Advertisement

Pharmaceutical Research

, Volume 32, Issue 10, pp 3309–3323 | Cite as

Stealth Nanogels of Histinylated Poly Ethyleneimine for Sustained Delivery of Methotrexate in Collagen-Induced Arthritis Model

  • SamiraSadat Abolmaali
  • AliMohammad TamaddonEmail author
  • Eskandar Kamali-Sarvestani
  • MohammadJavad Ashraf
  • Rasoul Dinarvand
Research Paper

ABSTRACT

Purpose

The study aimed to illustrate application of polycation Stealth nanogels for sustained delivery of methotrexate (MTX) in collagen induced arthritis (CIA) model in C57Bl/6 mice.

Methods

Nanogel synthesis involves metal ion coordinated self-assembly of PEGylated poly ethyleneimine (L-histidine substituted), chemical crosslinking and subsequent removal of the coordinated metal. The nanogels were characterized by TEM and DLS-zeta potential. Comparative efficacy and pharmacokinetics of the i.v. administred MTX-loaded nanogels were investigated in the CIA model. Inflammation site passive accumulation of the fluorophore-labeled nanogels was tested using in-vivo imaging of mice paw received unilateral injection of lipopolysaccharide.

Results

Uniform nanogels (sizes ~40 nm by TEM) were loaded with MTX (entrapment efficiency = 62% and drug loading = 54% at the MTX feeding ratio of 0.3 relative to total molar concentration of the polymer amines). The nanogels exhibited neutral surface charge and an acceptable biocompatibility in terms of albumin aggregation, hemolysis, erythrocyte aggregation and cytotoxicity. Single dose pharmacokinetics of the MTX-loaded nanogels, unlike free drug, showed a sustained plasma profile. When arthritis established as confirmed by histopathology, a remarkable decline of paw swelling and clinical scores was observed. Fluorescence intensity of the nanogels was enhanced about 2.7 folds at the inflamed than control normal ankle.

Conclusion

Sustained delivery of MTX and preferential accumulation of the nanogels in inflamed paw might explain the superior clinical outcome of the MTX-loaded nanogels.

KEY WORDS

clinical efficacy collagen induced arthritis methotrexate pharmacokinetics stealth nanogels 

ABBREVIATIONS

CFA

Complete Freund’s adjuvant

CIA

Collagen induced arthritis

CR

Molar ratio of the crosslink (DTDP) to NH2

FR

Molar ratio of methotrexate to total amines

H-PEI

Histidinylated poly ethyleneimine

HP-PEI

PEGylated poly ethyleneimine (L-histidine substituted)

MRT

Mean residence time

MTX

Methotrexate

PDI

Polydispersity index

P-PEI

PEGylated poly ethyleneimine

RA

Rheumatoid arthritis

Vss

Apparent volume of distribution at steady state

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

The authors gratefully acknowledge use of the facilities of Center for Nanotechnology in Drug Delivery, National Nanotechnology Laboratory Network and Shiraz University of Medical Sciences. Also, they would like to thank Mr. Kouhi from Central Animal Lab, Ms. Taki from Autoimmune Diseases Research Center and Ms. Abedini from Pathology Department at Khalili Hospital, Shiraz University of Medical Sciences.

Disclosure

The authors declare no competing financial interests.

Supplementary material

11095_2015_1708_MOESM1_ESM.doc (188 kb)
ESM 1 (DOC 188 kb)
11095_2015_1708_MOESM2_ESM.doc (53 kb)
ESM 2 (DOC 53 kb)
11095_2015_1708_MOESM3_ESM.doc (64 kb)
ESM 3 (DOC 64 kb)
11095_2015_1708_MOESM4_ESM.doc (64 kb)
ESM 4 (DOC 64 kb)
11095_2015_1708_MOESM5_ESM.doc (45 kb)
ESM 5 (DOC 45 kb)
11095_2015_1708_MOESM6_ESM.doc (862 kb)
ESM 6 (DOC 861 kb)
11095_2015_1708_MOESM7_ESM.doc (70 kb)
ESM 7 (DOC 70 kb)

