CN108794684A - Responsive to temperature type siRNA nanogel carriers and preparation method thereof - Google Patents
Responsive to temperature type siRNA nanogel carriers and preparation method thereof Download PDFInfo
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- CN108794684A CN108794684A CN201810584774.1A CN201810584774A CN108794684A CN 108794684 A CN108794684 A CN 108794684A CN 201810584774 A CN201810584774 A CN 201810584774A CN 108794684 A CN108794684 A CN 108794684A
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
- C08F220/30—Esters containing oxygen in addition to the carboxy oxygen containing aromatic rings in the alcohol moiety
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
- C08F220/30—Esters containing oxygen in addition to the carboxy oxygen containing aromatic rings in the alcohol moiety
- C08F220/302—Esters containing oxygen in addition to the carboxy oxygen containing aromatic rings in the alcohol moiety and two or more oxygen atoms in the alcohol moiety
Abstract
The present invention relates to a kind of responsive to temperature type siRNA nanogel carriers and preparation method thereof.The temperature sensitive cation nanogel feature of the present invention is：Alkyloxy-ethers poplar bundles primitive is used as temperature sensitive primitive, there is higher temperature sensitivity and the phase transition temperature close to body temperature and good biocompatibility；Secondly the same cation amino primitive for using poplar bundles structure, makes it have the stronger adsorption capacity for siRNA.Therefore, the nanogel of synthesis its can effectively realize the combination and protective effect of siRNA, and realized on this basis to the combination of siRNA and the regulation and control of release function by temperature switch.This experiment is the material has directive significance in the application of biomaterial, siRNA deliverings and field of gene etc..
Description
Technical field
The present invention relates to a kind of responsive to temperature type siRNA nanogel carriers and the preparation method and application thereof.
Background technology
RNA interference is a kind of natural phenomena of generally existing in biology, is the transcription of the sequence specific started by double-stranded RNA
Gene silencing process afterwards, by importing external source or endogenous double-stranded RNA（dsRNA）, can be with specific blockade after intracellular processing
The expression of gene makes endogenous mRNA（mRNA）Selective degradation occurs, so as to cause posttranscriptional gene silencing.It is specific
Mechanism of action be precursor RNA pass through a kind of ribonucleic acid cleavage, formation length be 21-23 base-pair sequences double-strand
Small RNA molecular is either inserted directly into the siRNA of artificial synthesized similar length, and it is compound to pass through RNA inductions silence in the cell
After the identification of object, the positive-sense strand in siRNA is removed, and antisense strand and the mRNA of the complementation containing its sequence are combined, so as to cause
The degradation of target gene.
But siRNA is since easily by nuclease decomposes, cell absorption efficiency is low etc., factors cause it to be difficult to solely in vivo for it
Vertical the completing gene therapy of the task, therefore excellent siRNA carrier material is in recent years by the extensive concern of scientist.And by
There is low immune response in non-virus carrier, there is better regulating power to structure and function, synthesize relatively simple and material
The advantages that material derives from a wealth of sources, and in the delivering of siRNA very good potentiality have been shown as carrier.And needle in recent years
Research to its non-virus carrier includes mainly cation nanogel carrier.
Nanogel be it is a kind of using water be decentralized medium by be physically or chemically cross-linked to form have swellability and inside
With tridimensional network and diameter is in 200 nanometers of nanostructures below, and the long, bio-compatible with blood circulation time
Property good and biodegradability the advantages that.Cation nanogel carrier due to can be combined with siRNA by electrostatic interaction and by
The ability of preferable cell internalizing and lysosome escape is made it have in the presence of " proton sponge effect ", is compared and other non-diseases
Poisonous carrier has preferable cell transfecting ability, so using it as the hot topic that carrier is current polymer support research.With
Can also prepare the biodegradable nanogel with stimulating responsive by being surface modified to gel, therefore
Nanogel becomes the another big hot spot of siRNA carrier research.Ahmed etc. is using the cationic monomer with temperature sensitive effect as core
With containing sugar copolymer to be hull shape into cationic polysaccharide nanogel with good biocompatibility and degradability, and it is right
This two kinds of monomers use the crosslinking agent progress Controlled Living Radical Polymerization unstable to acid to make the gel while having temperature
With the mechanism of pH double-responses, siRNA delivery efficiencies are effectively improved, and this cation gel and endothelial are grown
Factor siRNA combines the endothelial growth factor that can effectively inhibit human cervix cancer cells surface 65%.This method is effectively
The advantage for combining natural polysaecharides polymer and artificial-synthetic copolymer substantially increases transfection efficiency, is carried for subsequent research
Good thinking is supplied（M. Ahmed, et al.Polym Chem. 2013, 4, 3829-3836）.
