CN101633712A - Point-and-click temperature/pH-sensibility microgel - Google Patents
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Abstract
The invention provides a chemical approach which can adopt point-and-click chemistry to realize functional grouping on the bodies or the surfaces of high molecular hydrogel particles. The high molecular hydrogel particles are generally formed by the cross linking of a hydrophilic monomer and a functional group monomer. The invention mainly puts forward a point-and-click functional group which can be introduced by adopting a copolymerization mode and can carry out a 1,3-dipolar cycloaddition reaction of triazo-end alkynyl catalyzed by Cu (I). Simultaneously, a point-and-click reaction catalyzed by the Cu (I) and a coupling reaction of carboxyl-primary amine radicals initiated by 1-(3-dimethylin propyl)-3-ethyl carbon diimine hydrochloride are carried out in a water phase, are not disturbed mutually and are mutually orthogonal. The characteristic can be beneficial to the multi-function grouping of the microgel simultaneously. The temperature/pH-sensibility microgel containing the point-and-click functional group has potential application value in the aspects of targeting medicine release, molecular treatment, chemical/biologic sensors, water treatment and the like.
Description
Technical field
The invention belongs to the polymer synthetic chemistry field, be specifically related to the polymer microgel that generates temperature/pH-susceptibility and have the property clicked (clickable) in the aqueous phase free radical polymerization, be convenient to the multiple functionalized of microgel, discharge at targeted drug, biological/chemical sensor, there is potential using value aspects such as multi-function membrane.
Background technology
Little hydrogel of polymer (microgel) or hydrogel fines (hydrogelmicroparticles) are that a kind of nanometer is to micron-sized water swollen cross-linked polymer particulate.Just synthesized the polymer microgel of styrene-based as far back as nineteen thirty-five Staudinger etc., the swelling agent of this moment is organic solvents such as benzene or toluene, can be referred to as organic microgel (organo-microgel).(Staudinger, H.et al.Ber.1935,67,1164) Baker in 1949 has at first proposed this term of microgel (microgel), lay special stress on be that granule interior on micro-meter scale is the polymer crosslinking structure, microgel and common three-dimensional polymeric molecule gel are distinguished conceptive.(Baker, W.O.Ind.Eng.Chem.1949,41,511) on the other hand, Heskins and Guillet have found N-alkyl acrylamide, N-N-isopropylacrylamide (N-isopropylacrylamide particularly, NIPAm), can polymerization formation temperature sensitive polymer: when solvent (as water) temperature is elevated to minimum critical solution temperature (lowest criticalsolution temperature, LCST) time, (poly (N-isopropylacrylamide) pNIPAm) can be precipitated out from water dissolved poly N-isopropyl acrylamide when normal temperature.(Heskins, M.; Guillet, J.E.J.Macromol.Sci.Chem.1968, A2,1441) 1986 years Pelton etc. utilize the temperature-sensing property of pNIPAm to synthesize little hydrogel of pNIPAm first.(Pelton, R.H.et al.Colloid Surf.1986,120,247) subsequently, the little hydrogel of a series of multipolymers based on NIPAm is such as vinylformic acid (acrylic acid, AAc) etc. be developed, the introducing of AAc has increased the pH and the ionic strength sensibility of polymkeric substance.(Snowden, M.J.et al.J.Chem.Soc., Faraday Trans.1996,92,5013) yet, the monomer that has functional group's side chain is limited after all, can not be arbitrary with functional group, particularly sulfydryl (SH), enters little hydrogel by polymerization.Click chemistry (click chemistry) was proposed by Sharpless etc. in calendar year 2001, (Kolb, H.C.; Finn, M.G.; Sharples, K.B.Angew.Chem.Int.Ed.2001,40,2004) because its high atopic (specificity), high yield (yield), seldom or no coupling product (by-product), can tolerate the existence of water and oxygen, more and more be paid attention at present.(Sharpless K.B.et al., Angew.Chem.Int.Ed.2002,41,2596) up to the present, still no-trump click chemistry and the report that combines based on the little hydrogel of the polymer of NIPAm, this patent will be the favourable reaction environment of synchronous multiple functionalized creation by click chemistry being introduced little hydrogel.
