title: Stealth Nanogels of Histinylated Poly Ethyleneimine for Sustained Delivery of Methotrexate in Collagen-Induced Arthritis Model.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Sustained delivery of MTX and preferential accumulation of the nanogels in inflamed paw might explain the superior clinical outcome of the MTX-loaded nanogels.
authors.affiliation: Center for Nanotechnology in Drug Delivery, Department of Pharmaceutical Nanotechnology, Shiraz University of Medical Sciences, Shiraz, 71345, Iran. s.abolmaali@gmail.com.
authors.forename: SamiraSadat
authors.initials: S
authors.lastname: Abolmaali
authors.affiliation: Center for Nanotechnology in Drug Delivery, Department of Pharmaceutical Nanotechnology, Shiraz University of Medical Sciences, Shiraz, 71345, Iran. amtamadon@gmail.com.
authors.forename: AliMohammad
authors.initials: A
authors.lastname: Tamaddon
authors.affiliation: Autoimmune Diseases Research Center and School of Medicine Department of Immunology, Shiraz University of Medical Sciences, Shiraz, 71345, Iran. immunol2@gmail.com.
authors.forename: Eskandar
authors.initials: E
authors.lastname: Kamali-Sarvestani
authors.affiliation: Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, 71345, Iran. Ashrafm@sums.ac.ir.
authors.forename: MohammadJavad
authors.initials: M
authors.lastname: Ashraf
authors.affiliation: Nanotechnology Research Centre and Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 14174, Iran. dinarvand@tums.ac.ir.
authors.forename: Rasoul
authors.initials: R
authors.lastname: Dinarvand
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001388:Aziridines / Q000737:chemistry*; D003094:Collagen / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006639:Histidine / Q000737:chemistry*; D008727:Methotrexate / Q000008:administration & dosage* / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D000080385:Nanogels; D011092:Polyethylene Glycols / Q000737:chemistry*; D011094:Polyethyleneimine / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry
chemical_list: D001388:Aziridines; D004337:Drug Carriers; D000080385:Nanogels; D011108:Polymers; C413692:polyethylene glycol polyethyleneimine nanogel; C033223:polyhistidine; D011092:Polyethylene Glycols; D006639:Histidine; C033132:aziridine; D011094:Polyethyleneimine; D003094:Collagen; D008727:Methotrexate
keywords: clinical efficacy; collagen induced arthritis; methotrexate; pharmacokinetics; stealth nanogels