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In Vitro Efficacy of Polysaccharide-Based Nanoparticles Containing Disease-Modifying Antirheumatic Drugs

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ABSTRACT

Purpose

To evaluate the therapeutic efficacy of dexamethasone (DM) and methotrexate (MTX) entrapped within polysialic acid (PSA)-trimethyl chitosan (TMC) nanoparticles using an in vitro model of rheumatoid arthritis (RA).

Methods

The loading capacity of the PSA-TMC nanoparticles was determined. An RA in vitro model was developed by stimulating a synovial cell line with a proinflammatory mediator. Multiplex immunoassay was used to determine changes in the secretion of interleukin-6 (IL-6), interleukin-8 (IL-8), and granulocyte-macrophage colony-stimulating factor (GM-CSF) by the in vitro model following administration of the DM- and MTX-loaded nanoparticles.

Results

The loading capacity of the PSA-TMC nanoparticles was approximately 0.1 mg of drug/mg of nanoparticle. When applied to our in vitro model of RA, there were no significant differences in the concentrations of IL-6 and IL-8 when comparing the free drugs and drug-loaded nanoparticles, administered at concentration of 0.1 mg/ml and 1.0 mg/ml, respectively.

Conclusions

The present study verified that MTX and DM are able to retain bioactivity when loaded into PSA-TMC nanoparticles. Although in vitro efficacy was not increased, the in vivo efficacy will likely be enhanced by the site-specific targeting conferred by nanoparticle entrapment.

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Abbreviations

DM:

Dexamethasone

DMARD:

Disease-Modifying Antirheumatic Drug

GM-CSF:

Granulocyte-Macrophage Colony-Stimulating Factor

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

IL-8:

Interleukin-8

MTX:

Methotrexate

PSA:

Polysialic Acid

RA:

Rheumatoid Arthritis

TMC:

Trimethyl chitosan

TPP:

Tripolyphosphate

References

  1. Lindholm A, Kahan BD. Influence of cyclosporine pharmacokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation. Clin Pharmacol Ther. 1993;54(2):205–18.

    Article  PubMed  CAS  Google Scholar 

  2. Weinblatt ME, Kremer JM. Methotrexate in rheumatoid arthritis. J Am Acad Dermatol. 1988;19(1 Pt 1):126–8.

    Article  PubMed  CAS  Google Scholar 

  3. Mottram PL. Past, present and future drug treatment for rheumatoid arthritis and systemic lupus erythematosus. Immunol Cell Biol. 2003;81(5):350–3.

    Article  PubMed  CAS  Google Scholar 

  4. Goodman TA, Polisson RP. Methotrexate: adverse reactions and major toxicities. Rheum Dis Clin N Am. 1994;20(2):513–28.

    CAS  Google Scholar 

  5. Wolverton SE, Remlinger K. Suggested guidelines for patient monitoring: hepatic and hematologic toxicity attributable to systemic dermatologic drugs. Dermatol Clin. 2007;25(2):195–205. vi–ii.

    Article  PubMed  CAS  Google Scholar 

  6. Baschant U, Lane NE, Tuckermann J. The multiple facets of glucocorticoid action in rheumatoid arthritis. Nat Rev Rheumatol. 2012;8(11):645–55.

    Article  PubMed  CAS  Google Scholar 

  7. Liu Z, Jiao Y, Wang Y, Zhou C, Zhang Z. Polysaccharides-based nanoparticles as drug delivery systems. Adv Drug Deliv Rev. 2008;60(15):1650–62.

    Article  PubMed  CAS  Google Scholar 

  8. Prabaharan M, Mano JF. Chitosan-based particles as controlled drug delivery systems. Drug Deliv. 2005;12(1):41–57.

    Article  PubMed  CAS  Google Scholar 

  9. Ko JA, Park HJ, Hwang SJ, Park JB, Lee JS. Preparation and characterization of chitosan microparticles intended for controlled drug delivery. Int J Pharm. 2002;249(1–2):165–74.

    Article  PubMed  CAS  Google Scholar 

  10. Janes KA, Fresneau MP, Marazuela A, Fabra A, Alonso MJ. Chitosan nanoparticles as delivery systems for doxorubicin. J Control Release. 2001;73(2–3):255–67.

