CN105017495A - Preparation method of soybean protein-based dual-sensitive polymeric micro-porous gel, and application of gel as drug carrier - Google Patents
Preparation method of soybean protein-based dual-sensitive polymeric micro-porous gel, and application of gel as drug carrier Download PDFInfo
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Abstract
The invention discloses a preparation method of a soybean protein-based dual-sensitive polymeric micro-porous gel, and belongs to the biotechnical field. The micro-porous gel having pH and temperature dual sensitivity and good swelling and deswelling performances is obtained through cross-linking polymerization of biocompatible and biodegradable natural polymeric soybean protein isolate, a functional monomer N-isopropylacrylamide and acrylic acid as raw materials. In vitro drug release performance test shows that the polymeric micro-porous gel has a good release effect on model drugs especially micro-molecular model drugs, so the gel can be used in drug controlled release as a drug carrier.
Description
Technical field
The invention belongs to biological technical field, relate to a kind of preparation of dual-sensitivity high molecule micropore gel, particularly relate to a kind of preparation of soybean protein base dual-sensitivity high molecule micropore gel; The present invention also relates to the application of this soybean protein base dual-sensitivity high molecule micropore gel as pharmaceutical carrier simultaneously.
Background technology
Natural polymer aboundresources, renewable, nontoxic, good biocompatibility and the advantages such as degradable are widely used in each field.As typical natural polymer, soybean protein isolate is a kind of multifunctional protein, the polypeptide chain be formed by connecting by peptide bond by each seed amino acid, containing various active side base as amino, carboxyl, hydroxyl and sulfydryl, energy and many material generation chemical reactions, it has much important physiology and pharmacological effects.Simultaneously owing to having the advantages such as safety non-toxic, non-immunogenicity, biodegradable, good biocompatibility, usually used as carrier and starting material in pharmaceutical carrier and organizational project.
The macromolecular chain of poly N-isopropyl acrylamide (PNIPAM) have simultaneously hydrophilic amido and hydrophobic sec.-propyl, the aqueous solution of line style PNIPAM and the PNIPAM hydrogel after being cross-linked is made all to present temperature sensitive properties: to undergo phase transition when the aqueous solution of PNIPAM is warming up to about about 33 DEG C, nonhomogeneous system is transformed into by homogeneous system, PNIPAM hydrogel volume when being warming up to 32 DEG C of chemically crosslinked shrinks suddenly, smaller volume.Therefore, poly N-isopropyl acrylamide is requiring the smart system with temperature response " on-off " effect, as very deep in the research in Intelligent chemical mechanical valve, intellectual drug release vehicle etc.Contain a large amount of carboxylated hydrophilic base in polyacrylic hydrogels in addition, in different pH value, presenting contraction in various degree or solvent swelling state, is typical pH sensitive hydrogel.But when using as pharmaceutical carrier, it has certain defect on biocompatibility and biodegradability.
Summary of the invention
The object of the invention is the characteristic with NIPA and poly N-isopropyl acrylamide, N is passed through after soybean protein isolate modified, N-methylene-bisacrylamide is cross-linked, and prepares the method for soybean protein base pH and temperature dual-sensitivity high molecule micropore gel;
Another object of the present invention is the medicine-releasing performance by studying above-mentioned soybean protein based high molecular microporous, provides it as the application of pharmaceutical carrier in drug controlled release.
One, the preparation of dual-sensitivity high molecule micropore hydrogel
The preparation of soybean protein base dual-sensitivity high molecule micropore gel of the present invention is that urea is dispersion liquid, is obtained by crosslinking polymerization with soybean protein isolate, functional monomer NIPA, vinylformic acid for raw material.Concrete preparation technology is as follows:
0.1 ~ 2.0 g soybean protein isolate is scattered in 1 ~ 15 mL dispersion liquid, at room temperature stirs 3 ~ 24 h; Add 0.1 ~ 5.0 g NIPA to stir, then add 5 ~ 50uL vinylformic acid, 0.05 ~ 5 g linking agent, stirring reaction 5 ~ 40 min; Then under protection of inert gas, be warming up to 30 ~ 85 DEG C, add 0.01 ~ 0.5g initiator, leave standstill 3 ~ 12 h after stirring, obtain hydrogel; Hydrogel, through ethanol, water soaking, washing postlyophilization, obtains dual-sensitivity high molecule micropore gel.
Wherein, the granularity of soybean isolate protein powder is 50 ~ 200 orders; Dispersion liquid is the urea soln of concentration 0.8 ~ 10 mol/L; Linking agent adopts N,N methylene bis acrylamide; Initiator adopts ammonium persulphate or ammonium persulphate potassium; Rare gas element is nitrogen, argon gas or carbon dioxide.
