CN104258426A - Nuclear magnetic resonance visual injectable pH sensitive self-repairing water gel as well as preparation method and application thereof - Google Patents
Nuclear magnetic resonance visual injectable pH sensitive self-repairing water gel as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention provides nuclear magnetic resonance visual injectable pH sensitive self-repairing water gel. The gel consists of DTPA-modified chitosan (component A) and polyethylene glycol (component B) of which two ends are subjected to hydroformylation, and the component A solution complexed with Gd<3+> and the component B solution are mixed in a short time at room temperature so as to form in-situ gel. The gel has the pH sensitive self-repairing characteristic, a developing agent is not needed to be repeatedly injected to a patient, and developing can be guaranteed for a long time by using MRI (Magnetic Resonance Imaging), so that the lesion risk caused by Gd<3+> enrichment is reduced. The water gel provided by the invention can serve as drug carriers, embolism or filling materials and tissue scaffold materials in clinical application.
Description
Technical field
The invention belongs to chemistry and biomedicine field, particularly relate to a kind of nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel and its production and use.
Background technology
The material of hydrogel to be a kind of with water the be netted structure of high molecular crosslink of disperse medium, because it is rich in moisture, character softness also has certain form, usually there is the similarity of superior biocompatibility and biological tissue and have a wide range of applications in bio-medical field, can be used as medicament sustained-release matrix material, tissue renovation material etc.Wherein, natural polymer as hyaluronic acid, glucosan, alginic acid, chondroitin sulfate, chitosan, pectin, gelatin, fibrin etc. are because of its excellent biocompatibility and degradable or the feature such as can be absorbed, and in depth studied and be widely used in the Design and synthesis of medical aquogel.
In clinical practice use procedure, one can be flowable state in vitro, once the injectable gel (situ-gel) that just gel state can be become by process mixing in conduit or needle injection to body or certain condition triggering and play a role, attract the concern of large quantities of researcher because it is easy to use.The active force difference formed according to situ-gel is broadly divided into physical gel and chemical gel.Poloxamer 407 (Pluronic F-127) is exactly a kind of physical gel, 37 DEG C time, form gel, is used for the treatment of burn and other wound.Certain density Poloxamer 118 can reduce erythrocytic cohesion and blood viscosity, lubricant cell surface, reduce cell and intercellular friction [Du Guangzeng, Zhao Haoru (2008). " Synthesis and applications of Poloxamer 407 Thermo-sensitive instant gel is in progress. " pharmacy is in progress 32 (4): 163-167.].The commercialization of this gellike, its deficiency is that mechanical strength is inadequate, and the network structure of association is unstable, and the time maintained in vivo is shorter, and permeability is higher.And various chemical gel just in time makes up this deficiency.Hylan B (commodity are called HylaformTM) hydrogel is the product that hyaluronic acid and bivinyl sulfone are cross-linked, and is used as the subcutaneous embedded material of face-lifting recently at US and European.Hallen is studied treating vocal cord defect with HylaformTM, HylaformTM is injected in the vocal cords of rabbit, this material can increase the formation of soft tissue in vocal cords lastingly, and without inflammatory and other side reaction, show that HylaformTM is the good candidate material [Hallen for the treatment of vocal cords, L., et al. (1999). " Cross-linked hyaluronan (hylan B gel): a new injectable remedy for treatment of vocal fold insufficiency-an animal study. " Acta Oto-Laryngologica 119 (1): 107-111.].
