CN110354275A - Application of the MSN/miRNA hydrogel in preparation treatment myocardial infarction drug - Google Patents
Application of the MSN/miRNA hydrogel in preparation treatment myocardial infarction drug Download PDFInfo
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
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- 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
- A61K47/52—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 inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
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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
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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
- A61K47/61—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 the organic macromolecular compound being a polysaccharide or a derivative thereof
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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
- A61K47/69—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
- A61K47/6903—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 semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention discloses application of the MSN/miRNA hydrogel in preparation treatment myocardial infarction drug, and wherein MSN is porous nanometer microballoon, miRNA miR-21.The hydrogel has the advantage that 1, the schiff base reaction with aldehyde radical in hydrocolloid can occur by the modification of the amine functional group to MSN nanosphere surface, to realize precisely treatment using the weak acid environment of myocardial infarction；It 2, can be by cardiac muscular tissue's close attachment of the aldehyde radical in hydrocolloid and treatment region, to reach stable therapeutic effect；3, immune response can be regulated and controled by MSN nanosphere so as to improve the Reconstruction of The Function of cardiac muscular tissue；4, the vascularization of myocardial infarction region part can be promoted, to reduce the range of myocardial infarction by delivering miR-21 small molecule.Therefore, hydrogel of the present invention has important application value in the therapeutic effect of myocardial infarction.
Description
Technical field
The invention belongs to medical usage technical fields, and in particular to MSN/miRNA hydrogel treats myocardial infarction in preparation
Application in drug.
Background technique
Myocardial infarction is currently a kind of highest disease of the whole world death rate, and the intervention of early stage can be improved inpatient's
Survival rate, but it is often dead because of chronic heart failure after most of patient discharge, and main cause is the shape of heart infarction region scar
At the function of largely influencing heart.Mainly due to heart, the acute phase inflammatory reaction after hypoxic-ischemic is led for scar formation
Cause the hyperplasia of further connective tissue.Therefore many scholars attempt by inhibiting the activity of immunocyte to reduce heart infarction at present
The inflammatory reaction of acute stage after generation, however, these technologies only achieve certain as a result, converting in clinic in animal experiments
Curative effect is unsatisfactory in the process.Speculate its reason, be primarily due to scholars it is excessively high have estimated immunocyte in scar is formed
Effect, therefore, it is necessary to a kind of new means by inhibiting the scar that lapses to inhibit heart infarction region of " inflammation-scar "
It is formed.It perhaps can become a kind of improvement heart infarction region heart by the bioactive molecule of targeted inhibition " inflammation-scar " vesting period
The immunotherapeutic that flesh is rebuild.However the immune response of acute stage is inhibited to be merely capable of reducing ongoing damage, for
The cardiac muscle cell in heart ischemia region " being on the verge of desperate situation " is not helpful.By promoting the local vascular in myocardial infarction region,
It is expected to save the cardiac muscle cell of " being on the verge of desperate situation " to reduce the range of myocardial infarction.Therefore the immune connection with vascularization promoting
Therapeutic scheme is closed to be expected to become the means of effective treatment myocardial infarction.
Summary of the invention
Above of the existing technology in order to solve the problems, such as, the purpose of the present invention is to provide a kind of MSN/miRNA water-settings
Application of the glue in preparation treatment myocardial infarction drug.
To achieve the goals above, the present invention the following technical schemes are provided:
Application of the MSN/miRNA hydrogel in preparation treatment myocardial infarction drug, wherein MSN is porous nanometer
Microballoon, miRNA miR-21.
Further, the MSN/miRNA hydrogel preparation method the following steps are included:
(1) using cetab as template, prepare MSN nanosphere using sol-gel method, microballoon it is outer
Surface carries out amine functional group modification, and inner surface carries out quaternary ammonium cation modification, forms functional MSN-NH2- TMA nanometers micro-
Ball；
(2) microballoon made from step (1) by the positive charge of internal quaternary ammonium cation and the negative electrical charge of miRNA small molecule into
Row connection, so that the MSN nanosphere that load has miRNA small molecule be made；
(3) polyethylene glycol is carried out to double aldehyde group modified, formation CHO-PEG-CHO；
(4) load obtained of cyclodextrin, CHO-PEG-CHO and step (2) is had to the MSN nanosphere of miRNA small molecule
It is mixed, forms MSN/miRNA hydrogel.
Further, the pharmaceutical preparation include therapeutically effective amount of the present invention MSN/miRNA hydrogel and
Pharmaceutically acceptable auxiliary material.
Further, the pharmaceutical preparation is injection.
Further, the pharmaceutical preparation is one kind of controlled release or sustained release preparation.
