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Formulation and Evaluation of VCAM-1-Targeted Methotrexate Lipid Nanoparticles for Rheumatoid Arthritis Therapy.

Ren Na1, Jianmei Jing2, Hua Yang3

  • 1Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.

International Journal of Nanomedicine
|September 15, 2025
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Summary

This study developed targeted methotrexate-loaded lipid nanoparticles (MTX@LNP-PVCAM-1) for rheumatoid arthritis, enhancing drug delivery to inflamed sites and reducing side effects. The new nanoparticles showed improved anti-inflammatory effects and safety in animal models.

Keywords:
PVCAM-1lipid nanoparticlesmethotrexaterheumatoid arthritissynovial fibroblasts

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Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Pharmacology

Background:

  • Methotrexate (MTX) is a cornerstone therapy for rheumatoid arthritis (RA).
  • Current MTX formulations suffer from poor targeting efficiency and significant systemic toxicity.
  • Novel drug delivery systems are needed to improve MTX efficacy and reduce adverse effects in RA treatment.

Purpose of the Study:

  • To develop and characterize novel MTX-loaded lipid nanoparticles (MTX@LNP-PVCAM-1) modified with PVCAM-1 peptide.
  • To evaluate the enhanced targeting, cellular uptake, and anti-inflammatory efficacy of MTX@LNP-PVCAM-1.
  • To assess the safety and toxicity profile of the developed nanocarrier system.

Main Methods:

  • MTX@LNP-PVCAM-1 nanoparticles were synthesized using the thin-film dispersion method.
  • Physicochemical properties (size, morphology, zeta potential) were analyzed using DLS, TEM, and zeta potential measurements.
  • In vitro studies included biocompatibility assays (HUVEC, hemolysis), cellular uptake, cytotoxicity (CCK-8), cell migration (scratch assay), and inflammatory cytokine measurement (ELISA).
  • In vivo studies involved adjuvant-induced arthritis (AIA) rat models to assess biodistribution (in vivo imaging), therapeutic efficacy (paw volume, joint scores, histology), and systemic toxicity (blood tests).

Main Results:

  • MTX@LNP-PVCAM-1 nanoparticles exhibited optimal size (168.5 nm), PDI (0.142), and spherical morphology with pH responsiveness.
  • PVCAM-1 modification significantly enhanced cellular uptake and inhibited synovial fibroblast proliferation, migration, and inflammatory cytokine secretion (IL-1β, IL-6) compared to unmodified nanoparticles.
  • In AIA rats, MTX@LNP-PVCAM-1 demonstrated superior accumulation at inflamed sites, potent anti-inflammatory effects (reduced paw swelling and joint scores), and no significant systemic toxicity.
  • The targeted nanoparticles showed significantly higher accumulation in inflamed tissues compared to non-targeted ones (p<0.05).

Conclusions:

  • MTX@LNP-PVCAM-1 nanoparticles effectively combine passive and active targeting strategies for enhanced MTX delivery.
  • This targeted delivery system significantly improves anti-inflammatory efficacy in an AIA rat model.
  • The developed MTX@LNP-PVCAM-1 offers a promising low-toxicity therapeutic strategy for rheumatoid arthritis management.