# The development of a multifunctional nanoenzyme for AD treatment

> **NIH NIH R41** · ACEPRE, LLC · 2022 · $299,628

## Abstract

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 mod...

## Key facts

- **NIH application ID:** 10611675
- **Project number:** 1R41AG081124-01
- **Recipient organization:** ACEPRE, LLC
- **Principal Investigator:** Peisheng Xu
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $299,628
- **Award type:** 1
- **Project period:** 2022-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10611675

## Citation

> US National Institutes of Health, RePORTER application 10611675, The development of a multifunctional nanoenzyme for AD treatment (1R41AG081124-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10611675. Licensed CC0.

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