# Matrix Regenerative Nanotherapeutics for Small Abdominal Aortic Aneurysm Repair

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $401,042

## Abstract

Abstract
Our objective is to investigate a new, minimally-invasive regenerative nanotherapy to arrest or regress
growth of small (<5.5 cm diameter) abdominal aortic aneurysms (AAAs). AAAs are localized expansions of the
abdominal aorta that ultimately rupture. Early surgery on small AAAs provides no treatment benefit and no
other proven therapies exist. While reinstating homeostasis of the structural extracellular matrix (ECM;
collagen and elastic fibers) in the AAA wall is critical to stop or reverse AAA growth, this is impeded by a) their
chronic breakdown in the aorta wall by upregulated matrix metalloprotease (MMPs) enzymes and b) lack of
approaches to overcome intrinsically deficient and defective elastic fiber regenerative repair by adult vascular
smooth muscle cells (SMCs). Oral dosing of doxycycline (DOX) has been shown to inhibit MMPs in the AAA
wall to slow AAA growth, but has systemic side effects and inhibits elastin biosynthesis at the high doses. To
avoid this, we have formulated biodegradable polylactic-co- glycolic acid (PLGA) nanoparticles (NPs) for
steady, sustained release of doxycycline (DOX), an MMP inhibitor within the AAA wall following one-time,
catheter-wise infusion to a transiently flow-occluded AAA segment. At the much lower release levels (<10
g/ml), DOX was found to maintain its MMP inhibitory effects, but also to beneficially stimulate elastic matrix
neoassembly (elastogenesis). We also uniquely surface-functionalized our NPs with cationic amphiphiles that
have pro-elastogenic & anti-proteolytic separate from the effects of the released DOX. Building on this
promising preliminary data, we now propose to confirm the signaling mechanisms underlying the unique pro-
matrix regenerative and anti-MMP effects of DOX at sub-oral doses, identify DOX-NP formulations that provide
a significant stimulus to biomimetic and stable elastic fiber assembly, design and test a magnetic guidance
system for efficient NP delivery to the AAA wall, and demonstrate efficacy of the DOX-NPs in regressing
already formed small AAAs in a preclinical (rat) model. Our aims will test hypotheses that 1) pro-elastogenic
effects of DOX are mediated by JNK decreases which trigger increases in TGF-1, 2) quantity and quality of
elastic fiber assembly can be regulated by modulating severity of JNK inhibition by DOX, 3) DOX is more
effective than SP600125 (at their IC50 doses for JNK) in stimulating elastin since it also directly inactivates
MMPs, and 4) regenerative stimuli due to DOX-NPs will restore matrix homeostasis in the AAA wall to arrest its
growth. Aim 1 will correlate severity of DOX inhibition of JNK to downstream elastogenesis and anti-MMP
outcomes in rat AAA SMC cultures. Aim 2 will generate DOX-NP formulations with superior pro-elastogenic &
matrix reparative properties. Aim 3 will develop a magnetic system to target DOX-NPs to the AAA wall in a rat
model. Aim 4 will assess therapeutic efficacy of magnetically-responsive DOX-NPs in rat AAAs...

## Key facts

- **NIH application ID:** 9839672
- **Project number:** 5R01HL139662-03
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** ANAND RAMAMURTHI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $401,042
- **Award type:** 5
- **Project period:** 2017-12-15 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9839672

## Citation

> US National Institutes of Health, RePORTER application 9839672, Matrix Regenerative Nanotherapeutics for Small Abdominal Aortic Aneurysm Repair (5R01HL139662-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9839672. Licensed CC0.

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