A functional platelet bionic smart carrier and its application in anti-ischemic stroke

A platelet, functionalized technology, applied in the field of medicine, can solve the problems of decreased binding force and targeting, reduced tPA thrombolytic effect, short circulation time, etc., achieves good biocompatibility, improves therapeutic effect, and avoids phagocytosis. Effect

Active Publication Date: 2021-12-03
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Tracing it to its cause, it is mainly because tPA has the defects in the following aspects: 1) tPA has a short circulation time in the body, and its half-life is only 2-5min. Therefore, clinically, continuous intravenous infusion of large doses of tPA is required to maintain effective blood drug concentration. , which increases the risk of concurrent bleeding; 2) Although compared with other fibrinolytic drugs, tPA has a specific binding force to the fibrin of the thrombus, but the drug is subjected to a huge shear force at the thrombus stenosis, making The binding force and targeting of free tPA and thrombus are greatly reduced, thereby reducing the thrombolytic effect of tPA; At risk of ischemia-reperfusion injury, thus greatly shortening the time window for tPA
Tat peptide is a high-efficiency transmembrane peptide widely used to enhance the brain targeting of drug delivery systems, but because it is rich in arginine and lysine and has a strong positive charge, its uptake and distribution in the body are not specific sex

Method used

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  • A functional platelet bionic smart carrier and its application in anti-ischemic stroke
  • A functional platelet bionic smart carrier and its application in anti-ischemic stroke
  • A functional platelet bionic smart carrier and its application in anti-ischemic stroke

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Preparation of ZL006e-loaded polymer nanoparticles:

[0033] Take 2 mg of neuroprotective agent ZL006e and 20 mg of m-Dextran into a 15 ml centrifuge tube, add 2 ml of dichloromethane, vortex to dissolve completely, and add 4 ml of PVA solution prepared in 3% 1X PBS (pH 7.4). Ultrasonic cell crusher was sonicated in ice bath (35% power, ultrasonic for 2s / stop for 2s, 5min). The sonicated white emulsion was slowly introduced into 15 ml of a PVA solution prepared with 0.3% 1X PBS (pH 7.4) in high-speed stirring (800 rpm). After continuous stirring for about 1-2 hours, the dichloromethane was completely evaporated, and the solution was clear and transparent, showing blue nanoparticle opalescence. High-speed centrifugation (12000rpm, 40min), discard the supernatant, add water to reconstitute, repeat 2-3 times to wash off the emulsifier, and finally disperse in 1ml of deionized water to obtain a ZL006e-loaded polymer nanoparticle solution.

Embodiment 2

[0035] Preparation of ZL006e-loaded Polymer Nanoparticles Coated with Platelet Membrane

[0036] Take fresh blood and centrifuge at 500g, centrifuge the upper plasma at 2000g, discard the supernatant to obtain the lower layer of red blood cells, then add deionized water and mix with red blood cells, let stand for 1-2 hours at room temperature; 5 times), stored in 1X PBS (pH 7.4), and crushed by ultrasonic cell crusher to obtain platelet membrane stock solution.

[0037] The platelet membrane stock solution was added to the ZL006e-loaded polymer nanoparticle solution prepared in Example 1 (4 ml of platelet membrane stock solution was added to each 20 mg of ZL006e-loaded polymer nanoparticle solution), and slowly stirred for 8-10 hours to obtain coated platelets Membrane-coated polymer nanocarriers. Then add NHS-PEG 3500 -N 3 (Add 10 mg of NHS-PEG per 20 mg of ZL006e-loaded polymer nanoparticle solution 3500 -N 3 ), stirring rapidly for 2 to 3 hours. High-speed centrifugat...

Embodiment 3

[0039] Preparation of polypeptide-protein conjugates linked with thrombolytic drugs rtPA and Tat penetrating peptides and thrombin substrate peptides:

[0040] Dissolve 1 mg of tPA protein in deionized water, add Sulfo-SMCC, the molar ratio of tPA:SMCC is 1:15-20, stir at 800 rpm for 2-3 hours, and add excess Pro-Tat-LTPRGWRLGGC that can be sheared and cleaved by Thrombin Polypeptide (the molar ratio of tPA:peptide segment is 1:20~30), under the condition of 4℃, continue stirring at 800rpm for 2-3h, the reaction solution is passed through MidiTrap TM G-25 desalting column eluted to remove unreacted SMCC and polypeptides, dispersed in 20 mmol HEPES buffer (Ph7.2-7.4), and obtained the penetrating peptides connected with thrombolytic drugs tPA and Tat and peptides that can be cleaved by thrombin -Protein conjugate (Pro-Tat-LTPRGWRLGGC-tPA).

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Abstract

The invention discloses a functional platelet bionic intelligent carrier and its anti-ischemic stroke application. The biomimetic carrier is composed of platelet membrane-coated polymer nanoparticles loaded with neuroprotective agent ZL006e, Tat membrane-penetrating peptide, a substrate peptide segment that can be cleaved by thrombin, and a thrombolytic protein conjugate. The carrier system has the characteristics of good biocompatibility, can effectively prolong the circulation time in the body, and can target the microthrombus at the lesion site of ischemic stroke, and release thrombolytic drugs. At the same time, the exposed Tat wears Membrane peptides mediate neuroprotective agents to increase the permeability of the blood-brain barrier, and use pH as an intelligent drug release switch to respond to the pH-mediated degradation of the lesion, so that the drug can be released quickly at the cerebral ischemic lesion, maximizing the curative effect and reducing the blood pressure. toxic side effect.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to the construction of a functional platelet bionic intelligent carrier and its anti-ischemic stroke application. Background technique [0002] With the aging of the population and the deterioration of the ecological environment, the incidence of brain diseases is increasing year by year, becoming a major disease that endangers human life and health. Among them, stroke is a cerebrovascular and blood circulation disorder disease with high morbidity, high mortality, high disability and high recurrence rate, and has become the third largest killer of human beings after cardiovascular diseases and malignant tumors. In my country, it has jumped to the second leading cause of death. Statistics from the American Heart Association in 2016 show that in the United States, one person suffers from a stroke every 40 seconds, and one person dies of a stroke every four minutes. Accor...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/64A61K47/65A61K47/50A61K9/51A61K47/46A61K47/36A61K31/606A61K38/49A61P9/10
CPCA61K9/5161A61K9/5176A61K31/606A61K38/49A61K47/50A61K47/64A61K47/65A61P9/10A61K2300/00
Inventor 辛洪亮徐剑培王晓琪尹昊媛曹想
Owner NANJING MEDICAL UNIV
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