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Functional platelet bionic intelligent carrier and application thereof in anti-ischemic cerebral apoplexy

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, avoids phagocytosis, and improves therapeutic effect. Effect

Active Publication Date: 2019-02-22
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • Functional platelet bionic intelligent carrier and application thereof in anti-ischemic cerebral apoplexy
  • Functional platelet bionic intelligent carrier and application thereof in anti-ischemic cerebral apoplexy
  • Functional platelet bionic intelligent carrier and application thereof in anti-ischemic cerebral apoplexy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Preparation of polymer nanoparticles loaded with ZL006e:

[0033] Take 2mg of neuroprotective agent ZL006e and 20mg of m-Dextran in a 15ml centrifuge tube, add 2ml of dichloromethane, vortex until completely dissolved, add 4ml of PVA solution prepared with 3% 1X PBS (pH7.4). Ultrasonic cell disruptor ultrasonication in ice bath (35% power, ultrasonic 2s / stop 2s, 5min). The white emulsion after sonication was slowly introduced into 15 ml of PVA solution prepared with 0.3% 1X PBS (pH 7.4) in high-speed stirring (800 rpm). After continuous stirring for about 1-2h, the dichloromethane was completely volatilized, and the solution was clear and transparent, showing blue nanoparticle opalescence. Centrifuge at high speed (12000rpm, 40min), discard the supernatant, add water to redissolve, repeat 2-3 times to wash away the emulsifier, and finally disperse in 1ml deionized water to obtain a polymer nanoparticle solution loaded with ZL006e.

Embodiment 2

[0035] Preparation of ZL006e-loaded polymer nanoparticles coated with platelet membrane

[0036] Take 500g of fresh blood and centrifuge, take the upper layer of plasma and centrifuge at 2000g, then discard the upper layer to obtain the lower layer of red blood cells, then add deionized water and mix with red blood cells, let stand at room temperature for 1-2h; then centrifuge at 21000g, discard the supernatant (repeat 3~ 5 times), stored in 1X PBS (pH7.4), and ultrasonically pulverized by an ultrasonic cell disruptor to obtain platelet membrane stock solution.

[0037] Add the platelet membrane stock solution to the ZL006e-loaded polymer nanoparticle solution prepared in Example 1 (add 4ml of platelet membrane stock solution for every 20 mg of the ZL006e-loaded polymer nanoparticle solution), and stir slowly for 8-10 hours to obtain coated platelets Membrane-enveloped polymeric nanocarriers. Then join the NHS-PEG 3500 -N 3 (Add 10mg NHS-PEG per 20mg loaded ZL006e polymer n...

Embodiment 3

[0039] Preparation of polypeptide-protein conjugates connected with thrombolytic drug rtPA and Tat membrane-penetrating peptide and thrombin substrate peptide:

[0040] Dissolve 1mg of tPA protein in deionized water, add Sulfo-SMCC, the molar ratio of tPA:SMCC is 1:15~20, stir at 800rpm for 2-3h, add excess Pro-Tat-LTPRGWRLGGC that can be broken by Thrombin response shear Polypeptide (tPA:peptide molar ratio is 1:20~30), under the condition of 4℃, 800rpm continue to stir and react for 2-3h, and the reaction solution is passed through MidiTrap TM G-25 desalting column eluted to remove unreacted SMCC and peptides, dispersed in 20mmol HEPES buffer (Ph7.2-7.4), and obtained thrombolytic drugs tPA and Tat penetrating peptides and peptides that could 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 application thereof in anti-ischemic cerebral apoplexy. The bionic carrier is composed of polymer nanoparticles of a platelet membrane coated neuroprotectant ZL006e, a Tat cell-penetrating peptide as well as substrate peptide fragments and fibrinolytic protein conjugates capable of being cut by thrombin. The carrier system has the characteristics of excellent biocompatibility, capacity of effectively prolonging in-vivo cycle time and the like, and is capable of targeting micro-thrombus in lesions of ischemic cerebralapoplexy and releasing thrombolytic drugs. Meanwhile, the exposed Tat cell-penetrating peptide mediated neuroprotectant is capable of increasing blood-brain barrier permeability, the pH serves as an intelligent drug release switch, and the pH-mediated degradation at the lesions is responded, so that the drug is quickly released at lesions of cerebral ischemia, the curative effects are improved tothe greatest degree, and toxic and side effects are reduced.

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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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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