Engineered virus-like nanoparticles reverse heparin anticoagulation more consistently than protamine in plasma from heparin-treated patients

Gale, Andrew J.; Elias, Darlene J.; Averell, Patricia M.; Teirstein, Paul S.; Buck, Mitchell; Brown, Steven D.; Polonskaya, Zinaida; Udit, Andrew K.; Finn, M. G.

doi:10.1016/j.thromres.2011.03.021

Cited by 16 publications

(13 citation statements)

References 30 publications

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“…134 In patient samples, the modied Qb capsids also showed heparin reversal, even if high doses of heparin were administered to the patients. 135 In comparison to protamine, more consistent results were obtained for the VLPs.…”

Section: Virus-like Particlesmentioning

confidence: 67%

Functionalization of protein-based nanocages for drug delivery applications

2014

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Traditional drug delivery strategies involve drugs which are not targeted towards the desired tissue. This can lead to undesired side effects, as normal cells are affected by the drugs as well. Therefore, new systems are now being developed which combine targeting functionalities with encapsulation of drug cargo. Protein nanocages are highly promising drug delivery platforms due to their perfectly defined structures, biocompatibility, biodegradability and low toxicity. A variety of protein nanocages have been modified and functionalized for these types of applications. In this review, we aim to give an overview of different types of modifications of protein-based nanocontainers for drug delivery applications.

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Section: Virus-like Particlesmentioning

confidence: 67%

Functionalization of protein-based nanocages for drug delivery applications

2014

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“…In clinical trials patients' safety is paramount, therefore potential toxicity of new candidates for drugs is the most important issue. A number of compounds that have been primarily introduced as very effective antidotes of heparins such as delparantag (PMX-60056) (Mahan, 2014 ), REG1 Anticoagulation System (Burke, 2015 ), PM102 (Cushing et al, 2010 ), virus-like nanoparticles (VLP) (Gale et al, 2011 ) or HepArrestTM (Shenoy et al, 1999 ), later in the preclinical and even in the clinical trials revealed unacceptable side effects and failed.…”

Section: Introductionmentioning

confidence: 99%

The Toxicokinetic Profile of Dex40-GTMAC3—a Novel Polysaccharide Candidate for Reversal of Unfractionated Heparin

et al. 2016

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Though protamine sulfate is the only approved antidote of unfractionated heparin (UFH), yet may produce life threatening side effects such as systemic hypotension, catastrophic pulmonary vasoconstriction or allergic reactions. We have described 40 kDa dextrans (Dex40) substituted with glycidyltrimethylammonium chloride (GTMAC) as effective, immunogenically and hemodynamically neutral inhibitors of UFH. The aim of the present study was to evaluate in mice and rats toxicokinetic profile of the most promising polymer—Dex40-GTMAC3. Polymer was rapidly eliminated with a half-time of 12.5 ± 3.0 min in Wistar rats, and was mainly distributed to the kidneys and liver in mice. The safety studies included the measurement of blood count and blood biochemistry, erythrocyte osmotic fragility and the evaluation of the histological alterations in kidneys, liver and lungs of mice and rats in acute and chronic experiments. We found that Dex40-GTMAC3 is not only effective but also very well tolerated. Additionally, we found that protamine may cause overt hemolysis with appearance of permanent changes in the liver and kidneys. In summary, fast renal clearance behavior and generally low tissue accumulation of Dex40-GTMAC3 is likely to contribute to its superior to protamine biocompatibility. Intravenous administration of therapeutic doses to living animals does not result in the immunogenic, hemodynamic, blood, and organ toxicity. Dex40-GTMAC3 seems to be a promising effective and safe candidate for further clinical development as new UFH reversal agent.

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“…A particularly promising VLP for biomedical applications is bacteriophage Qβ, an icosahedral nanoparticle 28 nm in diameter that is composed of 180 copies of a 132 amino acid, 14.1 kDa coat protein. , The capsid has good stability toward extremes in pH and temperature, can tolerate a range of modifications made to its surface either through mutation or chemically post-assembly, − and can be expressed in E. coli in a high yield. Our group has examined various applications of Qβ; − current investigations delve into exploring the ability of Qβ variants to antagonize the anticoagulant activity of heparin. Heparin is a naturally occurring glycosaminoglycan derived primarily from porcine tissue as a heterogeneous mixture of polysaccharides with variable molecular weight (5–30 kDa) and degree of sulfation. , Its anticoagulant activity is due largely to the activation of antithrombin, which inactivates the coagulation serine proteases thrombin and factor Xa. , First put into use clinically in the 1940s, heparin remains the primary anticoagulant used today.…”

Section: Introductionmentioning

confidence: 99%

Polyvalent Hybrid Virus-Like Nanoparticles with Displayed Heparin Antagonist Peptides

et al. 2018

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The potential applications for nanomaterials continue to grow as new materials are developed and environmental and safety concerns are more adequately addressed. In particular, virus-like particles (VLPs) have myriad applications in medicine and biology, exploiting both the reliable, symmetric self-assembly mechanism and the ability to take advantage of surface functionalities that may be appropriately modified through mutation or bioconjugation. Herein we describe the design and application of hybrid VLPs for use as potent heparin antagonists, providing an alternative to the toxic heparin antidote protamine. A two-plasmid system was utilized to generate VLPs that contain both the wild-type coat protein and a second coat protein with either a C- or N-terminal cationic peptide extension (4-28 amino acids). Incorporation of the modified coat proteins varied from 8 to 31%, while activated partial thromboplastin time (APTT) assays revealed a range of the heparin antagonist activity. Notably, when examined on the basis of the quantity of peptide delivered due to the varied incorporation rates, it appeared that the VLPs largely followed a similar trend, with the quantity of peptide delivered more closely correlating with heparin antagonist activity. The particle with the highest incorporation rate and best antiheparin activity displayed the C-terminal peptide ARKAKA, which corresponds to the Cardin-Weintraub consensus sequence for binding to glycosaminoglycans. Analysis of this particle using heparin affinity chromatography with fraction collection revealed that particles eluting at higher salt concentration had a greater proportion of peptide incorporation. Preliminary dual polarization interferometry experiments further support a strong interaction between this particle and heparin.

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Engineered virus-like nanoparticles reverse heparin anticoagulation more consistently than protamine in plasma from heparin-treated patients

Cited by 16 publications

References 30 publications

Functionalization of protein-based nanocages for drug delivery applications

Functionalization of protein-based nanocages for drug delivery applications

The Toxicokinetic Profile of Dex40-GTMAC3—a Novel Polysaccharide Candidate for Reversal of Unfractionated Heparin

Polyvalent Hybrid Virus-Like Nanoparticles with Displayed Heparin Antagonist Peptides

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