Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood–brain barrier

Abstract

Drug targeting to inflammatory brain pathologies such as stroke and traumatic brain injury remains an elusive goal. Using a mouse model of acute brain inflammation induced by local tumor necrosis factor alpha (TNFα), we found that uptake of intravenously injected antibody to vascular cell adhesion molecule 1 (anti-VCAM) in the inflamed brain is >10-fold greater than antibodies to transferrin receptor-1 and intercellular adhesion molecule 1 (TfR-1 and ICAM-1). Furthermore, uptake of anti-VCAM/liposomes exceeded that of anti-TfR and anti-ICAM counterparts by ∼27- and ∼8-fold, respectively, achieving brain/blood ratio >300-fold higher than that of immunoglobulin G/liposomes. Single-photon emission computed tomography imaging affirmed specific anti-VCAM/liposome targeting to inflamed brain in mice. Intravital microscopy via cranial window and flow cytometry showed that in the inflamed brain anti-VCAM/liposomes bind to endothelium, not to leukocytes. Anti-VCAM/LNP selectively accumulated in the inflamed brain, providing de novo expression of proteins encoded by cargo messenger RNA (mRNA). Anti-VCAM/LNP-mRNA mediated expression of thrombomodulin (a natural endothelial inhibitor of thrombosis, inflammation, and vascular leakage) and alleviated TNFα-induced brain edema. Thus VCAM-directed nanocarriers provide a platform for cerebrovascular targeting to inflamed brain, with the goal of normalizing the integrity of the blood–brain barrier, thus benefiting numerous brain pathologies.

Nanomaterial Delivery Systems for mRNA Vaccines

“…The liver hepatocyte-directed LNP then became largely redirected to the lung. A similar approach using a VCAM ligand successfully targeted LNPs to inflamed regions of the brain and alleviated TNF-α-induced brain edema [ 159 ]. Dendritic cells in vitro were also more efficiently transfected using a mannosylated liposome, which may be a strategy applicable to vaccination [ 160 ].…”

Neuroinflammation after surgery: from mechanisms to therapeutic targets

“…SPMs are not the only target for PNDs, and other therapies aimed, for example, at stabilizing the BBB may precisely disengage this systemic-to-central immune response. One example is the use of targeted nanocarriers to finely regulate the cerebral vasculature, for example, via vascular cell adhesion molecule 1 (VCAM-1) expression 105 . Notably, endothelial VCAM-1 has been described as a key regulator of inflammation during aging, and administration of an anti-VCAM1 antibody reduces neuroinflammation and improves cognition in these mice 106 .…”

Recent Advances in Nanocarrier-Assisted Therapeutics Delivery Systems

“…This novel approach profoundly reduced the hepatic uptake and helped guiding the nanocarriers to the desired organs [21]. Using a similar approach, Marcos-Contreras et al developed a liposomal nanocarrier conjugated with antibodies that are specific to the endothelium while carrying the mRNA of thrombomodulin, a natural endothelial inhibitor of thrombosis, inflammation, and vascular leakage [22]. These liposomal mRNA nanocarriers were able to target the inflamed cerebral vasculature and alleviate TNF-induced acute brain inflammation [22].…”