Further, the injection is injected in myocardial infarction region.
The present invention is prepared as follows for treating the principle of myocardial infarction drug with the hydrogel:
The functional MSN- that outer surface carries out amine functional group modification, inner surface carries out quaternary ammonium cation modification is prepared first
NH2- TMA nanosphere carries out positive and negative charge connection using quaternary ammonium cation inside the microballoon and miR-21 small molecule, thus will
MiR-21 small molecule loads to the surface of microballoon, thus the delivering miR-21 small molecule of efficient stable.Face to further realize
Application on bed, polyethylene glycol progress is double aldehyde group modified, CHO-PEG-CHO is formed, it is micro- by functional MSN-NH2-TMA nanometers
Ball and CHO-PEG-CHO are using schiff base reaction formation schiff bases key, and on the one hand schiff bases key is acid-sensitive, since cardiac muscle obstructs
It is extremely weakly acidic environment, which can provide PH response to realize the accurate delivering of drug.
First layer cross-linked network finally is formed using cyclodextrin and double aldehyde group modified polyethylene glycol, on the one hand forms colloid
MSN/miRNA compound is strapped in gel by structure, and another aspect aldehyde radical can carry out chemistry with the protein of cardiac muscular tissue
In conjunction with, so that hydrogel is closely attached to myocardial tissue surface, even if in the state of heartbeat, it is also not easily to fall off.And
Second layer cross-linked network further is formed using above-mentioned schiff base reaction, MSN/miRNA compound is fixed, to construct acid
Property responsiveness can be realized it is immune+promote vascularization combination therapy MSN/miRNA injection aquagel system.
The utility model has the advantages that the answering in preparation treatment myocardial infarction drug the present invention provides a kind of MSN/miRNA hydrogel
Have the advantage that 1 with, the hydrogel, being capable of modification generation by the amine functional group to MSN nanosphere surface and glue
The schiff base reaction of aldehyde radical in body, to realize precisely treatment using the weak acid environment of myocardial infarction；2, glue can be passed through
Cardiac muscular tissue's close attachment of aldehyde radical and treatment region in body, to reach stable therapeutic effect；3, it can be received by MSN
Meter Wei Qiu regulation is immunoreacted the Reconstruction of The Function so as to improve cardiac muscular tissue；4, can be promoted by delivering miR-21 small molecule
The vascularization of myocardial infarction region part, to reduce the range of myocardial infarction.Therefore, hydrogel of the present invention is in cardiac muscle
There is important application value in the therapeutic effect of infarct.
Detailed description of the invention
Fig. 1 is that hydrogel is injected into the test result figure behind myocardial infarction region.
Specific embodiment
The invention will now be further described with reference to specific embodiments, but examples are merely exemplary, not to this hair
Bright range constitutes any restrictions.It will be understood by those skilled in the art that without departing from the spirit and scope of the invention
Can with the details and forms of the technical scheme of the invention are modified or replaced, but these modification and replacement each fall within it is of the invention
In protection scope.
1, MSN/miRNA hydrogel preparation method the following steps are included:
(1) configuration of injection aquagel A/B solution:
The configuration of A liquid: weighing 0.1gCHO-PEG5k-CHO in sample cell, is added 500 μ L ultrapure waters, ultrasonic dissolution, to
With.
The configuration of B liquid: weighing 0.05galpha-CD in sample cell, is added 500 μ L ultrapure waters, ultrasonic dissolution, for use.
(2) functionalization MSN microballoon the preparation method for preparing the MSN nanosphere the following steps are included:
(1) pH value of 1000mL deionized water is adjusted to 11, is warming up to 323 degree Kelvins, 1.12g hexadecyl is added
The tetraethoxysilane of trimethylammonium and 5.8mL, stirs evenly rapidly；After stirring 2 hours, stand overnight, next day is collected by centrifugation heavy
Sediment distilled water is replaced with ethyl alcohol and is sufficiently cleaned by starch, after ultrasonic vibration 30min, is added and water is with 1:1 volume mixture
1,3,5- mesitylene, by mixed liquor be placed in 140 degree apply casees in, stand 4 days；
(2) obtained white powder is resuspended in the absolute alcohol of 50mL, the 3- ammonia of 1mL50% alcoholic solution will be dissolved in
Base propyl-triethoxysilicane is added in re-suspension liquid, stirs 8 hours；Obtained solid is filtered, with alcohol washes, finally true
It is dry in empty desiccant, it obtains in mesoporous containing the porous MSN nanosphere for changing cetrimonium.
