CN113842397A - Medical nano-silver delivery system, preparation method, application and pharmaceutical composition - Google Patents

Medical nano-silver delivery system, preparation method, application and pharmaceutical composition Download PDF

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CN113842397A
CN113842397A CN202111121961.4A CN202111121961A CN113842397A CN 113842397 A CN113842397 A CN 113842397A CN 202111121961 A CN202111121961 A CN 202111121961A CN 113842397 A CN113842397 A CN 113842397A
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peg
crgd
solution
delivery system
silver
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CN113842397B (en
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缪文俊
李媛媛
牛培元
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Nanjing Tech University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A61K47/6935—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G01N33/491—Blood by separating the blood components

Abstract

The invention provides a medical nano silver delivery system, which comprises nano silver particles, wherein HS-PEG-N is used3And as bridging molecules, modifying the cRGD on the surface of the nano-silver particles to form a nano-silver delivery system cRGD-PEG-AgNPs with double modification of PEG and cRGD. The invention also provides a preparation method, application and pharmaceutical composition of the medical nano-silver delivery system. The medical nano-silver delivery system can specifically identify the activated platelets, realize active targeting and detection of thrombus, effectively inhibit aggregation and adhesion of the activated platelets, and simultaneously effectively inhibit further activation and synergy of the platelets, thereby effectively avoiding further increase of the thrombus.

Description

Medical nano-silver delivery system, preparation method, application and pharmaceutical composition
Technical Field
The invention relates to the technical field of medical metal-based nano materials, in particular to a medical nano silver delivery system, a preparation method, application and a pharmaceutical composition.
Background
Cardiovascular diseases have been fatal worldwide, the disability rate is high, and the formation of thrombus is a main cause of cardiovascular diseases. The formation of thrombus is caused by that the blood coagulation system is activated in a pathological state, so that local blood is coagulated to form thrombus, and simultaneously, activated platelets are easy to gather and adhere to the thrombus part to further enlarge the thrombus part, so that blood vessels are partially or completely blocked, so that hypoxia and ischemia of organ tissues and final necrosis are caused, and the clinical manifestations of myocardial infarction, pulmonary embolism, cerebral apoplexy and the like are shown. Therefore, early diagnosis and prevention of thrombus are of great significance to increase the cure rate and improve prognosis. Clinical research finds that the platelets have a key role in the generation and formation of thrombus, so that the reasonable regulation of platelet functions is beneficial to the prevention, detection and treatment of thrombus.
As one of the strategies for regulating platelet function, inhibition of platelet activation has received extensive attention and intensive research. At present, various medicines can be used for inhibiting the activation of blood platelets, such as aspirin and clopidogrel, and become common medicines for treating diseases related to thrombus. However, clinical research finds that the two drugs are easy to generate the phenomenon of drug resistance in the clinical treatment process, so that the treatment effect is remarkably reduced; meanwhile, the risk of major bleeding in the treatment process can be increased by increasing the administration dosage; in addition, as a prodrug, clopidogrel can play an antiplatelet role only by being metabolized and converted into an active drug through liver cytochrome P450 enzyme in two steps, and the effect is slow.
Aiming at the problems of the anti-platelet drugs in clinic, more and more new targets and corresponding anti-platelet drugs are developed, such as thrombin-mediated platelet activation antagonists, glycoprotein VI collagen-mediated platelet activation antagonists, phosphatidylinositol 3-kinase-beta (PI3K beta) antagonists, Protein Disulfide Isomerase (PDI) antagonists and the like, and the drugs mainly inhibit the activation, aggregation and adhesion of platelets to avoid the occurrence of thrombus or the further increase of existing thrombus. However, a large amount of activated platelets are often present at the thrombus site, and the activated platelets are continuously aggregated and adhered to the thrombus site, so that even though the resting platelets around the thrombus are not further activated, the activated platelets around the thrombus can still cause further expansion of the thrombus.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a medical nano-silver delivery system which can specifically identify activated platelets, realize active targeting and detection on thrombus, effectively inhibit aggregation and adhesion of the activated platelets, effectively inhibit further activation and synergism of resting platelets and effectively avoid further increase of thrombus.
According to the first aspect of the object of the invention, a medical nano silver delivery system is provided, which comprises nano silver particles, wherein HS-PEG-N is adopted3And as bridging molecules, modifying the cRGD on the surface of the nano-silver particles to form a nano-silver delivery system cRGD-PEG-AgNPs with double modification of PEG and cRGD.
Preferably, the cRGD-PEG-AgNPs have the particle size of 20-90 nm and the potential of-16 to-20 mV.
