Intra-articular Treatment of Osteoarthritis with Diclofenac-Conjugated Polymer Reduces Inflammation and Pain

Adrian Sulistio, Friederike M. Mansfeld, Felisa Reyes-Ortega, Asha M. D'Souza, Sarah M.Y. Ng, Stephen Birkett, Anton Blencowe, Greg G. Qiao, Christopher B. Little, Cindy C. Shu, Alison M. Bendele, David Valade, Andrew C. Donohue, John F. Quinn, Michael R. Whittaker, Thomas P. Davis, Russell J. Tait

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

The most common treatment for osteoarthritis is daily oral administration of a nonsteroidal anti-inflammatory drug such as diclofenac. This daily dosage regime is often associated with severe side effects. In this study, we explored the potential of utilizing a high molecular weight cross-linked polyurethane polymer covalently linked to diclofenac (C-DCF-PU) for intra-articular administration. We aim to exploit the advantages of local drug delivery by developing an implant with improved efficacy and reduced side effects. The polymer was synthesized from a diclofenac-functionalized monomer unit in a simple one-pot reaction, followed by cross-linking. In vitro drug release studies showed zero-order drug release for 4 days, followed by a gradual decline in drug release rate until diclofenac was depleted after 15 days. The cross-linked polymer was triturated to yield an injectable microgel formulation for administration. Whole animal fluorescence imaging of the rhodamine-labeled C-DCF-RH-PU showed good retention of the polymer in the knee joints of healthy rats, with approximately 30% of the injected dose still present 2 weeks post intra-articular administration. In a reactivation arthritis animal model, the C-DCF-RH-PU formulation reduced pain and significantly reduced inflammation after a short lag phase, showing that this drug delivery system warrants further development for long-term treatment of osteoarthritis with the benefit of reduced side effects.

Original languageEnglish
Pages (from-to)2822-2832
Number of pages11
JournalACS Applied Bio Materials
Volume2
Issue number7
DOIs
Publication statusPublished - 24 May 2019

Keywords

  • controlled drug release
  • intra-articular injection
  • local drug delivery
  • NSAID
  • osteoarthritis
  • polyurethane

Cite this

Sulistio, A., Mansfeld, F. M., Reyes-Ortega, F., D'Souza, A. M., Ng, S. M. Y., Birkett, S., ... Tait, R. J. (2019). Intra-articular Treatment of Osteoarthritis with Diclofenac-Conjugated Polymer Reduces Inflammation and Pain. ACS Applied Bio Materials, 2(7), 2822-2832. https://doi.org/10.1021/acsabm.9b00232
Sulistio, Adrian ; Mansfeld, Friederike M. ; Reyes-Ortega, Felisa ; D'Souza, Asha M. ; Ng, Sarah M.Y. ; Birkett, Stephen ; Blencowe, Anton ; Qiao, Greg G. ; Little, Christopher B. ; Shu, Cindy C. ; Bendele, Alison M. ; Valade, David ; Donohue, Andrew C. ; Quinn, John F. ; Whittaker, Michael R. ; Davis, Thomas P. ; Tait, Russell J. / Intra-articular Treatment of Osteoarthritis with Diclofenac-Conjugated Polymer Reduces Inflammation and Pain. In: ACS Applied Bio Materials. 2019 ; Vol. 2, No. 7. pp. 2822-2832.
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abstract = "The most common treatment for osteoarthritis is daily oral administration of a nonsteroidal anti-inflammatory drug such as diclofenac. This daily dosage regime is often associated with severe side effects. In this study, we explored the potential of utilizing a high molecular weight cross-linked polyurethane polymer covalently linked to diclofenac (C-DCF-PU) for intra-articular administration. We aim to exploit the advantages of local drug delivery by developing an implant with improved efficacy and reduced side effects. The polymer was synthesized from a diclofenac-functionalized monomer unit in a simple one-pot reaction, followed by cross-linking. In vitro drug release studies showed zero-order drug release for 4 days, followed by a gradual decline in drug release rate until diclofenac was depleted after 15 days. The cross-linked polymer was triturated to yield an injectable microgel formulation for administration. Whole animal fluorescence imaging of the rhodamine-labeled C-DCF-RH-PU showed good retention of the polymer in the knee joints of healthy rats, with approximately 30{\%} of the injected dose still present 2 weeks post intra-articular administration. In a reactivation arthritis animal model, the C-DCF-RH-PU formulation reduced pain and significantly reduced inflammation after a short lag phase, showing that this drug delivery system warrants further development for long-term treatment of osteoarthritis with the benefit of reduced side effects.",
keywords = "controlled drug release, intra-articular injection, local drug delivery, NSAID, osteoarthritis, polyurethane",
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Sulistio, A, Mansfeld, FM, Reyes-Ortega, F, D'Souza, AM, Ng, SMY, Birkett, S, Blencowe, A, Qiao, GG, Little, CB, Shu, CC, Bendele, AM, Valade, D, Donohue, AC, Quinn, JF, Whittaker, MR, Davis, TP & Tait, RJ 2019, 'Intra-articular Treatment of Osteoarthritis with Diclofenac-Conjugated Polymer Reduces Inflammation and Pain', ACS Applied Bio Materials, vol. 2, no. 7, pp. 2822-2832. https://doi.org/10.1021/acsabm.9b00232

Intra-articular Treatment of Osteoarthritis with Diclofenac-Conjugated Polymer Reduces Inflammation and Pain. / Sulistio, Adrian; Mansfeld, Friederike M.; Reyes-Ortega, Felisa; D'Souza, Asha M.; Ng, Sarah M.Y.; Birkett, Stephen; Blencowe, Anton; Qiao, Greg G.; Little, Christopher B.; Shu, Cindy C.; Bendele, Alison M.; Valade, David; Donohue, Andrew C.; Quinn, John F.; Whittaker, Michael R.; Davis, Thomas P.; Tait, Russell J.

In: ACS Applied Bio Materials, Vol. 2, No. 7, 24.05.2019, p. 2822-2832.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Ng, Sarah M.Y.

AU - Birkett, Stephen

AU - Blencowe, Anton

AU - Qiao, Greg G.

AU - Little, Christopher B.

AU - Shu, Cindy C.

AU - Bendele, Alison M.

AU - Valade, David

AU - Donohue, Andrew C.

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AU - Tait, Russell J.

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