Combining vascular targeting and the local first pass provides 100-fold higher uptake of ICAM-1-targeted vs untargeted nanocarriers in the inflamed brain

Abstract

New advances in intra-arterial (IA) catheters offer clinically proven local interventions in the brain. Here we tested the effect of combining local IA delivery and vascular immunotargeting. Microinjection of tumor necrosis factor alpha (TNFα) in the brain parenchyma causes cerebral overexpression of Inter-Cellular Adhesion Molecule-1 (ICAM-1) in mice. Systemic intravenous injection of ICAM-1 antibody (anti-ICAM-1) and anti-ICAM-1/liposomes provided nearly an order of magnitude higher uptake in the inflamed vs normal brain (from ~0.1 to 0.8 %ID/g for liposomes). Local injection of anti-ICAM-1 and anti-ICAM-1/liposomes via carotid artery catheter provided an additional respective 2-fold and 5-fold elevation of uptake in the inflamed brain vs levels attained by IV injection. The uptake in the inflamed brain of respective untargeted IgG counterparts was markedly lower (e.g., uptake of anti-ICAM-1/liposomes was 100-fold higher vs IgG/liposomes). These data affirm the specificity of the combined effect of the first pass and immunotargeting. Intravital real-time microscopy via cranial window revealed that anti-ICAM-1/ liposomes, but not IgG/liposomes bind to the lumen of blood vessels in the inflamed brain within minutes after injection. This straightforward framework provides the basis for translational efforts towards local vascular drug targeting to the brain.

Recent Progress in Bioconjugation Strategies for Liposome-Mediated Drug Delivery

“…Bioconjugation methods for attaching antibodies to liposomal surfaces typically involve covalent bonding of the antibody to the liposome surface [91]. Much of the current literature focuses on examining new antibody designs or antibody-drug variations for therapeutic applications [92][93][94][95]. For example, Nikkhoi and colleagues explored the development of a bivalent, bispecific VHH-domain HER2-antibody fragment attached to liposomes to treat HER2-positive breast cancer [85].…”

Neuroinflammation Treatment via Targeted Delivery of Nanoparticles

“…Marcos-Contreras et al reported that conjugating anti-ICAM-1 or anti-VCAM-1 antibodies to liposomes results in efficient cerebral accumulation of the conjugated-liposomes through active targeting of endothelial cells. Superior penetration rates were measured when compared to transferrin-conjugation, another commonly used strategy to enhance nanoparticle CNS penetration (Marcos-Contreras et al, 2019. Although CNS targeting was improved, some off-target effects were still detected in these approaches, such as nanoparticle accumulation in the lungs.…”

Bivalent engagement of endothelial surface antigens is critical to prolonged surface targeting and protein delivery in vivo

“…While a significant body of literature supports the utility of affinity targeting of PECAM‐1 and ICAM‐1 for endothelial drug delivery, 13,14,16,19,24,27,29‐33 much of this work has focused on multivalent polymeric, liposomal, and protein nanoparticles, and relatively few studies have investigated the cell types targeted in vivo 28 . To determine suitability for endothelial surface delivery, we first measured the distribution of intravenously injected, fluorescent PECAM and ICAM antibodies using flow cytometry of disaggregated organs.…”