Preferably, in the cRGD-PEG-AgNPs, the content of PEG is 20-30%.
Preferably, in the cRGD-PEG-AgNPs, the content of the cRGD is 10-20%.
According to a second aspect of the present invention, there is provided a method for preparing the medical nano silver delivery system, specifically comprising the following steps:
s1: mixing and stirring a silver nitrate solution and a citric acid solution to obtain a first mixed solution, dropwise adding a sodium borohydride solution into the first mixed solution in a stirring state, continuously stirring until the mixture is uniformly mixed to obtain a second mixed solution, heating the second mixed solution to boiling, obtaining a first suspension after a period of time, standing and cooling, and separating and purifying the first suspension to obtain a purified nano silver colloid;
s2: keeping the purified nano silver colloid in a stirring state, and adding HS-PEG-N3Dropwise adding the solution into the purified nano silver colloid at a constant speed, continuously stirring to obtain a second suspension, and separating and purifying the second suspension to obtain purified PEG modified nano silver;
s3: keeping the purified PEG-modified nano silver in a stirring state, and dropwise adding a cRGD solution to the purified PEG-modified nano silver to obtain a third suspension; mixing CuSO4·5H2And (3) carrying out vortex mixing on O and ascorbic acid in advance to obtain a third mixed solution, then dropwise adding the third suspension into the third mixed solution, stirring to obtain a fourth suspension, and then separating and purifying the fourth suspension to obtain the PEG and cRGD double-modified nano-silver delivery system cRGD-PEG-AgNPs.
Preferably, in the step S1, the molar ratio of the silver nitrate to the citric acid in the first mixed solution is (1:1) - (1:5), and the volume ratio of the silver nitrate solution to the citric acid solution is 1: 1.
Preferably, in the step S1, the concentration of the sodium borohydride solution is 0.01-0.1mg/L, and the volume ratio of the sodium borohydride solution, the silver nitrate solution and the citric acid solution is (1:10:10) - (1:20: 20);
the stirring speed of the first mixed solution is 1000-.
Preferably, in the step S2, HS-PEG-N is added to the second suspension3The solution concentration is 2-3mg/mL, HS-PEG-N3Solution and purified nano silverThe volume ratio of the colloid is 1: 10;
the stirring speed of the purified nano silver colloid is 400-500 rpm; the stirring speed is 800-900rpm when the second suspension is obtained by continuously stirring, and the stirring time is more than or equal to 8 h.
Preferably, in step S3, in the third suspension, the concentration of the cRGD solution is 0.2-0.4mM, and the volume ratio of the cRGD solution to the purified PEG-modified nano silver is 1: 13;
in the third mixed solution, CuSO4·5H2The concentration of the O solution is 2-8mM, the concentration of the ascorbic acid solution is 5-20mM, and the volume of the ascorbic acid solution added into the third mixed solution is 300-;
the stirring speed in the step S3 is 800-900rpm, and the stirring time of the fourth suspension obtained by stirring is more than or equal to 12 h.
According to a third aspect of the present invention, the present invention further provides a use of the foregoing medical nano silver delivery system, where the nano silver delivery system can specifically recognize and bind to an activated platelet, so as to achieve active targeting and detection of a thrombus, and inhibit adhesion behavior of the activated platelet by occupying an active site of the activated platelet and increasing steric hindrance, and at the same time, can inhibit further activation of a platelet in a resting state, so as to inhibit aggregation and adhesion of the platelet, thereby effectively avoiding further increase of the thrombus.
According to a fourth aspect of the object of the invention, the application of the medical nano silver delivery system in the preparation of the medicine for detecting and preventing thrombus is also provided.
According to a fifth aspect of the object of the present invention, there is also provided a pharmaceutical composition comprising the aforementioned medical nanosilver delivery system.
The invention has the beneficial effects that:
1. the nano silver delivery system can be combined with a GPIIb/IIIa receptor on the surface of the activated platelet, so that the active action sites of the adhesion behavior of the activated platelet are reduced, and the GPIIb/IIIa mediated adhesion behavior of the activated platelet is blocked; meanwhile, the hydrated grain size of the cRGD-PEG-AgNPs is 60nm, and the cRGD-PEG-AgNPs has good stability in a physiological environment, so that the cRGD-PEG-AgNPs and the activated platelets are combined to easily form a stable barrier layer, the action path of the adhesion action of the activated platelets is lengthened, and the steric hindrance is increased, so that the activated platelets are difficult to aggregate and adhere to the periphery of thrombus under the synergistic action of the cRGD-PEG-AgNPs and the activated platelets, and the adhesion action of the activated platelets is effectively inhibited.
