Immune-stealth VP28-conjugated heparin nanoparticles for enhanced and reversible anticoagulation
Document Type
Article
Publication Date
4-22-2024
Abstract
Heparins are a family of sulfated linear negatively charged polysaccharides that have been widely used for their anticoagulant, antithrombotic, antitumor, anti-inflammatory, and antiviral properties. Additionally, it has been used for acute cerebral infarction relief as well as other pharmacological actions. However, heparin’s self-aggregated macrocomplex may reduce blood circulation time and induce life-threatening thrombocytopenia (HIT) complicating the use of heparins. Nonetheless, the conjugation of heparin to immuno-stealth biomolecules may overcome these obstacles. An immunostealth recombinant viral capsid protein (VP28) was expressed and conjugated with heparin to form a novel nanoparticle (VP28-heparin). VP28-heparin was characterized and tested to determine its immunogenicity, anticoagulation properties, effects on total platelet count, and risk of inducing HIT in animal models. The synthesized VP28-heparin trimeric nanoparticle was non-immunogenic, possessed an average hydrodynamic size (8.81 ± 0.58 nm) optimal for the evasion renal filtration and reticuloendothelial system uptake (hence prolonging circulating half-life). Additionally, VP28-heparin did not induce mouse death or reduce blood platelet count when administered at a high dose in vivo (hence reducing HIT risks). The VP28-heparin nanoparticle also exhibited superior anticoagulation properties (2.2× higher prothrombin time) and comparable activated partial thromboplastin time, but longer anticoagulation period when compared to unfractionated heparin. The anticoagulative effects of the VP28-heparin can also be reversed using protamine sulfate. Thus, VP28-heparin may be an effective and safe heparin derivative for therapeutic use. © 2024 IOP Publishing Ltd.
Keywords
Platelets, Polysaccharides, Recombinant proteins, Self assembly, Sulfur compounds, Synthesis (chemical), Viruses, anticoagulant agent, capsid protein, heparin, heparin derivative, nanoparticle, polysaccharide, protamine sulfate, Activated partial thromboplastin time, Anti-coagulation, Heparin, Heparin-induced thrombocytopenium, Self-assembly of heparin, Thrombocytopenia, Vp28 protein of white spot syndrome virus, Vp28-heparin nanoparticle, White spot syndrome virus, activated partial thromboplastin time, animal model, anticoagulation, antineoplastic activity, antiviral activity, article, brain infarction, cancer inhibition, circulation time, conjugation, controlled study, drug mechanism, drug therapy, female, genetic recombination, glomerulus filtration, half life time, heparin induced thrombocytopenia, human, hydrodynamics, immunogenicity, male, mouse, nonhuman, platelet count, prothrombin time, reticuloendothelial system, surgical planning system, thrombocytopenia, virus capsid, White spot syndrome virus, Nanoparticles
Divisions
fac_med
Funders
National Science and Technology Council, Taiwanhttps://doi.org/10.13039/501100020950 [NSTC 112-2112-M-A49-003],National Science and Technology Council, Taiwanhttps://doi.org/10.13039/501100020950 [112-2927-I-A49-001],National Science and Technology Council, Taiwanhttps://doi.org/10.13039/501100020950 [111-2112-M-A49-025],National Science and Technology Council, Taiwanhttps://doi.org/10.13039/501100020950 [111-2321-B-A49-007],National Science and Technology Council, Taiwanhttps://doi.org/10.13039/501100020950 [111-2927-I-A49-004],National Science and Technology Council, Taiwanhttps://doi.org/10.13039/501100020950 [110-2923-M-009-005-MY3],National Science and Technology Council of Taiwan,Center for Intelligent Drug Systems and Smart Biodevices (IDS2B) of NYCU,Higher Education Sprout Project of the Ministry of Education (MOE), Taiwan
Publication Title
Nanotechnology
Volume
35
Issue
17
Publisher
Institute of Physics