    Article  PubMed  CAS  Google Scholar 

  11. Fernandez-Urrusuno R, Calvo P, Remunan-Lopez C, Vila-Jato JL, Alonso MJ. Enhancement of nasal absorption of insulin using chitosan nanoparticles. Pharm Res. 1999;16(10):1576–81.

    Article  PubMed  CAS  Google Scholar 

  12. Katas H, Alpar HO. Development and characterisation of chitosan nanoparticles for siRNA delivery. J Control Release. 2006;115(2):216–25.

    Article  PubMed  CAS  Google Scholar 

  13. Zhang N, Bader RA. Synthesis and characterization of polysialic acid-N-Trimethyl chitosan nanoparticles for drug delivery. NanoLIFE. 2012;2(3):1241003.

    Google Scholar 

  14. Jain S, Hreczuk-Hirst DH, McCormack B, Mital M, Epenetos A, Laing P, et al. Polysialylated insulin: synthesis, characterization and biological activity in vivo. Biochim Biophys Acta. 2003;1622(1):42–9.

    Article  PubMed  CAS  Google Scholar 

  15. Fernandes AI, Gregoriadis G. The effect of polysialylation on the immunogenicity and antigenicity of asparaginase: implication in its pharmacokinetics. Int J Pharm. 2001;217(1–2):215–24.

    Article  PubMed  CAS  Google Scholar 

  16. Fernandes AI, Gregoriadis G. Polysialylated asparaginase: preparation, activity and pharmacokinetics. Biochim Biophys Acta. 1997;1341(1):26–34.

    Article  PubMed  CAS  Google Scholar 

  17. Fernandes AGG. FC41 catalase-polysialic acid conjugates. Eur J Pharm Sci. 1994;2(1–2):111.

    Article  Google Scholar 

  18. Fernandes AI, Gregoriadis G. Synthesis, characterization and properties of sialylated catalase. Biochim Biophys Acta. 1996;1293(1):90–6.

    Article  PubMed  Google Scholar 

  19. Gregoriadis G, Jain S, Papaioannou I, Laing P. Improving the therapeutic efficacy of peptides and proteins: a role for polysialic acids. Int J Pharm [Article]. 2005;300(1-2):125–30.

    Article  CAS  Google Scholar 

  20. Gregoriadis G, Fernandes A, Mital M, McCormack B. Polysialic acids: potential in improving the stability and pharmacokinetics of proteins and other therapeutics. Cell Mol Life Sci. 2000;57(13–14):1964–9.

    Article  PubMed  CAS  Google Scholar 

  21. Gregoriadis G, Fernandes A, McCormack B, Mital M, Zhang X. Polysialic acids: potential role in therapeutic constructs. Biotechnol Genet Eng Rev. 1999;16:203–15.

    Article  PubMed  CAS  Google Scholar 

  22. Ritchlin C. Fibroblast biology. Effector signals released by the synovial fibroblast in arthritis. Arthritis Res. 2000;2(5):356–60.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429–42.

    Article  PubMed  CAS  Google Scholar 

  24. Yamazaki T, Yokoyama T, Akatsu H, Tukiyama T, Tokiwa T. Phenotypic characterization of a human synovial sarcoma cell line, SW982, and its response to dexamethasone. In Vitro Cell Dev Biol-Anim. 2003;39(8-9):337–9.

    Article  PubMed  CAS  Google Scholar 

  25. Choi EM, Lee YS. Luteolin suppresses IL-1 beta-induced cytokines and MMPs production via p38 MAPK, JNK, NF-kappaB and AP-1 activation in human synovial sarcoma cell line, SW982. Food Chem Toxicol. 2010;48(10):2607–11.

    Article  PubMed  CAS  Google Scholar 

  26. Wada Y, Shimada K, Kimura T, Ushiyama S. Novel p38 MAP kinase inhibitor R-130823 suppresses IL-6, IL-8 and MMP-13 production in spheroid culture of human synovial sarcoma cell line SW 982. Immunol Lett. 2005;101(1):50–9.

    Article  PubMed  CAS  Google Scholar 

  27. Wagoner KL, Bader RA. Evaluation of SV40-transformed synovial fibroblasts in the study of rheumatoid arthritis pathogenesis. Rheumatol Int. 2012;32(7):1885–91.

