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Notch-1 siRNA and Methotrexate towards a Multifunctional Approach in Rhematoid Arthritis Management: a Nanomedicine Approach

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ABSTRACT

Purpose

Rheumatoid arthritis (RA) is a chronic inflammatory disease and Notch pathway plays a pivotal role in synoviocytes involved in progression of RA.

Methods

Herein, we have designed a self-assembled polymeric micelles based on polycaprolactone-polyethylene glycol (PCL-PEG) and polyethylenimine-polyethylene glycol (PEI-PEG) was prepared and loaded with methotrexate and Notch-1 siRNA for the effective treatment of rheumatoid arthritis.

Results

The MTX/siRNA-loaded polymeric micelles (siM-PM) showed appreciable cellular uptake in Raw264.7 cells which were activated with LPS and did not exhibit any toxicity to Raw264.7 and HUVEC cells. The AUC of siM-PM was 4-fold higher compared to that of free MTX while t1/2 was 6 fold for siM-PM compared to that of free drug indicating the superior pharmacokinetic parameters. Importantly, siM-PM significantly reduced the paw thickness and slowed the disease progression remarkably, indicating that siM-PM is very effective in recovering the edema in arthritic animals. Importantly, 2-fold decrease in arthritic score was observed in siM-PM treated group at the end of day 24. The data clearly reveals anti-inflammatory effect of combinational nanoparticle due to the sequence specific downregulation of Notch-1 expression in the RA clinical models.

Conclusions

Overall, nanomedicine-based delivery of MTX and siRNA could overcome the side effects of small molecules and could improve the therapeutic effect of siRNA in rheumatoid arthritis.

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Abbreviations

DLS:

Dynamic light scattering analysis

MSPM:

MTX/siRNA-loaded polymeric micelles

MTX:

Methotrexate

RA:

Rheumatoid arthritis

RISC:

RNA-induced silencing complex

siRNA:

Small interfering RNA

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Authors and Affiliations

  1. Department of Orthopedics, The Fourth Affiliated Hospital, China Medical University, No.4 East Chongshan Road, Huanggu District, Shenyang, 110032, China

    Guang Zhao & Haifei Zhang

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  1. Guang Zhao
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  2. Haifei Zhang
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Correspondence to Haifei Zhang.

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Zhao, G., Zhang, H. Notch-1 siRNA and Methotrexate towards a Multifunctional Approach in Rhematoid Arthritis Management: a Nanomedicine Approach. Pharm Res 35, 123 (2018). https://doi.org/10.1007/s11095-018-2401-x

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  • DOI: https://doi.org/10.1007/s11095-018-2401-x

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