Self-healing property material is the New Intelligent Material that a class has self-regeneration material damage characteristic, and the hydrogel of self-healing property also becomes the field received much concern in recent years.When the crosslinking points of gel is dynamic chemical action, self-healing performance can be shown.One class be non-covalent bond as crosslinked action power, as hydrogen bond, Van der Waals force, coordination, hydrophobe effect etc., but this gellike is also due to mechanical strength deficiency, range of application is restricted; Another kind of be reversible covalent bond as crosslinked action power, as cystine linkage, acylhydrazone key, imine linkage etc.The hydrogel can injected the while that these features can being utilized to prepare this reparation.Bibliographical information is had to prepare with chitosan and the two terminal modified Polyethylene Glycol of aldehyde radical (PEG) injectable gel taking imine linkage as crosslinked action, because the forming process of imine linkage is reversible reaction, therefore this gel also has the feature of selfreparing, prove that it has response to multiple biochemistry stimulation simultaneously, such as pH, aminoacid and vitamin B 6 derivative.In addition chitosan can be caused gel degradation by enzyme as papain digestion.This gel will have prospect [Zhang widely at biomedical sector, Y., et al. (2011). " Synthesis of multiresponsive and dynamic chitosan-based hydrogels for controlled release of bioactive molecules. " Biomacromolecules 12 (8): 2894-2901.].
But in clinical practice, usual hydrogel is expelled to difficulty after in body and determines its position of injecting, and is also difficult to the change observing and monitor surrounding tissue or lesions position, therefore, inventing a kind of visual gel will be very helpful to this kind of problem of solution.
NMR (Nuclear Magnetic Resonance)-imaging (MRI) technology is rare to human body fanout free region, radiationless, high-resolution imaging technique at present, it is widely used in clinical diagnosis and [Nitzsche in research, H., et al. (2009). " Characterization of Scaffolds for Tissue Engineering by Benchtop-Magnetic Resonance Imaging. " Tissue Engineering Part C-Methods 15 (3): 513-521.].Utilize nmr imaging technique to osseous tissue [Hartman, E.H.M., et al. (2002). " In vivo magnetic resonance imaging explorative study of ectopic bone formation in the rat. " Tissue Engineering 8 (6): 1029-1036.] and cartilaginous tissue have good resolution [Neves, A.A., et al. (2002). " Tissue engineering of meniscal cartilage using perfusion culture. " Reparative Medicine:Growing Tissues and Organs 961:352-355.], and nondestructively can monitor their formation and change in vivo.The change of magnetic resonance parameters, as T1, T2, relaxation time and diffusion parameter, change [the van der Heiden of material character can be reflected, M.S., et al. (2012). " Accurate and efficient fiber optical shape sensor for MRI compatible minimally invasive instruments. " Optical Systems Design 20128550.; Reiter, D.A., et al. (2012). " Improved MR-based characterization of engineered cartilage using multiexponential T-2relaxation and multivariate analysis. " Nmr in Biomedicine 25 (3): 476-488.].So, gel is prepared into and the material of imaging in mri can will realizes that it is visual.
Clinically, usually can give patient injection contrast agent, to increase the density difference of pathological tissues and normal structure, allow focus " be completely exposed ".Conventional is that a kind of T1 class preparation is (as paramagnetic metal ion Gd
3+, Mn
2+, Fe
3+deng), enhancing signal intensity in T1 weighted imaging.1984, the Weinmann etc. of Schering AG company develop first item for clinical with diethylene triamine pentacetic acid (DTPA) (DTPA) for Gd
3+the contrast agent Gd-DTPA of chelating agent, greatly reduces Gd
3+toxicity, and there is good relaxation effect.But evidence show, this contrast agent of patient's excessive use likely causes renal fibrosis pathological changes.Therefore increasing research concentrates on how by Gd
3+macromolecular and targeting, to improve its action time in vivo and to reduce using dosage to reduce its toxic and side effects.DTPA is modified on glucosan by Hiroshi Tanaka etc., form the osteocyte tacking agent [Tanaka that a kind of MRI develops, H., et al. (2014). " Synthesis of a dextran-based bone tracer in vivo magnetic resonance and optical imaging by two orthogonal coupling reactions. " Rsc Advances 4 (15): 7561-7565.].Simith C.E. etc. chitosan will be modified DTPA, make the liposome [Smith of MRI development, C.E., et al. (2013). " A Polymeric Fastener Can Easily Functionalize Liposome Surfaces with Gadolinium for Enhanced Magnetic Resonance Imaging. " ACS Nano 7 (11): 9599-9610.].These examples have illustrated chelating Gd
3+dTPA be connected on macromole, the nano-particle of formation can develop on MRI.
