# Nonaddictive opioid prodrug nanomedicine for musculoskeletal pain

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $464,079

## Abstract

ABSTRACT
 Musculoskeletal disorders are among the most common causes of acute and chronic pain. Extensive use
of opioids for these conditions has made a substantial contribution to the current opioid epidemic. There is an
urgent need to develop potent analgesics that are as effective as opioids but avoids the side effects, including
the risk of dependency and addiction. To address this challenge, we have developed a macromolecular prodrug
(P-HMP) of hydromorphone (HMP) based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers. When
HMP content increased to ³ 16 wt%, the aqueous solution of P-HMP becomes thermoresponsive and transitions
from a liquid at 4°C to a hydrogel at ³ 30°C. The hydrogel, which was designate as ProGel-HMP, allows the
sustained retention of the opioid prodrug at sites of pathology. When tested in the destabilization of the medial
meniscus (DMM) model of osteoarthritis (OA), ProGel-HMP provided potent and sustained (³ 16 days) pain relief
without spinal cord analgesia. Once locally administration, P-HMP slowly dissolves from ProGel-HMP and is
processed subcellularly by phagocytic cells to release HMP for sustained local pain relief. The P-HMP that is
not sequestered by cells drains into the circulation and rapidly clears via the kidney, effectively limiting systemic
exposure. Importantly, the absence of spinal cord analgesia, indicates that the thermoresponsive P-HMP does
not permeate the blood-brain or spinal cord barriers, which circumvents the risks of eliciting centrally mediated
drug-dependency and addiction associated with conventional opioids. Based on these preliminary findings, we
hypothesize that (1) that ProGel-HMP can provide sustained and effective local post-operative analgesia and
pain amelioration at sites of musculoskeletal trauma, independent of CNS-mediated effects; (2) that the
formulation parameters of ProGel-HMP can be modified to regulate the duration and efficacy of local analgesia
to meet the specific needs for pain management in different musculoskeletal conditions. To test these
hypotheses, we propose to first establish the dimensions within which the ProGel-HMP formulation parameters
can be adjusted to regulate the duration and efficacy of local analgesia (Aim 1). Three pain-causing conditions
will then be simulated in mice to allow in vivo assessment of ProGel-HMP. The DMM mice will be used to identify
optimal ProGel-HMP formulations for both short-term amelioration of post-operative pain and sustained
amelioration of chronic OA pain. In addition to testing efficacy and safety, pharmacokinetics/biodistribution
(PK/BD) and functional physiological studies will be performed to dissect ProGel-HMP’s mechanism of action
(Aim 2). The final studies will employ a murine closed fracture model to screen for an optimal ProGel-HMP
formulation that provides medium-term pain relief in skeletal trauma through the stages of tissue inflammation
and early skeletal repair. Efficacy, safety and mechanistic studie...

## Key facts

- **NIH application ID:** 10881885
- **Project number:** 5R01AR080500-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Dong Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $464,079
- **Award type:** 5
- **Project period:** 2022-09-07 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881885

## Citation

> US National Institutes of Health, RePORTER application 10881885, Nonaddictive opioid prodrug nanomedicine for musculoskeletal pain (5R01AR080500-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10881885. Licensed CC0.

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