Hydrogel, application thereof and preparation method of magnetic resonance imaging embolism

Abstract

The invention discloses hydrogel and application thereof and a preparation method of a magnetic resonance imaging embolism, and belongs to the field of medical materials. The hydrogel comprises a metal complex and a high-molecular polymer which are combined through a functional group. Wherein the functional group comprises an acyloxy group, an acetal group or an ether group. The hydrogel has an excellent MRI (Magnetic Resonance Imaging) developing function, and also has good biocompatibility, particle uniformity and drug loading property, so that the clinical use requirements can be met, and the visualization of embolism treatment is really realized.

Description

Technical Field

[0001] The present application relates to the field of medical materials. Specifically, it relates to a hydrogel, its application, and a preparation method of a magnetic resonance imaging embolic agent. Background Art

[0002] Magnetic Resonance Imaging (MRI) is a new medical imaging technology that utilizes the principle of Nuclear Magnetic Resonance (NMR), and is also known as Nuclear Magnetic Resonance Imaging (NMRI). Nuclear magnetic resonance imaging has excellent diagnostic functions for parenchymal organs such as the brain, thyroid gland, liver, gallbladder, spleen, kidney, pancreas, adrenal gland, uterus, ovary, prostate, as well as the heart and large blood vessels.

[0003] Compared with other auxiliary examination methods, magnetic resonance imaging has the advantages of multiple imaging parameters, fast scanning speed, high tissue resolution, and clearer images. Currently, magnetic resonance imaging has become a powerful tool for early screening and treatment of tumors, heart diseases, and cerebrovascular diseases.

[0004] Interventional embolization therapy is to selectively or super-selectively insert a catheter into the target artery supplying blood to the tumor, and then inject an appropriate amount of embolic agent at an appropriate speed to occlude the target artery, interrupt blood supply, cause ischemic necrosis of the tumor tissue, and achieve the treatment purpose.

[0005] Currently, there are many products used for embolization therapy in clinical practice. These products include gelatin sponge, polyvinyl alcohol, iodized oil emulsion, and microspheres, etc., and among them, the embolization effect of microspheres is the best. Since the embolization products do not have imaging capabilities, interventional doctors cannot accurately inject the embolization microspheres into the specific location of the lesion, and cannot fully achieve the embolization effect on tumor blood vessels, that is, cannot achieve the purpose of embolization therapy.

[0006] In view of this, there is an urgent need for embolization microspheres with MRI imaging capabilities in clinical embolization therapy to monitor the embolization effect of the embolization microspheres on tumor blood vessels, and to evaluate the biological changes and treatment effects of tumors in real-time and dynamically. Summary of the Invention

[0007] Based on the above deficiencies, the present application provides a hydrogel, its application, and a preparation method of a magnetic resonance imaging embolic agent to partially or completely improve, or even solve, the problems in the related art.

[0008] The present application is implemented as follows:

[0009] In a first aspect, an example of the present application provides a hydrogel, which comprises a metal complex and a high molecular polymer bound through a functional group, wherein the functional group comprises an acyloxy group, an acetal group or an ether group.

[0010] In a second aspect, an example of the present application provides an application of the above-mentioned hydrogel in preparing a drug carrier, an embolic agent, a medical filling material or a medical tissue scaffold.

[0011] In a third aspect, an example of the present application provides a preparation method of a magnetoresonance embolic agent. The preparation method proceeds through the following reaction equation:

[0012]

[0013] Wherein, Pj represents a carboxyl group, an ester group, an aldehyde group, an acetal group or a halogen;

[0014] Wherein, W represents a hydrophilic macromonomer, which is formed by reacting a hydrophilic polymer with a terminal olefinic compound, and the optional reaction equation is as

[0015]

[0016] Wherein, H represents a functional group residue formed by Pj reacting with W and is an acyloxy group, an acetal or an ether;

[0017] Wherein, Y represents a copolymer monomer residue formed by W reacting with Pj;

[0018] Wherein, G represents a copolymerized high molecular polymer, and is formed by reacting Y groups with small molecule monomers;

[0019] Wherein, acid represents a protonic acid or a Lewis acid;

[0020] Wherein, M represents a metal ion and exists in the form of a salt, an oxide or a hydroxide. In the above implementation process, the solution of the example of the present application has at least the following characteristics:

[0021] 1. The hydrogel in the example can be organically combined with an imaging substance, so it is expected to be used for the visualization of embolization treatment. And it effectively avoids the problem caused by the separation of the embolization material and the contrast agent during the clinical embolization process, thereby improving the embolization effect and safety.

