ICAM-1-Targeted Nanocarriers Attenuate Endothelial Release of Soluble ICAM-1, an Inflammatory Regulator.

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TitleICAM-1-Targeted Nanocarriers Attenuate Endothelial Release of Soluble ICAM-1, an Inflammatory Regulator.
Publication TypeJournal Article
Year of Publication2017
AuthorsManthe, RL, Muro, S
JournalBioeng Transl Med
Date Published2017 Mar

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. Yet, 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 (TNF╬▒). 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.

Alternate JournalBioeng Transl Med
PubMed ID28713860
PubMed Central IDPMC5510616
Grant ListF31 HL128121 / HL / NHLBI NIH HHS / United States
R01 HL098416 / HL / NHLBI NIH HHS / United States