Stealth Nanogels of Histinylated Poly Ethyleneimine for Sustained Delivery of Methotrexate in Collagen-Induced Arthritis Model
- 434 Downloads
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.
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.
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.
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 WORDSclinical efficacy collagen induced arthritis methotrexate pharmacokinetics stealth nanogels
Complete Freund’s adjuvant
Collagen induced arthritis
Molar ratio of the crosslink (DTDP) to NH2
Molar ratio of methotrexate to total amines
Histidinylated poly ethyleneimine
PEGylated poly ethyleneimine (L-histidine substituted)
Mean residence time
PEGylated poly ethyleneimine
Apparent volume of distribution at steady state
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.
The authors declare no competing financial interests.
- 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
- 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
- 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
- 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
- 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