Abstract Number: OC 39.2
Meeting: ISTH 2021 Congress
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).
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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