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Targeted nanoparticles modify neutrophil function in vivo.

ABSTRACT: Neutrophils play critical roles in a broad spectrum of clinical conditions. Accordingly, manipulation of neutrophil function may provide a powerful immunotherapeutic approach. However, due to neutrophils characteristic short half-life and their large population number, this possibility was considered impractical. Here we describe the identification of peptides which specifically bind either murine or human neutrophils. Although the murine and human neutrophil-specific peptides are not cross-reactive, we identified CD177 as the neutrophil-expressed binding partner in both species. Decorating nanoparticles with a neutrophil-specific peptide confers neutrophil specificity and these neutrophil-specific nanoparticles accumulate in sites of inflammation. Significantly, we demonstrate that encapsulating neutrophil modifying small molecules within these nanoparticles yields specific modulation of neutrophil function (ROS production, degranulation, polarization), intracellular signaling and longevity both in vitro and in vivo. Collectively, our findings demonstrate that neutrophil specific targeting may serve as a novel mode of immunotherapy in disease.

SUBMITTER: Vols S

PROVIDER: S-EPMC9580275 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Targeted nanoparticles modify neutrophil function <i>in vivo</i>.

Völs Sandra S Kaisar-Iluz Naomi N Shaul Merav E ME Ryvkin Arik A Ashkenazy Haim H Yehuda Avishag A Atamneh Ronza R Heinberg Adina A Ben-David-Naim Meital M Nadav Menucha M Hirsch Shira S Mitesser Vera V Salpeter Seth J SJ Dzikowski Ron R Hayouka Zvi Z Gershoni Jonathan M JM Fridlender Zvi G ZG Granot Zvi Z

Frontiers in immunology 20221005

Neutrophils play critical roles in a broad spectrum of clinical conditions. Accordingly, manipulation of neutrophil function may provide a powerful immunotherapeutic approach. However, due to neutrophils characteristic short half-life and their large population number, this possibility was considered impractical. Here we describe the identification of peptides which specifically bind either murine or human neutrophils. Although the murine and human neutrophil-specific peptides are not cross-reac ...[more]

PMID: 36275643

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Project description:Attaching affinity ligands to nanoparticles (NPs) increases selectivity for targeting cells and tissues, and can result in improved sensitivity and reduced off-target toxicity in diagnostic and therapeutic systems. The decision over key features - NP size, shape, coating strategies and targeting ligands for clinical translation is often hampered by a lack of quantitative in vivo NP homing assays. Sensitive, internally controlled assays are needed which allow for quantitative comparisons (auditions) among various formulations of targeted NPs. We recently reported the development of peptide-functionalized, isotopically-barcoded silver NPs (AgNPs) for ultrasensitive studies centered on measuring relative ratios of NP internalization into cultured cells. Here we evaluated the application of this technology for NP homing studies in live mice using peptides with previously described tissue tropism; one peptide that favors vascular beds of the normal lungs (RPARPAR; receptor neuropilin-1, or NRP-1) and another that is selective for central nervous system vessels (CAGALCY). Equimolar mixtures of the peptide-targeted Ag107-NPs and Ag109 control particles were mixed and injected intravenously. Distribution profiles of Ag107 and Ag109 in tissue extracts were determined simultaneously through inductively coupled plasma mass spectrometry (ICP-MS). Compared to non-targeted particles up to ?9-fold increased lung accumulation was seen for RPARPAR-OH AgNPs (but not for AgNPs functionalized with RPARPAR-NH2, which does not bind to NRP-1). Similarly, AgNPs functionalized with the brain-homing CAGALCY peptide were overrepresented in brain extracts. Spatial distribution (mapping) analysis by laser ablation ICP-MS (LA-ICP-MS) was used to determine the ratio Ag107/Ag109 in tissue cryosections. The mapping demonstrated preferential accumulation of the RPARPAR-AgNPs in the perivascular areas around pulmonary veins, and CAGALCY AgNPs accumulated in discrete areas of the brain (e.g. in the vessels of cerebellar fibrillary tracts). Based on these results, the internally controlled ratiometric AgNP system is suitable for quantitative studies of the effect of targeting ligands on NP biodistribution, at average tissue concentration and distribution at the microscopic level. The platform might be particularly relevant for target sites with high local variability in uptake, such as tumors.

Project description:BackgroundCommunity-acquired pneumonia (CAP) is considered the leading cause of death from infectious disease in developed countries, while complications of CAP - sepsis being the most common and challenging - increase the risk of mortality. During the progression of sepsis, a state of neutrophil 'paralysis' develops resulting in the impairment of neutrophil anti-microbial functions including: chemotaxis, production of reactive oxygen species, and formation of neutrophil extracellular traps (NETs). Mechanisms underlying defective neutrophil function remain elusive although NET formation has been implicated in the immunosuppression and increased rates of sepsis observed in neonates. There is, however, increasing evidence that statins are able to modulate neutrophil function in sepsis as several systematic reviews have concluded that statins have a role in improving infection-related outcomes and mortality while, in vitro, statins have also been shown to boost NET formation in healthy individuals.Methods/designThe 'SNOOPI' trial is a phase 4, randomised placebo-controlled trial. The aim of this study is to determine whether oral treatment with simvastatin compared to placebo optimises neutrophil anti-microbial functions in elderly patients with septic pneumonia improving patient outcomes in the elderly. The primary outcome will be NET production within 72 to 96 hours of treatment with simvastatin or placebo measured in response to a number of inflammatory mediators, including IL8, f-Met-Leu-Phe and lipopolysaccharide. Secondary outcomes include neutrophil migratory capacity; reactive oxygen species production; neutrophil phagocytic capacity; safety and tolerability of simvastatin administration within this patient group; biological markers of neutrophil activation, the inflammatory response, alveolar epithelial and endothelial injury; systemic endothelial function biomarkers and pulmonary extracellular matrix degradation. This study aims to recruit 60 patients admitted into Queen Elizabeth Hospital Birmingham NHS-Foundation Trust.DiscussionThis study will investigate the ability of in vivo simvastatin therapy to modulate neutrophil anti-microbial functions in CAP-associated sepsis.Trial registrationEudraCT number: 2012-003343-29 (Trial Registered: 26 November 2012).

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Targeted nanoparticles modify neutrophil function in vivo.

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Targeted nanoparticles modify neutrophil function <i>in vivo</i>.

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