2. The nano silver delivery system can be combined with a GPIIb/IIIa receptor on the surface of an activated platelet, so that platelet-rich thrombus is actively targeted, accurate detection of the thrombus is realized, the nano silver delivery system is suitable for early diagnosis of the thrombus, continuous monitoring and preventive treatment of the treatment process, the disease process of the thrombus is relieved, related complications caused by the thrombus are prevented and avoided, and more favorable conditions are provided for treatment.
3. The nano silver delivery system of the invention passes through HS-PEG-N3One end of the chemical coupling is fixed on the AgNPs surface through Ag-S bond as bridging molecule to improve the stability of the AgNPs, and the other end is connected with the AgNPs-PEG-N through alkynyl in cRGD3The azide group of the conjugate is subjected to azide-alkynyl Husigen cycloaddition reaction under the action of a catalyst, so that PEG and cRGD are sequentially modified on the surfaces of nano-silver particles to form a stable protection structure, the conjugate has good in vitro stability and in vivo safety, can more stably play a role in vivo, ensures the targeting and inhibiting processes of the conjugate, reduces the toxic and side effects of nano-silver on normal tissues, can be stably placed in a normal-temperature PBS solution for more than one month, and is favorable for later storage, transportation and clinical transformation.
4. The preparation method provided by the invention is simple to operate, few in reaction steps, and the prepared nano system is strong in targeting capability, good in stability and high in safety.
Drawings
Fig. 1 is a schematic diagram of the synthesis of the medical nanosilver delivery system of the present invention.
Fig. 2 is a schematic diagram of the action mechanism of the medical nano silver delivery system of the invention.
FIG. 3 is an infrared spectrum of PEG-AgNPs and cRGD-PEG-AgNPs of example 1.
FIG. 4 is a graph comparing the cytotoxicity of cRGD-PEG-AgNPs in example 1 against HUVEC cells and HDFs cells at different concentrations.
FIG. 5 is a comparison of thrombus detection in PEG-AgNPs, cRGD-PEG-AgNPs and saline control group in example 1.
FIG. 6 is a graph comparing the inhibition of platelet aggregation by cRGD, PEG-AgNPs, cRGD-PEG-AgNPs and saline control groups in example 1.
FIG. 7 is a graph comparing the inhibition of activated platelet adhesion by cRGD, PEG-AgNPs, cRGD-PEG-AgNPs and saline control groups of example 1.
Detailed Description
In order to better understand the technical content of the present invention, specific embodiments are described below with reference to the accompanying drawings.
In this disclosure, aspects of the present invention are described with reference to the accompanying drawings, in which a number of illustrative embodiments are shown. Embodiments of the present disclosure are not necessarily intended to include all aspects of the invention. It should be appreciated that the various concepts and embodiments described above, as well as those described in greater detail below, may be implemented in any of numerous ways.
With reference to fig. 1, the invention provides a medical nano silver delivery system, which is prepared by taking silver nitrate as a raw material through a reduction reaction, and the surface of the nano silver is sequentially modified with PEG and cRGD, so that the adhesion behavior of activated platelets can be effectively inhibited, further activation of the platelets can be inhibited, and the activated platelets can be used for thrombus detection.
In a specific embodiment, a medical nano silver delivery system is provided, which comprises nano silver particles, wherein HS-PEG-N is adopted3And as bridging molecules, modifying the cRGD on the surface of the nano-silver particles to form a nano-silver delivery system cRGD-PEG-AgNPs with double modification of PEG and cRGD.
In a preferred embodiment, the cRGD-PEG-AgNPs have the particle size of 20-90 nm and the potential of-16-20 mV.
In a preferred embodiment, the content of PEG in the cRGD-PEG-AgNPs is 20-30%.
In a preferred embodiment, the content of cRGD in the cRGD-PEG-AgNPs is 10-20%.
According to an exemplary embodiment of the present invention, there is also provided a method for preparing the foregoing medical nano silver delivery system, as shown in fig. 1, the nano silver particles are synthesized by a chemical reduction method using silver nitrate as a raw material, and HS-PEG-N is used for the synthesis of the nano silver particles3One end of the chemical coupling is fixed on the AgNPs surface through Ag-S bond as bridging molecule to improve the stability of the AgNPs, and the other end is connected with the AgNPs-PEG-N through alkynyl in cRGD3The azide group of the double-modified nano silver delivery system cRGD-PEG-AgNPs is subjected to azide-alkynyl Husigen cycloaddition reaction under the action of a catalyst, so that PEG and cRGD are sequentially modified on the surfaces of nano silver particles to form a stable protection structure, and the double-modified nano silver delivery system cRGD-PEG-AgNPs is prepared for the first time.
