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



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.


clinical 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




Polydispersity index


PEGylated poly ethyleneimine


Rheumatoid arthritis


Apparent volume of distribution at steady state



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.

Supplementary material

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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

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