Summary of the invention
In order to overcome the deficiency that existing gel can not develop, the invention provides a kind of hydrogel of energy NMRI, and this gel have simultaneously injectable, can the characteristic of self-regeneration within the scope of certain pH, its concrete technical scheme is as follows:
A kind of nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel, it is characterized in that: described hydrogel comprises complex and the B component of component A, described component A be the side-chain amino group of chitosan through diethylene triamine pentacetic acid (DTPA) (DTPA) partially substituted product (Ch-DTPA), its structural formula is
Wherein m, n are natural number, m/n=5% ~ 50%;
The derivant (PEG-DF) of described B component to be Polyethylene Glycol two ends be aldehyde radical, its structural formula is:
Wherein
the molecular weight of Polyethylene Glycol is 1000-4000, y is natural number, and y=22 ~ 90; Amino in described component A is 4:1 ~ 1:1 with the ratio of the molal quantity of aldehyde radical in B component.
The complex of described component A is component A and Gd
3+complex (Ch-DTPA/Gd
3+), its structural representation formula is
Wherein m, n are natural number, m/n=5% ~ 50%.
Above-mentioned nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel, it is characterized in that: preferred scope is m/n=10% ~ 40%, y=22 ~ 66, the molecular weight of Polyethylene Glycol is 1000-3000, and amino in component A is 2:1 with the ratio of the molal quantity of aldehyde radical in B component.
Above-mentioned nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel, it is characterized in that: preferred scope is m/n=20%, y=44, the molecular weight of Polyethylene Glycol is 2000, and amino in component A is 2:1 with the ratio of the molal quantity of aldehyde radical in B component.
The present invention also provides the preparation method of above-mentioned nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel, and step is as follows:
(1) formulation components solution A: get component A, is made into the acetum that mass percentage concentration is 2% the component solution A that mass percentage concentration is 3%;
(2) getting containing concentration is the Gd of 0.1mol/L
3+aqueous solution, by a certain amount of Gd
3+aqueous solution mix with component solution A, different Gd can be obtained
3+the Ch-DTPA/Gd of concentration
3+solution,
(3) formulation components B solution: get B component and be mixed with the B component aqueous solution that concentration is 20%;
(4) Ch-DTPA/Gd is got
3+solution and B component solution, make it fully mix, and namely obtains nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel.
Prepare the method for nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel as above, it is characterized in that: the preparation process of component A is as follows:
(1) get chitosan, add dilute hydrochloric acid and be heated to 65 DEG C of stirrings and make it dissolve, obtain solution 1;
(2) get DTPA with after appropriate second distillation water dissolution, regulate pH to 4.7 with N, N, N', N'-tetramethylethylenediamine (TEMED), obtain solution 2 (wherein DTPA consumption is 5% ~ 50% of the sugared ring element sum of chitosan);
Be added dropwise in solution 1 together with solution 2 is after 0 DEG C of mix homogeneously after getting the dilute hydrochloric acid solution dissolving of N-hydroxy-succinamide (NHS) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (NHS with EDC consumption is 1.2 times of DTPA mole) 50mM, then stirring reaction 30h in the oil bath of 75 DEG C, continue stirring at room temperature 12h, loading molecular cut off is the bag filter of 8k ~ 14k, be that medium dialysis is completely removed to micromolecule with intermediate water, last dialyzed solution obtains buff powder through lyophilization, be component A.
Prepare the method for nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel as above, it is characterized in that: the deacetylation of described chitosan is 85%, and viscosity is 50 ~ 300cps.
Nuclear magnetic resonance, NMR prepared by the present invention visual injectable pH responsive type selfreparing hydrogel can be used as pharmaceutical carrier, thromboembolism/packing material, tissue stent material.