Two, soybean protein base dual-sensitivity polymeric gel structure characterizes
1, macro morphology
Fig. 1 is the macro morphology of soybean protein base dual-sensitivity high molecule micropore gel, and as can be seen from Figure 1, soybean protein base dual-sensitivity high molecule micropore gel prepared by the present invention is loose porous solid material.
2, infared spectrum
Fig. 2 is the infared spectrum of soybean protein base dual-sensitivity high molecule micropore gel.In Fig. 2, at 1718 cm
-1near there is in NIPA and acrylic copolymer P (NIPAM-co-AA) C=O stretching vibration absorption peak, simultaneously at 1652 cm
-1, 1538 cm
-1, 1215 cm
-1near occurred soybean protein isolate acid amides I, II, III band charateristic avsorption band, soybean protein isolate and the effective compound of multipolymer are described.
3, thermogravimetric analysis
Fig. 3 is the thermogravimetric curve TG(test condition of soybean protein base dual-sensitivity high molecule micropore gel: N
2protection; Temperature elevating range: 25 ~ 800 DEG C; Heat-up rate: 10 DEG C/min).Result shows, the main weightlessness of soybean protein base dual-sensitivity high molecule micropore gel is interval at 200 ~ 450 DEG C, and compared with raw soybeans protein isolate, its thermostability is significantly improved.
4, scanning electron microscope (SEM) photograph
Fig. 4 is the scanning electron microscope (SEM) photograph of soybean protein base dual-sensitivity high molecule micropore gel.Can be found out by scanning electron microscope, the aperture of soybean protein base dual-sensitivity high molecule micropore gel is 2 ~ 5um, and pore size differs, can well by the drug loading of different molecular weight in pore structure.In addition, adding of soybean protein isolate, the swelling capacity of gel can be improved, be conducive to drug loading.
Three, the performance of soybean protein base dual-sensitivity high molecule micropore gel
1, swelling behavior
In order to evaluate the suitability of soybean protein base dual-sensitivity high molecule micropore gel as biomaterial, test the swelling ratio of micropore gel in different simulation biological solutions (at lower 37 DEG C).Result shows: the swelling capacity of soybean protein base dual-sensitivity high molecule micropore gel in two water is greater than NIPA and acrylic copolymer, and what soybean protein isolate was described adds the swelling behavior that can improve gel.In addition, the again swelling behavior of (37 DEG C) soybean protein base dual-sensitivity high molecule micropore gel in water under testing body temperature, result is as shown in Figure 5: first time water suction dried gel absorption ability is removing 89.47% of equilibrium swelling ratio in intermediate water for the first time, show that soybean protein base dual-sensitivity polymer-network method can be repeatedly swelling at intermediate water, reuse.
2, temperature, pH susceptibility
In order to evaluate the susceptibility of gel to temperature, test gel swelling ratio (see figure 6) at different temperatures.Find at 4 ~ 25 DEG C, gel swelling increases gradually, and after about 32 DEG C, swelling capacity starts to decline.Illustrate that soybean protein base dual-sensitivity high molecule micropore gel has temperature sensitivity.
In order to evaluate the susceptibility of gel to pH value, the swelling ratio change (see figure 7) in test different pH value.Result shows: in the stronger environment of acidity, gel swelling performance is less, and along with pH raises, its swelling behavior improves gradually.
3, vitro drug release performance
With dual-sensitivity high molecule micropore gel for pharmaceutical carrier, select small molecule anticancer drug (doxorubicin hydrochloride), investigate the vitro drug release performance of dual-sensitivity micropore gel.Under human body temperature (37 DEG C), investigated the release performance of dual-sensitivity micropore gel under the environment (i.e. gastric juice (pH=1.2), blood (pH=7.4)) of different pH value, result as shown in Figure 8.Under visible acidic conditions, (pH=1.2) release rate is slow, and during 12h, maximum release rate is 23.9%, and most of medicine retention is in hydrogel; Under neutrallty condition (pH=7.4), drug releasing rate is the fastest, and after 12 h, preparation can reach 51.77%, and along with time of releasing extends, preparation reaches as high as 93.8%.Illustrate that (blood environment) release rate is fast in neutral conditions, and in sour environment, (gastric juice) release rate is the slowest, illustrates that gel has sensitivity to acid.In addition, under also having investigated other temperature (25 DEG C, 37 DEG C, 42 DEG C) in experiment, environmental pH, to the release performance of gel, the results are shown in Figure 9.At finding 40 DEG C, the accumulative release rate of doxorubicin hydrochloride is higher, and drug release littlely reaches balance constantly 36, reaches as high as 98.5%; And at 25 DEG C, the release of medicine is comparatively steady, the highest adding up is released to 66.1%.This illustrates that gel has temperature sensitivity.