REFERENCES

  1. 1.
    Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 2003;2(6):473–88.CrossRefPubMedGoogle Scholar
  2. 2.
    Purcell WT, Ettinger DS. Novel antifolate drugs. Curr Oncol Rep. 2003;5(2):114–25.CrossRefPubMedGoogle Scholar
  3. 3.
    Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001;358(9285):903–11.CrossRefPubMedGoogle Scholar
  4. 4.
    Grim J, Chladek J, Martinkova J. Pharmacokinetics and pharmacodynamics of methotrexate in non-neoplastic diseases. Clin Pharmacokinet. 2003;42(2):139–51.CrossRefPubMedGoogle Scholar
  5. 5.
    Abolmaali S, Tamaddon A, Dinarvand R. A review of therapeutic challenges and achievements of methotrexate delivery systems for treatment of cancer and rheumatoid arthritis. Cancer Chemother Pharmacol. 2013;71(5):1115–30.CrossRefPubMedGoogle Scholar
  6. 6.
    Levick JR. Microvascular architecture and exchange in synovial joints. Microcirculation. 1995;2(3):217–33.CrossRefPubMedGoogle Scholar
  7. 7.
    Koch AE, Distler O. Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis. Arthritis Res Ther. 2007;9 Suppl 2:S3.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Levick JR. Hypoxia and acidosis in chronic inflammatory arthritis; relation to vascular supply and dynamic effusion pressure. J Rheumatol. 1990;17(5):579–82.PubMedGoogle Scholar
  9. 9.
    Nagai T, Tanaka M, Tsuneyoshi Y, Matsushita K, Sunahara N, Matsuda T, et al. In vitro and in vivo efficacy of a recombinant immunotoxin against folate receptor beta on the activation and proliferation of rheumatoid arthritis synovial cells. Arthritis Rheum. 2006;54(10):3126–34.CrossRefPubMedGoogle Scholar
  10. 10.
    Wunder A, Muller-Ladner U, Stelzer EH, Funk J, Neumann E, Stehle G, et al. Albumin-based drug delivery as novel therapeutic approach for rheumatoid arthritis. J Immunol. 2003;170(9):4793–801.CrossRefPubMedGoogle Scholar
  11. 11.
    Williams AS, Camilleri JP, Amos N, Williams BD. Differential effects of methotrexate and liposomally conjugated methotrexate in rat adjuvant-induced arthritis. Clin Exp Immunol. 1995;102(3):560–5.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Liang LS, Jackson J, Min W, Risovic V, Wasan KM, Burt HM. Methotrexate loaded poly (L-lactic acid) microspheres for intra-articular delivery of methotrexate to the joint. J Pharm Sci. 2004;93(4):943–56.CrossRefPubMedGoogle Scholar
  13. 13.
    Oh JK, Drumright R, Siegwart DJ, Matyjaszewski K. The development of microgels/nanogels for drug delivery applications. Prog Polym Sci. 2008;33(4):448–77.CrossRefGoogle Scholar
  14. 14.
    Akiyoshi K, Kobayashi S, Shichibe S, Mix D, Baudys M, Wan Kim S, et al. Self-assembled hydrogel nanoparticle of cholesterol-bearing pullulan as a carrier of protein drugs: complexation and stabilization of insulin. J Control Release. 1998;54(3):313–20.CrossRefPubMedGoogle Scholar
  15. 15.
    Legros C, Wirotius A-L, De Pauw-Gillet M-C, Tam KC, Taton D, Lecommandoux S. Poly(2-oxazoline)-based nanogels as biocompatible pseudopolypeptide nanoparticles. Biomacromolecules. 2015;16(1):183–91.CrossRefPubMedGoogle Scholar
  16. 16.
    Abolmaali S, Tamaddon A, Najafi H, Dinarvand R. Effect of l-Histidine substitution on Sol–Gel of transition metal coordinated poly ethyleneimine: synthesis and biochemical characterization. J Inorg Organomet Polym. 2014:1–11.Google Scholar
  17. 17.
    Park TG, Jeong JH, Kim SW. Current status of polymeric gene delivery systems. Adv Drug Deliv Rev. 2006;58(4):467–86.CrossRefPubMedGoogle Scholar
  18. 18.
    Romberg B, Hennink W, Storm G. Sheddable coatings for long-circulating nanoparticles. Pharm Res. 2008;25(1):55–71.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Abolmaali S, Tamaddon A, Yousefi G, Javidnia K, Dinarvand R. Sequential optimization of methotrexate encapsulation in micellar nano-network of polyethyleneimine ionomer containing redox-sensitive cross-links. Int J Nanomedicine. 2014;9:1–16.CrossRefGoogle Scholar
  20. 20.