The present invention is made up of the Polyethylene Glycol (B component) of the chitosan modified through DTPA (component A) and two terminal aldehyde groups, complexation Gd
3+after component solution A at room temperature the short time mixes and can form situ-gel with B component solution, this gel has the responsive self-healing properties of pH, and without the need to just can ensureing with MRI development within the longer time repeatedly to patient injection developing agent, thus reduction is because of Gd
3+enrichment and the risk of pathological changes.
The present invention has the following advantages and beneficial effect:
The present invention by DTPA this can chelating Gd
3+group introduce in injectable selfreparing multiple response gel rubber system, make this gel have the visual effect of MRI.The state that the advantage of this gel is not need repeatedly injection of contrast medium just can continue with MRI tracking and monitoring lesions position, and this gel can adopt and to inject or the mode of conduit importing arrives desired area, the little or hurtless measure of wound.In addition, Gd
3+be by the more stable connection of chemical bond on polymer, therefore, without the need to repeatedly to patient injection developing agent just can ensure to develop within the longer time, thus reduction is because of Gd
3+enrichment and the risk of pathological changes.Along with gel active time prolongation in vivo, the enzyme in chitosan main chain meeting body is degraded gradually, Gd
3+concentration can slowly reduce, the palliating degradation degree of this gel can be indicated, thus effective and easily guiding clinical treatment, and take out gel without the need to second operation.Injectable gel provided by the invention can also be loaded into the clinical reagents such as medicine, tracer, somatomedin easily, can realize the multi-efficiencies such as administering drug combinations, spike, organization bracket.Gel has self-repairability within the scope of certain pH, gives the mechanical property that gel is suitable, can adapt to the environment at thromboembolism or filling position well, avoids the blood vessel blockage or inflammatory reaction that cause because of Gel shift or fragmentation.Prepare gel of the present invention component A used and B component all can obtain commercial sources easily, derivatization reaction step is simple and direct, mild condition, convenient post-treatment, is easy to industrialization.
Accompanying drawing explanation
Fig. 1 is DTPA, chitosan, the FT-IR collection of illustrative plates of Ch-DTPA and DTPA and chitosan physical mixture (mixture).
Fig. 2 is the nuclear magnetic resonance map of PEG-DF.
Fig. 3 is the FT-IR collection of illustrative plates of PEG and PEG-DF.
Fig. 4 is gel core nuclear magnetic resonance image.
Fig. 5 is gel self-healing properties photo.
Fig. 6 is the in-vitro simulated long-time development effect of gel.
Detailed description of the invention
Below in conjunction with specific embodiment, the invention will be further described, and following detailed description is not for the restriction to technical solution of the present invention.
Embodiment 1
The preparation of Ch-DTPA
1g chitosan (Chitosan) is heated to 65 DEG C of stirring 3h with the dilute hydrochloric acid of 70mL 50mM and dissolves completely.The a small amount of intermediate water of DTPA (0.9102g, 2.3mmol) dissolves, and regulates pH to 4.7 with TEMED.NHS (0.3199g, 2.8mmol), EDC (0.5328g, 2.8mmol) are added dropwise in Chitosan solution after dissolving with the dilute hydrochloric acid solution of 50mM together with DTPA solution is after 0 DEG C of mix homogeneously.Stirring reaction 30h in the oil bath of 75 DEG C, continues stirring at room temperature 12h.After reaction stops, loading molecular cut off is the bag filter of 8k ~ 14k, and intermediate water is that medium is dialysed 3 days.Dialyzed solution obtains buff powder Ch-DTPA through lyophilization.This compound characterizes through FT-IR.
