Intravenous synthetic platelet (SynthoPlate) nanoconstructs reduce bleeding and improve ‘golden hour’ survival in a porcine model of traumatic arterial hemorrhage

Hickman, DaShawn A.; Pawlowski, Christa L.; Shevitz, Andrew J.; Luc, Norman; Kim, Ann; Girish, Aditya; Marks, Joyann; Ganjoo, Simi; Huang, Stephanie; Niedoba, Edward; Sekhon, Ujjal Didar Singh; Sun, Michael; Dyer, Mitchell; Neal, Matthew D.; Kashyap, Vikram S.; Gupta, Anirban Sen

doi:10.1038/s41598-018-21384-z

Cited by 61 publications

(66 citation statements)

References 67 publications

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“…FMP‐decorated nanoparticles do not activate (and aggregate) quiescent platelets (Figure S1) but only interact with active platelets . Therefore, such particles do not have systemic pro‐thrombotic risk but provide an effective way to bind active platelet‐rich clots . The FMP was conjugated to the lipid DSPE‐PEG 2k ‐Azide via copper‐catalyzed cycloaddition (Figure A).…”

Section: Methodsmentioning

confidence: 99%

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Trauma‐targeted delivery of tranexamic acid improves hemostasis and survival in rat liver hemorrhage model

Girish

Hickman

Banerjee

et al. 2019

Journal of Thrombosis and Haemostasis

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Background Trauma‐associated hemorrhage and coagulopathy remain leading causes of mortality. Such coagulopathy often leads to a hyperfibrinolytic phenotype where hemostatic clots become unstable because of upregulated tissue plasminogen activator (tPA) activity. Tranexamic acid (TXA), a synthetic inhibitor of tPA, has emerged as a promising drug to mitigate fibrinolysis. TXA is US Food and Drug Administration‐approved for treating heavy menstrual and postpartum bleeding, and has shown promise in trauma treatment. However, emerging reports also implicate TXA for off‐target systemic coagulopathy, thromboembolic complications, and neuropathy. Objective We hypothesized that targeted delivery of TXA to traumatic injury site can enable its clot‐stabilizing action site‐selectively, to improve hemostasis and survival while avoiding off‐target effects. To test this, we used liposomes as a model delivery vehicle, decorated their surface with a fibrinogen‐mimetic peptide for anchorage to active platelets within trauma‐associated clots, and encapsulated TXA within them. Methods The TXA‐loaded trauma‐targeted nanovesicles (T‐tNVs) were evaluated in vitro in rat blood, and then in vivo in a liver trauma model in rats. TXA‐loaded control (untargeted) nanovesicles (TNVs), free TXA, or saline were studied as comparison groups. Results Our studies show that in vitro, the T‐tNVs could resist lysis in tPA‐spiked rat blood. In vivo, T‐tNVs maintained systemic safety, significantly reduced blood loss and improved survival in the rat liver hemorrhage model. Postmortem evaluation of excised tissue from euthanized rats confirmed systemic safety and trauma‐targeted activity of the T‐tNVs. Conclusion Overall, the studies establish the potential of targeted TXA delivery for safe injury site‐selective enhancement and stabilization of hemostatic clots to improve survival in trauma.

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Section: Methodsmentioning

confidence: 99%

“…49 Therefore, such particles do not have systemic pro-thrombotic risk but provide an effective way to bind active platelet-rich clots. 50,51 The FMP was conjugated to the lipid DSPE-PEG 2k -Azide via copper-catalyzed cycloaddition ( Figure 3A).…”

Section: Txa-loaded Targeted Nanovesicle (T-tnv) Preparation and Chmentioning

confidence: 99%

Trauma‐targeted delivery of tranexamic acid improves hemostasis and survival in rat liver hemorrhage model

Girish

Hickman

Banerjee

et al. 2019

Journal of Thrombosis and Haemostasis

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“…31 SynthoPlate also improved mortality in a swine femoral artery injury model. 32 This consisted of a 3.5-mm arterial punch (near transection) of the femoral artery, followed by administration of saline, unmodified control particles, or SynthoPlate 1 min after injury, and monitoring of the animals for 120 min after injury. Seventy-five percent of saline-treated animals died within the first 60 min after injury, whereas 75% of animals treated with unmodified control particles died within 60-120 min after injury.…”

Section: Synthoplatementioning

confidence: 99%

“…Seventy-five percent of saline-treated animals died within the first 60 min after injury, whereas 75% of animals treated with unmodified control particles died within 60-120 min after injury. 32 Impressively, animals treated with SynthoPlate had 100% survival at 60 min and 75% survival at 120 min 32 Efficacy of SynthoPlate was further evaluated in their established mouse liver hemorrhage model. 33 This consisted of a laceration of 75% of the left middle lobe of the liver with injection of SynthoPlate particles (30 mg/kg), control particles (30 mg/kg), or saline, either 30 min before injury or 1 min after liver laceration, with surgeons blinded to the treatment group.…”