In sum, the present invention is to have the natural polymer soybean protein isolate of biocompatibility and biodegradability, functional monomer NIPA and vinylformic acid for raw material, prepare and a kind of there is pH and temperature dual-sensitivity and well swelling and micropore gel of deswelling performance, to model drug especially small molecule model medicine, there is good slow release effect.Therefore, can be used as pharmaceutical carrier to be applied in drug controlled release.
Accompanying drawing explanation
Fig. 1 is the macro morphology of soybean protein base sensitive high molecule micropore gel.
Fig. 2 is the infrared spectrogram of soybean protein base sensitive high molecule micropore gel.
Fig. 3 is the thermogravimetric analysis figure of soybean protein base sensitive high molecule micropore gel.
Fig. 4 is the scanning electron microscope (SEM) photograph of soybean protein base sensitive high molecule micropore gel.
Fig. 5 is the again Swelling Dynamics of soybean protein base sensitive high molecule micropore gel in water (37 DEG C).
Fig. 6 is soybean protein base sensitive high molecule micropore gel swelling ratio at different temperatures.
Fig. 7 is the swelling ratio of soybean protein base sensitive high molecule micropore gel under different pH.
Fig. 8 be under different acidity condition micropore gel to the release in vitro performance (37 DEG C) of cancer therapy drug.
Fig. 9 be under condition of different temperatures micropore gel to the release in vitro performance (pH=7.4) of cancer therapy drug.
Embodiment
Below by specific embodiment, the preparation of micropore gel of the present invention and performance are described further.
Embodiment 1: get granularity 50 ~ 200 object soybean isolate protein powder 0.1 g, is scattered in 1mL and must disperses (concentration of urea soln is 0.8 mol/L) in urea soln, stirring at room temperature 24 h; Add 0.1 g NIPA to stir; Add 5uL vinylformic acid again, 0.05g linking agent N,N methylene bis acrylamide, continue stirring 10 about min; Then 30 DEG C are warming up under nitrogen protection; Add 0.01g initiator ammonium persulfate to stir; Pour reaction solution into reaction flask, be placed in water-bath, leave standstill 12 h at 30 DEG C, obtain hydrogel; Hydrogel is placed in ethanol successively, water soaks, washing, and then lyophilize, obtains soybean protein base dual-sensitivity micropore gel.The involve release rate of this gel to small molecule anticancer drug doxorubicin hydrochloride (37 DEG C) is 76%.
Embodiment 2: get granularity 50 ~ 200 object soybean isolate protein powder 0.5 g and be scattered in 5 mL dispersion urea solns (concentration of urea soln is 1.0 mol/L), stirring at room temperature 10 h, adds 0.5 g NIPA and stir; Add 20 uL vinylformic acid again, 0.1 g linking agent N,N methylene bis acrylamide, continue stirring 10 min; Then 50 DEG C are warming up under nitrogen protection; Add 0.02g initiator ammonium persulfate to stir; Pour reaction solution into reaction flask, be placed in water-bath, leave standstill 10 h at 50 DEG C, obtain hydrogel; Hydrogel is placed in ethanol successively, water soaks, washing, and then lyophilize, obtains soybean protein base dual-sensitivity micropore gel.The involve release rate of this gel to small molecule anticancer drug doxorubicin hydrochloride (37 DEG C) is 88%.
Embodiment 3: get granularity 50 ~ 200 object soybean isolate protein powder 1.0 g and be scattered in 10 mL dispersion urea solns (concentration of urea soln is 1.5 mol/L), stirring at room temperature 18 h, adds 1.0 g NIPAs and stir; Add 30uL vinylformic acid again, 0.5 g linking agent N,N methylene bis acrylamide, continue stirring 30 min; Then 60 DEG C are warming up under nitrogen protection; Add 0.03g initiator ammonium persulfate potassium to stir; Pour reaction solution into reaction flask, be placed in water-bath, leave standstill 8h at 60 DEG C, obtain hydrogel; Hydrogel is placed in successively ethanol, water soaks, washing, then lyophilize, obtains soybean protein base dual-sensitivity micropore gel.The involve release rate of this gel to small molecule anticancer drug doxorubicin hydrochloride (37 DEG C) is 81%.