    Article  PubMed  CAS  Google Scholar 

  28. Polakovic M, Gorner T, Gref R, Dellacherie E. Lidocaine loaded biodegradable nanospheres. II. Modelling of drug release. J Control Release. 1999;60(2–3):169–77.

    Article  PubMed  CAS  Google Scholar 

  29. Huber LC, Distler O, Tarner I, Gay RE, Gay S, Pap T. Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology (Oxford). 2006;45(6):669–75.

    Article  CAS  Google Scholar 

  30. Pap T, Muller-Ladner U, Gay RE, Gay S. Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res. 2000;2(5):361–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Boddohi S, Moore N, Johnson PA, Kipper MJ. Polysaccharide-based polyelectrolyte complex nanoparticles from chitosan, heparin, and hyaluronan. Biomacromolecules. 2009;10(6):1402–9.

    Article  PubMed  CAS  Google Scholar 

  32. Janes KA, Calvo P, Alonso MJ. Polysaccharide colloidal particles as delivery systems for macromolecules. Adv Drug Deliv Rev. 2001;47(1):83–97.

    Article  PubMed  CAS  Google Scholar 

  33. Nagpal K, Singh SK, Mishra DN. Chitosan nanoparticles: a promising system in novel drug delivery. Chem Pharm Bull (Tokyo). 2010;58(11):1423–30.

    Article  CAS  Google Scholar 

  34. Nakahara H, Song J, Sugimoto M, Hagihara K, Kishimoto T, Yoshizaki K, et al. Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. Arthritis Rheum. 2003;48(6):1521–9.

    Article  PubMed  CAS  Google Scholar 

  35. Nanki T, Nagasaka K, Hayashida K, Saita Y, Miyasaka N. Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis. J Immunol. 2001;167(9):5381–5.

    Article  PubMed  CAS  Google Scholar 

  36. Koch AE. Chemokines and their receptors in rheumatoid arthritis future targets? Arthritis Rheum. 2005;52(3):710–21.

    Article  PubMed  Google Scholar 

  37. Seitz M, Loetscher P, Dewald B, Towbin H, Rordorf C, Gallati H, et al. Methotrexate action in rheumatoid arthritis: stimulation of cytokine inhibitor and inhibition of chemokine production by peripheral blood mononuclear cells. Br J Rheumatol. 1995;34(7):602–9.

    Article  PubMed  CAS  Google Scholar 

  38. Maillefert JF, Puechal X, Falgarone G, Lizard G, Ornetti P, Solau E, et al. Prediction of response to disease modifying antirheumatic drugs in rheumatoid arthritis. Joint Bone Spine. 2010;77(6):558–63.

    Article  PubMed  CAS  Google Scholar 

  39. Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis. 2001;60(8):729–35.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Chan ESL, Cronstein BN. Methotrexate-how does it really work? Nat Rev Rheumatol. 2010;6(3):175–8.

    Article  PubMed  CAS  Google Scholar 

  41. Chan ESL, Cronstein BN. Molecular action of methotrexate in inflammatory diseases. Arthritis Res. 2002;4(4):266–73.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Cronstein BN. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev. 2005;57(2):163–72.

    Article  PubMed  CAS  Google Scholar 

  43. Sung JY, Hong JH, Kang HS, Choi I, Lim SD, Lee JK, et al. Methotrexate suppresses the interleukin-6 induced generation of reactive oxygen species in the synoviocytes of rheumatoid arthritis. Immunopharmacology. 2000;47(1):35–44.

    Article  PubMed  CAS  Google Scholar 

  44. Seitz M, Loetscher P, Dewald B, Towbin H, Baggiolini M. In vitro modulation of cytokine, cytokine inhibitor, and prostaglandin E release from blood mononuclear cells and synovial fibroblasts by antirheumatic drugs. J Rheumatol. 1997;24(8):1471–6.

    PubMed  CAS  Google Scholar 

  45. Inoue H, Takamori M, Nagata N, Nishikawa T, Oda H, Yamamoto S, et al. An investigation of cell proliferation and soluble mediators induced by interleukin 1beta in human synovial fibroblasts: comparative response in osteoarthritis and rheumatoid arthritis. Inflamm Res. 2001;50(2):65–72.

