Vascular Targeting of Nanocarriers: Perplexing Aspects of the Seemingly Straightforward Paradigm

Abstract

Targeted nanomedicine holds promise to find clinical use in many medical areas. Endothelial cells that line the luminal surface of blood vessels represent a key target for treatment of inflammation, ischemia, thrombosis, stroke, and other neurological, cardiovascular, pulmonary, and oncological conditions. In other cases, the endothelium is a barrier for tissue penetration or a victim of adverse effects. Several endothelial surface markers including peptidases (e.g., ACE, APP, and APN) and adhesion molecules (e.g., ICAM-1 and PECAM) have been identified as key targets. Binding of nanocarriers to these molecules enables drug targeting and subsequent penetration into or across the endothelium, offering therapeutic effects that are unattainable by their nontargeted counterparts. We analyze diverse aspects of endothelial nanomedicine including (i) circulation and targeting of carriers with diverse geometries, (ii) multivalent interactions of carrier with endothelium, (iii) anchoring to multiple determinants, (iv) accessibility of binding sites and cellular response to their engagement, (v) role of cell phenotype and microenvironment in targeting, (vi) optimization of targeting by lowering carrier avidity, (vii) endocytosis of multivalent carriers via molecules not implicated in internalization of their ligands, and (viii) modulation of cellular uptake and trafficking by selection of specific epitopes on the target determinant, carrier geometry, and hydrodynamic factors. Refinement of these aspects and improving our understanding of vascular biology and pathology is likely to enable the clinical translation of vascular endothelial targeting of nanocarriers.

Uptake of citrate-coated iron oxide nanoparticles into atherosclerotic lesions in mice occurs via accelerated transcytosis through plaque endothelial cells

“…To date, only a few studies have investigated the influence of flow on nanoparticle uptake into ECs [37][38][39]. Whether the uptake is inhibited [38] or enhanced [37] in response to laminar flow most probably depends on the binding partner on the cell surface and on the size and charge of the particles [40].…”

Particle Targeting in Complex Biological Media

“…[73] Therefore, particles with different shapes can exhibit differing adhesion strengths to the vascular wall, which can influence both passive and active targeting outcomes. [29,73] Another set of factors that substantially impacts the targeting ability is the surface characteristics of the particles, including surface charge, hydrophobicity, roughness, and additional surface modifications. [2b,63a,74] These surface characteristics influence the coupling efficiency of targeting ligands onto the surface of particles, which directly determines the particle multivalency.…”

Targeting delivery of simvastatin using ICAM-1 antibody-conjugated nanostructured lipid carriers for acute lung injury therapy

“…The bio-distribution of anti-ICAM/SV/NLCs was evaluated in healthy mice, sham-operated mice, and LPS-challenged mice known with increased ICAM-1 expression (Calderon et al, 2011). which was likely due to the up-regulated ICAM-1 expression or the EPR effect in inflammation foci (Howard et al, 2014), given the potential inflammation triggered by surgery. The results demonstrated the positively correlated impact of targeted determinant expression on carriers binding in vivo.…”