    Abolmaali S, Tamaddon A, Dinarvand R. Nano-hydrogels of methoxy polyethylene glycol-grafted branched polyethyleneimine via biodegradable cross-linking of Zn2 + -ionomer micelle template. J Nanopart Res. 2013;15(12):1–21.CrossRefGoogle Scholar
  21. 21.
    Kim JO, Sahay G, Kabanov AV, Bronich TK. Polymeric micelles with ionic cores containing biodegradable cross-links for delivery of chemotherapeutic agents. Biomacromolecules. 2010;11(4):919–26.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm. 1983;15(1):25–35.CrossRefGoogle Scholar
  23. 23.
    Parnham MJ, Wetzig H. Toxicity screening of liposomes. Chem Phys Lipids. 1993;64(1–3):263–74.CrossRefPubMedGoogle Scholar
  24. 24.
    Cerda-Cristerna BI, Flores H, Pozos-Guillen A, Perez E, Sevrin C, Grandfils C. Hemocompatibility assessment of poly(2-dimethylamino ethylmethacrylate) (PDMAEMA)-based polymers. J Control Release: Off J Control Release Soc. 2011;153(3):269–77.CrossRefGoogle Scholar
  25. 25.
    Holder DJ, Hsuan F, Dixit R, Soper K. A method for estimating and testing area under the curve in serial sacrifice, batch, and complete data designs. J Biopharm Stat. 1999;9(3):451–64.CrossRefPubMedGoogle Scholar
  26. 26.
    Bevaart L, Vervoordeldonk M, Tak P. Collagen-induced arthritis in mice. In: Proetzel G, Wiles MV, editors. Mouse models for drug discovery: Humana Press; 2010. p. 181–92.Google Scholar
  27. 27.
    Chen W-T, Mahmood U, Weissleder R, Tung C-H. Arthritis imaging using a near-infrared fluorescence folate-targeted probe. Arthritis Res Ther. 2005;7(2):1–8.CrossRefGoogle Scholar
  28. 28.
    Bronstein LM, Sidorov SN, Gourkova AY, Valetsky PM, Hartmann J, Breulmann M, et al. Interaction of metal compounds with ‘double-hydrophilic’ block copolymers in aqueous medium and metal colloid formation. Inorg Chim Acta. 1998;280(1–2):348–54.CrossRefGoogle Scholar
  29. 29.
    Solomatin SV, Bronich TK, Bargar TW, Eisenberg A, Kabanov VA, Kabanov AV. Environmentally responsive nanoparticles from block ionomer complexes: effects of pH and ionic strength. Langmuir. 2003;19(19):8069–76.CrossRefGoogle Scholar
  30. 30.
    Liu J, Detrembleur C, Hurtgen M, Debuigne A, De Pauw-Gillet M-C, Mornet S, et al. Reversibly crosslinked thermo- and redox-responsive nanogels for controlled drug release. Polym Chem. 2014;5(1):77–88.CrossRefGoogle Scholar
  31. 31.
    Kim JO, Kabanov AV, Bronich TK. Polymer micelles with cross-linked polyanion core for delivery of a cationic drug doxorubicin. J Control Release: Off J Control Release Soc. 2009;138(3):197–204.CrossRefGoogle Scholar
  32. 32.
    Vinogradov SV, Bronich TK, Kabanov AV. Nanosized cationic hydrogels for drug delivery: preparation, properties and interactions with cells. Adv Drug Deliv Rev. 2002;54(1):135–47.CrossRefPubMedGoogle Scholar
  33. 33.
    Vinogradov SV, Kabanov AV. Synthesis of nanogel carriers for delivery of active phosphorylated nucleoside analogues. Polymer Prepr. 2004;228(Pt 2):296.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Jeong Y, Seo D, Kim D, Choi C, Jang MJ, Nah JW, et al. Methotrexate-incorporated polymeric micelles composed of methoxy poly (ethyleneglycol)-grafted chitosan. Macromol Res. 2009;17(7):538–43.CrossRefGoogle Scholar
  35. 35.
    Ruckmani K, Sivakumar M, Ganeshkumar PA. Methotrexate loaded solid lipid nanoparticles (SLN) for effective treatment of carcinoma. J Nanosci Nanotechnol. 2006;6(9–10):2991–5.CrossRefPubMedGoogle Scholar
  36. 36.
    Azadi A, Hamidi M, Khoshayand M-R, Amini M, Rouini M-R. Preparation and optimization of surface-treated methotrexate-loaded nanogels intended for brain delivery. Carbohydr Polym. 2012;90(1):462–71.CrossRefPubMedGoogle Scholar
  37. 37.
    Petersen H, Fechner PM, Martin AL, Kunath K, Stolnik S, Roberts CJ, et al. Polyethylenimine-graft-poly(ethylene glycol) copolymers: influence of copolymer block structure on DNA complexation and biological activities as gene delivery system. Bioconjug Chem. 2002;13(4):845–54.CrossRefPubMedGoogle Scholar
  38. 38.
    Neu M, Sitterberg J, Bakowsky U, Kissel T. Stabilized nanocarriers for plasmids based upon cross-linked poly (ethylene imine). Biomacromolecules. 2006;7(12):3428–38.CrossRefPubMedGoogle Scholar
