The Development of a Macromolecular Analgesic for Arthritic Pain

Laura Weber, Xiaobei Wang, Rongguo Ren, Xin Wei, Gang Zhao, Junxiao Yang, Hongjiang Yuan, Huiling Pang, Hanjun Wang, Dong Wang

Research output: Contribution to journalArticle

Abstract

The addictive potential of clinically used opioids as a result of their direct action on the dopaminergic reward system in the brain has limited their application. In an attempt to reduce negative side effects as well as to improve the overall effectiveness of these analgesics, we have designed, synthesized, and evaluated an N-(2-hydroxypropyl)methacrylamide (HPMA)-based macromolecular prodrug of hydromorphone (HMP), a commonly used opioid. To this end, P-HMP was synthesized via RAFT polymerization and a subsequent polymer analogous reaction. Its interaction with inflammatory cells in arthritic joints was evaluated in vitro using a RAW 264.7 cell culture, and subsequent confocal microscopy analysis confirmed that P-HMP could be internalized by the cells via endocytosis. In vivo imaging studies indicated that the prodrug can passively target the arthritic joint after systemic administration in a rodent model of monoarticular adjuvant-induced arthritis (MAA). The inflammatory pain-alleviating properties of the prodrug were assessed in MAA rats using the incapacitance test and were observed to be similar to dose-equivalent HMP. Analgesia through mechanisms at the spinal cord level was further measured using the tail flick test, and it was determined that the prodrug significantly reduced spinal cord analgesia versus free HMP, further validating the peripheral restriction of the macromolecular prodrug. Immunohistochemical analysis of cellular uptake of the P-HMP within the MAA knee joint proved the internalization of the prodrug by phagocytic synoviocytes, colocalized with HMP's target receptor as well as with pain-modulating ion channels. Therefore, it can be concluded that the novel inflammation-targeting polymeric prodrug of HMP (P-HMP) has the potential to be developed as an effective and safe analgesic agent for musculoskeletal pain.

Original languageEnglish (US)
Pages (from-to)1234-1244
Number of pages11
JournalMolecular Pharmaceutics
Volume16
Issue number3
DOIs
StatePublished - Mar 4 2019

Fingerprint

Prodrugs
Arthritis
Analgesics
Pain
Hydromorphone
Experimental Arthritis
Analgesia
Opioid Analgesics
Spinal Cord
Joints
Musculoskeletal Pain
Knee Joint
Endocytosis
Reward
Ion Channels
Confocal Microscopy
Polymerization
Tail
Rodentia
Polymers

Keywords

  • ELVIS mechanism
  • HPMA copolymer
  • analgesic
  • opioid
  • rheumatoid arthritis

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

The Development of a Macromolecular Analgesic for Arthritic Pain. / Weber, Laura; Wang, Xiaobei; Ren, Rongguo; Wei, Xin; Zhao, Gang; Yang, Junxiao; Yuan, Hongjiang; Pang, Huiling; Wang, Hanjun; Wang, Dong.

In: Molecular Pharmaceutics, Vol. 16, No. 3, 04.03.2019, p. 1234-1244.

Research output: Contribution to journalArticle

Weber, Laura ; Wang, Xiaobei ; Ren, Rongguo ; Wei, Xin ; Zhao, Gang ; Yang, Junxiao ; Yuan, Hongjiang ; Pang, Huiling ; Wang, Hanjun ; Wang, Dong. / The Development of a Macromolecular Analgesic for Arthritic Pain. In: Molecular Pharmaceutics. 2019 ; Vol. 16, No. 3. pp. 1234-1244.
@article{0370ed65e8474a5aade58885b18efaff,
title = "The Development of a Macromolecular Analgesic for Arthritic Pain",
abstract = "The addictive potential of clinically used opioids as a result of their direct action on the dopaminergic reward system in the brain has limited their application. In an attempt to reduce negative side effects as well as to improve the overall effectiveness of these analgesics, we have designed, synthesized, and evaluated an N-(2-hydroxypropyl)methacrylamide (HPMA)-based macromolecular prodrug of hydromorphone (HMP), a commonly used opioid. To this end, P-HMP was synthesized via RAFT polymerization and a subsequent polymer analogous reaction. Its interaction with inflammatory cells in arthritic joints was evaluated in vitro using a RAW 264.7 cell culture, and subsequent confocal microscopy analysis confirmed that P-HMP could be internalized by the cells via endocytosis. In vivo imaging studies indicated that the prodrug can passively target the arthritic joint after systemic administration in a rodent model of monoarticular adjuvant-induced arthritis (MAA). The inflammatory pain-alleviating properties of the prodrug were assessed in MAA rats using the incapacitance test and were observed to be similar to dose-equivalent HMP. Analgesia through mechanisms at the spinal cord level was further measured using the tail flick test, and it was determined that the prodrug significantly reduced spinal cord analgesia versus free HMP, further validating the peripheral restriction of the macromolecular prodrug. Immunohistochemical analysis of cellular uptake of the P-HMP within the MAA knee joint proved the internalization of the prodrug by phagocytic synoviocytes, colocalized with HMP's target receptor as well as with pain-modulating ion channels. Therefore, it can be concluded that the novel inflammation-targeting polymeric prodrug of HMP (P-HMP) has the potential to be developed as an effective and safe analgesic agent for musculoskeletal pain.",
keywords = "ELVIS mechanism, HPMA copolymer, analgesic, opioid, rheumatoid arthritis",
author = "Laura Weber and Xiaobei Wang and Rongguo Ren and Xin Wei and Gang Zhao and Junxiao Yang and Hongjiang Yuan and Huiling Pang and Hanjun Wang and Dong Wang",
year = "2019",
month = "3",
day = "4",
doi = "10.1021/acs.molpharmaceut.8b01197",
language = "English (US)",
volume = "16",
pages = "1234--1244",
journal = "Molecular Pharmaceutics",
issn = "1543-8384",
publisher = "American Chemical Society",
number = "3",

