# Intra-Articular Delivery of Sustained Release NF-kB Antagonists in Arthritis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $337,656

## Abstract

Injury or trauma to the knee, hip, or ankle is a well-documented contributor to premature onset of joint
degeneration and osteoarthritis (OA). Nuclear factor kappa B (NF-B) is a transcription factor that has early
involvement in post-traumatic OA by activating genes involved in extracellular matrix catabolism and joint
inflammation. Increased NF-B activity has also been implicated in the development of pain following joint injury
and other musculoskeletal pathologies. Despite the availability of numerous compounds that inhibit NF-B,
pharmacologic inhibition of NF-B via systemic administration or even local delivery to the joint has not been
successful in the treatment of OA. We hypothesize that intra-articular delivery of NF-B antagonists from
a safe, sustained-release carrier (silk) will have value in attenuating pain related sensitivities, joint
dysfunction, and progressive joint pathology in a non-surgical, intra-articular fracture model of OA. We
have previously identified a strong correlation between NF-B activity and pain-related sensitivity in a model of
inflammatory joint injury using the NF-B-luciferase reporter mouse. Here, we will similarly track NF-B activity,
but in a mouse model of closed tibial fracture as a non-surgical model of joint injury which is known to progress
to OA. In Specific Aim 1, we will evaluate the temporal and spatial development of NF-B activity, pain-
related sensitivities, and joint dysfunction in mice following intra-articular fracture out to 8 weeks. We will
identify relationships between systemic and local NF-B activation, patterns for sensitivity, gait and weight-
bearing, and arthritis progression following joint fracture. Results will identify “therapeutic windows” for timing of
intra-articular drug delivery in Specific Aim 3. In Specific Aim 2, we will optimize silk fibroin microparticle
depots for sustained release of two small molecule NF-B inhibitors, SC-514 or PHA-408. We have
previously demonstrated increased residence times for silk fibroin microparticles when delivered to the joint
space, but have not incorporated a drug for sustained release. Silk fibroin microparticles (10-60 microns) will be
fabricated specific to each NF-B inhibitor, and tested to verify high drug loading and sustained release out to 4
weeks. In Specific Aim 3, we will evaluate if a single, intra-articular injection of SC-514 or PHA-408-loaded
silk fibroin microparticles can attenuate NF-B activation, pain-related sensitivities, joint dysfunction,
and joint pathology after intra-articular fracture. Intra-articular injections of drug-loaded microparticles will
be administered to the injured limb at either early or late times after injury, with longitudinal monitoring of effects
on NF-B activation, pain-related sensitivities, joint dysfunction and arthritis development. Results will reveal
whether either compound, and at which time, can modulate defined outcome measures of arthritis symptoms
and/or pathology progre...

## Key facts

- **NIH application ID:** 9848501
- **Project number:** 5R01AR070975-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Lori A. Setton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $337,656
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9848501

## Citation

> US National Institutes of Health, RePORTER application 9848501, Intra-Articular Delivery of Sustained Release NF-kB Antagonists in Arthritis (5R01AR070975-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9848501. Licensed CC0.

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