Derivatized chitosan polymers and methods of treating vascular disorders
Inventors
Baker, Shenda M. • Wiesmann, William P.
Assignees
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Publication Number
US-11911412-B2
Publication Date
2024-02-27
Expiration Date
Abstract
Described herein are methods for treating inflammation, swelling and secondary damage of the vascular and lymphatic system in a subject, for example of the brain, spinal cord, and lungs; from organ reperfusion, e.g., resulting from endothelial leakage, glycocalyx dysfunction or loss of structural integrity of the glycocalyx.
Core Innovation
The described invention provides derivatized chitosan, also described as polyglucosamine-derived cationic polymers, for treating vascular and lymphatic disorders associated with endothelial glycocalyx dysfunction or loss of structural integrity of the glycocalyx. The patent links endothelial abnormalities such as inflammation, edema, capillary leak, abnormal fluid transport, endothelial leakage, and loss of normal blood transport to glycocalyx dysfunction and endothelial integrity.
The polymer compounds include polyglucosamine derivatives, including polyglucosamine-arginine and other polyglucosamine derivative classes selected from polyglucosamine-natural amino acid derivatives, polyglucosamine-unnatural amino acid derivatives, polyglucosamine-acid amine derivatives, polyglucosamine-guanidine derivatives, and neutral polyglucosamine derivatives. The polymers include cationic moieties and are defined by structural substitution constraints including R1 substituent distribution and an integer repeat-unit parameter.
Treatment is carried out by intravenously administering an effective amount of the polymer, including intravenous bolus, continuous infusion, or intraarterial administration. The disclosed applications associate the polymer with restoring normal blood transport, endothelial integrity, and glycocalyx integrity, including reductions in endothelial leakage, blood-brain barrier permeability, and VEGF-mediated deterioration and BBB leak.
Claims Coverage
The independent claim is directed to a method of treating hemorrhagic shock by intravenous administration of a polymer defined by a repeat-unit structure and R1 substitution constraints. The dependent claims add inventive features relating to glycocalyx dysfunction or loss of structural integrity, blood-brain barrier permeability reduction, polymer charge and molecular weight, and intravenous bolus administration.
Hemorrhagic shock treatment by intravenous polymer administration
A method of treating hemorrhagic shock in a subject in need thereof, comprising intravenously administering an effective amount of a polymer to the subject, thereby treating the hemorrhagic shock.
Polymer repeat-unit structure with R1 substitution constraints
The polymer is a compound of a specified structure, wherein n is an integer between 20 and 6000, and each R1 is independently selected from hydroaen and acetyl, with substitution constraints stating that at least 25% of R1 substituents are H, at least 1% of R1 substituents are acetyl, and at least 2% of R1 substituents are a specified substituent.
Glycocalyx dysfunction or loss of structural integrity
The method includes using the treatment in hemorrhagic shock caused by dysfunction of the glycocalyx or loss of structural integrity of the glycocalyx.
Reducing blood-brain barrier permeability
The method includes reducing the permeability of the blood brain barrier.
Charged polycationic polymer
The method includes using a charged polymer that is a polycationic polymer.
Molecular weight range of the polymer
The method is carried out using a polymer whose molecular weight is between 30 and 300 kDa.
Intravenous bolus administration
The intravenous administration is performed via bolus administration.
Overall, the claim set covers treating hemorrhagic shock using an intravenously administered derivatized chitosan/polyglucosamine-derived polymer defined by a repeat-unit structure and R1 substitution distribution constraints, with additional limitations specifying glycocalyx dysfunction or integrity loss, effects on blood-brain barrier permeability, polymer being charged or policationic, a defined molecular weight range, and intravenous bolus administration.
Stated Advantages
Restoring normal blood transport and promoting endothelial integrity.
Restoring glycocalyx integrity.
Reducing endothelial leakage and blood-brain barrier permeability.
Reducing VEGF-mediated deterioration and BBB leak.
Preserving glycocalyx thickness and reducing glycocalyx shedding and Syndecan-1 levels versus LR alone.
Documented Applications
Treatment of hemorrhagic shock in a subject, including studies comparing PAAG plus LR versus LR alone.
Traumatic brain injury with reduced blood-brain barrier permeability and associated changes including microglial activation and neutrophil infiltration.
Reperfusion injury and inflammation-associated vascular dysfunction characterized by endothelial leakage, edema, and capillary leak.
Endothelial glycocalyx dysfunction or loss of structural integrity driven vascular and lymphatic disorders.
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