Test DTPA respectively with FT-IR, Chitosan, Ch-DTPA and DTPA and Chitosan are through the mixture M ixture of physical mixed.From in Fig. 1, due to-the NH on Chitosan
2formation-CONH-is reacted, 1654cm with DTPA
-1and 1589cm
-1the bimodal further enhancing at place, becomes 1635cm
-1the broad peak at place, in addition, amide II is with 1530cm
-1the peak at place is only visible in Ch-DTPA, and not this peak in the physical mixture of Chitosan and DTPA, proves that DTPA is incorporated on the main chain of Chitosan by the mode of amido link.PEG
2kthe preparation of-DF
Polyethylene Glycol PEG 2000 (2.00g; 1.0mmol) be dissolved in after the vacuum drying oven dried overnight of 50 DEG C in the oxolane of 50mL drying; add 4-formylbenzoate (0.66g; 4.40mmol) with DMAP (0.05g, 0.4mmol).Dicyclohexylcarbodiimide (DCC) (1.10g, 5.33mmol) is dissolved in the oxolane of 15mL drying, is added dropwise under nitrogen protection in above-mentioned solution.At room temperature after magnetic agitation 20h, elimination solid is also concentrated into about 5mL, precipitates in 100mL ice ether, and collected by filtration is crude product.Take dichloromethane as solvent again, ice ether is precipitant, repeats precipitation twice, obtains white waxy solid 1.80g (productive rate is 85%).This compound characterizes through 1H NMR and FT-IR.
PEG is shown from infared spectrum
2k-DF is at 1640cm
-1the peak of new generation belongs to aldehyde radical and ester bond, the aldehyde radical of also high-visible introducing in proton nmr spectra and benzene ring hydrogen.And all connect aldehyde radical by the known PEG two ends of integral and calculating.
The preparation of gel
Component A:Ch-DTPA with 2% acetum be made into 3% solution; B component: PEG
2k-DF is mixed with the aqueous solution of 20%.By calculating, making amino in component A is that 2:1 mixes with the ratio of the molal quantity of aldehyde radical in B component, namely gets the component solution A of 0.7g and adds 25 μ L0.1M GdCl
3solution, the PEG-DF solution vortex mixed 60 seconds with 0.25mL, can obtain MRI visual injectable selfreparing gel.
Embodiment 2
The preparation of Ch-DTPA
1g chitosan (Chitosan) is heated to 65 DEG C of stirring 3h with the dilute hydrochloric acid of 70mL 50mM and dissolves completely.The a small amount of intermediate water of DTPA (0.9102g, 2.3mmol) dissolves, and regulates pH to 4.7 with TEMED.NHS (0.3199g, 2.8mmol), EDC (0.5328g, 2.8mmol) are added dropwise in Chitosan solution after dissolving with the dilute hydrochloric acid solution of 50mM together with DTPA solution is after 0 DEG C of mix homogeneously.Stirring reaction 30h in the oil bath of 75 DEG C, continues stirring at room temperature 12h.After reaction stops, loading molecular cut off is the bag filter of 8k ~ 14k, and intermediate water is that medium is dialysed 3 days.Dialyzed solution obtains buff powder Ch-DTPA through lyophilization.
PEG
1kthe preparation of-DF
Polyethylene Glycol PEG 1000 (10.00g; 10.0mmol) be dissolved in after the vacuum drying oven dried overnight of 50 DEG C in the oxolane of 100mL drying; add 4-formylbenzoate (7.01g; 46.69mmol) with DMAP (0.66g, 5.40mmol).DCC (6.10g, 29.61mmol) is dissolved in the oxolane of 30mL drying, is added dropwise under nitrogen protection in above-mentioned solution.At room temperature after magnetic agitation 20h, elimination solid also removes solvents tetrahydrofurane.Dissolve with 150mL dichloromethane, use dilute hydrochloric acid solution successively, Na
2cO
3solution and saturated NaCl solution wash twice, finally collect organic facies and are spin-dried for, dissolve, elimination insoluble matter postlyophilization with intermediate water.Gained PEG
1k-DF product is faint yellow mucus 9.6g (productive rate is 76%).
The preparation of gel
Component A:Ch-DTPA with 2% acetum be made into 2% solution; B component: PEG
2k-DF is mixed with the aqueous solution of 40%.By calculating, making amino in component A is 1:1 with the ratio of the molal quantity of aldehyde radical in B component, namely gets the solution A of 0.79g and adds 20 μ L 0.1M GdCl
3solution, the PEG-DF solution vortex mixed 60 seconds with 0.19mL, can obtain MRI visual injectable selfreparing gel.