In recent years, on the one hand we have certain understanding to various obstacles in siRNA delivery process each stage,
The method much to improving each stage efficiency is produced, but it is often to contradict that such strategy, which combines,
Such as can improve the blood circulation time to carrier surface is polyethyleneglycol modified and can but reduce transfection abilities, so in recent years people by
It gradually concentrates in the research joined in for stimulating responsive " intelligent carrier ".But since human body is for the sensitivity of temperature-responsive
Relatively low, therefore, people lack enough research for the siRNA carrier of temperature sensitivity and study.
Invention content
One of the objects of the present invention is to provide a kind of responsive to temperature type siRNA nanogel carriers.
The second object of the present invention is to provide the preparation method of the carrier.
The present invention is prepared by MOLECULE DESIGN with the alkyloxy-ethers with excellent temperature sensitive behavior and good biocompatibility
Based on poplar bundles primitive, and introduces poplar bundles cation primitive and obtain that there is certain topology by precipitation polymerization mode respectively
The tree-like nanogel of novel cation of structure.The tree-like nanogel of novel cation prepared by research can be by poplar bundles alkane
Oxygen ether member excellent temperature-sensing property and topological structure, realize the combination and release realized with the means of regulation of temperature to siRNA.
The present invention uses amino-terminated poplar bundles primitive for amino primitive monomer, occurs with generation alkyloxy-ethers poplar bundles monomer
Precipitation polymerization reacts, and synthesizes the cation nanogel with temperature-responsive.The copolymer and nanogel are in phase transition temperature
The absorption to siRNA and the degradation from nuclease may be implemented below, more than temperature rise to phase transition temperature may be implemented pair
The release of siRNA.
Based on above-mentioned principle, the present invention uses following technical proposals：
A kind of responsive to temperature type siRNA nanogel carriers, it is characterised in that the carrier is by using amino-terminated alkyloxy-ethers tree
Cladodification primitive is amino primitive monomer and alkyloxy-ethers poplar bundles monomer, by crosslinking agent ethylene glycol dimethacrylate, by drawing
Hair agent azo-bis-isobutyrate hydrochloride causes free radical polymerization and answers, and the temperature-responsive cation with topological structure of formation is received
Rice gel, wherein the molar ratio of amino-terminated alkyloxy-ethers poplar bundles primitive and alkyloxy-ethers poplar bundles monomer is 1:5~1:20, crosslinking
Agent is the 4% ~ 6% of monomer integral molar quantity, and the amount of initiator is the 0.4% ~ 0.6% of monomer gross mass；The amino-terminated alcoxyl
The structural formula of ether poplar bundles primitive is：
Or；
The alkyloxy-ethers poplar bundles monomer
Or
Wherein Y=MeO or X=EtO；X = NH3 +。
A method of preparing above-mentioned responsive to temperature type siRNA nanogel carriers, it is characterised in that the tool of this method
Body synthesis step is as follows：
A. the poplar bundles alcoxyl ether monomer MG1-OEt containing tertbutyloxycarbonyl and trifluoroacetic acid are pressed 1:50~1:100 mass ratio
It is dissolved in dichloromethane, 3 ~ 4 h of normal-temperature reaction, after, methanol dissolving is added into reaction solution, and be evaporated methanol, takes out true
Sky obtains amino-terminated alkyloxy-ethers poplar bundles primitive；
B. amino-terminated alkyloxy-ethers poplar bundles primitive obtained by step a and alkyloxy-ethers poplar bundles monomer are pressed 1:5~1:20 molar ratio
It is dissolved in dichloromethane, crosslinking agent and surfactant cetyl trimethylammonium bromide is added, wherein crosslinking agent is that monomer is total
The 4% ~ 6% of mole, the quality of surfactant are the 8 ~ 10% of monomer gross mass；Under inert atmosphere protection, 60 ~ 65oC is simultaneously
Stablize 30 min, and initiator azo-bis-isobutyrate hydrochloride system be added, the quality of initiator be monomer gross mass 0.4% ~
0.6%；3 ~ 4 h are stirred to react, after reaction solution is cooled to room temperature, by 0.45 μm, then the nylon leaching film of Rephile uses
The bag filter purifying dialysis that molecular cut off is 10,000 5 days, obtains nanogel.
