Skip to main content

Advertisement

SpringerLink
Log in

The Evaluation of the Therapeutic Efficacy and Side Effects of a Macromolecular Dexamethasone Prodrug in the Collagen-Induced Arthritis Mouse Model

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To investigate the efficacy and safety of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex) in the collagen-induced arthritis (CIA) mouse model.

Methods

HPMA copolymer labeled with a near infrared fluorescence (NIRF) dye was administered to mice with CIA to validate its passive targeting to inflamed joints and utility as a drug carrier system. The CIA mice were treated with P-Dex, dexamethasone (Dex) or saline and the therapeutic efficacy and skeletal toxicity evaluated using clinical scoring and micro-computed tomography (μ-CT).

Results

The NIRF signal of the HPMA copolymer localized to arthritic joints consistent with its passive targeting to sites of inflammation. While the CIA mice responded more rapidly to P-Dex compared to Dex, the final clinical score and endpoint μ-CT analyses of localized bone erosions indicated that both single dose P-Dex and dose equivalent daily Dex led to comparable clinical efficacy after 30 days. μ-CT analysis of the proximal tibial metaphyses showed that P-Dex treatment was associated with significantly higher BMD and BV/TV compared to Dex and the saline control, consistent with reduced glucocorticoid (GC) skeletal toxicity.

Conclusion

These results validate the therapeutic efficacy of P-Dex in the CIA mouse model. P-Dex treatment averted the adverse effects of GC’s on systemic bone loss, supporting its utility in clinical development for the management of rheumatoid arthritis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

AA:

Adjuvant-induced arthritis

AIBN:

2,2’-Azobisisobutyronitrile

BMD:

Bone mineral density

BS/TV:

Bone surface to tissue volume or bone surface density

BV/TV:

Bone volume to tissue volume or bone volume density

CIA:

Collagen-induced arthritis

Dex:

Dexamethasone

DIPEA:

N,N-Diisopropylethylamine

DMF:

Dimethylformamide

ELVIS:

Extravasation through leaky vasculature and inflammatory cell-mediated sequestration

GC:

Glucocorticoid

HPMA:

N-(2-hydroxypropyl) methacrylamide

MA-Dex:

N-methacryloylglycylglycylhydrazyl dexamethasone

Mw :

Weight average molecular weight

NIRF:

Near infrared fluorescence

NS:

Non-significant

P-Dex:

Dexamethasone prodrug based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer

PDI:

Polydispersity index

PTM:

Proximal tibial metaphysis

RA:

Rheumatoid arthritis

RAFT:

Reversible addition-fragmentation chain transfer

ROI:

Region of interest

Tb.Sp:

Trabecular separation

Th.N:

Trabecular number

VOI:

Volume of interest

References

  1. Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet. 2009;373(9664):659–72.

    Article  PubMed  CAS  Google Scholar 

  2. van Vollenhoven RF. Treatment of rheumatoid arthritis: state of the art 2009. Nat Rev Rheumatol. 2009;5(10):531–41.

    Article  PubMed  Google Scholar 

  3. Hoes JN, Jacobs JW, Buttgereit F, Bijlsma JW. Current view of glucocorticoid co-therapy with DMARDs in rheumatoid arthritis. Nat Rev Rheumatol. 2010;6(12):693–702.

    Article  PubMed  CAS  Google Scholar 

  4. Wang D, Miller SC, Liu XM, Anderson B, Wang XS, Goldring SR. Novel dexamethasone-HPMA copolymer conjugate and its potential application in treatment of rheumatoid arthritis. Arthritis Res Ther. 2007;9(1):R2.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Liu XM, Quan LD, Tian J, Alnouti Y, Fu K, Thiele GM, et al. Synthesis and evaluation of a well-defined HPMA copolymer-dexamethasone conjugate for effective treatment of rheumatoid arthritis. Pharm Res. 2008;25(12):2910–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Quan LD, Purdue PE, Liu XM, Boska MD, Lele SM, Thiele GM, et al. Development of a macromolecular prodrug for the treatment of inflammatory arthritis: mechanisms involved in arthrotropism and sustained therapeutic efficacy. Arthritis Res Ther. 2010;12(5):R170.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Waksman BH. Immune regulation in adjuvant disease and other arthritis models: relevance to pathogenesis of chronic arthritis. Scand J Immunol. 2002;56(1):12–34.

