ICAM‐1‐targeted nanocarriers attenuate endothelial release of soluble ICAM‐1, an inflammatory regulator

Abstract

Targeting of drug nanocarriers (NCs) to intercellular adhesion molecule‐1 (ICAM‐1), an endothelial‐surface protein overexpressed in many pathologies, has shown promise for therapeutic delivery into and across this lining. However, due to the role of ICAM‐1 in inflammation, the effects of targeting this receptor need investigation. Since ICAM‐1 binding by natural ligands (leukocyte integrins) results in release of the “soluble ICAM‐1” ectodomain (sICAM‐1), an inflammatory regulator, we investigated the influence of targeting ICAM‐1 with NCs on this process. For this, sICAM‐1 was measured by ELISA from cell‐medium supernatants, after incubation of endothelial cell (EC) monolayers in the absence versus presence of anti‐ICAM NCs. In the absence of NCs, ECs released sICAM‐1 when treated with a pro‐inflammatory cytokine. This was reduced by inhibiting matrix metalloproteinases MMP‐9 or MMP‐2, yet inhibiting both did not render additive effects. Release of sICAM‐1 mainly occurred at the basolateral versus apical side, and both MMP‐9 and MMP‐2 influenced apical release, while basolateral release depended on MMP‐9. Interestingly, anti‐ICAM NCs reduced sICAM‐1 to a greater extent than MMP inhibition, both at the apical and basolateral sides. This effect was enhanced with time, although NCs had been removed after binding to cells, ruling out a “trapping” effect of NCs. Instead, inhibiting anti‐ICAM NC endocytosis counteracted their inhibition on sICAM‐1 release. Hence, anti‐ICAM NCs inhibited sICAM‐1 release by mobilizing ICAM‐1 from the cell‐surface into intracellular vesicles. Since elevated levels of sICAM‐1 associate with numerous diseases, this effect represents a secondary benefit of using ICAM‐1‐targeted NCs for drug delivery.

ICAM-1 targeting, intracellular trafficking, and functional activity of polymer nanocarriers coated with a fibrinogen-derived peptide for lysosomal enzyme replacement

“…Given that inflammation develops and contributes significantly to the progression and response to treatment of LDs [1,4], this would represent a secondary benefit of using this targeting strategy. As an example, our recent study using anti-ICAM NCs indicated that since ICAM-1 is endocytosed bound to anti-ICAM NCs, this temporarily removes ICAM-1 from the endothelial surface and, in turn, reduces the levels of soluble ICAM-1 released by endothelial cells [45]. Soluble ICAM-1 has been shown to be generated upon cleavage of membrane-expressed ICAM-1 and is a pro-inflammatory mediator [46].…”

Lysosomal enzyme replacement therapies: Historical development, clinical outcomes, and future perspectives

“…Also, by providing such an enhancement in the delivery to multiple tissues and across endothelial barriers, this strategy may help reduce the dose and, perhaps, frequency of administration, altogether lowering side effects. To this extent, a thorough investigation is warranted in order to advance this strategy, yet preliminary results show that mice tolerate these injections well and lack gross effects, including histological appearance, lack of edema or decrease in the endothelial permeability, and actually reduction of endothelial release of soluble ICAM-1, a factor involved in inflammation [448]. …”

Editorial: The launch phase of Bioengineering & Translational Medicine

“…In terms of scientific topics, BioTM has focused on subjects where Engineering, Chemical Engineering in particular, has made a strong fundamental and translational impact on the field. These topics include drug delivery, Nucleic acid delivery, Regenerative Medicine, Biotechnology, Nanomedicine, Biomedical Devices, and immunotherapy . We look forward to continue building our strengths in these fields and expand the list to include additional key areas.…”