Summary of the invention
The object of the present invention is to provide a kind of (clickable) temperature of clicking-/the little hydrogel of polymer of pH-susceptibility, and as the means of the multiple functionalized modification of polymer.In order to realize the clickization of the little hydrogel of polymer, the present invention uses following compound to carry out copolymerization: the first, and temperature sensitivity monomer: N-N-isopropylacrylamide (NIPAm); The second, pH-sensitive monomer: vinylformic acid (AAc); The 3rd, can click monomer: the epoxypropyl methacrylic ester (glycidylmethacrylate, GMA)+sodiumazide (NaN
3), perhaps, and the propargyl acrylate (propargylacrylate, PA); The 4th, linking agent: N, N '-methylene-bisacrylamide (N, N '-methylenebisacrylamide, BIS).
The monomeric general formula of temperature sensitivity is as follows:
R wherein
1Be hydrogen or methyl; R
2Be alkyl, particularly sec.-propyl, ethyl; R
3Be hydrogen or methyl, ethyl; Certain R
2, R
3Also can Cheng Huan, such as pyrrolidone (pyrrolidone) etc.
The general formula of acid pH-sensitive monomer is as follows:
Wherein R ' is hydrogen or methyl;
The general formula of pyridine type alkaline pH-sensitive monomer is as follows:
Wherein R ' is hydrogen or methyl, R " be hydrogen or alkyl, as methyl, ethyl etc.
The general formula of allyl group ammonium salt type alkaline pH-sensitive monomer is as follows:
R wherein
1, R
2, R
3Can be hydrogen, methyl, any or several combinations in the ethyl.
It is as follows that azido-can be clicked monomeric general formula:
R wherein
1Be hydrogen or methyl, R2 can be that ester bond or amido linkage connect an alkyl (as methyl, ethyl, hydroxyethyl, propyl group, hydroxypropyl etc.)
It is as follows that the acetylene end group can be clicked monomeric general formula:
Wherein R1 is hydrogen or methyl, and R2 can be that ester bond or amido linkage connect an alkyl (as methyl, ethyl, hydroxyethyl, propyl group, hydroxypropyl etc.)
Description of drawings
Fig. 1 is the N-N-isopropylacrylamide (NIPAm) that ammonium persulphate among the present invention (APS) causes, vinylformic acid (AAc), epoxypropyl methacrylic ester (GMA), and sodiumazide the copolymerization of water free radical precipitation generate can click contain azido-, the reaction of the microgel of the temperature of carboxyl/pH sensitivity;
Fig. 2 is the N-N-isopropylacrylamide (NIPAm) that ammonium persulphate among the present invention (APS) causes, vinylformic acid (AAc), with the propargyl acrylate the copolymerization of water free radical precipitation generate can click contain Terminal Acetylenes base, the reaction of the microgel of the temperature of carboxyl/pH sensitivity;
Fig. 3 is used for microgel synthetic reaction experiment device among the present invention, mainly by the electromagnetism heating stirrer, and silicone oil bath, three neck round-bottomed flasks, prolong, nitrogen importing/delivery line, thermometer stirs magneton and forms.
Fig. 4 is CuSO among the present invention
4And the click-reaction between the Terminal Acetylenes base that contains of the azido-that carries on the synthetic little hydrogel of Cu (I) catalysis of L-sodium ascorbate original position and fluorescein FPTC;
Fig. 5 is CuSO among the present invention
4And the complete quadrature of linked reaction of the amino that contains of the carboxyl that carries on click-reaction between the Terminal Acetylenes base that contains of the azido-that carries on the synthetic little hydrogel of Cu (I) catalysis of L-sodium ascorbate original position and fluorescein FPTC and the catalytic little hydrogel of EDC and fluorescein TMRC and carrying out simultaneously, carboxyl-primary amine groups coupling reaction that EDC participates in and Cu (I)-catalytic Terminal Acetylenes base-folded amino 1, the 3-Dipolar Cycloaddition is carried out at water simultaneously, their complete quadratures (orthogonal) are independent of each other;
Fig. 6 is the fluorescence excitation emmission spectrum of FPTC among the present invention;
Fig. 7 is the fluorescence excitation emmission spectrum of AzF among the present invention;
Fig. 8 is the fluorescence excitation emmission spectrum of TMRC among the present invention.