A kind of application of above-mentioned responsive to temperature type siRNA nanogel carriers, it is characterised in that：Right before phase change
SiRNA carries out more efficient absorption and discharges siRNA to siRNA from the degradation of nuclease and by the phase transformation that heats up.
As the present invention is based on the preparation method of the siRNA carrier of temperature sensitive cation nanogel, nanogel be by
Alcoxyl ether monomer generation upon generation of polymerize with cation amino primitive monomer precipitation after by dialysis by system.
The present invention compared with prior art, has following obvious substantive distinguishing features and remarkable advantage：
1. the present invention uses nanogel grain size prepared by precipitation polymerization for 90-120 nanometers and with the uniform performance of dispersibility；
2. the present invention uses temperature sensitive generation poplar bundles alkyloxy-ethers for supermolecule main block, using its sensitive temperature-sensing property,
To construct a kind of novel more easy temperature-responsive carrier；
3. the present invention successfully realizes the protection to guest molecule siRNA using the special topological structure of dendroid alkyloxy-ethers；
4. nanogel surface of the present invention is due to containing higher charge density so that it has under the conditions of lower amino ratio
There are higher absorption and release efficiency, and can be by with the delivering of temperature sensitive means control siRNA, being expected to examine in gene
There is good application prospect in the fields such as disconnected, treatment and medicine controlled releasing.
Description of the drawings
Fig. 1 is the reaction schematic diagram of responsive to temperature type siRNA nanogel carriers；
Fig. 2 is the nuclear magnetic spectrogram of cation amino primitive monomer；
The AFM of Fig. 3 nanogels schemes；
The UV absorption spectrogram of Fig. 4 nanogel phase transition process；
Gel electrophoresis imaging under Fig. 5 different times；
Fig. 6 25oGel electrophoresis imaging under C；
Fig. 7 45oGel electrophoresis imaging under C.
Specific implementation mode
It please provide the complete embodiment of preparation temperature responsive type siRNA nanogel carriers
Details are as follows for the preferred embodiment of the present invention：
1. the preparation MG1-NH of the cation amino primitive monomer of alkyloxy-ethers poplar bundles structure3 +Preparation：
MG1-Boc is dissolved in dichloromethane/trifluoroacetic acid（1:1 volume ratio）In, reaction overnight, is confirmed anti-by thin layer chromatography
After answering completely, reaction is quenched with methanol, solvent evaporated dichloromethane is added methanol and dissolves and be evaporated 3 times, uses dichloromethane repeatedly
Extraction, is subsequently dried filtering, obtains target compound MG1-NH3 +, the results are shown in Figure 1 for nuclear-magnetism.
2. the preparation of responsive to temperature type siRNA nanogel carriers:
A. appropriate poplar bundles alcoxyl ether monomer MG1-OEt is weighed respectively（106.05 mg, 0.15 mmol）It is dissolved in 1mL DMF,
Cationic monomer MG1-NH3 +（14.7 mg, 0.015 mmol）, crosslinking agent ethylene glycol dimethacrylate（0.06 mg）, table
Face lammonium bromide（4.5 mg）In three-necked flask plus distilled water to total volume is 15 milliliters；
B. by the raw materials such as monomer stirring and dissolving and it is passed through the oxygen after nitrogen atmosphere about 15 minutes in removing system, at the same time will
Solution is to slowly warm up to 65oC.Wait for that system temperature is stablized 65o30 min under the conditions of C will be dissolved in 500 μ L distilled water
Initiator azo-bis-isobutyrate hydrochloride（1.02 mg）Addition system causes polymerization；
C. 4 h of successive reaction in a nitrogen atmosphere is reacted；
D. after reaction solution is cooled to room temperature, nanogel solution is passed through into nylon leaching film first（0.45 μm, Rephile) it removes
Issuable condensation product and impurity molecule；
E. it uses the bag filter purified nanotubes gel solution that molecular cut off is 10000 to dialyse 5 days, 3 water is replaced daily, to go
Except unreacted monomer and other small-molecule substances.