In a specific embodiment, the method specifically comprises the following steps:
s1: mixing and stirring a silver nitrate solution and a citric acid solution to obtain a first mixed solution, dropwise adding a sodium borohydride solution into the first mixed solution in a stirring state, continuously stirring until the mixture is uniformly mixed to obtain a second mixed solution, heating the second mixed solution to boiling, obtaining a first suspension after a period of time, standing and cooling, and separating and purifying the first suspension to obtain a purified nano silver colloid;
s2: keeping the purified nano silver colloid in a stirring state, and adding HS-PEG-N3Dropwise adding the solution into the purified nano silver colloid at a constant speed, continuously stirring to obtain a second suspension, and separating and purifying the second suspension to obtain purified PEG modified nano silver;
s3: keeping the purified PEG-modified nano silver in a stirring state, and dropwise adding a cRGD solution to the purified PEG-modified nano silver to obtain a third suspension; mixing CuSO4·5H2Vortex mixing O and ascorbic acid to obtain a third mixed solution, and mixing with the third mixed solutionAnd dropwise adding the third suspension into the mixed solution, stirring to obtain a fourth suspension, and separating and purifying the fourth suspension to obtain the PEG and cRGD double-modified nano-silver delivery system cRGD-PEG-AgNPs.
In a preferred embodiment, in the step S1, the molar ratio of the silver nitrate to the citric acid in the first mixed solution is (1:1) - (1:5), and the volume ratio of the silver nitrate solution to the citric acid solution is 1: 1.
In a preferred embodiment, in the step S1, the concentration of the sodium borohydride solution is 0.01-0.1mg/L, and the volume ratio of the sodium borohydride solution, the silver nitrate solution and the citric acid solution is 1:10:10-1:20: 20.
The stirring speed of the first mixed solution is 1000-.
Stirring is continued until the second mixed solution is uniformly mixed, the stirring speed is 1000-1200rpm, the solution is heated to boiling and then kept for 90-100min, and the standing and cooling time is more than or equal to 5 h.
In another preferred embodiment, silver nitrate, citric acid and sodium borohydride are respectively dissolved in deionized water and precooled for 1h at 4 ℃, so that hydrolysis of the sodium borohydride in the reaction process is avoided, and the reaction rate is improved.
And then adding the silver nitrate solution and the sodium citrate solution into the round-bottom flask in sequence, stirring at the speed of 1000-.
In a preferred embodiment, in step S2, HS-PEG-N is added to the second suspension3The solution concentration is 2-3mg/mL, HS-PEG-N3The volume ratio of the solution to the purified nano silver colloid is 1: 10.
The stirring speed of the purified nano silver colloid is 400-500 rpm; the stirring speed is 800-900rpm when the second suspension is obtained by continuously stirring, and the stirring time is more than or equal to 8 h.
In a preferred embodiment, in step S3, the concentration of the cRGD solution in the third suspension is 0.2-0.4mM, and the volume ratio of the cRGD solution to the purified PEG-modified nano silver is 1: 13.
In the third mixed solution, CuSO4·5H2The concentration of the O solution is 2-8mM, the concentration of the ascorbic acid solution is 5-20mM, and the volume of the ascorbic acid solution added into the third mixed solution is 300-;
the stirring speed in the step S3 is 800-900rpm, and the stirring time of the fourth suspension obtained by stirring is more than or equal to 12 h.
In other preferred embodiments, in steps S1, S2 and S3, the separation and purification are performed by using an ultrafiltration tube, the molecular cut-off of the ultrafiltration tube is 10KDa, the centrifugation time is 10-20min, the rotation speed is 4000rpm, and the centrifugation times are 3-4 times, all at a temperature of 4 ℃.
In another embodiment, as shown in fig. 2, there is also provided a use of the foregoing medical nano silver delivery system, where the nano silver delivery system (cRGD-PEG-AgNPs) can specifically recognize and bind to Activated platelets (Activated platelets), so as to achieve active targeting and detection of thrombus, and inhibit adhesion behavior of the Activated platelets by occupying active sites of the Activated platelets and increasing steric hindrance, and at the same time, inhibit further activation of Resting platelets (Resting platelets), so as to inhibit aggregation and adhesion of platelets, thereby inhibiting aggregation and adhesion of erythrocytes (erythrocytes) and Activated platelets to form emboli to adhere to blood vessel walls, and effectively preventing thrombus from further enlargement.