Embodiment
The present invention proposes the mode of the precipitation copolymerization of carrying out at water with the free radical thermal initiation synthetic have can the click type temperature-/microgel of pH-sensitivity, and by confirming the feasibility of " click " with the click-reaction of the fluorescein that can click.In addition, hit carboxyl-primary amine groups linked reaction that reaction and EDC cause and confirmed that click-reaction and other linked reactions are independent of each other, complete quadrature by carrying out the catalytic azido-of Cu (I)-Terminal Acetylenes basic point simultaneously.
One, can click the synthetic of little hydrogel
Lift the building-up process of little hydrogel that two routine explanations can click below, be used to illustrate that a kind of temperature sensitive type can click the synthetic of little hydrogel, can be applied to different monomer copolymerizations with the appropriate reaction condition by changing monomer.
Example 1:
At first with 1.6 gram N-N-isopropylacrylamide (NIPAm), 200 microlitre vinylformic acid (AAc), 0.04 gram N, N-methylene-bisacrylamide (BIS) weighs up with analytical balance, adopt 60 ml deionized water to be dissolved in 200 ml beakers, can use 30 seconds accelerate dissolution processes of ultrasonoscope sonic oscillation in case of necessity.By having 0.8 micron pore size filtration syringe above solution transfer is entered 250 milliliter of three neck round-bottomed flask then.Use 30 ml deionized water rinse beaker and sonic oscillations in addition, the solution of rinse is shifted entering 250 milliliter of three neck round-bottomed flask by 0.8 micron filtration syringe.Be arranged on flask in the silicone oil bath this moment, and the left side bottleneck feeds nitrogen, and the right side bottleneck is plugged in thermometer, and middle bottleneck chain is connected to the prolong of nitrogen outlet, fixes on iron stand.Silicone oil bath is by the thermopair controlled temperature on the temperature control magnetic stirrer.At experimental installation after setting completed, the silicone oil bath temperature is set in 60 degrees centigrade, heat-up rate is arranged on 60 degrees centigrade/hour, and mixing speed is arranged on 450 rev/mins, begins to heat up from room temperature.Simultaneously, begin to feed nitrogen and get rid of oxygen in the original flask, nitrogen flow rate is 30 ml/min.Below the liquid level, the bubble take-off rate is even in flask for the syringe needle of nitrogen feeding this moment usefulness, and the electronics stirrer rotates normal, waits for that after 60 minutes, flask internal reaction liquid-phase system temperature is raised to 65 degrees centigrade, and oxygen also is replaced into nitrogen substantially in the system.At this moment, weighing 0.05 gram ammonium persulphate (APS) is as initiators for polymerization, and is dissolved in 3 ml deionized water and forms solution, by 0.8 micron filtration syringe the APS aqueous solution dripped and enters reaction system.After about 5 minutes, system begins to occur muddy, and rise to 65 degree centigrade with temperature of reaction this moment.After about 20 minutes, weighing 200 microlitre epoxypropyl methacrylic esters (GMA) also are dissolved in 3 milliliters of acetone, by 0.8 micron filtration syringe the GMA acetone soln are dripped and enter reaction system.After 5 minutes, weighing 0.15 gram sodiumazide (NaN
3) be dissolved in 6 ml deionized water.In order to prevent the too high a large amount of gathering sedimentations that cause little hydrogel of reaction system ionic strength, with NaN
3The aqueous solution divides 4 times by 0.8 micron filtration syringe, and each 1.5 milliliters, the interval is 30 minutes between twice, adds reaction system one by one.At NaN
3After adding, determine temperature of reaction system about 65 degrees centigrade, induction stirring allows reaction carry out stopped reaction after 20 hours after 450 rev/mins.This reaction as shown in Figure 1; This reaction unit as shown in Figure 3.Product solution is entered 150 milliliters of wide-necked bottles to remove the bigger hydrogel of volume (coagulum) by the glass fibre filtration, transfer to a plurality of 10 milliliters of high speed centrifugation pipes with transfer pipet then, remove supernatant liquid behind the high speed centrifugation, add 8 milliliters of left and right sides deionized waters then, vibration is spent the night and is disperseed little hydrogel again on the double vibrations device.After 4 centrifugal-dispersion circulations, will remove residual monomer, little water gel of initiator and oligopolymer ties up to 40 * 10
-3Millibar is done through about 70 hours low temperature ice down for-50 degrees centigrade.Final product is the very strong polymeric solid of white water-absorbent.
Example 2:
At first with 1.6 gram N-N-isopropylacrylamide (NIPAm), 200 microlitre vinylformic acid (AAc), 0.04 gram N, N '-methylene-bisacrylamide (BIS) weighs up with analytical balance, adopt 60 ml deionized water to be dissolved in 200 ml beakers, can use 30 seconds accelerate dissolution processes of ultrasonoscope sonic oscillation in case of necessity.By having 0.8 micron pore size filtration syringe above solution transfer is entered 250 milliliter of three neck round-bottomed flask then.Use 30 ml deionized water rinse beaker and sonic oscillations in addition, the solution of rinse is shifted entering 250 milliliter of three neck round-bottomed flask by 0.8 micron filtration syringe.Be arranged on flask in the silicone oil bath this moment, and the left side bottleneck feeds nitrogen, and the right side bottleneck is plugged in thermometer, and middle bottleneck chain is connected to the prolong of nitrogen outlet, fixes on iron stand.Silicone oil bath is by the thermopair controlled temperature on the temperature control magnetic stirrer.At experimental installation after setting completed, the silicone oil bath temperature is set in 40 degrees centigrade, heat-up rate is arranged on 60 degrees centigrade/hour, and mixing speed is arranged on 450 rev/mins, begins to heat up from room temperature.Simultaneously, begin to feed nitrogen and get rid of oxygen in the original flask, the nitrogen flow rate moons 30 ml/min.Below the liquid level, the bubble take-off rate is even in flask for the syringe needle of nitrogen feeding this moment usefulness, and the electronics stirrer rotates normal, waits for that after 60 minutes, flask internal reaction liquid-phase system temperature is raised to 40 degrees centigrade, and oxygen also is replaced into nitrogen substantially in the system.At this moment, weighing 0.05 gram ammonium persulphate (APS) is as initiators for polymerization, and is dissolved in 3 ml deionized water and forms solution, by 0.8 micron filtration syringe the APS aqueous solution dripped and enters reaction system.After about 15 minutes, system begins to occur muddy, and rise to 65 degrees centigrade with temperature of reaction by raise 1 degree centigrade speed of per minute this moment.After about 25 minutes, weighing 200 microlitre propargyl acrylate (PA) also are dissolved in 3 milliliters of acetone, by 0.8 micron filtration syringe the PA acetone soln are dripped and enter reaction system.After PA adds, determine temperature of reaction system about 65 degrees centigrade, induction stirring allows reaction carry out stopped reaction after 48 hours after 450 rev/mins.This reaction as shown in Figure 2; This reaction unit as shown in Figure 3.Product solution is entered 150 milliliters of wide-necked bottles to remove the bigger hydrogel of volume (coagulum) by the glass fibre filtration, transfer to a plurality of 10 milliliters of high speed centrifugation pipes with transfer pipet then, remove supernatant liquid behind the high speed centrifugation, add 8 milliliters of left and right sides deionized waters then, vibration is spent the night and is disperseed little hydrogel again on the double vibrations device.After 4 centrifugal-dispersion circulations, will remove residual monomer, little water gel of initiator and oligopolymer ties up to 40 * 10
-3Millibar is done through about 70 hours low temperature ice down for-50 degrees centigrade.Final product is the very strong polymeric solid of white water-absorbent.