  39. 39.
    Fischer D, Li Y, Ahlemeyer B, Krieglstein J, Kissel T. In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis. Biomaterials. 2003;24(7):1121–31.CrossRefPubMedGoogle Scholar
  40. 40.
    Ryser HJ. A membrane effect of basic polymers dependent on molecular size. Nature. 1967;215(5104):934–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Rezwan K, Meier LP, Rezwan M, Vörös J, Textor M, Gauckler LJ. Bovine serum albumin adsorption onto colloidal Al2O3 particles: a new model based on zeta potential and UV − Vis measurements. Langmuir. 2004;20(23):10055–61.CrossRefPubMedGoogle Scholar
  42. 42.
    Dobrovolskaia MA, Patri AK, Zheng J, Clogston JD, Ayub N, Aggarwal P, et al. Interaction of colloidal gold nanoparticles with human blood: effects on particle size and analysis of plasma protein binding profiles. Nanomedicine: Nanotechnol Biol Med. 2009;5(2):106–17.CrossRefGoogle Scholar
  43. 43.
    Rau R, Herborn G. Benefit and risk of methotrexate treatment in rheumatoid arthritis. Clin Exp Rheumatol. 2004;22(5 Suppl 35):S83–94.PubMedGoogle Scholar
  44. 44.
    Ji J, Wu D, Liu L, Chen J, Xu Y. Preparation, evaluation, and in vitro release of folic acid conjugated O-carboxymethyl chitosan nanoparticles loaded with methotrexate. J Appl Polym Sci. 2012;125 SUPPL 2:E208–15.CrossRefGoogle Scholar
  45. 45.
    Kohler N, Sun C, Wang J, Zhang MQ. Methotrexate-modified superparamagnetic nanoparticles and their intracellular uptake into human cancer cells. Langmuir. 2005;21(19):8858–64.CrossRefPubMedGoogle Scholar
  46. 46.
    Park JM, Ahn B-N, Yoon EJ, Lee MG, Shim C-K, Kim C-K. The pharmacokinetics of methotrexate after intravenous administration of methotrexate-loaded proliposomes to rats. Biopharm Drug Dispos. 1994;15(5):391–407.CrossRefPubMedGoogle Scholar
  47. 47.
    Kim MM, Lee SH, Lee MG, Hwang SJ, Kim C-K. Pharmacokinetics of methotrexate after intravenous and intramuscular injection of methotrexate-bearing positively charged liposomes to rats. Biopharm Drug Dispos. 1995;16(4):279–93.CrossRefPubMedGoogle Scholar
  48. 48.
    Inglis J, Criado G, Medghalchi M, Andrews M, Sandison A, Feldmann M, et al. Collagen-induced arthritis in C57BL/6 mice is associated with a robust and sustained T-cell response to type II collagen. Arthritis Res Ther. 2007;9(5):1–8.CrossRefGoogle Scholar
  49. 49.
    Campbell IK, Hamilton JA, Wicks IP. Collagen-induced arthritis in C57BL/6 (H-2b) mice: new insights into an important disease model of rheumatoid arthritis. Eur J Immunol. 2000;30(6):1568–75.CrossRefPubMedGoogle Scholar
  50. 50.
    Fiehn C, Kratz F, Sass G, Müller-Ladner U, Neumann E. Targeted drug delivery by in vivo coupling to endogenous albumin: An albumin-binding prodrug of methotrexate (MTX) is better than MTX in the treatment of murine collagen-induced arthritis. Ann Rheum Dis. 2008;67(8):1188–91.CrossRefPubMedGoogle Scholar
  51. 51.
    Hollingsworth JW, Atkins E. Synovial inflammatory response to bacterial endotoxin. Yale J Biol Med. 1965;38(3):241–56.PubMedCentralPubMedGoogle Scholar
  52. 52.
    Park KS, Kang JH, Sa KH, Koo HB, Cho HJ, Nam EJ, et al. In vivo quantitative measurement of arthritis activity based on hydrophobically modified glycol chitosan in inflammatory arthritis: more active than passive accumulation. Mol Imaging. 2012;11(5):389–400.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • SamiraSadat Abolmaali
    • 1
  • AliMohammad Tamaddon
    • 1
    Email author
  • Eskandar Kamali-Sarvestani
    • 2
  • MohammadJavad Ashraf
    • 3
  • Rasoul Dinarvand
    • 4
  1. 1.Center for Nanotechnology in Drug Delivery, Department of Pharmaceutical NanotechnologyShiraz University of Medical SciencesShirazIran
  2. 2.Autoimmune Diseases Research Center and School of Medicine Department of ImmunologyShiraz University of Medical SciencesShirazIran
  3. 3.Department of Pathology, School of MedicineShiraz University of Medical SciencesShirazIran
  4. 4.Nanotechnology Research Centre and Faculty of PharmacyTehran University of Medical SciencesTehranIran

Personalised recommendations