The process of functionalization MSN microballoon preparation is from 1.-four-stage 4., in which: 1. novel porous high surface area
(1500m2/ g) nanometer microballoon (partial size 100nm)；2. inner surface carry out quaternary ammonium cation modification, formed MSN-TMA with
Realize the connection of the positive and negative charge between miR-21 small molecule；3. outer surface carries out amine functional group modification, MSN-NH is formed2-
TMA forms acid responsiveness chemical bond with the aldehyde radical in aquogel system to realize；④MSN-NH2- TMA-RNA nanosphere.
(3) being prepared in sample cell for hydrogel weighs functionalization MSN microballoon made from 0.01g step (2), and 500 μ are added
After 100W ultrasound 10min, 250 μ LA liquid are added in LB liquid, and 100W ultrasound 5min is placed in syringe, static 10min.
2, the model of the myocardial infarction of pig is established in effect of the MSN/miRNA hydrogel in myocardial infarction treatment, after opening chest,
It recognizes the left Circumflex branch of heart and ligatures, during heart infarction model foundation, connect ECG monitor monitor ECG, hemodynamic
It learns variation and hydrogel is injected into the region of myocardial infarction after ischemic area occurs in observation cardiac muscle.
Fig. 1 is that hydrogel is injected into the test result figure behind myocardial infarction region.Figure 1A be ejection fraction (EF) at any time
Change curve, Figure 1B be left ventricular end diastolic volume (LVEDV) versus time curve；
Fig. 1 C is that the experiment of left room posterior wall thickness at end-diastole (LVPWd) is divided into four groups of versus time curves.
Saline is physiological saline group in figure, and miR-21 is individually to add miR-21 group, MSN/miR-NChydrogel MSN
Add microRNA negative control hydrogel group, MSN/miR-21hydrogel is that MSN adds miR-21 hydrogel group, can from figure
To find out: after heart infarction generation, MSN adds miR-21 hydrogel group that can effectively maintain the ejection fraction of left ventricle, Neng Gouyou
Effect slows down left ventricle in the volume expansion of diastasis, can effectively maintain left room posterior wall thickness at end-diastole.Therefore, originally
Inventing the hydrogel has important application value to the treatment of myocardial infarction.
Claims (6)
- Application of the 1.MSN/miRNA hydrogel in preparation treatment myocardial infarction drug, wherein MSN is that porous nanometer is micro- Ball, miRNA miR-21.
- 2. application according to claim 1, which is characterized in that the preparation method of the MSN/miRNA hydrogel include with Lower step:(1) using cetab as template, MSN nanosphere, the outer surface of microballoon are prepared using sol-gel method Amine functional group modification is carried out, inner surface carries out quaternary ammonium cation modification, forms functional MSN-NH2-TMA nanosphere；(2) microballoon made from step (1) is connected by the positive charge of internal quaternary ammonium cation and the negative electrical charge of miRNA small molecule It connects, so that the MSN nanosphere that load has miRNA small molecule be made；(3) polyethylene glycol is carried out to double aldehyde group modified, formation CHO-PEG-CHO；4) the MSN nanosphere of miRNA small molecule mixes the load obtained of cyclodextrin, CHO-PEG-CHO and step (2) It closes, forms MSN/miRNA hydrogel.
- 3. a kind of for treating the pharmaceutical preparation of myocardial infarction, which is characterized in that the pharmaceutical preparation includes claim 1 institute The MSN/miRNA hydrogel and pharmaceutically acceptable auxiliary material for the therapeutically effective amount stated.
- 4. according to claim 3 a kind of for treating the pharmaceutical preparation of myocardial infarction, which is characterized in that the drug system Agent is injection.
- 5. according to claim 3 a kind of for treating the pharmaceutical preparation of myocardial infarction, which is characterized in that the drug system Agent is one kind of controlled release or sustained release preparation.
- 6. according to claim 3 a kind of for treating the pharmaceutical preparation of myocardial infarction, which is characterized in that the injection note It penetrates in myocardial infarction region.
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Cited By (2)
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| CN111529504A (en) * | 2020-03-25 | 2020-08-14 | 西安组织工程与再生医学研究所 | Functional chimeric apoptotic body and preparation method and application thereof |
| CN111588704A (en) * | 2020-07-01 | 2020-08-28 | 西安组织工程与再生医学研究所 | Targeted responsive release system and preparation method and application thereof |
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| CN111588704A (en) * | 2020-07-01 | 2020-08-28 | 西安组织工程与再生医学研究所 | Targeted responsive release system and preparation method and application thereof |
| CN111588704B (en) * | 2020-07-01 | 2023-04-11 | 西安组织工程与再生医学研究所 | Targeted responsive release system and preparation method and application thereof |
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