Unchain My Blood: Lessons Learned from Self-Assembled Dendrimers as Nanoscale Heparin Binders

This review work reports a collection of coupled experimental/computational results taken from our own experience in the field of self-assembled dendrimers for heparin binding. These studies present and discuss both the potentiality played by this hybrid methodology to the design, synthesis, and development of possible protamine replacers for heparin anticoagulant activity reversal in biomedical applications, and the obstacles this field has still to overcome before these molecules can be translated into nanomedicines available in clinical settings.

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Pharmacokinetics of Full Length and Two-Domain Tissue Factor Pathway Inhibitor in Combination with Heparin in Rabbits

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649604 ◽

1993 ◽

Vol 70 (03) ◽

pp. 454-457 ◽

Cited By ~ 14

Author(s):

Claus Bregengaard ◽

Ole Nordfang ◽

Per Østergaard ◽

Jens G L Petersen ◽

Giorgio Meyn ◽

...

Keyword(s):

Tissue Factor ◽

Tissue Factor Pathway Inhibitor ◽

Anticoagulant Activity ◽

Fold Increase ◽

Volume Of Distribution ◽

Full Length ◽

Heparin Binding ◽

Extrinsic Pathway ◽

C Terminus ◽

Tissue Factor Pathway

SummaryTissue factor pathway inhibitor (TFPI) is a feed back inhibitor of the initial activation of the extrinsic pathway of coagulation. In humans, injection of heparin results in a 2-6 fold increase in plasma TFPI and recent studies suggest that TFPI may be important for the anticoagulant activity of heparin. Full length (FL) TFPI, but not recombinant two-domain (2D) TFPI, has a poly cationic C-terminus showing very strong heparin binding. Therefore, we have investigated if heparin affects the pharmacokinetics of TFPI with and without this C-terminus.FL-TFPI (608 U/kg) and 2D-TFPI (337 U/kg) were injected intravenously in rabbits with and without simultaneous intravenous injections of low molecular weight heparin (450 anti-XaU/kg).Heparin decreased the volume of distribution and the clearance of FL-TFPI by a factor 10-15, whereas the pharmacokinetics of 2D-TFPI were unaffected by heparin. When heparin was administered 2 h following TFPI the recovery of FL-TFPI was similar to that found in the group receiving the two compounds simultaneously, suggesting that the releasable pool of FL-TFPI is removed very slowly in the absence of circulating heparin.

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Comparison of the Non-Specific Binding of Unfractionated Heparin and Low Molecular Weight Heparin (Enoxaparin) to Plasma Proteins

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649639 ◽

1993 ◽

Vol 70 (04) ◽

pp. 625-630 ◽

Cited By ~ 71

Author(s):

Edward Young ◽

Benilde Cosmi ◽

Jeffrey Weitz ◽

Jack Hirsh

Keyword(s):