}

TY - JOUR

T1 - The Development of a Macromolecular Analgesic for Arthritic Pain

AU - Weber, Laura

AU - Wang, Xiaobei

AU - Ren, Rongguo

AU - Wei, Xin

AU - Zhao, Gang

AU - Yang, Junxiao

AU - Yuan, Hongjiang

AU - Pang, Huiling

AU - Wang, Hanjun

AU - Wang, Dong

PY - 2019/3/4

Y1 - 2019/3/4

N2 - The addictive potential of clinically used opioids as a result of their direct action on the dopaminergic reward system in the brain has limited their application. In an attempt to reduce negative side effects as well as to improve the overall effectiveness of these analgesics, we have designed, synthesized, and evaluated an N-(2-hydroxypropyl)methacrylamide (HPMA)-based macromolecular prodrug of hydromorphone (HMP), a commonly used opioid. To this end, P-HMP was synthesized via RAFT polymerization and a subsequent polymer analogous reaction. Its interaction with inflammatory cells in arthritic joints was evaluated in vitro using a RAW 264.7 cell culture, and subsequent confocal microscopy analysis confirmed that P-HMP could be internalized by the cells via endocytosis. In vivo imaging studies indicated that the prodrug can passively target the arthritic joint after systemic administration in a rodent model of monoarticular adjuvant-induced arthritis (MAA). The inflammatory pain-alleviating properties of the prodrug were assessed in MAA rats using the incapacitance test and were observed to be similar to dose-equivalent HMP. Analgesia through mechanisms at the spinal cord level was further measured using the tail flick test, and it was determined that the prodrug significantly reduced spinal cord analgesia versus free HMP, further validating the peripheral restriction of the macromolecular prodrug. Immunohistochemical analysis of cellular uptake of the P-HMP within the MAA knee joint proved the internalization of the prodrug by phagocytic synoviocytes, colocalized with HMP's target receptor as well as with pain-modulating ion channels. Therefore, it can be concluded that the novel inflammation-targeting polymeric prodrug of HMP (P-HMP) has the potential to be developed as an effective and safe analgesic agent for musculoskeletal pain.

AB - The addictive potential of clinically used opioids as a result of their direct action on the dopaminergic reward system in the brain has limited their application. In an attempt to reduce negative side effects as well as to improve the overall effectiveness of these analgesics, we have designed, synthesized, and evaluated an N-(2-hydroxypropyl)methacrylamide (HPMA)-based macromolecular prodrug of hydromorphone (HMP), a commonly used opioid. To this end, P-HMP was synthesized via RAFT polymerization and a subsequent polymer analogous reaction. Its interaction with inflammatory cells in arthritic joints was evaluated in vitro using a RAW 264.7 cell culture, and subsequent confocal microscopy analysis confirmed that P-HMP could be internalized by the cells via endocytosis. In vivo imaging studies indicated that the prodrug can passively target the arthritic joint after systemic administration in a rodent model of monoarticular adjuvant-induced arthritis (MAA). The inflammatory pain-alleviating properties of the prodrug were assessed in MAA rats using the incapacitance test and were observed to be similar to dose-equivalent HMP. Analgesia through mechanisms at the spinal cord level was further measured using the tail flick test, and it was determined that the prodrug significantly reduced spinal cord analgesia versus free HMP, further validating the peripheral restriction of the macromolecular prodrug. Immunohistochemical analysis of cellular uptake of the P-HMP within the MAA knee joint proved the internalization of the prodrug by phagocytic synoviocytes, colocalized with HMP's target receptor as well as with pain-modulating ion channels. Therefore, it can be concluded that the novel inflammation-targeting polymeric prodrug of HMP (P-HMP) has the potential to be developed as an effective and safe analgesic agent for musculoskeletal pain.

KW - ELVIS mechanism

KW - HPMA copolymer

KW - analgesic

KW - opioid

KW - rheumatoid arthritis

UR - http://www.scopus.com/inward/record.url?scp=85061918831&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061918831&partnerID=8YFLogxK

U2 - 10.1021/acs.molpharmaceut.8b01197

DO - 10.1021/acs.molpharmaceut.8b01197

M3 - Article

C2 - 30702897

AN - SCOPUS:85061918831

VL - 16

SP - 1234

EP - 1244

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 3

ER -