Advanced drug delivery systems for antithrombotic agents

Greineder, Colin F.; Howard, Melissa D.; Carnemolla, Ronald; Cines, Douglas B.; Muzykantov, Vladimir R.

doi:10.1182/blood-2013-03-453498

Cited by 85 publications

(82 citation statements)

References 99 publications

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“…[48][49][50][51][52] Our priority was to establish a comparatively straightforward model, suitable for testing and comparing targeted scFv/TM with other antithrombotic drugs. 18,[53][54][55] Although the model lacks subendothelial components of a true vessel, including epithelial tissues, it allows for control over endothelial and leukocyte activation, manipulation and treatment of human WB, and quantification of therapeutic effects with high spatial and temporal resolution. While the present focus was on abrogation of fibrin deposition, additional readouts of inflammatory biology such as leukocyte adhesion and generation of neutrophil extracellular traps were also shown to be possible using this model system.…”

Section: Discussionmentioning

confidence: 99%

“…17 Our laboratory has pursued a pharmacologic approach to attenuate inflammation by specifically targeting TM to activated cellular surfaces. 18 In the first report of this strategy, recombinant mouse TM was fused to a single-chain antibody fragment (scFv) specific for mouse intracellular adhesion molecule 1 (ICAM-1, or CD54). In a murine model of acute lung injury, ICAM-1-targeted scFv/TM was found to facilitate interaction with endogenous EPCR, reduce inflammatory markers, and improve transendothelial plasma protein leakage.…”

Section: Introductionmentioning

confidence: 99%

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ICAM-1–targeted thrombomodulin mitigates tissue factor–driven inflammatory thrombosis in a human endothelialized microfluidic model

Greineder¹,

Johnston

Villa

et al. 2017

Blood Advances

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ICAM-1–targeted thrombomodulin mitigates tissue factor–driven inflammatory thrombosis in a human endothelialized microfluidic model

Greineder¹,

Johnston

Villa

et al. 2017

Blood Advances

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“…54 Studies conducted in a variety of pre-clinical animal models have established immunotargeting as a means of increasing both the pulmonary delivery and protective effects of a number of different therapeutics, including antioxidant enzymes, 55–59 antithrombotic agents, 42, 44, 60 and small-molecule drugs. 45, 61, 62 Despite this substantial body of work, it remains unclear what biophysical characteristics are optimal for the delivery of targeted drug carriers to the pulmonary endothelium.…”

Section: Discussionmentioning

confidence: 99%

Vascular Accessibility of Endothelial Targeted Ferritin Nanoparticles

Khoshnejad¹,

Shuvaev²,

Pulsipher³

et al. 2016

Bioconjugate Chem.

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Targeting nanocarriers to the endothelium, using affinity ligands to cell adhesion molecules such as ICAM-1 and PECAM-1, holds promise to improve the pharmacotherapy of many disease conditions. This approach capitalizes on the observation that antibody-targeted carriers of 100 nm and above accumulate in the pulmonary vasculature more effectively than free antibodies. Targeting of prospective nanocarriers in the 10–50 nm range, however, has not been studied. To address this intriguing issue, we conjugated monoclonal antibodies (Ab) to ICAM-1 and PECAM-1 or their single chain antigen-binding fragments (scFv) to ferritin nanoparticles (FNPs, size 12 nm), thereby producing Ab/FNPs and scFv/FNPs. Targeted FNPs retained their typical symmetric core-shell structure with sizes of 20–25 nm and ~4–5 Ab (or ~7–9 scFv) per particle. Ab/FNPs and scFv/FNPs, but not control IgG/FNPs, bound specifically to cells expressing target molecules and accumulated in the lungs after intravenous injection, with pulmonary targeting an order of magnitude higher than free Ab. Most intriguing, the targeting of Ab/FNPs to ICAM-1, but not PECAM-1, surpassed that of larger Ab/carriers targeted by the same ligand. These results indicate that: i) FNPs may provide a platform for targeting endothelial adhesion molecules with carriers in the 20 nm size range, which has not been previously reported; and, ii) ICAM-1 and PECAM-1 (known to localize in different domains of endothelial plasmalemma) differ in their accessibility to circulating objects of this size, common for blood components and nanocarriers.

