A Platelet-Inspired Paradigm for Nanomedicine Targeted to Multiple Diseases

Modery-Pawlowski, Christa L.; Kuo, Hsiao Hsuan; Baldwin, William M.; Gupta, Anirban Sen

doi:10.2217/nnm.13.113

Cited by 22 publications

(12 citation statements)

References 122 publications

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“…Additionally, systemic direct delivery of such serine protease agents can lead to indiscriminate off-target action, leading to major side effects including hemorrhage. The Sen Gupta lab has engineered platelet-inspired nanoparticle-based synthetic delivery vehicles that can bind to clot-associated activated platelets and proteins under hemodynamic shear flow 25–27 . We thus examined whether these nanoparticles can bind to the actively forming thrombi in an artery.…”

Section: Representative Resultsmentioning

confidence: 99%

Ferric Chloride-induced Murine Thrombosis Models

Nieman

Gupta

2016

JoVE

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Arterial thrombosis (blood clot) is a common complication of many systemic diseases associated with chronic inflammation, including atherosclerosis, diabetes, obesity, cancer and chronic autoimmune rheumatologic disorders. Thrombi are the cause of most heart attacks, strokes and extremity loss, making thrombosis an extremely important public health problem. Since these thrombi stem from inappropriate platelet activation and subsequent coagulation, targeting these systems therapeutically has important clinical significance for developing safer treatments. Due to the complexities of the hemostatic system, in vitro experiments cannot replicate the blood-to-vessel wall interactions; therefore, in vivo studies are critical to understand pathological mechanisms of thrombus formation. To this end, various thrombosis models have been developed in mice. Among them, ferric chloride (FeCl3) induced vascular injury is a widely used model of occlusive thrombosis that reports platelet activation and aggregation in the context of an aseptic closed vascular system. This model is based on redox-induced endothelial cell injury, which is simple and sensitive to both anticoagulant and anti-platelets drugs. The time required for the development of a thrombus that occludes blood flow gives a quantitative measure of vascular injury, platelet activation and aggregation that is relevant to thrombotic diseases. We have significantly refined this FeCl3-induced vascular thrombosis model, which makes the data highly reproducible with minimal variation. Here we describe the model and present representative data from several experimental set-ups that demonstrate the utility of this model in thrombosis research.

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Section: Representative Resultsmentioning

confidence: 99%

Ferric Chloride-induced Murine Thrombosis Models

Nieman

Gupta

2016

JoVE

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“…In vivo hemostatic efficacy has been reported for this product in terms of reducing bleeding in preclinical animal models. Interestingly, isolated platelet membrane based technologies have also been recently reported by several research groups in the context of coating drug delivery vehicles (e.g., polymeric and silica nano/microparticles) to demonstrate targeted action in treating cancer and bacterial infection, thereby emphasizing the potential utilization of platelet's role in multiple pathologies for unique treatment strategies . Figure shows selected results from hemostatic studies with IPM, where addition of IPM in thrombocytopenic blood perfused ex vivo in rabbit aorta segments dose‐dependently increased fibrin deposition at low and high shear rates (shown in Figure A) and in vivo administration of IPM in thrombocytopenic rabbits resulted in reduction of bleeding time (shown in Figure B).…”

Section: Hemostatic Materials and Technologies For Intravenous Applicmentioning

confidence: 99%

Biomaterials and Advanced Technologies for Hemostatic Management of Bleeding

et al. 2017

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Bleeding complications arising from trauma, surgery, and as congenital, disease-associated, or drug-induced blood disorders can cause significant morbidities and mortalities in civilian and military populations. Therefore, stoppage of bleeding (hemostasis) is of paramount clinical significance in prophylactic, surgical, and emergency scenarios. For externally accessible injuries, a variety of natural and synthetic biomaterials have undergone robust research, leading to hemostatic technologies including glues, bandages, tamponades, tourniquets, dressings, and procoagulant powders. In contrast, treatment of internal noncompressible hemorrhage still heavily depends on transfusion of whole blood or blood's hemostatic components (platelets, fibrinogen, and coagulation factors). Transfusion of platelets poses significant challenges of limited availability, high cost, contamination risks, short shelf-life, low portability, performance variability, and immunological side effects, while use of fibrinogen or coagulation factors provides only partial mechanisms for hemostasis. With such considerations, significant interdisciplinary research endeavors have been focused on developing materials and technologies that can be manufactured conveniently, sterilized to minimize contamination and enhance shelf-life, and administered intravenously to mimic, leverage, and amplify physiological hemostatic mechanisms. Here, a comprehensive review regarding the various topical, intracavitary, and intravenous hemostatic technologies in terms of materials, mechanisms, and state-of-art is provided, and challenges and opportunities to help advancement of the field are discussed.

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“…In vivo , SynthoPlate vesicles showed reasonably long circulation periods, and were primarily cleared by the liver and spleen. The SynthoPlate technology may also find potential uses in the emergency treatment of traumatic hemorrhage, and as a targeted drug delivery platform in various platelet‐relevant diseases .…”

Section: Discussionmentioning

confidence: 99%

In vitro characterization of SynthoPlate™ (synthetic platelet) technology and its in vivo evaluation in severely thrombocytopenic mice

Shukla

Sekhon

Betapudi

et al. 2017

Journal of Thrombosis and Haemostasis

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Summary Background Platelet transfusion applications face severe challenges due to the limited availability and portability, high risk of contamination and short shelf-life of platelets. Therefore there is significant interest in synthetic platelet substitutes that can render hemostasis while avoiding these issues. Platelets promote hemostasis by injury site-selective adhesion and aggregation, and propagation of coagulation reactions on their membrane. Based on these mechanisms, we have developed a synthetic platelet technology (SynthoPlateTM) that integrates platelet-mimetic site-selective ‘adhesion’ and ‘aggregation’ functionalities via heteromultivalent surface-decoration of lipid vesicles with Von Willebrand Factor-binding, collagen-binding and active platelet integrin GPIIb-IIIa-binding peptides. Objective SynthoPlateTM was evaluated for its effects on platelets and plasma in vitro, and for systemic safety and hemostatic efficacy in severely thrombocytopenic mice in vivo. Methods In vitro, SynthoPlateTM was evaluated using aggregometry, fluorescence microscopy, microfluidics, and thrombin and fibrin generation assays. In vivo, SynthoPlateTM was evaluated for systemic safety using prothrombin and fibrin assays on plasma and for hemostatic effect on tail-transection bleeding time in severely thrombocytopenic (TCP) mice. Results SynthoPlateTM did not aggregate resting platelets or spontaneously promote coagulation in plasma, but could amplify recruitment and aggregation of active platelets at the bleeding site and thereby site-selectively enhance fibrin generation. SynthoPlateTM dose-dependently reduced bleeding time in TCP mice, to levels comparable to normal mice. SynthoPlateTM has a reasonable circulation residence time and is cleared mostly by the liver and spleen. Conclusion The results demonstrate the promise of SynthoPlateTM as a synthetic platelet substitute in transfusion treatment of platelet-related bleeding complications.

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A Platelet-Inspired Paradigm for Nanomedicine Targeted to Multiple Diseases

Cited by 22 publications

References 122 publications

Ferric Chloride-induced Murine Thrombosis Models

Ferric Chloride-induced Murine Thrombosis Models

Biomaterials and Advanced Technologies for Hemostatic Management of Bleeding

In vitro characterization of SynthoPlate™ (synthetic platelet) technology and its in vivo evaluation in severely thrombocytopenic mice

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