    Article  PubMed  CAS  Google Scholar 

  46. Swierkot J, Szechinski J. Methotrexate in rheumatoid arthritis. Pharmacol Rep. 2006;58(4):473–92.

    PubMed  CAS  Google Scholar 

  47. Scheinman RI, Gualberto A, Jewell CM, Cidlowski JA, Baldwin AS. Characterization of mechanisms involved in transrepression of NF-Kappa-B by activated glucocorticoid receptors. Mol Cell Biol. 1995;15(2):943–53.

    PubMed  CAS  PubMed Central  Google Scholar 

  48. Barnes PJ, Adcock IM. How do corticosteroids work in asthma? Ann Intern Med. 2003;139(5):359–70.

    Article  PubMed  CAS  Google Scholar 

  49. Leung DYM, Bloom JW. Update on glucocorticoid action and resistance. J Allergy Clin Immunol. 2003;111(1):3–23.

    Article  PubMed  CAS  Google Scholar 

  50. Muller-Ladner U, Nishioka K. p53 in rheumatoid arthritis: friend or foe? Arthritis Res. 2000;2(3):175–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Tan PL, Farmiloe S, Yeoman S, Watson JD. Expression of the interleukin 6 gene in rheumatoid synovial fibroblasts. J Rheumatol. 1990;17(12):1608–12.

    PubMed  CAS  Google Scholar 

  52. Filonzi EL, Zoellner H, Stanton H, Hamilton JA. Cytokine regulation of granulocyte-macrophage colony stimulating factor and macrophage colony-stimulating factor production in human arterial smooth muscle cells. Atherosclerosis. 1993;99(2):241–52.

    Article  PubMed  CAS  Google Scholar 

  53. Hamilton JA, Piccoli DS, Cebon J, Layton JE, Rathanaswani P, McColl SR, et al. Cytokine regulation of colony-stimulating factor (CSF) production in cultured human synovial fibroblasts. II. Similarities and differences in the control of interleukin-1 induction of granulocyte-macrophage CSF and granulocyte-CSF production. Blood. 1992;79(6):1413–9.

    PubMed  CAS  Google Scholar 

  54. Rodrigues S, Dionisio M, Lopez CR, Grenha A. Biocompatibility of chitosan carriers with application in drug delivery. Funct Biomater. 2012;3:615–41.

    Article  CAS  Google Scholar 

  55. Guzman-Morales J, Ariganello MB, Hammami I, Thibault M, Jolicoeur M, Hoemann CD. Biodegradable chitosan particles induce chemokine release and negligible arginase-1 activity compared to IL-4 in murine bone marrow-derived macrophages. Biochem Biophys Res Commun. 2011;405(4):538–44.

    Article  PubMed  CAS  Google Scholar 

  56. Witschi C, Mrsny RJ. In vitro evaluation of microparticles and polymer gels for use as nasal platforms for protein delivery. Pharm Res. 1999;16(3):382–90.

    Article  PubMed  CAS  Google Scholar 

  57. Li X, Min M, Du N, Gu Y, Hode T, Naylor M, et al. Chitin, chitosan, and glycated chitosan regulate immune responses: the novel adjuvants for cancer vaccine. Clin Dev Immunol. 2013;2013:387023.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments AND DISCLOSURES

We thank David Wilson for assistance with the HPLC in evaluating controlled release of DM from the nanoparticles. Cellular uptake of the nanoparticles was observed under the direction of Dr. Martin B. Forstner. This work was supported by NSF grant CBET-1032506.

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Authors and Affiliations

  1. Syracuse Biomaterials Institute Department of Biomedical and Chemical Engineering, Syracuse University, 318 Bowne Hall, Syracuse, New York, 13244, USA

    Nan Zhang, Patricia R. Wardwell & Rebecca A. Bader

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  1. Nan Zhang
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  2. Patricia R. Wardwell
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  3. Rebecca A. Bader
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Correspondence to Rebecca A. Bader.

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Zhang, N., Wardwell, P.R. & Bader, R.A. In Vitro Efficacy of Polysaccharide-Based Nanoparticles Containing Disease-Modifying Antirheumatic Drugs. Pharm Res 31, 2326–2334 (2014). https://doi.org/10.1007/s11095-014-1329-z

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  • DOI: https://doi.org/10.1007/s11095-014-1329-z

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