Molecular Weight ◽

Unfractionated Heparin ◽

Plasma Proteins ◽

Low Molecular Weight Heparin ◽

Specific Binding ◽

Anticoagulant Activity ◽

Factor Xa ◽

Low Molecular Weight ◽

Heparin Binding ◽

Fixed Amount

SummaryThe non-specific binding of anticoagulantly-active heparin to plasma proteins may influence its anticoagulant effect. We used low affinity heparin (LAH) essentially devoid of anti-factor Xa activity to investigate the extent and possible mechanism of this non-specific binding. The addition of excess LAH to platelet-poor plasma containing a fixed amount of unfractionated heparin doubled the anti-factor Xa activity presumably because it displaces anticoagulantly-active heparin from plasma proteins. Although dextran sulfates of varying molecular weights also increased the anti-factor Xa activity, less sulfated heparin-like polysaccharides had no effect. These findings suggest that the ability to displace active heparin from plasma protein binding sites is related to charge and may be independent of molecular size. In contrast to its effect in plasma containing unfractionated heparin, there was little augmentation in anti-factor Xa activity when LAH was added to plasma containing low molecular weight heparin (LMWH), indicating that LMWH binds less to plasma proteins than unfractionated heparin. This concept is supported by studies comparing the anticoagulant activity of unfractionated heparin and LMWH in plasma with that in buffer containing antithrombin III. The anti-factor Xa activity of unfractionated heparin was 2-fold less in plasma than in the purified system. In contrast, LMWH had identical anti-factor Xa activity in both plasma and buffer, respectively. These findings may be clinically relevant because the recovered anti-factor Xa activity of unfractionated heparin was 33% lower in plasma from patients with suspected venous thrombosis than in plasma from healthy volunteers. The reduced heparin recovery in patient plasma reflects increased heparin binding to plasma proteins because the addition of LAH augmented the anti-factor Xa activity. In contrast to unfractionated heparin, there was complete recovery of LMWH added to patient plasma and little increase of anti-factor Xa activity after the addition of LAH. These findings may explain why LMWH gives a more predictable dose response than unfractionated heparin.

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Structurally nanoengineered antimicrobial peptide polymers: design, synthesis and biomedical applications

World Journal of Microbiology and Biotechnology ◽

10.1007/s11274-021-03109-z ◽

2021 ◽

Vol 37 (8) ◽

Author(s):

Ronisha Ramamurthy ◽

Chetan H. Mehta ◽

Usha Y. Nayak

Keyword(s):

Health Care ◽

Antimicrobial Peptide ◽

Biomedical Applications ◽

Multidrug Resistant ◽

Chronic Infections ◽

Synthesis Mechanism ◽

Design Synthesis ◽

Global Health Care ◽

Conventional Antibiotics ◽

Peptide Polymers

Abstract Antimicrobial resistance not only increases the contagiousness of infectious diseases but also a threat for the future as it is one of the health care concern around the globe. Conventional antibiotics are unsuccessful in combating chronic infections caused by multidrug-resistant (MDR) bacteria, therefore it is important to design and develop novel strategies to tackle this problems. Among various novel strategies, Structurally Nanoengineered Antimicrobial Peptide Polymers (SNAPPs) have been introduced in recent years to overcome this global health care issue and they are found to be more efficient in their performance. Many facile methods are adapted to synthesize complex SNAPPs with required dimensions and unique functionalities. Their unique characteristics and remarkable properties have been exploited for their immense applications in various fields including biomedicine, targeting therapies, gene delivery, bioimaging, and many more. This review article deals with its background, design, synthesis, mechanism of action, and wider applications in various fields of SNAPPs. Graphic abstract

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Nanochitosan: Commemorating the Metamorphosis of an ExoSkeletal Waste to a Versatile Nutraceutical

Nanomaterials ◽

10.3390/nano11030821 ◽

2021 ◽

Vol 11 (3) ◽

pp. 821

Author(s):

Iyyakkannu Sivanesan ◽

Manikandan Muthu ◽

Judy Gopal ◽

Nazim Hasan ◽

Syed Kashif Ali ◽

...

Keyword(s):

Drug Delivery ◽

Biomedical Applications ◽

Antitumor Drug ◽

Organic Polymer ◽

Clinical Settings ◽

Future Perspectives ◽

Research Focus ◽

Nano Structures

Chitin (poly-N-acetyl-D-glucosamine) is the second (after cellulose) most abundant organic polymer. In its deacetylated form—chitosan—becomes a very interesting material for medical use. The chitosan nano-structures whose preparation is described in this article shows unique biomedical value. The preparation of nanochitosan, as well as the most vital biomedical applications (antitumor, drug delivery and other medical uses), have been discussed in this review. The challenges confronting the progress of nanochitosan from benchtop to bedside clinical settings have been evaluated. The need for inclusion of nano aspects into chitosan research, with improvisation from nanotechnological inputs has been prescribed for breaking down the limitations. Future perspectives of nanochitosan and the challenges facing nanochitosan applications and the areas needing research focus have been highlighted.

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