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.
总结。阿尔茨海默病(AD)的发展是毒性诱导的集体后果
项目成果
期刊论文数量(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:














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