Systemic administration of platelet-activating factor in rat reduces specific pulmonary uptake of circulating monoclonal antibody to angiotensin-converting enzyme

Atochina, Elena N.; Hiemisch, Holger; Muzykantov, Vladimir R.; Danilov, Sergei M.

doi:10.1007/bf00177581

Cited by 19 publications

(13 citation statements)

References 21 publications

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“…15,24,28,31,33 Certain pathological conditions suppress targeting to other constitutive endothelial determinants, such as thrombomodulin and ACE. 18,35,36 For example, endotoxin inhibits anti-ACE targeting in rats by 50% ( Figure 5). In contrast, cytokines, oxidants, abnormal shear stress, and thrombin 37 are all known to enhance endothelial ICAM-1 expression 34,38 and augment anti-ICAM vascular targeting in vivo.…”

Section: Discussionmentioning

confidence: 99%

ICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface

Murciano

Muro

Koniaris

et al. 2003

Blood

101

156

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Drug targeting to a highly expressed, noninternalizable determinant up-regulated on the perturbed endothelium may help to manage inflammation and thrombosis. We tested whether inter-cellular adhesion molecule-1 (ICAM-1) targeting is suitable to deliver antithrombotic drugs to the pulmonary vascular lumen. ICAM-1 antibodies bind to the surface of endothelial cells in culture, in perfused lungs, and in vivo. Proinflammatory cytokines enhance anti-ICAM binding to the endothelium without inducing internalization. (125)I-labeled anti-ICAM and a reporter enzyme (beta-Gal) conjugated to anti-ICAM bind to endothelium and accumulate in the lungs after intravenous administration in rats and mice. Anti-ICAM is seen to localize predominantly on the luminal surface of the pulmonary endothelium by electron microscopy. We studied the pharmacological effect of ICAM-directed targeting of tissue-type plasminogen activator (tPA). Anti-ICAM/tPA, but not control IgG/tPA, conjugate accumulates in the rat lungs, where it exerts plasminogen activator activity and dissolves fibrin microemboli. Therefore, ICAM may serve as a target for drug delivery to endothelium, for example, for pulmonary thromboprophylaxis. Enhanced drug delivery to sites of inflammation and the potential anti-inflammatory effect of blocking ICAM-1 may enhance the benefit of this targeting strategy.

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Section: Discussionmentioning

confidence: 99%

ICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface

Murciano

Muro

Koniaris

et al. 2003

Blood

101

156

View full text Add to dashboard Cite

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“…Endothelial cells internalize anti-ACE and anti-ACE conjugates, which thereby deliver drugs intracellularly (Muzykantov et al 1996a). Oxidants, cytokines, and other pathological agents suppress ACE expression and thus inhibit targeting to ACE (Watanabe et al 1992; Atochina et al 1992). Monoclonal anti-ACE with species specificity including rat, mouse, cat, primate, and human ACE selectively accumulate in the pulmonary vasculature after IV injection in these species (Danilov et al 2001, 1989; Balyasnikova et al 2005, 2006).…”

Section: Surface Determinants For Endothelial Targetingmentioning

confidence: 99%

Targeted delivery of therapeutics to endothelium

2008

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The endothelium is a target for therapeutic and diagnostic interventions in a plethora of human disease conditions including ischemia, inflammation, edema, oxidative stress, thrombosis and hemorrhage, and metabolic and oncological diseases. Unfortunately, drugs have no affinity to the endothelium, thereby limiting the localization, timing, specificity, safety, and effectiveness of therapeutic interventions. Molecular determinants on the surface of resting and pathologically altered endothelial cells, including cell adhesion molecules, peptidases, and receptors involved in endocytosis, can be used for drug delivery to the endothelial surface and into intracellular compartments. Drug delivery platforms such as protein conjugates, recombinant fusion constructs, targeted liposomes, and stealth polymer carriers have been designed to target drugs and imaging agents to these determinants. We review endothelial target determinants and drug delivery systems, describe parameters that control the binding of drug carriers to the endothelium, and provide examples of the endothelial targeting of therapeutic enzymes designed for the treatment of acute vascular disorders including ischemia, oxidative stress, inflammation, and thrombosis.

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“…The pulmonary vasculature is enriched in ACE: ~100% vs. <15% of endothelial cells are ACE-positive in the alveolar as compared with the extra-pulmonary capillaries [91]. Oxidants, cytokines and other pathological agents suppress ACE expression and thus inhibit targeting to ACE [110,111]…”

Section: Endothelial Target Determinantsmentioning

confidence: 99%

“…Reduction of the pulmonary uptake of anti-ACE is an indicator of endothelial disturbance in models of endotoxemia, edema, and ischemia–reperfusion [84,111, 113]. Limited clinical studies using thoracic imaging revealed that pulmonary uptake of isotope-labeled anti-ACE is reduced in the patients with sarcoidosis, in comparison with healthy volunteers [62].…”

Section: Endothelial Target Determinantsmentioning

confidence: 99%

Targeted endothelial nanomedicine for common acute pathological conditions

Shuvaev

Brenner

Muzykantov

2015

Journal of Controlled Release

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Endothelium, a thin monolayer of specialized cells lining the lumen of blood vessels is the key regulatory interface between blood and tissues. Endothelial abnormalities are implicated in many diseases, including common acute conditions with high morbidity and mortality lacking therapy, in part because drugs and drug carriers have no natural endothelial affinity. Precise endothelial drug delivery may improve management of these conditions. Using ligands of molecules exposed to the bloodstream on the endothelial surface enables design of diverse targeted endothelial nanomedicine agents. Target molecules and binding epitopes must be accessible to drug carriers, carriers must be free of harmful effects, and targeting should provide desirable sub-cellular addressing of the drug cargo. The roster of current candidate target molecules for endothelial nanomedicine includes peptidases and other enzymes, cell adhesion molecules and integrins, localized in different domains of the endothelial plasmalemma and differentially distributed throughout the vasculature. Endowing carriers with an affinity to specific endothelial epitopes enables an unprecedented level of precision of control of drug delivery: binding to selected endothelial cell phenotypes, cellular addressing and duration of therapeutic effects. Features of nanocarrier design such as choice of epitope and ligand control delivery and effect of targeted endothelial nanomedicine agents. Pathological factors modulate endothelial targeting and uptake of nanocarriers. Selection of optimal binding sites and design features of nanocarriers are key controllable factors that can be iteratively engineered based on their performance from in vitro to pre-clinical in vivo experimental models. Targeted endothelial nanomedicine agents provide antioxidant, anti-inflammatory and other therapeutic effects unattainable by non-targeted counterparts in animal models of common acute severe human disease conditions. The results of animal studies provide the basis for the challenging translation endothelial nanomedicine into the clinical domain.

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Systemic administration of platelet-activating factor in rat reduces specific pulmonary uptake of circulating monoclonal antibody to angiotensin-converting enzyme

Cited by 19 publications

References 21 publications

ICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface

ICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface

Targeted delivery of therapeutics to endothelium

Targeted endothelial nanomedicine for common acute pathological conditions

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