性质。T-CeNP的最大耐受剂量(MTD)将首先是
在C57 BL/6 J小鼠中测定T-CeNP的药代动力学性质;然后在小鼠中检查T-CeNP的药代动力学性质。
SA 2:在AD小鼠模型中测试T-CeNP的治疗效率并评估其全身毒性。我们
初步研究显示T-CeNP在5xFAD AD小鼠模型中的功效。为了进一步验证T-CeNP是否可以
为了用于AD治疗,我们将评估T-CeNP在3xTg-AD小鼠中的抗炎作用
显示AD的所有三个病理标志的模型评估了T-CeNP在保护学习方面的作用
采用Morris水迷宫实验和小鼠巢建造实验检测小鼠的学习记忆能力,并测定小鼠的系统记忆能力。
毒性在第一期工程完成后,我们会展开一项可供创新发展的短期信托基金第二期工程,
在GLP环境中使用大型AD动物模型进行更先进的毒理学和疗效研究,
人用T-CeNP的cGMP制造。我们专有的AD脑靶向给药技术还可以
可用于递送不穿过BBB但可能对AD治疗有效的其它药剂。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Peisheng Xu其他文献
Peisheng Xu的其他文献
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{{ truncateString('Peisheng Xu', 18)}}的其他基金
Cancer cell selective killing nanoparticle for advanced ovarian cancer treatment
癌细胞选择性杀伤纳米颗粒用于晚期卵巢癌治疗
- 批准号:
10680585 - 财政年份:2022
- 资助金额:
$ 29.96万 - 项目类别:
Cancer cell selective killing nanoparticle for advanced ovarian cancer treatment
癌细胞选择性杀伤纳米颗粒用于晚期卵巢癌治疗
- 批准号:
10453919 - 财政年份:2022
- 资助金额:
$ 29.96万 - 项目类别:
Brain targeted nanoparticle for Alzheimer's disease therapy
用于治疗阿尔茨海默病的脑靶向纳米颗粒
- 批准号:
9329544 - 财政年份:2017
- 资助金额:
$ 29.96万 - 项目类别:
Nano-cocktail overcomes multidrug-resistance for ovarian cancer therapy
纳米鸡尾酒克服了卵巢癌治疗的多重耐药性
- 批准号:
8958102 - 财政年份:2015
- 资助金额:
$ 29.96万 - 项目类别:
Dual responsive nanoparticle for brain targeted drug delivery
用于大脑靶向药物输送的双响应纳米颗粒
- 批准号:
8653312 - 财政年份:
- 资助金额:
$ 29.96万 - 项目类别:
Dual responsive nanoparticle for brain targeted drug delivery
用于大脑靶向药物输送的双响应纳米颗粒
- 批准号:
8885856 - 财政年份:
- 资助金额:
$ 29.96万 - 项目类别:
Dual responsive nanoparticle for brain targeted drug delivery
用于大脑靶向药物输送的双响应纳米颗粒
- 批准号:
9061734 - 财政年份:
- 资助金额:
$ 29.96万 - 项目类别: