Abstract
Inflammation is in part defined by the transient upregulation of cell adhesion molecules on the surface of endothelial cells (ECs) in response to cytokines. We hypothesized that liposomes with a complementary surface presentation of antibodies to the pattern of molecules on the EC surface may enhance targeting. We quantified the expression of vascular cell adhesion molecule-1 (VCAM1) and endothelial leukocyte cell adhesion molecule-1 (E-selectin) on ECs upon exposure to either tumor necrosis factor-α (TNF-α) or interleukin-1α (IL-1α) as a function of time. Liposomes, composed of 95 mol% dioleoyl phosphatidylcholine (DOPC) and 5 mol% dodecanyl phosphatidylethanolamine (N-dod-PE), were prepared by conjugating different molar ratios of antibodies against VCAM1 (aVCAM1) and E-selectin (aE-selectin). Increased binding was observed when immunoliposomes complemented the presentation of VCAM1:E-selectin expressed on TNF-α activated ECs. The 1:1 aVCAM1:aE-selectin liposomes had maximal binding at both 6 and 24 h on IL-1α activated ECs due to differences in molecular organization. The results demonstrate that liposomes targeting to inflamed endothelium may be optimized by exploiting the dynamic expression of VCAM1 and E-selectin on the EC surface.
Highlights
The transient expression of cell adhesion molecules on endothelial cells (ECs) presents a targeting opportunity for inflamed endothelium [1,2,3]
We quantified the expression of vascular cell adhesion molecule-1 (VCAM1) and endothelial leukocyte cell adhesion molecule-1 (E-selectin) on ECs upon exposure to either tumor necrosis factor-α (TNF-α) or interleukin-1α (IL-1α) as a function of time
After conjugation with against VCAM1 (aVCAM1) and aE-selectin, liposome diameters increased to 223 ± 3 nm; the diameters were similar for all liposome formulations
Summary
The transient expression of cell adhesion molecules on endothelial cells (ECs) presents a targeting opportunity for inflamed endothelium [1,2,3]. (ICAM1), endothelial leukocyte adhesion molecule-1 (E-selectin), and vascular cell adhesion molecule-1 (VCAM1) are upregulated on ECs upon activation with inflammatory cytokines [46]. Each of these molecules has been investigated for targeting [7,8,9]; no binding studies have correlated the ratio of antibodies on drug delivery vehicles with the presentation of target molecules on ECs. Targeting multiple, transiently-upregulated cell adhesion molecules on ECs may amplify binding specificity and cellular uptake of drug delivery vehicles. Our previous reports demonstrated that the antibody ratio (aICAM1:aE-selectin) and lipid mobility influenced cellular binding [13]
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