Section: Synthoplatementioning

confidence: 99%

Emerging Therapies for Prehospital Control of Hemorrhage

Klein

Tsihlis

Pritts

et al. 2020

Journal of Surgical Research

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Background: The aim of this review was to describe emerging therapies that could serve as a prehospital intervention to slow or stop noncompressible torso hemorrhage in the civilian and military settings. Hemorrhage accounts for 90% of potentially survivable military deaths and 30%-40% of trauma deaths. There is a great need to develop novel therapies to slow or stop noncompressible torso hemorrhage at the scene of the injury. Methods: A comprehensive literature search was performed using PubMed (1966 to present) for therapies not approved by the Food and Drug Administration for noncompressible torso hemorrhage in the prehospital setting. Therapies were divided into compressive versus intravascular injectable therapies. Ease of administration, skill required to use the therapy, safety profile, stability, shelf-life, mortality benefit, and efficacy were reviewed. Results: Multiple potential therapies for noncompressible torso hemorrhage are currently under active investigation. These include (1) tamponade therapies, such as gas insufflation and polyurethane foam injection; (2) freeze-dried blood products and alternatives such as lyophilized platelets; (3) nanoscale injectable therapies such as polyethylene glycol nanospheres, polyethylenimine nanoparticles, SynthoPlate, and tissue factoretargeted nanofibers; and (4) other injectable therapies such as polySTAT and adenosine, lidocaine, and magnesium. Although each of these therapies shows great promise at slowing or stopping hemorrhage in animal models of noncompressible hemorrhage, further research is needed to ensure safety and efficacy in humans. Conclusions: Multiple novel therapies are currently under active investigation to slow or stop noncompressible torso hemorrhage in the prehospital setting and show promising results.

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“…For example, small peptides that can bind to VWF, collagen, integrin αIIbβ3, and P-selectin on stimulated platelets have been used to surface-modify liposomes, to allow targeting to sites of endothelial injury, endothelial denudation, platelet activation, and thrombosis in vascular pathologies. [210][211][212][213][214][215][216][217][218][219][220] Therefore, these liposomal systems can be potentially utilized for spatio-temporally targeted drug delivery to sites of vascular disease and dysregulation. Besides liposomes, other lipidic and polymeric micelles have also been ligand-modified for vascularly targeted drug delivery.…”

Section: Incorporation Of Therapeutic Agents In Nanoparticles With Acmentioning

confidence: 99%

Vascular Nanomedicine: Current Status, Opportunities, and Challenges

Sun

Gupta

2019

Semin Thromb Hemost

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The term “nanotechnology” was coined by Norio Taniguchi in the 1970s to describe the manipulation of materials at the nano (10−9) scale, and the term “nanomedicine” was put forward by Eric Drexler and Robert Freitas Jr. in the 1990s to signify the application of nanotechnology in medicine. Nanomedicine encompasses a variety of systems including nanoparticles, nanofibers, surface nano-patterning, nanoporous matrices, and nanoscale coatings. Of these, nanoparticle-based applications in drug formulations and delivery have emerged as the most utilized nanomedicine system. This review aims to present a comprehensive assessment of nanomedicine approaches in vascular diseases, emphasizing particle designs, therapeutic effects, and current state-of-the-art. The expected advantages of utilizing nanoparticles for drug delivery stem from the particle's ability to (1) protect the drug from plasma-induced deactivation; (2) optimize drug pharmacokinetics and biodistribution; (3) enhance drug delivery to the disease site via passive and active mechanisms; (4) modulate drug release mechanisms via diffusion, degradation, and other unique stimuli-triggered processes; and (5) biodegrade or get eliminated safely from the body. Several nanoparticle systems encapsulating a variety of payloads have shown these advantages in vascular drug delivery applications in preclinical evaluation. At the same time, new challenges have emerged regarding discrepancy between expected and actual fate of nanoparticles in vivo, manufacturing barriers of complex nanoparticle designs, and issues of toxicity and immune response, which have limited successful clinical translation of vascular nanomedicine systems. In this context, this review will discuss challenges and opportunities to advance the field of vascular nanomedicine.

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Intravenous synthetic platelet (SynthoPlate) nanoconstructs reduce bleeding and improve ‘golden hour’ survival in a porcine model of traumatic arterial hemorrhage

Cited by 61 publications

References 67 publications

Trauma‐targeted delivery of tranexamic acid improves hemostasis and survival in rat liver hemorrhage model

Trauma‐targeted delivery of tranexamic acid improves hemostasis and survival in rat liver hemorrhage model

Emerging Therapies for Prehospital Control of Hemorrhage

Vascular Nanomedicine: Current Status, Opportunities, and Challenges

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