Embodiment 3
The preparation of Ch-DTPA
The dilute hydrochloric acid of 1g chitosan Chitosan 70mL 50mM is heated to 65 DEG C of stirring 3h and dissolves completely.The a small amount of intermediate water of DTPA (1.21g, 3.1mmol) dissolves, and regulates pH to 4.7 with N, N, N', N'-tetramethylethylenediamine TEMED.N-hydroxy-succinamide NHS (0.43g, 3.72mmol), EDC (0.7131g, 3.72mmol) are added dropwise in Chitosan solution after dissolving with the dilute hydrochloric acid solution of 50mM together with DTPA solution is after 0 DEG C of mix homogeneously.Stirring reaction 30h in the oil bath of 75 DEG C, continues stirring at room temperature 12h.After reaction stops, loading molecular cut off is the bag filter of 8k ~ 14k, and intermediate water is that medium is dialysed 3 days.Dialyzed solution obtains buff powder Ch-DTPA through lyophilization.This compound characterizes through FT-IR.PEG
4Kthe preparation of-DA
Polyethylene Glycol PEG 4000, acetic anhydride and dimethyl sulfoxine mix than for the ratio of 1:80:140 with amount of substance, at room temperature stirring reaction 4h.Product repeats precipitation 3 times in ice ether, obtains white powdery solids and is PEG
4K-DA.
The preparation of gel
Component A:Ch-DTPA with 2% acetum be made into 5% solution; B component: PEG
4k-DA is mixed with the aqueous solution of 15%.By 5 μ L 0.1M GdCl
3solution mixes with component solution A, and calculates and make the amino in component A and the aldehyde radical mol ratio in B component be 4:1, namely gets the PEG-DF solution vortex mixed 60 seconds of this solution of 0.42g and 0.667mL, can obtain MRI visual injectable selfreparing gel.
In the present invention, Ch-DTPA is to Gd
3+the mensuration of complexing capacity
Xylenol orange can with free Gd
3+complexation, color from pale yellow complexion changed is aubergine, and with the monitoring of UV, visible light spectrophotometer, maximum absorption wavelength moves to 572nm from 433nm.As the Gd in solution
3+by other chelating agen complexations, then not free Gd
3+, therefore can not make xylenol orange variable color.
Therefore with xylenol orange as indicator, Ch-DTPA complexation Gd can be measured
3+ability.Concrete grammar is: GdCl
3be made into 1mM aqueous solution, the Acetic acid-sodium acetate buffer of xylenol orange tetrasodium salt pH=5.8 becomes the solution of 50mM as indicator.Accurately take the Ch-DTPA that quality is m (about 8mg), add Acetic acid-sodium acetate buffer and the 1mL xylenol orange indicator of 200mL pH=5.8, use GdCl
3solution titration, is terminal when solution becomes aubergine from yellow, writes down GdCl
3the volume V (mL) of solution, the complexing capacity of Ch-DTPA is:
Such as, the Ch-DTPA of two kinds of different grafting degrees in this experiment is as follows through complexing capacity test result:
Gel core nuclear magnetic resonance experiment prepared by the present invention
In 96 orifice plates, every hole first adds 0,0.5,1.5,3.0,6.0, the 0.1MGd of 10.0 μ L
3+solution, and with intermediate water, the cumulative volume in every hole is complemented to 10 μ L, then add Ch-DTPA solution 0.28g, PEG-DF solution 100 μ L, makes Gd in each hole
3+concentration be respectively 0,0.125,0.375,0.75,1.5,2.0mM.
Nucleus in Vitro nuclear magnetic resonance effect uses 3.0T nuclear magnetic resonance imaging instrument (Magnetom Tim Trio; Siemens Medical Solutions, Erlangen, Germany) evaluate.Being fixed on nuclear magnetic resonance imaging instrument by 96 orifice plates that sample is housed, is 20 DEG C in temperature, and under 3.0T, 10MHz field intensity, carry out quick echographic, parameter setting is: TR=2000ms, TE=11ms, the number of plies=12, thickness=1mm.
