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Nanomedicine platform for targeting activated neutrophils and neutrophil-platelet complexes using an α₁-antitrypsin-derived peptide motif.

ABSTRACT: Targeted drug delivery to disease-associated activated neutrophils can provide novel therapeutic opportunities while avoiding systemic effects on immune functions. We created a nanomedicine platform that uniquely utilizes an α₁-antitrypsin-derived peptide to confer binding specificity to neutrophil elastase on activated neutrophils. Surface decoration with this peptide enabled specific anchorage of nanoparticles to activated neutrophils and platelet-neutrophil aggregates, in vitro and in vivo. Nanoparticle delivery of a model drug, hydroxychloroquine, demonstrated significant reduction of neutrophil activities in vitro and a therapeutic effect on murine venous thrombosis in vivo. This innovative approach of cell-specific and activation-state-specific targeting can be applied to several neutrophil-driven pathologies.

SUBMITTER: Cruz MA

PROVIDER: S-EPMC9909445 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Nanomedicine platform for targeting activated neutrophils and neutrophil-platelet complexes using an α<sub>1</sub>-antitrypsin-derived peptide motif.

Cruz Michelle A MA Bohinc Dillon D Andraska Elizabeth A EA Alvikas Jurgis J Raghunathan Shruti S Masters Nicole A NA van Kleef Nadine D ND Bane Kara L KL Hart Kathryn K Medrow Kathryn K Sun Michael M Liu Haitao H Haldeman Shannon S Banerjee Ankush A Lessieur Emma M EM Hageman Kara K Gandhi Agharnan A de la Fuente Maria M Nieman Marvin T MT Kern Timothy S TS Maas Coen C de Maat Steven S Neeves Keith B KB Neal Matthew D MD Sen Gupta Anirban A Stavrou Evi X EX

Nature nanotechnology 20220718 9

Targeted drug delivery to disease-associated activated neutrophils can provide novel therapeutic opportunities while avoiding systemic effects on immune functions. We created a nanomedicine platform that uniquely utilizes an α<sub>1</sub>-antitrypsin-derived peptide to confer binding specificity to neutrophil elastase on activated neutrophils. Surface decoration with this peptide enabled specific anchorage of nanoparticles to activated neutrophils and platelet-neutrophil aggregates, in vitro and ...[more]

PMID: 35851383

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Project description:BackgroundConflicting results have been reported on platelet activity ex vivo and responsiveness in vitro among patients with COVID-19 with or without thromboembolic complications.ObjectivesTo assess platelet reactivity in patients with moderate disease at early stages of COVID-19.MethodsWe performed a prospective, descriptive analysis of 100 consecutive patients presenting with suspected SARS-CoV-2 infection at University Medical Center Freiburg during the first or second wave of the pandemic. Following polymerase chain reaction testing and compliance with study inclusion criteria, 20 SARS-CoV-2-positive and 55 SARS-CoV-2-negative patients (serving as patient controls) were enrolled. In addition, 15 healthy subjects were included. Platelet reactivity was assessed using whole-blood impedance aggregometry and flow cytometry in response to various agonists.ResultsPlatelet aggregation was significantly impaired in the patients with COVID-19 compared with that in the patient controls or healthy subjects. The reduced platelet responsiveness in the patients with COVID-19 was associated with impaired activation of GPIIb/IIIa (αIIbβ3). In contrast, low expression of P-selectin at baseline and intact secretion upon stimulation in vitro suggest that no preactivation in vivo, leading to "exhausted" platelets, had occurred. The proportion of circulating platelet-neutrophil complexes was significantly higher in the patients with COVID-19 (mean ± SD, 41% ± 13%) than in the patient controls (18% ± 7%; 95% CI, 11.1-34.1; P = .0002) or healthy subjects (17% ± 4%; 95% CI, 13.8-33.8; P < .0001). An analysis of neutrophil adhesion receptors revealed upregulation of CD11b (α-subunit of αMβ2) and CD66b (CEACAM8) but not of CD162 (PSGL-1) in the patients with COVID-19.ConclusionDespite reduced platelet responsiveness, platelet-neutrophil complexes are increased at early stages of moderate disease. Thus, this cellular interaction may occur during COVID-19 without preceding platelet activation.

Project description:Inactivation of the plasma serine-proteinase inhibitor alpha 1-antitrypsin (alpha 1-AT) by neutrophil metalloproteinases has been reported [Vissers, George, Bathurst, Brennan & Winterbourn (1987) Fed. Proc. Fed. Am. Soc. Exp. Biol. 46, 1390a; (1988) J. Clin. Invest. 82, 706-711; Desrochers & Weiss (1988) J. Clin. Invest. 81, 1646-1650]. To identify the enzyme responsible, supernatant from neutrophils stimulated with phorbol 12-myristate 13-acetate was subjected to preparative SDS/PAGE, both with and without activation of latent metalloproteinases with HgCl2. The lanes were subsequently sliced into pieces, the slices incubated with equimolar amounts of type I collagen and alpha 1-AT in the presence of HgCl2, and the reaction products separated by SDS/PAGE. With the latent supernatant, the characteristic collagen-cleavage products and cleaved alpha 1-AT were present in the same slices, corresponding to an Mr of 80,000-85,000. On treatment with HgCl2 both degradative activities underwent the same molecular-mass shift to a position corresponding to Mr 60,000-65,000. Western blots of neutrophil supernatants, using a polyclonal antibody to purified collagenase, showed Mr values of 83,000 for the latent enzyme and 63,000 for the HgCl2-activated enzyme. Neutrophil collagenase was purified to homogeneity and shown also to exist in a second latent form with Mr 70,000. When activated to the Mr-63,000 form by HgCl2 and incubated with equimolar amounts of collagen and alpha 1-AT, collagenase cleaved alpha 1-AT at almost twice the rate at which collagen was cleaved. alpha 1-AT cleavage was inhibited by 1,10-phenanthroline and by high concentrations of collagen. That the purified collagenase did not contain a contaminant proteinase such as stromelysin was indicated by inability of the preparation to cleave casein. Taken together these results lead us to conclude that neutrophil collagenase is capable of degrading alpha 1-AT. Neutrophil gelatinase also cleaved alpha 1-AT, but cleavage was slow when compared with its activity against gelatin.

Dataset Information

Nanomedicine platform for targeting activated neutrophils and neutrophil-platelet complexes using an α₁-antitrypsin-derived peptide motif.

Publications

Nanomedicine platform for targeting activated neutrophils and neutrophil-platelet complexes using an α<sub>1</sub>-antitrypsin-derived peptide motif.

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Dataset Information

Nanomedicine platform for targeting activated neutrophils and neutrophil-platelet complexes using an α1-antitrypsin-derived peptide motif.

Publications

Nanomedicine platform for targeting activated neutrophils and neutrophil-platelet complexes using an α<sub>1</sub>-antitrypsin-derived peptide motif.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Nanomedicine platform for targeting activated neutrophils and neutrophil-platelet complexes using an α₁-antitrypsin-derived peptide motif.