Abstract

Intercellular adhesion molecule-1 (ICAM-1), a transmembrane glycoprotein expressed on activated endothelium and many other cells, represents a suitable target for delivery of drug nanocarriers (NCs) to disease areas. Numerous works have shown efficient targeting and intracellular transport of ICAM-1-targeted NCs, rendering significant therapeutic potential. This is the case for enzyme delivery for treatment of multitissue lysosomal storage disorders. However, those studies used formulations targeted to ICAM-1 by antibodies (anti-ICAM NCs). This poses an obstacle to preclinical evaluation of long-term treatment of such chronic maladies, caused by immunogenicity of foreign proteins administered to animals, compelling development of alternative strategies. In this work, we used radioisotope tracing, fluorescence and electron microscopy, and in vitro, cell cultures, and mouse models to evaluate polymer nanocarriers targeted to ICAM-1 by a 17-mer linear peptide derived from the ICAM-1-binding sequence of fibrinogen (γ3). Our results show that γ3 NCs target ICAM-1 with efficiency and specificity similar to that of anti-ICAM NCs, determined by using immobilized ICAM-1, native ICAM-1 expressed on endothelial cell cultures, and intravenous administration in mice. Furthermore, γ3 NCs are internalized by cells in culture and in vivo and transported to lysosomes via cell adhesion molecule-mediated endocytosis, without apparent disruption of cell junctions, similar to anti-ICAM counterparts. The degree of conservation of fibrinogen γ3 sequence and its cognate site on ICAM-1 among species (e.g., mouse, chimpanzee, and humans) reflects the interspecies targeting found for γ3 NCs, providing an avenue for exploring the translation of ICAM-1-targeting platforms in the preclinical and, perhaps, future clinical realm.