Known in Fig. 4, along with Gd in aperture
3+the increase of concentration, in the image that T1 strengthens, show the more bright visual field, the pcolor picture of below is more obvious.And work as Gd
3+concentration when reaching more than 0.75mM, the degree that the brightness of image increases weakens to some extent, and this also shows, in actual use, only need use the Gd of suitable concn
3+, too much Gd
3+more effectively can not improve the ability that development strengthens.
PH of latex gel responsive type self-healing properties test prepared by the present invention
This gel can disconnect in acid condition because of crosslinked chemical bond imine linkage, and is again formed under alkali condition, so this gel has the characteristic of pH sensitivity.
Regulate the pH value of component A with NaOH, the sample of numbering 1 ~ 8, its pH is followed successively by: 3.40,3.53,3.98,4.95,5.30,5.57,6.17 and 6.81.The self-reparing capability of gel depends on pH value, when pH lower than 4.5 time, gel can not be formed, and pH is when 4.8-5.3, and gel has repair function, when pH is greater than 5.6, forms the gel that can not repair.
Gel extracorporeal simulating experiment prepared by the present invention
As following table configuration configures the gel sample of different pH value respectively with the Ch-DTPA of two kinds of different degree of substitution, after loading nylon wire, then add 30mL intermediate water, be placed in 37 DEG C, take out after 30h in the constant-temperature table of rotating speed 60rad/s, load in the centrifuge tube of 4mL, be fixed on test tube rack, again carry out quick echographic with nuclear magnetic resonance imaging instrument, test parameter is set as: TR=700ms, TE=9.6ms, the number of plies=20, thickness=3mm.Blank sample Blank is the gel sample be not directly configured in through dialysis procedure in the centrifuge tube of 4mL.
Signal intensity as can be seen from Figure 6 without the blank sample of dialysis is the highest, and this is due to all Gd
3+all be retained in gel.And do not connect the chitosan 1 of DTPA chelating agen, after 30h, almost there is no reinforced effects, do not add Gd with No. 2 control samples
3+brightness almost identical.And 3,4,5, No. 6 samples are due to Gd
3+there is certain chelation and after the dialysis of 30h, still have the effect highlighted.Find simultaneously, the effect of the long-time development of No. 4 and No. 6 samples that pH value is lower all slightly high not as good as pH No. 3 and No. 5 strong, this may be because selfreparing gel causes Gd at repair process faster
3+run off faster and cause.
Claims (8)
1. a nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel, it is characterized in that: described hydrogel comprises complex and the B component of component A, described component A be the side-chain amino group of chitosan through the partially substituted product of diethylene triamine pentacetic acid (DTPA), its structural formula is
Wherein m, n are natural number, m/n=5% ~ 50%;
The derivant of described B component to be Polyethylene Glycol two ends be aldehyde radical, its structural formula is:
Wherein
the molecular weight of Polyethylene Glycol is 1000-4000, y is natural number, and y=22 ~ 90; Amino in described component A is 4:1 ~ 1:1 with the ratio of the molal quantity of aldehyde radical in B component.
2. nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel as claimed in claim 1, is characterized in that: the complex of described component A is component A and Gd
3+complex.
3. nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel as claimed in claim 1, is characterized in that: described m/n=10% ~ 40%, y=22 ~ 66, and amino in component A is 2:1 with the ratio of the molal quantity of aldehyde radical in B component.
4. nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel as claimed in claim 1, is characterized in that: described m/n=20% ~ 30%, y=44 ~ 66.
5. prepare a method for nuclear magnetic resonance, NMR as claimed in claim 1 visual injectable pH responsive type selfreparing hydrogel, it is characterized in that: step is as follows:
(1) formulation components solution A: get component A is the component solution A that 1% ~ 5% acetum is made into that mass percentage concentration is 2 ~ 5% by mass percentage concentration;
(2) Ch-DTPA/Gd is prepared
3+solution: get GdCl
3aqueous solution, adds in component A, makes Gd
3+concentration be 0.5 ~ 2.5mM;
(3) formulation components B solution: get B component and be mixed with the B component aqueous solution that concentration is 15 ~ 40%;
(4) Ch-DTPA/Gd is got
3+solution and B component solution, make it fully mix, and namely obtains nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel.