Embodiment 4: get granularity 50 ~ 200 object soybean isolate protein powder 1.5 g and be scattered in 10mL dispersion urea soln (concentration of urea soln is 5 mol/L), stirring at room temperature 10 h, adds 3.0 g NIPAs and stir; Add 40uL vinylformic acid again, 1.5 g linking agent N,N methylene bis acrylamides, continue stirring 15 min; Then 70 DEG C are warming up under nitrogen protection; Add 0.4g initiator ammonium persulfate to stir, then pour reaction solution into reaction flask, be placed in water-bath, leave standstill 5 h at 70 DEG C, obtain hydrogel; Hydrogel is placed in successively ethanol, water soaks, washing, then lyophilize, obtains soybean protein base dual-sensitivity micropore gel.The involve release rate of this gel to small molecule anticancer drug doxorubicin hydrochloride (37 DEG C) is 71%.
Embodiment 5: get granularity 50 ~ 200 object soybean isolate protein powder 2.0 g and be scattered in 15 mL dispersion urea solns (concentration of urea soln is 10 mol/L), stirring at room temperature 10 h, adds 5.0 g NIPAs and stir; Add 50uL vinylformic acid again, 5g linking agent N,N methylene bis acrylamide, continue stirring 10 min; Then 85 DEG C are warming up under nitrogen protection; Add 0.5g initiator ammonium persulfate potassium to stir; Pour reaction solution into reaction flask, be placed in water-bath, leave standstill 3 h at 85 DEG C, obtain hydrogel; Hydrogel is placed in successively ethanol, water soaks, washing, then lyophilize, obtains soybean protein base dual-sensitivity micropore gel.The involve release rate of this gel to small molecule anticancer drug doxorubicin hydrochloride (37 DEG C) is 65%.
Claims (8)
1. a preparation method for soybean protein base dual-sensitivity high molecule micropore gel is that urea is dispersion liquid, is obtained by crosslinking polymerization with soybean protein isolate, functional monomer NIPA, vinylformic acid for raw material.
2. the preparation method of soybean protein base dual-sensitivity high molecule micropore gel as claimed in claim 1, is characterized in that: be scattered in 1 ~ 15 mL dispersion liquid by 0.1 ~ 2.0 g soybean isolate protein powder, at room temperature stir 3 ~ 24 h; Add 0.1 ~ 5.0 g NIPA to stir, then add 5 ~ 50uL vinylformic acid, 0.05 ~ 5 g linking agent, stirring reaction 5 ~ 40 min; Then under protection of inert gas, be warming up to 30 ~ 85 DEG C, add 0.01 ~ 0.5g initiator, leave standstill 3 ~ 12 h after stirring, obtain hydrogel; Hydrogel, through ethanol, water soaking, washing postlyophilization, obtains dual-sensitivity high molecule micropore gel.
3. the preparation method of soybean protein base dual-sensitivity high molecule micropore gel as claimed in claim 1 or 2, is characterized in that: the granularity of soybean isolate protein powder is 50 ~ 200 orders.
4. the preparation method of soybean protein base dual-sensitivity high molecule micropore gel as claimed in claim 1 or 2, is characterized in that: dispersion liquid is the urea soln of concentration 0.8 ~ 10 mol/L.
5. the preparation method of soybean protein base dual-sensitivity high molecule micropore gel as claimed in claim 1 or 2, is characterized in that: linking agent is N,N methylene bis acrylamide.
6. the preparation method of soybean protein base dual-sensitivity high molecule micropore gel as claimed in claim 1 or 2, is characterized in that: initiator is ammonium persulphate or ammonium persulphate potassium.
7. the preparation method of soybean protein base dual-sensitivity high molecule micropore gel as claimed in claim 1 or 2, is characterized in that: the drying of hydrogel adopts lyophilize.
8. as claimed in claim 1 the soybean protein base dual-sensitivity high molecule micropore gel prepared of method as the application of pharmaceutical carrier.
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| CN107523136A (en) * | 2016-12-09 | 2017-12-29 | 杭州铭众生物科技有限公司 | The degradable 3D printing bio-ink of temperature-responsive and 3D printing method |
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| US4863613A (en) * | 1985-10-25 | 1989-09-05 | Regents Of The University Of Minnesota | Soy protein isolation process using swellable poly(N-isopropylacrylamide) gels |
| CN103524764A (en) * | 2013-09-27 | 2014-01-22 | 西北师范大学 | Preparation method of isolated soy protein macromolecular interpenetrating network hydrogel and application of hydrogel serving as medicine controlled release carrier |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107523136A (en) * | 2016-12-09 | 2017-12-29 | 杭州铭众生物科技有限公司 | The degradable 3D printing bio-ink of temperature-responsive and 3D printing method |
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