Development of antithrombotic nanoconjugate blocking integrin α2β1-collagen interactions
نویسندگان
چکیده
An antithrombotic nanoconjugate was designed in which a designed biomimetic peptide LWWNSYY was immobilized to the surface of poly(glycidyl methacrylate) nanoparticles (PGMA NPs). Our previous work has demonstrated LWWNSYY to be an effective inhibitor of integrin α2β1-collagen interaction and subsequent thrombus formation, however its practical application suffered from the formation of clusters in physiological environment caused by its high hydrophobicity. In our present study, the obtained LWWNSYY-PGMA nanoparticles (L-PGMA NPs) conjugate, with an improved dispersibility of LWWNSYY by PGMA NPs, have shown binding to collagen receptors with a Kd of 3.45 ± 1.06 μM. L-PGMA NPs have also proven capable of inhibiting platelet adhesion in vitro with a reduced IC50 of 1.83 ± 0.29 μg/mL. High inhibition efficiency of L-PGMA NPs in thrombus formation was further confirmed in vivo with a 50% reduction of thrombus weight. Therefore, L-PGMA NPs were developed as a high-efficiency antithrombotic nanomedicine targeted for collagen exposed on diseased blood vessel wall.
منابع مشابه
The crucial role of collagen-binding integrins in maintaining the mechanical properties of human scleral fibroblasts-seeded collagen matrix
PURPOSE The aim of this study was to identify the presence of collagen-binding integrin subunits in human scleral fibroblasts (HSFs) and investigate their actual functions in maintaining the mechanical creep properties of the HSFs-seeded collagen matrix. METHODS Primary HSFs were cultured in vitro. Reverse- transcription PCR was used to detect mRNA expression of integrin α1, α2, and β1 subuni...
متن کاملSulfonamide inhibitors of α2β1 integrin reveal the essential role of collagen receptors in in vivo models of inflammation
Small molecule inhibitors of α2β1 integrin, a major cellular collagen receptor, have been reported to inhibit platelet function, kidney injury, and angiogenesis. Since α2β1 integrin is abundantly expressed on various inflammation-associated cells, we tested whether recently developed α2β1 blocking sulfonamides have anti-inflammatory properties. Integrin α2β1 inhibitors were shown to reduce the ...
متن کاملEffects of collagenase-cleavage of type I collagen on α2β1 integrin-mediated cell adhesion
In this paper we show that collagenase-3 cleavage of type I collagen has a marked effect on α2β1 integrin-mediated interactions with the collagen fragments generated. Isolated α2β1 integrin and α2 integrin A-domain were found to bind to both native collagen and native K fragment and, to a lesser degree, native S fragment. Whole integrin and integrin A-domain binding were lost after heat denatur...
متن کاملIntegrin α2β1 mediates interactions between developing embryonic retinal cells and collagen
In the developing nervous system, the extracellular matrix provides a source of extrinsic cues to guide determination of cell fate, neuroblast migration, axon outgrowth and synapse formation. In the neural retina, undifferentiated neuroepithelial precursor cells contact extracellular matrix that contains multiple collagen types. Collagens have been shown to support retinal cell adhesion and neu...
متن کاملDiscoidin Domain Receptors Promote α1β1- and α2β1-Integrin Mediated Cell Adhesion to Collagen by Enhancing Integrin Activation
The discoidin domain receptors, DDR1 and DDR2, are receptor tyrosine kinases that bind to and are activated by collagens. Similar to collagen-binding β1 integrins, the DDRs bind to specific motifs within the collagen triple helix. However, these two types of collagen receptors recognize distinct collagen sequences. While GVMGFO (O is hydroxyproline) functions as a major DDR binding motif in fib...
متن کامل