[0022] 2. The hydrogel in the example has good biocompatibility, particle uniformity and drug loading property, and the preparation process is simple and the cost is low, which is suitable for large-scale production. Description of the Drawings

[0023] To more clearly illustrate the technical solutions of the embodiments of the present application, the following will briefly introduce the accompanying drawings required for the embodiments. It should be understood that the following drawings only show some embodiments of the present application and should not be regarded as limiting the scope. For those of ordinary skill in the art, without creative efforts, other related drawings can also be obtained based on these drawings.

[0024] Figure 1 This is the first performance graph of the embolization microspheres provided in Embodiment 1 of the present application.

[0025] Figure 2 This is the external shape diagram of the embolization microspheres provided in Embodiment 1 of the present application before pressurization;

[0026] Figure 3 This is the external shape diagram of the embolization microspheres provided in Embodiment 1 of the present application after pressurization;

[0027] Figure 4 This is the schematic diagram of the drug loading amount of the embolization microspheres;

[0028] Figure 5 This is the nuclear magnetic resonance imaging diagram after adding different concentrations of DOTA-Gd in the embolization microspheres provided in Embodiment 1 of the present application. Detailed implementation manners

[0029] As a hydrogel with an inner hydrophilic three-dimensional network structure gel, the hydrogel can rapidly swell in water due to absorbing a large amount of water and can remain insoluble. Due to this characteristic of the hydrogel, it has potential application value in many fields.

[0030] In the example of the present application, the inventors proposed a hydrogel material that can be used in the MRI field, and this hydrogel also exhibits good biocompatibility and drug loading capacity (it can load some anti-tumor drugs). Since it can be used as a drug carrier, therefore, according to the different indications of the loaded drugs, the combination obtained by combining this hydrogel material with the loaded drugs can be used to treat various related diseases.

[0031] And this hydrogel material also has the characteristics of loose pores. Therefore, it has a higher water absorption rate and water absorption speed, and at the same time it also has high elasticity. Further, in the example, this hydrogel can be an elastic microsphere (the radius can reach 50 microns to 1000 microns; or 50 microns to 500 microns; or 100 microns to 300 microns), and the particle uniformity.

[0032] Based on the above characteristics, the hydrogel material in this example can be used to prepare drug carriers, embolization agents, medical filling materials or medical tissue scaffolds. And this hydrogel is particularly suitable as a vascular embolization agent.

[0033] In addition, since the hydrogel can be particulate matter or spherical particles with magnetic resonance imaging properties (e.g., visible by MRI) by binding selected metal ions, it is convenient for medical imaging, and thus the application of visualizing the embolizing agent can be realized. Of course, particulate matter or spherical particles without magnetic resonance imaging properties can also be obtained without binding the above-mentioned selected metal ions, and this application does not make any limitations.

[0034] Generally speaking, the hydrogel involves a bonded substance of a complex (such as a metal complex with magnetic resonance properties), a hydrophilic polymer, a terminal olefinic bond compound, and a small molecule monomer. Or rather, in some examples, the hydrogel is a substance formed by chemically bonding a functionalized polymer compound, a small molecule monomer, and a trivalent or divalent metal complex.

[0035] The polymer compound therein is, for example, polyvinyl alcohol or polyethylene glycol. Further, the functionalized polymer compound is a compound obtained by modifying the polymer compound with a specific group so as to have the properties exhibited by the specific group. For example, the functionalized polymer compound is polyvinyl alcohol and polyethylene glycol modified with allyl or acryloyl. The allyl group can be provided by allyl alcohol, allyl chloride, allyl bromide, or allyl iodide, etc.; the acryloyl group can be provided by acrylic acid or acrylate, and the acrylate as an example can be lithium acrylate, sodium acrylate, or potassium acrylate.

[0036] The small molecule monomer can be, for example, 2-acrylamido-2-methylpropanesulfonic acid, or 2-acrylamido-2-methylpropanesulfonate.

[0037] The trivalent or divalent metal complex therein is, for example, a substance formed by binding a metal ion and a ligand. The metal ion (M 3+ / 2+ , that is, the trivalent or divalent metal ion) can be an ion provided by Fe, Mn, Dy, or Gd. The ligand can be:

[0038] DTPA (CAS: 67-43-6; diethylenetriaminepentaacetic acid);

[0039] DOTA (CAS: 60239-18-1; cyclen tetraacetic acid, or tenoxicam tetraacetic acid, or 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid),

[0040] BOPTA (4-carboxy-5, 8, 11-tris(carboxymethyl)-1-phenyl-2-oxa-5, 8, 11-triazatridecane-13-acid),

[0041] DO3A (CAS: 217973-03-0; Sodium 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate);

[0042] DPDP (CAS: 26544-23-0; Diphenylisodecyl phosphite).

[0043] From another perspective, the hydrogels in the examples of this application include metal complexes and polymer polymers bound through functional groups; the functional groups therein include acyloxy groups, acetal groups or ether groups.

