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Nanomedicine Targeting to Activated Neutrophils and Neutrophil-platelet Complexes Provides Effective Thromboprotection

1Case Western Reserve University School of Medicine, Cleveland, United States, 2Case Western Reserve University, Cleveland, United States, 3University of Pittsburgh Medical Center, Pittsburgh, United States, 4Colorado School of Mines, Golden, United States, 5University of Pittsburgh Medical Center., Pittsburgh, United States, 6University of California Irvine, Irvine, United States, 7University of Michigan, Ann Arbor, United States, 8University of Colorado Denver | Anschutz Medical Campus, Aurora, United States, 9University of Pittsburgh School of Medicine, Pittsburgh, United States

Abstract Number: OC 39.2

Meeting: ISTH 2021 Congress

Theme: Diagnostics and OMICs » Nanotechnology and Novel Biomolecules

Background: Neutrophils are the first responders to tissue damage and play a critical role in host defense against infection. However, unrestricted recruitment and function of activated neutrophils can prolong inflammation and contribute to the development of pathologic conditions such as vascular thrombosis, tumor progression, autoimmune diseases, and chronic, non-healing wounds. Increasing evidence has uncovered an unexpected phenotypic heterogeneity within the neutrophil population. Functional characterization of neutrophils isolated from individuals with chronic inflammatory states identified a distinct sub-population that exhibits a proinflammatory, activated phenotype with prolonged lifespan and susceptibility to form neutrophil extracellular traps (NETs).

Aims: To develop a therapeutic strategy that specifically targets activated, pathogenic neutrophil subsets without the ubiquitous inhibition of resting cells.

Methods: We created a nanomedicine platform that uniquely utilizes peptide surface decorations to confer binding specificity to neutrophil elastase (NE) on activated neutrophils and P-selectin on activated platelets.

Results: Nanoparticle (NP) assembly with peptide decorations enabled specific anchorage of NPs [henceforth called, platelet-neutrophil targeted nanoparticles (PNT-NP)] to activated neutrophils and platelet-neutrophil aggregates in vitro under static conditions (Fig 1A) and in a microfluidic model of deep vein thrombosis (DVT) (Fig 1B-C). Nanoparticle half-life in vivo was determined to be ~8 hours (Fig 1D). Delivery of a model drug (hydroxychloroquine) with NPs led to significant reduction of NE activity and reduced NETosis in vitro (Fig 1E-F). Importantly, pre-treatment of wild type (WT) mice with drug-loaded NPs resulted in significant reduction of inferior vena cava (IVC) thrombus weights, compared to mice treated with empty NPs (Fig 1G-H).

Platelet-neutrophil targeted nanoparticles (PNT-NP) bind to thromboinflammatory sites and effectively deliver therapeutic cargo to reduce thrombus size.

 

 

Conclusions: This targeted delivery strategy can be applied to several neutrophil-driven pathologies and minimize off-target effects associated with systemic drug administration and global inhibition of neutrophil functions.  

To cite this abstract in AMA style:

Bohinc D, Cruz M, Alvikas J, Masters N, Haldeman S, Bane K, Medrow K, Sun M, Liu H, Banerjee A, Lessieur E, Hageman K, Gandhi A, de la Fuente M, Nieman M, Kern T, Neeves K, Neal M, Sen Gupta A, Stavrou EX. Nanomedicine Targeting to Activated Neutrophils and Neutrophil-platelet Complexes Provides Effective Thromboprotection [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/nanomedicine-targeting-to-activated-neutrophils-and-neutrophil-platelet-complexes-provides-effective-thromboprotection/. Accessed December 5, 2021.

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