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Thrombin-responsive reticular polymer and application thereof

A technology of thrombin and polymer, which is applied in the field of thrombin-responsive network polymer and its application in the delivery of closed-loop thrombin inhibitors, can solve the problems of adverse reactions and low bioavailability, and achieve the goal of improving thrombus target effect on efficiency

Active Publication Date: 2020-11-03
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In order to solve the technical problems of low bioavailability and adverse reactions after administration of existing thrombin inhibitors, the present invention provides a thrombin-responsive network polymer, which is used to entrap thrombin inhibitors Agent, which can adaptively release the loaded thrombin inhibitor quickly under the action of high concentration of thrombin and slowly release it at low concentration, and finally used for closed-loop thrombin inhibitor delivery, improving its antithrombotic activity and reducing adverse reactions

Method used

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  • Thrombin-responsive reticular polymer and application thereof
  • Thrombin-responsive reticular polymer and application thereof
  • Thrombin-responsive reticular polymer and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Preparation and evaluation of "closed-loop regulation" single-molecule protein nanocapsules

[0054] 1. Preparation of single-molecule protein nanocapsules loaded with peptide or protein-like thrombin inhibitors

[0055] 1. Preparation of single-molecule protein nanocapsules (ctNCs) with thrombus targeting and thrombin responsiveness

[0056] Using solid-phase synthesis (Merrifield, R.B., Solid phase synthesis. Science 1986, 232, 341-348), synthesize thrombin-degradable peptide G(allyl) with N-terminal and C-terminal modification of allylglycine (G(allyl)) -PPRSFL-G(allyl) and the thrombus targeting peptide G(allyl)-CREKA with G(allyl) modified at the N-terminus.

[0057] Dissolve 1 mg of peptide or protein thrombin inhibitors hirudin (HV), lepirudin (Lep), desirudin (Des) and bivalirudin (Biv) in 1 mL of carbonate buffer (5 mM , pH 9.0), N-isopropylacrylamide (40mg), G(allyl)-PPRSFL-G(allyl) (10mg) and G(allyl)-CREKA (5mg) were added sequentially under stirring in an...

Embodiment 2

[0097] Preparation and evaluation of "closed-loop regulation" nanogel

[0098] 1. Preparation of nanogels loaded with thrombin inhibitors

[0099] 1. Preparation of nanogels (ctNGs) with thrombus targeting and thrombin responsiveness

[0100] The thrombus-targeting peptide G(allyl)-GCR(NMe)EKA modified with G(allyl) at the N-terminal and the thrombin-degradable peptide G(allyl)-GGLVPRGSGG modified with G(allyl) at both ends were synthesized by solid-phase synthesis -G (allyl).

[0101] The thrombin inhibitors hirudin (HV), lepirudin (Lep), desirudin (Des), bivalirudin (Biv), dabigatran etexilate (Dab), argatroban ( Arg), d-phenylalanyl-1-prolyl arginine-chloromethyl ketone (PPACK), enoxagatran (Ino), melagatran (Mel), ximelagatran (Xim), or RWJ-671818(RWJ) and acrylamide (AAm), G(allyl)-GCR(NMe)EKA, G(allyl)-GGLVPRGSGG-G(allyl)(60:2:1,mol:mol:mol) and dissolved In 0.5 mL of water, the aqueous phase was obtained. Docusate sodium (356 mg) and laureth (688 mg) were dissolved...

Embodiment 3

[0150] Preparation and evaluation of "closed-loop regulation" hydrogel

[0151] 1. Construction of "closed-loop regulation" hydrogel loaded with thrombin inhibitors

[0152] 1. Preparation of thrombus-targeting and thrombin-responsive hydrogel (ctHG)

[0153] 1 mg thrombin inhibitors hirudin (HV), lepirudin (Lep), desirudin (Des), bivalirudin (Biv), dabigatran etexilate (Dab), argatroban (Arg), d-phenylalanyl-1-prolyl arginine-chloromethyl ketone (PPACK), enoxagatran (Ino), melagatran (Mel), simelagatran (Xim) , RWJ-671818(RWJ) and methacrylamide, thrombin response peptide G(allyl)-TPRSFL-G(allyl), glycoprotein receptor antagonist G(allyl)RGD(60:2:1,mol:mol :mol) were mixed and dissolved in 2 mL of normal saline, then APS (5 mg) and TEMED (10 μL) were added, and left to stand for 5 min to form a hydrogel (ctHG).

[0154] The results show that the hydrogel can carry various thrombin inhibitors, and HV / ctHG, Lep / ctHG, Des / ctHG, Biv / ctHG, Dab / ctHG, Arg / ctHG, PPACK / ctHG, Ino / ct...

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Abstract

The invention discloses a thrombin-responsive reticular polymer and an application thereof in closed-loop thrombin inhibitor delivery, and belongs to the technical field of pharmaceutical preparations. The thrombin-responsive reticular polymer is obtained by a polymerization reaction of a polymer monomer, a thrombin degradable peptide and a thrombin targeting ligand. The polymer is used for entrapping a thrombin inhibitor, can adaptively and quickly release the loaded thrombin inhibitor under the action of high-concentration thrombin, can slowly release the thrombin inhibitor under low concentration, and is finally used for closed-loop thrombin inhibitor delivery, so that the antithrombotic activity of the thrombin inhibitor is improved, and adverse reactions are reduced.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, in particular to a thrombin-responsive network polymer and its application in the delivery of closed-loop thrombin inhibitors. Background technique [0002] Thrombus is a solid substance precipitated and formed when blood coagulates, and its main components include red blood cells, activated platelets, and fibrin. Abnormal thrombosis is the underlying cause of many cardiovascular and cerebrovascular diseases, such as pulmonary embolism, myocardial infarction, and ischemic stroke. Thrombosis in the body is a complex physiological process, and various coagulation factors participate in the coagulation cascade reaction. Among them, thrombin is an important coagulation factor that mediates the coagulation cascade reaction and converts fibrinogen into fibrin, thereby forming a stable thrombus clot. [0003] Thrombin inhibitors can specifically bind to thrombin, inhibit its activi...

Claims

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Application Information

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IPC IPC(8): A61K47/42A61K47/32A61K45/06A61K38/58A61K9/51A61K9/06A61P7/02
CPCA61K47/42A61K47/32A61K45/06A61K38/58A61K9/5138A61K9/5169A61K9/06A61P7/02
Inventor 莫然徐霄黄雪超
Owner CHINA PHARM UNIV
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