# Local Control of endochondral ossification by retinoid-loaded nano-particles

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $356,024

## Abstract

The goal of this project is to develop a novel pharmacotherapeutic strategy for targeting the endochondral
ossification process with spatiotemporal control. Accurate regulation of endochondral ossification is essential for
musculoskeletal tissues. It govens normal skeletal formation and growth at childhood and is required for proper
skeleton function and musculoskleletal repair in adults. A variety of orthopaedic pathologies are caused by or
associated with impairment of systemic or local endochondral ossification. Fractures in the growth-plate (GP)
could attenuate endochondral ossification progress, resulting in stunted bone growth whereas diaphyseal
fractures in long bones provoke excessive bone growth, presumably due to regional activation of the GP function.
In either case, the serious imbalance in bone growth inevitably leads to progressive deformity and significant
physical problems. Heterotopic ossification (HO) is another pathological condition driven by ectopic induction of
abnormal endochondral ossification. Therapeutic management of the long bone growth and genetic HO requires
a long-term, site-specific treatment. Currently there is no drug that has shown adequate therapeutic effectiveness
with local administration. During the pre-clinical and clinical studies on the selective nuclear retinoid receptors
gamma agonist (RARγ agonist) for HO therapy, we have found that systemic administration of high doses of
RARγ agonists causes early closure of GP and inhibits consequent bone growth while RARγ antagonists
enhances cartilage growth and delay maturation of GP chondrocytes. These findings led us to hypothesize that
RARγ agonists/antagonists may have a marked therapeutic potential for the treatment of conditions involving
dysregulated endochondral ossification and bone growth. To this end, we designed nanoparticle (NP)
formulations providing controlled release of a potent RARγ agonist. Locally applied drug-loaded NPs showed
long retention in muscle and bone, releasing biologically activite RARγ agonist that strongly inhibited ectopic
bone formation and logitudinal growth of the targeted bone. Guided by our preliminary results, the current project
examines the central hypothesis that RAR γ-specific retinoids formulated in biodegradable nanoparticles
for site-specific delivery to the musculoskeletal tissues will effectively control longitudinal growth of the
targeted bone and inhibit HO. This hypothesis will be tested by pursuing two specific aims: Aim 1, To develop
and characterize the NP-based delivery system for RAR agonists and antagonists; and Aim 2, To determine
pharmacological and therapeutic efficacy of these retionid-NPs. The outcomes should provide proof-of-principle
for developing novel, nanocarrier-basede drug therapies for HO and for correcting bone growth imbalance that
pose an unmet need for new, safer and more effective, treatment strategies.

## Key facts

- **NIH application ID:** 9983594
- **Project number:** 5R01AR072713-03
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Michael Chorny
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $356,024
- **Award type:** 5
- **Project period:** 2018-09-07 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983594

## Citation

> US National Institutes of Health, RePORTER application 9983594, Local Control of endochondral ossification by retinoid-loaded nano-particles (5R01AR072713-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9983594. Licensed CC0.

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