Two, the nitrine-Terminal Acetylenes basic point that can click little hydrogel hits reaction
1, click-reaction (nitrine-Terminal Acetylenes base Cu (I) catalyzed reaction) example
In order to test the click-reaction of the azido-clicked that carries on little hydrogel, the present invention adopts the fluorescein that carries the Terminal Acetylenes base, and (fluorescein propargyl thiocarbamate FPTC) follows the tracks of click-reaction.Concrete operations are as follows:
Little hydrogel (N that will contain azido-earlier
3-Microgel) pressed powder 20mg is dissolved in the 10mL deionized water in the 20mL reagent bottle, and is standby behind the homodisperse on the earthquake device.Weighing 3mg L-sodium ascorbate is dissolved in the 2mL deionized water then, adds hydrogel dispersion system in a subtle way.Add 1mL 0.04mg/mL FPTC ethanolic soln again, in little hydrogel dispersion system, mix.In system, feed nitrogen after about 5 minutes, add the CuSO of 50 μ L 0.1M
4The aqueous solution.System is enclosed in the reagent bottle high-speed stirring (400rpm) at room temperature, and the system color becomes bright orange green after 15 minutes, and color is thin out gradually afterwards.After 10 hours, reaction stops, and product is shifted entering dialysis membrane, dialyses in deionized water, changes water every day once, and dialysis was no less than for 2 week, to remove Cu (I) ion, excessive FPTC, sodium ascorbate.After the dialysis with the product dispersion system in-50C, 40 * 10
-3Ice is done under the condition of millibar, obtains slightly yellowish water-absorbent pressed powder.This reaction can be represented as shown in Figure 4.
2, orthogonal reaction example (nitrine-Terminal Acetylenes base Cu (I) catalysis click-reaction and EDC coupling reaction carry out simultaneously and do not disturb mutually):
(HC ≡ C-, COOH-Microgel) pressed powder 20mg is dissolved in the 10mL deionized water in the 20mL reagent bottle, and is standby behind the homodisperse on the earthquake device will to contain little hydrogel of alkynes end group and carboxyl earlier.Weighing 3mg L-sodium ascorbate is dissolved in the 2mL deionized water then, adds hydrogel dispersion system in a subtle way.Add 1mL 0.04mg/mL again and contain the fluorescein of azido-, 5-azidofluorescein (AzF) ethanolic soln mixes in little hydrogel dispersion system.Adding 100 μ L another kinds then contains amino fluorescein TMRC (tetramethylrhodamine cadaverine) DMF solution and 2.8mg EDC (1-ethyl-3-(3-dimethylamino-propyl) carbodiimidehydrochloride) and enters reaction system.In reaction system, feed nitrogen after about 5 minutes, add the CuSO of 50 μ L 0.1M
4The aqueous solution.System is enclosed in the reagent bottle high-speed stirring (400rpm) at room temperature, and the system color becomes yellowish brown after 15 minutes, and color is thin out gradually afterwards.After 10 hours, reaction stops, and product is shifted entering dialysis membrane, dialyses in deionized water, changes water every day once, and dialysis was no less than for 2 week, to remove Cu (I) ion, excessive FPTC and TMRC, sodium ascorbate and EDC hydrolysate etc.After the dialysis with the product dispersion system at 50C, ice is done under the condition of 40 μ bar, obtains brown slightly water-absorbent pressed powder.The reaction expression as shown in Figure 5.
3, little hydrogel of fluorescence microscope reaction 1,2
A, nitrine-Terminal Acetylenes base Cu (I) catalyzed reaction (reaction 1 is seen shown in Figure 4)
The fluorescein FPTC that carries the Terminal Acetylenes base makes microgel send sap green fluorescence under the 450-490nm blue light excites after clicking and being coupled on the microgel that carries azido-, and its fluorescence excitation emmission spectrum as shown in Figure 6.
B, nitrine-Terminal Acetylenes base Cu (I) catalysis click-reaction and carboxyl-amino EDC coupling reaction quadrature carries out (reaction 2): the EDC linked reaction takes place with the TMRC that contains amino in little hydrogel simultaneously that contain carboxyl (COOH) and Terminal Acetylenes base, Cu (I) catalysis click-reaction takes place with the AzF that contains azido-, two reactions are not disturbed mutually, fully quadrature.The fluorescein AzF that carries azido-makes microgel send green fluorescence under the 450-490nm blue light excites after clicking and being coupled on the microgel that carries the Terminal Acetylenes base; The tetramethyl-rhodamine TMRC that carries primary amine groups accordingly makes microgel send red fluorescence under the 510-560nm green light excites be coupled on the microgel that carries carboxyl by EDC after.The fluorescence excitation emmission spectrum of AzF and TMRC such as Fig. 7, shown in Figure 8 for reference.