In another embodiment, the application of the medical nano silver delivery system in the preparation of a medicament for detecting and preventing thrombus is further provided.
In other embodiments, a pharmaceutical composition is also provided, comprising the foregoing medical nanosilver delivery system; for example, the thrombolytic drug is loaded on the medical nano silver delivery system, so that the thrombus which is formed is treated while the thrombus is accurately targeted and inhibited.
In other embodiments, the medical nano silver delivery system can be used as a drug delivery carrier, and can accurately target a focus through specific recognition of activated platelets, so that accurate drug delivery is realized.
The preparation of the aforementioned medical nanosilver delivery system and its effects will be exemplified and compared below with specific examples and tests. Of course, the embodiments of the invention are not limited thereto.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents, and the like used in the following embodiments are commercially available unless otherwise specified.
Among them, HS-PEG-N used in the following examples3Purchased from Xiamen Sainuo Pong Biotech, Inc., molecular weight 2000Da, purity 95%.
The cRGD polypeptide was purchased from shanghai intense biotechnology limited.
[ example 1 ]
Respectively preparing 0.2mg/mL silver nitrate solution, 0.4mg/mL sodium citrate solution and 0.05mg/mL sodium borohydride solution, and storing at 4 ℃ in the dark for 1 hour.
(1) Mixing 50mL of silver nitrate solution and 50mL of sodium citrate solution, adding the mixture into a round-bottom flask, placing the round-bottom flask on a magnetic stirrer, violently stirring the mixture for 5min at the rotating speed of 1000rpm, dropwise adding 5mL of sodium borohydride solution, continuing stirring the mixture for 10min at the rotating speed of 1000rpm at room temperature after the sodium borohydride solution is completely injected, slowly heating the mixture until the mixture is boiled, maintaining the mixture in an azeotropic state for 90min, preparing a first suspension containing nano-silver colloid, and standing and cooling the first suspension for 5 h; and separating the first suspension containing the nano-silver colloids (AgNPs) by using an ultrafiltration tube, adding 10mL of freshly prepared deionized water each time, repeating for 3 times, finally concentrating the AgNPs to 50mL, transferring the purified nano-silver colloids to a sample bottle, and storing the sample bottle in a refrigerator for later use.
(2) Weighing 10mg of HS-PEG-N3Adding 5mL of deionized water, and dissolving for later use; sucking 50mL of the nano silver colloid in the step (1), placing the nano silver colloid in a round bottom flask, stirring at the rotating speed of 400rpm, and adding 5mL of HS-PEG-N3The solution is dripped into the nano silver colloid at a constant speed until HS-PEG-N3After the solution is completely injected, continuously stirring at the rotating speed of 800rpm for 8 hours to obtain a second suspension; separating the second suspension using an ultrafiltration tube, each time adding freshly prepared supernatantAnd (3) repeating the step of adding 10mL of ionized water for 3 times to obtain purified PEG-modified nano silver (PEG-AgNPs), transferring the purified PEG-AgNPs into a sample bottle, and storing the sample bottle in a refrigerator for later use.
(3) Weighing 10mg of cRGD, and adding 10mL of deionized water for dissolving; weighing a certain mass of CuSO4·5H2O, dissolving in water to make the concentration of the O0.02 mg/mL; weighing 5mg ascorbic acid, adding 100ml deionized water, and dissolving for later use; sucking the PEG-AgNPs in the step (2) into a reaction bottle, dropwise adding 3mL of cRGD solution under the high-speed stirring state at the rotating speed of 800rpm to obtain a third suspension, and simultaneously adding CuSO4·5H2Vortex mixing O and ascorbic acid in advance, dropwise adding the mixture into the third suspension under a high-speed stirring state, and continuously stirring for 12 hours to obtain a fourth suspension; and separating the fourth suspension by using an ultrafiltration tube, adding 10mL of freshly prepared deionized water each time, repeating for 3 times to obtain a purified PEG and cRGD double-modified nano-silver delivery system (cRGD-PEG-AgNPs), transferring the purified cRGD-PEG-AgNPs into a sample bottle, and storing in a refrigerator for later use.
In the above process, in the separation and purification process, the molecular cut-off of the ultrafiltration centrifugal tube is 10KDa, and the conditions are as follows: the centrifugation time was 15min, the temperature was 4 ℃ and the rotation speed was 4000 rpm.
