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

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

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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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