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“…For example, platelets are efficient vectors for delivery of cargo to sites of vascular injury. It is plausible that by enhancing prothrombotic or antithrombotic properties, engineered platelets could provide novel treatment options for hemorrhagic or thrombotic diseases (26,27). Thus, with further enhancements to platelet quality and yield, the approach proposed by Noh et al could be developed into a practical platform in which to produce platelets at clinical scale.…”

Section: Thrombocytopenia and The Need For Alternative Platelet Sourcesmentioning

confidence: 99%

Embryonic stem cells as sources of donor-independent platelets

Canver¹,

Bauer²,

Orkin³

2015

J. Clin. Invest.

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C o m m e n t a r y Thrombocytopenia and the need for alternative platelet sourcesThe blood system comprises a hierarchy of rare, largely quiescent, self-renewing hematopoietic stem cells (HSCs) and highly proliferative lineage-committed progenitors and precursors in the bone marrow, which yield a continual supply of mature blood cells of diverse lineages (1). The nearly one trillion platelets present in circulation derive from bone marrow-resident, multinucleated megakaryocytes, which in turn derive from bipotential megakaryocyte-erythroid progenitors (MEPs). The master transcription factor GATA1 is required for maturation of MEPs into both megakaryocytic and erythroid lineages (1, 2). It is estimated that each megakaryocyte produces approximately 10 3 to 10 4 platelets, which have half-lives of only about three days in the circulation (3-6). Reduction in the number of circulating platelets, termed thrombocytopenia, is a common clinical condition with a variety of etiologies, including infectious and heritable disease, malignancy, liver failure, chemotherapy, and medication side effects (1, 4, 7-9).Transfusion of donor-derived platelets is employed with increasing frequency to treat patients with thrombocytopenia and places a high demand on platelet donation (10). Over two million platelet units are transfused annually in the United States (8, 10); however, there are multiple factors that hinder platelet transfusion. Donor platelets have only a three-to seven-day shelf life, limiting the ability to store and transport these cells and generating substantial waste through the disposal of aged platelets. Intermittent shortages arise due to a mismatch between supply and demand (11,12). Further, donor-derived platelets carry the inherent risk of viral transmission and bacterial contamination due to extended room temperature storage (8). Together, these limitations have motivated the development of sustainable donor-independent platelet sources to meet the growing need for these cells (7,11).Pluripotent embryonic stem (ES) cells or induced pluripotent stem (iPS) cells have been proposed as a potential donor-independent source of platelets. One vision is that either ES cells or iPS cells could be used to produce a renewable and immortalized progenitor-like cell line that retains the capacity to differentiate into mature megakaryocytes, which in turn would produce functional platelets. To date, attempts to employ this strategy have suffered from a poor output of PS cell-derived megakaryocytes. Moreover, inefficient generation of platelets from megakaryocytes in vitro has been an additional challenge (4,6,11,13,14). The GATA switch and regulation of megakaryopoiesisThe study of the GATA transcription factors GATA1 and GATA2 has provided insight into normal and disease-associated megakaryopoiesis. While GATA2 is highly expressed in early stem and progenitor cells, megakaryopoiesis and erythropoiesis are accompanied by a concurrent downregulation of GATA2 and upregulation of the closely related GATA1, a process referred t...

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Advanced drug delivery systems for antithrombotic agents

Cited by 85 publications

References 99 publications

ICAM-1–targeted thrombomodulin mitigates tissue factor–driven inflammatory thrombosis in a human endothelialized microfluidic model

ICAM-1–targeted thrombomodulin mitigates tissue factor–driven inflammatory thrombosis in a human endothelialized microfluidic model

Vascular Accessibility of Endothelial Targeted Ferritin Nanoparticles

Embryonic stem cells as sources of donor-independent platelets

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