Targeting CD34+ cells of the inflamed synovial endothelium by guided nanoparticles for the treatment of rheumatoid arthritis

Federico Colombo, Paolo Durigutto, Luca De Maso, Stefania Biffi, Beatrice Belmonte, Claudio Tripodo, Romina Oliva, Paola Bardini, Giada M. Marini, Enzo Terreno, Gabriele Pozzato, Enrico Rampazzo, Jessica Bertrand, Bernd Feuerstein, Jakub Javurek, Jana Havrankova, Costantino Pitzalis, Luis Nuñez, Pierluigi Meroni, Francesco TedescoDaniele Sblattero, Paolo Macor

Research output: Contribution to journalArticlepeer-review

Abstract

Despite the advances in the treatment of rheumatoid arthritis (RA) achieved in the last few years, several patients are diagnosed late, do not respond to or have to stop therapy because of inefficacy and/or toxicity, leaving still a huge unmet need. Tissue-specific strategies have the potential to address some of these issues. The aim of the study is the development of a safe nanotechnology approach for tissue-specific delivery of drugs and diagnostic probes. CD34 + endothelial precursors were addressed in inflamed synovium using targeted biodegradable nanoparticles (tBNPs). These nanostructures were made of poly-lactic acid, poly-caprolactone, and PEG and then coated with a synovial homing peptide. Immunofluorescence analysis clearly demonstrated their capacity to selectively address CD34 + endothelial cells in synovial tissue obtained from human, mouse, and rat. Biodistribution studies in two different animal models of rheumatoid arthritis (antigen-induced arthritis/AIA and collagen-induced arthritis/CIA) confirmed the selective accumulation in inflamed joints but also evidenced the capacity of tBNP to detect early phases of the disease and the preferential liver elimination. The therapeutic effect of methotrexate (MTX)-loaded tBNPs were studied in comparison with conventional MTX doses. MTX-loaded tBNPs prevented and treated CIA and AIA at a lower dose and reduced administration frequency than MTX. Moreover, MTX-loaded tBNP showed a novel mechanism of action, in which the particles target and kill CD34 + endothelial progenitors, preventing neo-angiogenesis and, consequently, synovial inflammation. tBNPs represent a stable and safe platform to develop highly-sensitive imaging and therapeutic approaches in RA targeting specifically synovial neo-angiogenesis to reduce local inflammation.

Original languageEnglish
Article number102288
JournalJournal of Autoimmunity
Volume103
DOIs
Publication statusPublished - Sep 2019

Keywords

  • CD34 cells
  • Neoangiogenesis
  • Rheumatoid arthritis
  • Targeted nanoparticles
  • Targeted therapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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