6. the preparation method of nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel as claimed in claim 5, is characterized in that: in described step 1, the mass percentage concentration of acetum is 1.5% ~ 2.5%.
7. the preparation method of nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel as claimed in claim 5, is characterized in that: in described step 1, the mass percentage concentration of acetum is 2%.
8. the application of nuclear magnetic resonance, NMR visual injectable pH responsive type selfreparing hydrogel as claimed in claim 1, is characterized in that: described hydrogel is as pharmaceutical carrier, thromboembolism/packing material, tissue stent material.
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| CN107233629A (en) * | 2017-06-21 | 2017-10-10 | 深圳市第二人民医院 | Injection aquagel and its preparation and application |
| CN108142935A (en) * | 2018-01-24 | 2018-06-12 | 上海市第十人民医院 | A kind of slimming capsule that natural polymer subbase gel inner nuclear material is controllably constructed based on dynamic chemical key |
| CN110142190A (en) * | 2019-05-31 | 2019-08-20 | 中国科学院大学 | Selfreparing composite coating and its application and anticorrosion material and preparation method thereof |
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| CN113621144A (en) * | 2021-06-11 | 2021-11-09 | 四川大学 | Magnetoelectric response bionic hydrogel and magnetoelectric response bionic hydrogel capable of adjusting cell electricity microenvironment and preparation method thereof |
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| CN107233629A (en) * | 2017-06-21 | 2017-10-10 | 深圳市第二人民医院 | Injection aquagel and its preparation and application |
| CN107233629B (en) * | 2017-06-21 | 2020-02-14 | 深圳市第二人民医院 | Injectable hydrogels and their preparation and use |
| CN108142935A (en) * | 2018-01-24 | 2018-06-12 | 上海市第十人民医院 | A kind of slimming capsule that natural polymer subbase gel inner nuclear material is controllably constructed based on dynamic chemical key |
| CN110142190A (en) * | 2019-05-31 | 2019-08-20 | 中国科学院大学 | Selfreparing composite coating and its application and anticorrosion material and preparation method thereof |
| CN110142190B (en) * | 2019-05-31 | 2020-09-11 | 中国科学院大学 | Self-repairing composite coating and application thereof, anti-corrosion material and preparation method thereof |
| CN110172010A (en) * | 2019-06-11 | 2019-08-27 | 中国工程物理研究院化工材料研究所 | A kind of polymer matrix binary explosive and preparation method thereof damaging self-healing |
| CN110585121A (en) * | 2019-10-18 | 2019-12-20 | 武汉布润脑医学科技有限责任公司 | Temozolomide nuclear magnetic resonance visual injectable hydrogel, preparation method and application |
| CN111773429A (en) * | 2020-01-09 | 2020-10-16 | 中国科学院长春应用化学研究所 | Hydrogel dressing and preparation method thereof, multifunctional nano composite dressing and preparation method and application thereof |
| CN111558040A (en) * | 2020-04-17 | 2020-08-21 | 华南农业大学 | High-molecular self-healing gel integrating magnetic resonance imaging and photothermal therapy and preparation and application thereof |
| CN111558040B (en) * | 2020-04-17 | 2021-03-26 | 华南农业大学 | High-molecular self-healing gel integrating magnetic resonance imaging and photothermal therapy and preparation and application thereof |
| CN113621144A (en) * | 2021-06-11 | 2021-11-09 | 四川大学 | Magnetoelectric response bionic hydrogel and magnetoelectric response bionic hydrogel capable of adjusting cell electricity microenvironment and preparation method thereof |
| CN113621144B (en) * | 2021-06-11 | 2022-04-15 | 四川大学 | Magnetoelectric response bionic hydrogel and magnetoelectric response bionic hydrogel capable of adjusting cell electricity microenvironment and preparation method thereof |
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