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

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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.

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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

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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.

Author information

Authors and Affiliations

  1. Center for Nanotechnology in Drug Delivery, Department of Pharmaceutical Nanotechnology, Shiraz University of Medical Sciences, Shiraz, 71345, Iran

    SamiraSadat Abolmaali & AliMohammad Tamaddon

  2. Autoimmune Diseases Research Center and School of Medicine Department of Immunology, Shiraz University of Medical Sciences, Shiraz, 71345, Iran

    Eskandar Kamali-Sarvestani

  3. Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, 71345, Iran

    MohammadJavad Ashraf

  4. Nanotechnology Research Centre and Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 14174, Iran

    Rasoul Dinarvand

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  1. SamiraSadat Abolmaali
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Correspondence to AliMohammad Tamaddon.

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Abolmaali, S., Tamaddon, A., Kamali-Sarvestani, E. et al. Stealth Nanogels of Histinylated Poly Ethyleneimine for Sustained Delivery of Methotrexate in Collagen-Induced Arthritis Model. Pharm Res 32, 3309–3323 (2015). https://doi.org/10.1007/s11095-015-1708-0

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  • DOI: https://doi.org/10.1007/s11095-015-1708-0

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