[ example 2 ]
The nano-silver micelles (AgNPs), PEG-modified nano-silver (PEG-AgNPs) and nano-silver delivery system (cRGD-PEG-AgNPs) prepared according to the method of example 1 were diluted with deionized water, respectively, to prepare solutions having an Ag concentration of 20 μ g/mL, and then the particle sizes thereof were measured at 25 ℃.
The particle size results of the three nano systems are shown in table 1, and the particle size of the nano silver micelles (AgNPs) is 22.1 +/-0.1 nm; the grain diameter of the PEG modified nano silver (PEG-AgNPs) is 34.2 +/-0.2 nm; the particle size of the nanosilver delivery system (cRGD-PEG-AgNPs) was 58.2 + -1.8 nm. The result shows that the hydrated particle size is gradually increased along with the modification of PEG and cRGD, namely the cRGD-PEG-AgNPs are successfully prepared.
TABLE 1
Figure BDA0003277574870000081
[ example 3 ]
PEG-modified nano-silver (PEG-AgNPs) and a nano-silver system (cRGD-PEG-AgNPs) for inhibiting platelet activation and targeting thrombus prepared according to the method in the embodiment 1 are respectively freeze-dried, a proper amount of powder is taken to be mixed with potassium bromide, the mixture is ground and tableted and then placed in a Fourier-infrared spectrometer, and the wave number range is determined to be 4000-500 cm--1Internal absorption spectrum data.
The results of the IR spectroscopy analysis of PEG-AgNPs and cRGD-PEG-AgNPs are shown in FIG. 3, the IR spectrogram of PEG-AgNPs is 840-1102cm-1,1240-1462cm-1And 2718-2958cm-1The characteristic peak is the stretching vibration of PEG, which shows that the PEG is successfully coupled with the nano silver; the infrared spectrogram of cRGD-PEG-AgNPs is 1611cm-1And 1715cm-1Is a characteristic peak of amido bond, and shows that the cRGD-PEG-AgNPs are successfully prepared.
[ example 4 ]
HUVEC cells and HDFs cells were revived and seeded separately
Figure BDA0003277574870000082
Into the culture dish, 5mL of DMEM complete medium (containing 90% 1640DMEM medium, 10% fetal bovine serum, 1% penicillin-streptomycin double antibody) was added and placed in a constant temperature and humidity incubator (37 ℃, 5% CO)290% relative humidity), collecting cells by trypsinization and resuspending the cells in a DMEM complete medium; HUVEC cells and HDFs cells (1X 10)4Cells/hole) are respectively inoculated into a 96-hole plate for culturing for 12h, the culture solution is discarded, the culture solution is replaced by a nano silver system (cRGD-PEG-AgNPs, 0, 5, 10, 20, 30, 50 and 100 mu g/mL) containing different concentrations for inhibiting platelet activation and targeting thrombus, the culture is continued for 12h, 20 mu L of MTT (2.5mg/mL) solution is added into each hole, and the culture is continued to be placed in an incubator for incubation for 4 h; the medium was discarded, and formazan was dissolved by adding DMSO (150. mu.L) with shaking, and the absorbance of the sample at 570nm was measured using a microplate reader. PBS groups were used as negative controls for the experiments, with six replicates per group.
The results are shown in FIG. 4, when the concentration of cRGD-PEG-AgNPs is less than 30 μ g/mL, the survival rate of HUVEC cells and HDFs cells is greater than 95%, the survival rate of HUVEC cells and HDFs cells is slightly reduced along with the increase of the concentration, and when the concentration of cRGD-PEG-AgNPs is 100 μ g/mL, the survival rate of HUVEC cells and HDFs cells is greater than 80%, which indicates that the cRGD-PEG-AgNPs have good biocompatibility.
[ example 5 ]
Balb/c mice (20-25g) were injected with FITC (0.5%) labeled platelets via the tail vein and anesthetized with 4% chloral hydrate, the carotid artery exposed by blunt dissection, and treated with 5% FeCl3The carotid artery is incubated by the filter paper to construct a carotid artery thrombus model, after the thrombus model is successfully constructed, Cy5.5-labeled PEG-AgNPs and cRGD-PEG-AgNPs (2mg/kg) are respectively injected into the carotid artery and the carotid artery through the tail vein, the mouse is killed after administration for 1h, the carotid artery thrombus is separated and is placed under a fluorescence microscope for observation and photographing.
Results the ability of cRGD-PEG-AgNPs to actively target and detect thrombi was evaluated by different treatments as shown in fig. 5. Compared with a control group, the cRGD-PEG-AgNPs can actively target and enrich the thrombus part, clearly outline the thrombus and facilitate the realization of accurate detection of the thrombus. The results prove that the cRGD-PEG-AgNPs can realize the specific combination and accurate detection of the thrombus.