    Article  PubMed  CAS  Google Scholar 

  8. Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, et al. Bone histomorphometry: standardization of nomenclature, symbols, and units. J Bone Miner Res. 1987;2(6):595–610.

    Article  PubMed  CAS  Google Scholar 

  9. Brand DD, Latham KA, Rosloniec EF. Collagen-induced arthritis. Nat Protoc. 2007;2(5):1269–75.

    Article  PubMed  CAS  Google Scholar 

  10. Seeuws S, Jacques P, Van Praet J, Drennan M, Coudenys J, Decruy T, et al. A multiparameter approach to monitor disease activity in collagen-induced arthritis. Arthritis Res Ther. 2010;12(4):R160.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ren K, Purdue PE, Burton L, Quan LD, Fehringer EV, Thiele GM, et al. Early detection and treatment of wear particle-induced inflammation and bone loss in a mouse calvarial osteolysis model using HPMA copolymer conjugates. Mol Pharm. 2011;8(4):1043–51.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Bendele AM. Animal models of rheumatoid arthritis. J Musculoskelet Neuronal Interact. 2001;1(4):377–85.

    PubMed  CAS  Google Scholar 

  13. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285(6):785–95.

    Article  Google Scholar 

  14. Angeli A, Guglielmi G, Dovio A, Capelli G, de Feo D, Giannini S, et al. High prevalence of asymptomatic vertebral fractures in post-menopausal women receiving chronic glucocorticoid therapy: a cross-sectional outpatient study. Bone. 2006;39(2):253–9.

    Article  PubMed  CAS  Google Scholar 

  15. Weinstein RS. Glucocorticoid-induced osteoporosis. Rev Endocr Metab Disord. 2001;2(1):65–73.

    Article  PubMed  CAS  Google Scholar 

  16. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med. 1990;112(5):352–64.

    Article  PubMed  CAS  Google Scholar 

  17. Goldstein MF, Fallon Jr JJ, Harning R. Chronic glucocorticoid therapy-induced osteoporosis in patients with obstructive lung disease. Chest. 1999;116(6):1733–49.

    Article  PubMed  CAS  Google Scholar 

  18. Yuan F, Quan LD, Cui L, Goldring SR, Wang D. Development of macromolecular prodrug for rheumatoid arthritis. Adv Drug Deliv Rev. 2012;64(12):1205–19.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Quan L, Zhang Y, Crielaard BJ, Dusad A, Lele SM, Rijcken CJ, et al. Nanomedicines for inflammatory arthritis: head-to-head comparison of glucocorticoid-containing polymers, micelles, and liposomes. ACS Nano. 2014;8(1):458–66.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Ren K, Dusad A, Yuan F, Yuan H, Purdue PE, Fehringer EV, et al. Macromolecular prodrug of dexamethasone prevents particle-induced peri-implant osteolysis with reduced systemic side effects. J Control Release Off J Control Release Soc. 2014;175:1–9.

    Article  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

Research reported in this manuscript was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number R01 AR053325 and Nebraska Arthritis Outcome Research Center (NAORC). We thank Mr. Arun Tatiparthi of Micro Photonics for his assistance with the micro-CT analysis. Y.Z. was supported by the Bukey Fellowship from University of Nebraska Medical Center.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA

    Lingdong Quan, Yijia Zhang, Anand Dusad, Ke Ren & Dong Wang

  2. Hospital for Special Surgery, New York, New York, 10021, USA

    P. Edward Purdue & Steven R. Goldring

Authors
  1. Lingdong Quan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yijia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anand Dusad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ke Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. Edward Purdue
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Steven R. Goldring
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dong Wang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Quan, L., Zhang, Y., Dusad, A. et al. The Evaluation of the Therapeutic Efficacy and Side Effects of a Macromolecular Dexamethasone Prodrug in the Collagen-Induced Arthritis Mouse Model. Pharm Res 33, 186–193 (2016). https://doi.org/10.1007/s11095-015-1776-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-015-1776-1

KEY WORDS

Search

Navigation