# Dendrimer nanoparticles for assessment of microglial activation and therapeutic response to neonatal brain injury

> **NIH NIH F31** · UNIVERSITY OF WASHINGTON · 2020 · $42,171

## Abstract

Project Summary
Perinatal asphyxia (PA) is the leading cause of morbidity and mortality around the time of birth. In patients born
with PA, many develop moderate or severe hypoxic-ischemic encephalopathy (HIE) and 20 to 30% will develop
long term effects including cerebral palsy, epilepsy, mental retardation, or learning disability. PA is difficult to
prevent or predict, and the current treatment strategy of therapeutic hypothermia only offers a 15% absolute
reduction in the risk of death and disability. Thus, strategies to identify a therapeutic window or improve
therapeutic efficacy have significant clinical potential. Inflammation is implicated in the development of HIE and
is a useful therapeutic target since it broadly describes multiple pathways which perpetuate and increase the
severity of injury. In neuroinflammation, microglia, the resident immune cells of the brain, adopt an activated
phenotype with increased phagocytic behavior. Previous studies have leveraged this effect to demonstrate
increased small molecule, specifically dendrimer nanoparticle, uptake within microglia in injured tissue.
Accumulation of drug-loaded dendrimers in microglia, mediators of HIE injury, allows for targeted delivery of a
therapeutic payload. Curcumin, our proposed therapeutic, has been shown by our lab to have significant
neuroprotective effect in a rat model of neonatal HIE due to its anti-inflammatory and antioxidant properties. We
will formulate two dendrimer conjugates, a fluorescent Cy5-dendrimer particle and a drug loaded Cy5-dendrimer-
curcumin particle, using established chemistries. We will use Cy5-dendrimers to evaluate the timeline of
microglia activation in response to injury in the neonatal rat model, finding time points of peak microglial activation
by immunohistochemistry (semi-quantification based on phenotype and dendrimer-Cy5 co-localization) and
fluorescent activated cell sorting (quantification based on antibody expression and Cy5 fluorescence). Using
these same techniques, we will then evaluate microglial response to therapeutic dendrimer administration after
systemic injection of the curcumin-loaded conjugate. This project will provide key answers including (1) the ideal
time to provide therapeutic intervention after ischemic injury for suppression of inflammation, and (2) the ability
of anti-inflammatory therapeutics to reverse injury on a cellular level. The overall goal of this project is to
demonstrate the therapeutic potential of engineered dendrimer nanoparticles in neonatal HIE during a
determined optimal therapeutic window. Identifying the injury timeline and a nanoparticle platform to leverage
the disease pathophysiology will lead to improved therapeutic intervention in neonatal brain injury, with
implications that can be translated to adult neurological disorders, where inflammation also plays a critical role.

## Key facts

- **NIH application ID:** 9894818
- **Project number:** 5F31HD095572-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Andrea Joseph
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $42,171
- **Award type:** 5
- **Project period:** 2018-03-16 → 2021-03-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894818

## Citation

> US National Institutes of Health, RePORTER application 9894818, Dendrimer nanoparticles for assessment of microglial activation and therapeutic response to neonatal brain injury (5F31HD095572-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9894818. Licensed CC0.

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