[ example 6 ]
Placing freshly collected rabbit blood in a centrifuge tube containing an anticoagulant, centrifuging at 1000rpm for 12min, removing upper layer platelet-rich plasma, placing the upper layer platelet-rich plasma in an EP tube (500 mu L), adding PBS, cRGD, PEG-AgNPs and cRGD-PEG-AgNPs (the concentration of Ag is 20 mu g/mL) into each tube, gently mixing the tubes, placing the tubes in a water bath at 37 ℃ for incubation for 2min, adding a platelet activator Collagen (Collagen), and monitoring the absorbance change of all samples at 680nm by using an ultraviolet visible spectrophotometer until the absorbance value of all samples is stable and unchanged.
As shown in fig. 6, the aggregation rate of the cRGD-treated platelets was slightly decreased by 17.2% compared to the PBS group (positive control), which is probably because cRGD can bind to GPIIb/IIIa receptors on activated platelets to inhibit GPIIb/IIIa-mediated platelet aggregation, but the inhibitory effect was not significant. In contrast, the platelets of the PEG-AgNPs and cRGD-PEG-AgNPs groups do not obviously aggregate, and the light transmittance of the platelets does not obviously change along with the time extension, which indicates that the PEG-AgNPs and the cRGD-PEG-AgNPs can effectively inhibit the activation and aggregation of the platelets, thereby inhibiting the formation and development of thrombus.
[ example 7 ]
Placing freshly collected rabbit blood in a centrifuge tube containing an anticoagulant, centrifuging at 1000rpm for 12min, transferring the upper platelet-rich plasma, placing the upper platelet-rich plasma in an EP tube, incubating the upper platelet-rich plasma with rhodamine 6G (2 mu M) for 30min at room temperature, centrifuging to remove unbound rhodamine 6G, resuspending the rhodamine 6G-labeled platelets with PBS, adding a platelet activator adenosine diphosphate (ADP, 20 mu M), and incubating the platelets in a water bath at 37 ℃ for 20min to prepare the rhodamine 6G-labeled activated platelets.
At the same time, the O-shaped ring is arranged
Figure BDA0003277574870000091
And placing the glass slide on a glass slide, adding 30 mu L of collagen solution (200 mu g/mL) into the O-shaped ring, incubating the glass slide in a water bath at 37 ℃ for 1h, and washing out uncoagulated collagen by PBS to obtain the collagen-coated glass slide.
Incubating activated platelets (500 mu L) marked by rhodamine 6G with PBS, cRGD, PEG-AgNPs and cRGD-PEG-AgNPs (the concentration of Ag is 20 mu G/mL) for 5min, then transferring 50 mu L of activated platelets marked by rhodamine 6G into an O-shaped ring, incubating for 1h, washing the non-adhered platelets, fixing by using 4% paraformaldehyde solution, and observing and photographing under a fluorescence microscope to record the adhesion condition of the activated platelets.
The results are shown in fig. 7, where the collagen coating layer in the PBS group adhered a large number of activated platelets, indicating that the activated platelets adhered to the collagen basal layer very easily, resulting in the formation of a thrombus. Compared with the PBS group, the adhesion rates of the activated platelets of the cRGD and PEG-AgNPs groups are respectively reduced by 26.7 percent and 24.4 percent, which indicates that neither cRGD nor PEG-AgNPs can effectively inhibit the adhesion behavior of the activated platelets to collagen, but the adhesion capability of the activated platelets treated by the cRGD-PEG-AgNPs is obviously weakened and reduced by 90.3 percent, which indicates that the cRGD-PEG-AgNPs can effectively inhibit the adhesion and aggregation behavior of the activated platelets, and the phenomenon may cause the reduction of active action sites of the adhesion behavior of the activated platelets and block the GPIIb/IIIa mediated adhesion behavior of the activated platelets because the cRGD-PEG-AgNPs can be combined with GPIIb/IIIa receptors on the surfaces of the activated platelets; meanwhile, the hydrated grain diameter of the cRGD-PEG-AgNPs is 60nm and has better stability in physiological environment, so that the cRGD-PEG-AgNPs are combined with activated platelets to easily form a stable barrier layer, the action path of the adhesion behavior of the activated platelets is lengthened, the steric hindrance is increased, the adhesion behavior of the activated platelets is effectively inhibited under the synergistic action of the cRGD-PEG-AgNPs and the activated platelets, and the formation and development of thrombus are further prevented.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, the protection scope of the present invention should be determined by the appended claims.

