Folate‐targeted nanoparticles show efficacy in the treatment of inflammatory arthritis

Abstract

Objective To investigate the uptake of a poly(amidoamine) dendrimer (generation 5 (G5)) nanoparticle covalently conjugated to polyvalent folic acid (FA) as the targeting ligand into macrophages, and the activity of a FA- and methotrexate-conjugated dendrimer (G5-FA-MTX) as a therapeutic for the inflammatory disease of arthritis. Methods In vitro studies were performed in macrophage cell lines and in isolated mouse macrophages to check the cellular uptake of fluorescently tagged G5-FA nanoparticles, using flow cytometry and confocal microscopy. In vivo studies were conducted in a rat model of collagen-induced arthritis to evaluate the therapeutic potential of G5-FA-MTX. Results Folate targeted dendrimer bound and internalized in a receptor-specific manner into both folate receptor β-expressing macrophage cell lines and primary mouse macrophages. The G5-FA-MTX acts as a potent anti-inflammatory agent and reduces arthritis-induced inflammatory parameters such as ankle swelling, paw volume, cartilage damage, bone resorption and body weight decrease. Conclusion The use of folate-targeted nanoparticles to specifically target MTX into macrophages may provide an effective clinical approach for anti-inflammatory therapy in rheumatoid arthritis.

Advanced nanomedicine for rheumatoid arthritis treatment: focus on active targeting

“…Several receptors such as CD44, CD64, folate receptor-beta (FR-β), vasoactive intestinal peptide (VIP) receptor, scavenger receptor class A, toll-like receptors, transforming growth factor-beta receptors, etc. were over-expressed on activated macrophages [1,[11][12][13][14][15][16].…”

“…Thomas et al [15] synthesized a folic acid-and methotrexate-conjugated poly(amidoamine) dendrimer (generation 5) to specifically target activated macrophages. Therapeutic effects were revealed by using CIA mice.…”

Molecular Concepts of Macrophage Targeting

“…As a result, the most potent of the selected ligands, 9-N-(4H-thieno[3,2-c]chromene-2-carbamoyl)-Neu5Acα2-3Galβ1-4GlcNAc ( TCC Neu5Ac), was conjugated to lipids for display on a liposomal nanoparticle, which later showed high level of in vivo affi nity toward Sn-positive macrophages. A review presenting some aspects of Sn structure and function and summarizing up-to-date progress on the identifi cation of sialic acid based high-affi nity ligands of certain well explored Siglec receptors has been done by Magesh et al [17].…”

The Development of Targeted Drug Delivery Systems for Rheumatoid Arthritis Treatment

“…Furthermore, a recent study demonstrated that PAMAM dendrimers covalently linked to both folate and methotrexate could be used to selectively deliver methotrexate to synovial macrophages (Thomas et al, 2011). Although the antifolate MTX does not have a high affinity for any MFRs, several other folate analogs have been identified that possess high affinity for FR with low affinities for other MFRs and the RFC (van der Heijden et al, 2009).…”