[0044] Metal complex

[0045] Among them, in the metal complex (or metal coordination compound), the coordination bond is formed by bonding the oxygen atom of the dehydroxylated carboxyl group with the metal. And, in terms of composition, the metal complex has a central atom / central ion (abbreviated as the central body) and a monodentate or polydentate ligand coordinated with this central body.

[0046] Furthermore, the metal complex can be a chelate, and thus the chelate in the example has a central metal ion and a ligand in the form of a chelating agent. The chelating agent molecule can have multiple heteroatoms, two to six nitrogen atoms and four to eight oxygen atoms. Based on the above chelating agent molecule, some of the heteroatoms therein are coordinated with the metal ion through coordination bonds.

[0047] Exemplarily, the chelating agent molecule includes but is not limited to EDTA, EGTA, DTPA, BOPTA, DTPA-BMA, NOTA, DO3A, DOTA, TETA or HP-DO3A. The central atom is in the form of a metal ion and comes from oxides, hydroxides, hydrochlorides, sulfates, nitrates or trifluoromethanesulfonates. Then, the exemplary central body in the form of a metal ion is Fe 3+ 、Mn 2+ 、Gd 3+ 、Dy 3+ or Ho 3+ . Correspondingly, the metal complexes, i.e., chelates, composed of the above chelating agent molecules and metal ions include but are not limited to Gd-DTPA, Gd-DTPA-BMA, Gd-EOB-DTPA, Gd-DOTA, Gd-BOPTA, Gd-DO3A, Mn-DPDP or Dy-DTPA.

[0048] Polymer

[0049] The polymer in the example is hydrophilic and can endow the hydrogel with hydrophilicity - the adsorption property of water. As an alternative example, the polymer is formed by cross-linking copolymer monomers and small molecule monomers, and the copolymer monomers are formed by covalently connecting hydrophilic polymers and terminal olefinic compounds.

[0050] Among the components constituting the polymer, the hydrophilic polymer can have one or more hydrophilic groups. The hydrophilic groups include, but are not limited to, hydroxyl, amino, amine, carboxyl, amide, sulfonic acid group, sulfonyl group or sulfate group. For example, the hydrophilic group of the hydrophilic polymer can be 1,2-dihydroxy or 1,3-dihydroxy.

[0051] As specific examples of some specific optional hydrophilic polymers, the hydrophilic polymers include, but are not limited to, one or more of polyvinyl alcohol, polyethylene glycol, fucoidan, methyl cellulose, ethyl cellulose, amylose and polysaccharide macromolecules. An exemplary polysaccharide macromolecule can be chitosan.

[0052] Among the components constituting the polymer, the terminal olefinic compound has the following structure:

[0053] where n 10 is the number of carbon atoms in the carbon chain, and n 10 has a value of 1 to 20;

[0054] where n 20 is the number of carbon atoms in the carbon chain, and n 20 has a value of 0 to 20;

[0055] R1 is various different optional first groups, such as including Cl, Br, I, COOH, CHO, acetal, ester or acyl halide. And when n 20 ≠0, R2 is various different optional second groups, and includes, but is not limited to, Cl, Br, I, COOH, CHO, acetal, ester or acyl halide. When n 20 =0, then R2 can be selected as Cl, Br or OH.

[0056] The small molecule monomer used to form the polymer in the examples of the present application can have the following structure, for example:

[0057] where n3 represents the number of carbon atoms in the carbon chain, and the value of n3 can be any integer from 1 to 20. And R4 represents an ion or a substituent. As an example, the ion represented by R4 can be a cation, such as including Na + , K + or NH4 +; and the substituent represented by R4 may include H, Me (methyl; -CH3), Et (ethyl; CH3CH2-), i Pr (isopropyl; -CH(CH3)2) or n Bu (n-butyl; CH3-CH2-CH2-CH2-).

[0058] And as an example, the hydrogel has a structure represented by the following Formula 1 or Formula 2:

[0059]

[0060] Wherein, Z represents a carbon atom or a nitrogen atom;

[0061] n1 represents the number of carbons in the carbon chain connected to Z;

[0062] M is a metal that provides the source of the central atom in the formation of the metal complex;

[0063] H represents a functional group;

[0064] G represents a high molecular polymer.

[0065] As an alternative example, the functional group represented by H is generated by reaction through the structures represented by the following Formula 3, Formula 4, Formula 5 or Formula 6;

[0066]

[0067] Wherein, P w represents a carboxyl group, an ester group, an aldehyde group, an acetal group or a halogen [such as fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At)], and the group represented by P w forms the functional group represented by H through reaction.

[0068] The above hydrogel material in the examples of this application can be prepared by means related to chemical synthesis in the art. To enable those skilled in the art to more conveniently implement the example solutions of this application, a preparation method of a magnetic resonance hydrogel with magnetic resonance imaging characteristics is also provided in the examples.

[0069] And this preparation method proceeds through the following first reaction equation.

