# The Conundrum of Absentee Receptors: Efficacy Potentiation Through Drug-Receptor Modulation

> **NIH NIH R01** · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · 2024 · $628,970

## Abstract

PROJECT SUMMARY/ABSTRACT
This proposal outlines an advanced drug delivery methodology, argues for the power of biotherapeutics, and
demonstrates increased biotherapeutic efficacy through receptor upregulation. The benefit of specificity that is
inherent to targeted biotherapeutics comes at the cost of predicated efficacy based on the cognate receptor
being present at a high enough density to achieve a therapeutic effect. Current advances in delivery systems
are enabling localized and prolonged drug release. However, localization is only one component of effective drug
administration. Here, we propose an advanced drug delivery system, rationally designed to potentiate drug
activity while simultaneously localizing and prolonging biotherapeutic concentration. As a clinically relevant
example, this proposal outlines the coordinated localization and potentiation of the natural antifibrotic peptide
hormone, relaxin-2 (RLX), and its receptor, RXFP1, to both treat the underlying causes of shoulder contracture
and to restore joint range of motion. RLX remodels extracellular matrix (ECM) proteins via upregulating matrix
metalloproteases (MMPs) and decreasing collagen levels. We recently made the exciting discovery that
dexamethasone (DEX) increases RXFP1 expression in fibrotic synoviocytes and further exploration of the
molecular mechanism of actions of RLX and DEX will enhance rational drug design. We will test the hypothesis
that co-administration of RLX and DEX from polymeric microparticles (MPs) via a local single intraarticular (IA)
injection into the synovial space, will rapidly alleviate arthrofibrosis symptoms (increased joint stiffness and
decreased range of motion, ROM) and reduce fibrotic tissue accumulation in the afflicted joint. Further, DEX
potentiation of RLX’s antifibrotic activity will decrease the minimum effective dose and increase recovery rate by
modulating RXFP1 receptor density. Successful completion of this proposal will provide a novel treatment for
arthrofibrosis, a debilitating condition which affects more than 15 million people in the United States, and
demonstrate the importance of both delivering a biotherapeutic while also increasing the target receptor density
to maximize efficacy. Importantly, significant preliminary data support the proposed studies, well-characterized
materials and rigorous experimental designs are established, and essential cross-disciplinary collaborations and
expertise are in place to address these hypotheses. The specific aims of this five-year proposal are as follows.
Aim 1 determines RLX’s ligand-receptor binding mechanics and the novel role of TGF-β1 and DEX in regulating
RXFP1 expression, as well as RLX’s antifibrotic mechanism of action. Aim 2 identifies the material property
characteristics of biodegradable and biocompatible polymeric MPs loaded with either DEX or RLX. Aim 3
evaluates the pharmacokinetics and efficacy of the optimal DEX MP + RLX MP codelivery formulation cocktail
identified in ...

## Key facts

- **NIH application ID:** 10894132
- **Project number:** 5R01AR081264-03
- **Recipient organization:** BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
- **Principal Investigator:** MARK W. GRINSTAFF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $628,970
- **Award type:** 5
- **Project period:** 2022-09-21 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894132

## Citation

> US National Institutes of Health, RePORTER application 10894132, The Conundrum of Absentee Receptors: Efficacy Potentiation Through Drug-Receptor Modulation (5R01AR081264-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10894132. Licensed CC0.

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