3. atomic force microscope（AFM）Test is surveyed by 8 atomic force microscope of Multi Mode of German Bruker companies
?.The microscope configures " E " flying-spot tube, and using Scanasyst-air patterns, sweep speed is generally 0.997 Hz.Scanning is visited
Needle is SCANASYST-AIR carbonization silicon probes, and cantilever parameter is followed successively by T: 650 nm,L: 115 µm,W: 25 µm,f0: 70
kHz,k: 0.6 N/m.Gel sample is configured to the PBS aqueous solutions of 0.02 mg mL-1, and mica table is spin-coated to 3000 rpm
Face, the results are shown in Figure 2.
4. nanogel tests the protection of siRNA：
According to specific N/P ratio by polymer solution（A concentration of 5 milligrams every milliliter）With 1 μ L siRNA（A concentration of 10 micromole
Every liter）In conjunction with after compound room temperature stands half an hour, by complex solution and 1 μ L RNase A（0.2 milligram every milliliter）?
At room temperature at set time intervals（0,0.5,1,3,6,9,12,24 hour）It carries out mixing and stands.Then by mixture
1 μ L EDTA are further added（50 mMs）（Since RNase A need bivalent cation as co-factor（Such as Ca, Mg
Deng）.Therefore its nuclease activity can because EDTA there are due to block）With 1 μ L Calciparine/sodium salts（26.4 every microlitre of micrograms）（With
In displacing the siRNA in polymer and siRNA compounds）It is incubated respectively 10 minutes and 1 hour, uses Ago-Gel later
Electrophoresis detects siRNA, and the results are shown in Figure 3, and nanogel has siRNA is effectively protected effect for a long time.
5. the test of nanogel phase transition temperature：
Temperature-sensitive nano-gel is soluble in water, using ultraviolet/visible spectrophotometer polymer and nanometer are tracked in 600 nanometers
Gel is in phosphate buffer solution（PH=7.4, every milliliter of C=0.5 milligram）Phase transition process and test copolymer respectively
With transformation behavior of the nanogel in various concentration.It is as shown in Figure 4 to measure temperature sensitive polymer turbidity transformation curve.It is a concentration of
At 0.5 milligram every milliliter, the phase transition temperature of polymer is 34oC。
6. the test of nanogel and siRNA bonding states after before phase change
The concrete operations of the 2 % agarose gel electrophoresis experiment used are as follows：According to different N/P ratios by polymer solution（Concentration
It is 5 milligrams every milliliter）With 1 microlitre of siRNA（A concentration of 10 every liter of micromole）After standing half an hour in conjunction with, compound room temperature again with
1 microlitre of loading buffer is sufficiently mixed, and is then added into ethidium bromide（EB）The 2 % fine jades of a concentration of 0.5 μ g/mL
In sepharose.Using 1 × electrophoretic buffer TBE, electrophoresis 20 minutes under 120 volts of voltage are later 254 nanometers of purples in wavelength
Pass through gel imager under outer and observes siRNA electrophoretic images.The results are shown in Figure 5.Thereafter complex solution is placed in 45oC water
It is heated 10 ~ 15 minutes in bath, 45oAgarose gel electrophoresis test is done under C, the results are shown in Figure 6.
SiRNA can be trapped in hole slot together with polymer after forming compound with polymer or slightly have reversed swimming, and
SiRNA under free state can swim out with electrophoresis process forms light tone band, to can be with according to bright band position and brightness
Analyze combination and the releasability of siRNA and polymer.
The embodiment of the present invention is illustrated above in conjunction with attached drawing, but the present invention is not limited to the above embodiments, it can be with
The purpose of innovation and creation according to the present invention makes a variety of variations, under the Spirit Essence and principle of all technical solutions according to the present invention
The changes, modifications, substitutions, combinations, simplifications done should be equivalent substitute mode, as long as meeting the goal of the invention of the present invention, only
Otherwise away from the present invention is based on the siRNA controlled release carriers of poplar bundles alkyloxy-ethers temperature-sensitive nano-gel, preparation method and applications
Technical principle and inventive concept, belong to protection scope of the present invention.