Claims (12)

1. The medical nano silver delivery system is characterized by comprising nano silver particles, wherein HS-PEG-N is used3And as bridging molecules, modifying the cRGD on the surface of the nano-silver particles to form a nano-silver delivery system cRGD-PEG-AgNPs with double modification of PEG and cRGD.
2. The medical nano-silver delivery system according to claim 1, wherein the cRGD-PEG-AgNPs have a particle size of 20-90 nm and a potential of-16-20 mV.
3. The medical nano-silver delivery system according to claim 1, wherein the content of PEG in the cRGD-PEG-AgNPs is 20-30%.
4. The medical nanosilver delivery system of claim 1, wherein the cRGD-PEG-AgNPs contains 10-20% cRGD.
5. The preparation method of the medical nano silver delivery system according to any one of claims 1 to 4, which is characterized by comprising the following steps:
s1: mixing and stirring a silver nitrate solution and a citric acid solution to obtain a first mixed solution, dropwise adding a sodium borohydride solution into the first mixed solution in a stirring state, continuously stirring until the mixture is uniformly mixed to obtain a second mixed solution, heating the second mixed solution to boiling, obtaining a first suspension after a period of time, standing and cooling, and separating and purifying the first suspension to obtain a purified nano silver colloid;
s2: keeping the purified nano silver colloid in a stirring state, and adding HS-PEG-N3Dropwise adding the solution into the purified nano silver colloid at a constant speed, continuously stirring to obtain a second suspension, and separating and purifying the second suspension to obtain purified PEG modified nano silver;
s3: keeping the purified PEG-modified nano silver in a stirring state, and dropwise adding a cRGD solution to the purified PEG-modified nano silver to obtain a third suspension; mixing CuSO4·5H2And (3) carrying out vortex mixing on O and ascorbic acid in advance to obtain a third mixed solution, then dropwise adding the third suspension into the third mixed solution, stirring to obtain a fourth suspension, and then separating and purifying the fourth suspension to obtain the PEG and cRGD double-modified nano-silver delivery system cRGD-PEG-AgNPs.
6. The method for preparing a medical nano silver delivery system according to claim 5, wherein in the step S1, the molar ratio of silver nitrate to citric acid in the first mixed solution is (1:1) - (1:5), and the volume ratio of the silver nitrate solution to the citric acid solution is 1: 1.
7. The method for preparing a medical nano silver delivery system according to claim 5, wherein in the step S1, the concentration of the sodium borohydride solution is 0.01-0.1mg/L, and the volume ratio of the sodium borohydride solution, the silver nitrate solution and the citric acid solution is (1:10:10) - (1:20: 20);
the stirring speed of the first mixed solution is 1000-.
8. The method for preparing the medical nano silver delivery system according to claim 5, wherein in the step S2, in the second suspension, HS-PEG-N3The solution concentration is 2-3mg/mL, HS-PEG-N3The volume ratio of the solution to the purified nano silver colloid is 1: 10;
the stirring speed of the purified nano silver colloid is 400-500rpm, the stirring speed when the second suspension is obtained by continuously stirring is 800-900rpm, and the stirring time is not less than 8 h.
9. The method for preparing a medical nanosilver delivery system according to claim 5, wherein in step S3, the concentration of cRGD solution in the third suspension is 0.2-0.4mM, and the volume ratio of the cRGD solution to the purified PEG-modified nanosilver is 1: 13;
in the third mixed solution, CuSO4·5H2The concentration of the O solution is 2-8mM, the concentration of the ascorbic acid solution is 5-20mM, and the volume of the ascorbic acid solution added into the third mixed solution is 300-;
the stirring speed in the step S3 is 800-900rpm, and the stirring time of the fourth suspension obtained by stirring is more than or equal to 12 h.
10. The use of the medical nano silver delivery system according to any one of claims 1 to 4, wherein the nano silver delivery system can specifically recognize and combine with activated platelets to realize active targeting and detection of thrombus, and inhibit adhesion behavior of the activated platelets by occupying active sites of the activated platelets and increasing steric hindrance, and simultaneously inhibit further activation of resting platelets to inhibit aggregation and adhesion of the platelets, thereby effectively avoiding further increase of thrombus.
11. Use of the medical nanosilver delivery system of any one of claims 1 to 4 in the manufacture of a medicament for detecting prophylaxis of thrombosis.
12. A pharmaceutical composition comprising the medical nanosilver delivery system of any one of claims 1 to 4.
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