Claims (12)
1, a kind of temperature of clicking/pH-sensibility microgel is characterized in that, by temperature sensitivity monomer, pH-sensitive monomer, can click the hydrogel that monomer and linking agent are polymerized and can click.
2, microgel as claimed in claim 1 is characterized in that, described temperature sensitive monomer comprises: N-N-isopropylacrylamide, N-isopropyl methyl acrylamide, the hydrogel of clicking of formation, promptly little hydrogel particle.The temperature sensitive monomer mass content is between 50-95%.
3, microgel as claimed in claim 1 is characterized in that, described pH-/ionic strength-Min monomer comprises: vinylformic acid particularly, methacrylic acid, 4-vinylpridine.PH-/ionic strength-sensitive monomer mass content is between 5-50%.
4, microgel as claimed in claim 1 is characterized in that, (side chain contains epoxy group(ing) to described monomer that can click type side chain, amino, hydroxyl, sulfydryl, halogen, isocyanic ester, isothiocyanic acid ester, alkynyl, the monomer of azido-isoreactivity functional group) comprising: epoxypropyl (methyl) acrylate particularly, alkynes ethyl (methyl) acrylate, (methyl) Hydroxyethyl acrylate.Have can click type side chain monomer mass content between 1-20%.
5, microgel as claimed in claim 1 is characterized in that, described linking agent is N, N '-methylene-bisacrylamide (BIS), ethylene glycol dimethacrylate (EDGMA) etc.We notice is not having under the condition of linking agent because the existence of chain transfer, and microgel also can form.The mass content of linking agent is between 0-20%.
6, hydrogel as claimed in claim 1, it is characterized in that, the hydrogel that the crosslinking copolymerization that causes by free radical in from 20 to 85 degrees centigrade of intervals of temperature forms, particularly diameter is from the microgel of 50 nanometers to 5 micron, in the polymerization by adjusting controlling reaction temperature gel size and productive rate.
7, hydrogel as claimed in claim 1 is characterized in that, adds tensio-active agent in the polymerization process, as sodium laurylsulfonate (SDS) etc., reduces the microgel size.
8, hydrogel as claimed in claim 1 is characterized in that, polymerization process is the redox initiation under the normal temperature, as adopting Sodium Persulfate-sodium bisulfite, waits all suitable redox initiation systems; Or, carry out the organic phase initiation as adopting all suitable thermal initiators such as ammonium persulphate to carry out all suitable thermal initiators such as water initiation and employing Diisopropyl azodicarboxylate by the thermal initiation that is higher than normal temperature; Or adopt light-initiatedly, cause to adopt Irgacur series to wait all suitable light triggers and adopt radiation to cause as UV-light, such as X-ray, plasma body.
9, hydrogel as claimed in claim 1 is characterized in that, adds linking agent in the polymerization process, or does not add linking agent.
10, hydrogel as claimed in claim 1 is characterized in that, polymerization process is carried out in water or organic phase.
11, hydrogel as claimed in claim 1 is characterized in that, polymerization process is an one-step synthesis, or two steps are synthetic, little hydrogel particle of clicking of the uniform or nucleocapsid structure that these two kinds of synthesis strategies form.
12, hydrogel as claimed in claim 1 is characterized in that, can click dialysis or the centrifugal-dispersion again adopted in the microgel product purification.
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| CN113350572A (en) * | 2020-12-03 | 2021-09-07 | 深圳市第二人民医院(深圳市转化医学研究院) | Medical temperature-sensitive hydrogel and preparation method and application thereof |
| CN113350572B (en) * | 2020-12-03 | 2023-07-14 | 深圳市第二人民医院(深圳市转化医学研究院) | Medical temperature-sensitive hydrogel and preparation method and application thereof |
| CN113290964A (en) * | 2021-05-07 | 2021-08-24 | 武汉理工大学 | Automobile skylight functional film with temperature regulation and rainfall sensing functions |
| CN114316132A (en) * | 2022-01-28 | 2022-04-12 | 赛纳生物科技(北京)有限公司 | Method for synthesizing functional polymer microspheres by emulsion polymerization |
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