Claims (3)
1. a kind of responsive to temperature type siRNA nanogel carriers, it is characterised in that the carrier is by using amino-terminated alkyloxy-ethers
Poplar bundles primitive is amino primitive monomer and alkyloxy-ethers poplar bundles monomer, by crosslinking agent ethylene glycol dimethacrylate, by
Initiator azo-bis-isobutyrate hydrochloride causes free radical polymerization and answers, the temperature-responsive cation with topological structure of formation
Nanogel, wherein the molar ratio of amino-terminated alkyloxy-ethers poplar bundles primitive and alkyloxy-ethers poplar bundles monomer is 1:5~1:20, it hands over
Join 4% ~ 6% that agent is monomer integral molar quantity, the amount of initiator is the 0.4% ~ 0.6% of monomer gross mass；The amino-terminated alkane
The structural formula of oxygen ether poplar bundles primitive is：
Or；
The alkyloxy-ethers poplar bundles monomer
Or
Wherein Y=MeO or X=EtO；X = NH3 +。
2. a kind of method preparing responsive to temperature type siRNA nanogel carriers according to claim 1, it is characterised in that
The specific synthesis step of this method is as follows：
Poplar bundles alcoxyl ether monomer MG1-OEt containing tertbutyloxycarbonyl and trifluoroacetic acid are pressed 1:50~1:100 mass ratio is molten
In dichloromethane, 3 ~ 4 h of normal-temperature reaction, after, methanol dissolving is added into reaction solution, and be evaporated methanol, vacuumizes
Obtain amino-terminated alkyloxy-ethers poplar bundles primitive；
Amino-terminated alkyloxy-ethers poplar bundles primitive obtained by step a and alkyloxy-ethers poplar bundles monomer are pressed 1:5~1:20 molar ratio is molten
In dichloromethane, crosslinking agent and surfactant cetyl trimethylammonium bromide is added, wherein crosslinking agent is that monomer always rubs
The 4% ~ 6% of that amount, the quality of surfactant are the 8 ~ 10% of monomer gross mass；Under inert atmosphere protection, 60 ~ 65oC is simultaneously steady
Fixed 30 min, and initiator azo-bis-isobutyrate hydrochloride system is added, the quality of initiator be monomer gross mass 0.4% ~
0.6%；3 ~ 4 h are stirred to react, after reaction solution is cooled to room temperature, by 0.45 μm, then the nylon leaching film of Rephile uses
The bag filter purifying dialysis that molecular cut off is 10,000 5 days, obtains nanogel.
3. a kind of application according to the responsive to temperature type siRNA nanogel carriers described in claim 1, it is characterised in that：
More efficient absorption is being carried out to siRNA before phase change and to siRNA from the degradation of nuclease and by the phase transformation that heats up
Discharge siRNA.
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| CN109867799A (en) * | 2019-03-16 | 2019-06-11 | 济南敏杰电子有限责任公司 | A kind of heat sensitive compounds and preparation method thereof |
| CN110128588A (en) * | 2019-04-17 | 2019-08-16 | 上海大学 | Temperature sensitive antibacterial cationic tree shaped polymer and preparation method thereof |
| CN110183595A (en) * | 2019-03-13 | 2019-08-30 | 上海大学 | Alkyloxy-ethers tree shaped polymer/gelatin-compounded freezing gel, preparation method and application |
| CN113514407A (en) * | 2021-06-25 | 2021-10-19 | 上海大学 | Visual nucleic acid detection method based on nucleic acid regulation and control of temperature-sensitive phase change of polymer |
| CN114288423A (en) * | 2022-02-23 | 2022-04-08 | 西北大学 | TA-siRNA nanogel and preparation method and application thereof |
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| CN113514407A (en) * | 2021-06-25 | 2021-10-19 | 上海大学 | Visual nucleic acid detection method based on nucleic acid regulation and control of temperature-sensitive phase change of polymer |
| CN114288423A (en) * | 2022-02-23 | 2022-04-08 | 西北大学 | TA-siRNA nanogel and preparation method and application thereof |
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Application publication date: 20181113 |
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| RJ01 | Rejection of invention patent application after publication |