Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium

TLDR

Vascular endothelium is a key therapeutic target for cancer, cardiovascular disease, inflammation, and oxidative stress, and research has focused on developing antibody- or peptide-based agents and nanoparticles to deliver drugs to diseased endothelial tissues. This study investigates whether engineering the shape of ligand‑displaying nanoparticles can further enhance endothelial targeting specificity. Mathematical modeling shows that nanorods achieve higher avidity and specificity through a balance of polyvalent adhesion and shear‑induced detachment that reduces nonspecific binding. In vitro microfluidic assays and in vivo mouse experiments demonstrate that rod‑shaped nanoparticles exhibit higher specific and lower nonspecific accumulation than spherical particles in lung and brain vasculature.

Abstract

Vascular endothelium offers a variety of therapeutic targets for the treatment of cancer, cardiovascular diseases, inflammation, and oxidative stress. Significant research has been focused on developing agents to target the endothelium in diseased tissues. This includes identification of antibodies against adhesion molecules and neovascular expression markers or peptides discovered using phage display. Such targeting molecules also have been used to deliver nanoparticles to the endothelium of the diseased tissue. Here we report, based on in vitro and in vivo studies, that the specificity of endothelial targeting can be enhanced further by engineering the shape of ligand-displaying nanoparticles. In vitro studies performed using microfluidic systems that mimic the vasculature (synthetic microvascular networks) showed that rod-shaped nanoparticles exhibit higher specific and lower nonspecific accumulation under flow at the target compared with their spherical counterparts. Mathematical modeling of particle–surface interactions suggests that the higher avidity and specificity of nanorods originate from the balance of polyvalent interactions that favor adhesion and entropic losses as well as shear-induced detachment that reduce binding. In vivo experiments in mice confirmed that shape-induced enhancement of vascular targeting is also observed under physiological conditions in lungs and brain for nanoparticles displaying anti–intracellular adhesion molecule 1 and anti-transferrin receptor antibodies.