Publications

Intercellular adhesion molecule-1 (ICAM-1) is a membrane protein whose expression is enhanced at pathological sites, supporting drug delivery using nanocarriers (NCs). Any of its five extracellular domains (D1 to D5) can be targeted, yet most NC studies have used antibody (Ab) R6.5, which targets domain D2. While this provided efficient NC targeting and intracellular transport, literature indicates the absence of D2 in about 50 % of ICAM-1 isoforms expressed in mouse models. In this study, we verified the presence of ICAM-1 isoforms lacking D2 in human cells at both mRNA and protein levels, supporting the need to test Abs targeting other ICAM-1 domains. We developed a new cell model specifically lacking ICAM-1 D2 and compared R6.5 to Abs targeting D1 (Ab 15.2), D3D4 (Ab G-5), and D5 (Ab H-4). Abs G-5 and H-4 showed best targeting results, for which they were coated on model polymeric NCs. Compared to non-specific IgG NCs, both anti-ICAM-1 formulations targeted recombinant cells expressing human ICAM-1 lacking D2 and also primary cells naturally expressing the whole ICAM-1 isoform pattern observed. Both formulations were efficiently internalized by cells and trafficked to lysosomes, as previously observed for ICAM-1-targeting systems. Furthermore, NCs coated with either one of these two Abs showed good cross-species reactivity, being amenable for future pre-clinical testing. Therefore, Abs G-5 or H-4 are good options to provide ICAM-1 targeting without missing ICAM-1 isoforms lacking D2, present in human.

JTD Keywords: Adhesion molecule-1 icam-1, Anti-icam-1 antibody, Antibody-targeted nanocarriers, Design, Different receptor epitopes, Domai, Endothelial delivery, Enlimomab, Icam-1 extracellular domains, Icam-1 isoforms, Identification, Intercellular adhesion molecule 1, Monoclonal-antibodies, Nanoparticles, Targeting and endocytosi, Transport

Cell-material interactions are regulated by mimicking bone extracellular matrix on the surface of biomaterials. In this regard, reproducing the extracellular conditions that promote integrin and growth factor (GF) signaling is a major goal to trigger bone regeneration. Thus, the use of synthetic osteogenic domains derived from bone morphogenetic protein 2 (BMP-2) is gaining increasing attention, as this strategy is devoid of the clinical risks associated with this molecule. In this work, the wrist and knuckle epitopes of BMP-2 are screened to identify peptides with potential osteogenic properties. The most active sequences (the DWIVA motif and its cyclic version) are combined with the cell adhesive RGD peptide (linear and cyclic variants), to produce tailor-made biomimetic peptides presenting the bioactive cues in a chemically and geometrically defined manner. Such multifunctional peptides are next used to functionalize titanium surfaces. Biological characterization with mesenchymal stem cells demonstrates the ability of the biointerfaces to synergistically enhance cell adhesion and osteogenic differentiation. Furthermore, in vivo studies in rat calvarial defects prove the capacity of the biomimetic coatings to improve new bone formation and reduce fibrous tissue thickness. These results highlight the potential of mimicking integrin-GF signaling with synthetic peptides, without the need for exogenous GFs.© 2022 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.

JTD Keywords: adhesion formation, bmp-2, cell adhesions, in-vivo, integrin, mesenchymal stem-cells, morphogenetic protein-2, multifunctionality, osteoblastic differentiation, osteogenic differentiation, rgd-dwiva, rgd-peptides, titanium biofunctionalization, titanium surfaces, Animals, Biocompatible materials, Biomimetic peptides, Bone morphogenetic protein 2, Bone regeneration, Cell adhesions, Cell differentiation, Epitopes, Extracellular matrix, Integrins, Marrow stromal cells, Multifunctionality, Osteogenesis, Osteogenic differentiation, Peptides, Rats, Rgd-dwiva, Titanium, Titanium biofunctionalization