[0070] First reaction equation:

[0071]

[0072] Alternatively, the production method can also be carried out in the following manner of the second reaction equation:

[0073]

[0074] Alternatively, the preparation method can also be carried out according to the following third reaction equation:

[0075]

[0076] In the above three reaction equations, the organic substance represented by K is used as the starting material, and the target substance is obtained through multi-step reactions. For example, the organic substance represented by K can be 6-(carboxymethyl)-3,9-bis[2-(1,1-dimethylethoxy)-2-oxoethyl]-13,13-dimethyl-11-oxo-12-oxa-3,6,9-triazatetradecanoic acid-1-tert-butyl ester, or tri-tert-butyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

[0077] Here, Pj represents a carboxyl group, an ester group, an aldehyde group, an acetal group or a halogen.

[0078] Wherein, W represents a hydrophilic polymer monomer. Exemplarily, the hydrophilic polymer monomer is formed by reacting a hydrophilic polymer with a terminal olefinic compound. For example, the preparation reaction equation of the hydrophilic polymer monomer represented by W is as follows:

[0079] That is, the hydrophilic polymer monomer represented by W is prepared by polycondensation reaction of the polyvinyl alcohol represented by A and a terminal olefinic compound having R1 or R2 as a leaving group.

[0080] Here, H represents a functional group residue formed by the reaction of Pj with W, and the functional group residue is, for example, an acyloxy group, an acetal, or an ether.

[0081] Here, Y represents the monomer residue of the copolymer formed by W and Pj.

[0082] Wherein, G represents a high molecular polymer formed by copolymerization, and is a polymer composed of a group represented by Y and a small molecule monomer (such as the aforementioned ) reaction.

[0083] Wherein, acid represents a protonic acid or a Lewis acid. Exemplary acids may be formic acid, p-toluenesulfonic acid, tartaric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or a mixture of several thereof.

[0084] Wherein, M represents a metal ion and is provided in the form of a salt, an oxide or a hydroxide. The oxide can generate the metal ion M by reacting under acidic conditions; the salt can be a hydrochloride, a sulfate, a nitrate or a trifluoromethanesulfonate.

[0085] In the above first reaction equation, during the process where the intermediate product represented by O forms the G group in the target product through copolymerization, the reaction temperature is, for example, 50°C to 100°C (including but not limited to 55°C, 65°C, 75°C, 85°C, or 95°C), and the reaction solution system includes an emulsifier, potassium persulfate, and tetramethylethylenediamine.

[0086] Alternatively, in the above second reaction equation, during the process where the intermediate product represented by L forms the G group in the intermediate product represented by Q through copolymerization, the reaction temperature is, for example, 20°C to 100°C (including but not limited to 23°C, 28°C, 36°C, 41°C, 44°C, 49°C, 50°C, 52°C, 58°C, 61°C, 66°C, 70°C, 73°C, 76°C, 82°C, 89°C, or 94°C), and the reaction solution system includes an emulsifier, potassium persulfate, and tetramethylethylenediamine.

[0087] The above emulsifier includes anionic or nonionic surfactants, or a mixture of anionic and nonionic surfactants. Exemplarily, the emulsifier includes: carboxylates, sulfates and sulfonates, sodium stearate, sodium dodecyl sulfate, sodium dodecylbenzenesulfonate, Tween 20, Tween 60, Tween 80, or Span.

[0088] Furthermore, during the reaction process represented by the two reaction equations, each step can be carried out in a polar aprotic solvent. The polar aprotic solvents therein include but are not limited to one or more mixtures of dioxane, tetrahydrofuran, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, and N,N-dimethylformamide. The multiple mixtures therein, for example, are mixtures of two substances, exemplarily a mixed solution of tetrahydrofuran and N,N-dimethylacetamide, or a mixed solution of dimethyl sulfoxide and N,N-dimethylformamide. Or, the multiple mixtures therein, for example, are mixtures of three substances, exemplarily a mixed solution of dioxane, tetrahydrofuran, and dimethyl sulfoxide, or N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0089] Hereinafter, the embodiments of the present application will be described in detail in conjunction with examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present application and should not be regarded as limiting the scope of the present application. For those not specified in the examples, they are carried out under conventional conditions or conditions recommended by the manufacturer. For those reagents or instruments without indicating the manufacturer, they are all conventional products that can be obtained by purchasing in the market.

[0090] Example 1

[0091] Prepare the embolization microspheres for magnetic resonance imaging - magnetic resonance hydrogel according to the aforementioned first reaction equation.

[0092] Preparation of Compound L

[0093] a. Weigh 1 g of polyvinyl alcohol (hydrophilic polymer; Compound A) and 1 g of Compound K [6-(carboxymethyl)-3,9-bis[2-(1,1-dimethylethoxy)-2-oxoethyl]-13,13-dimethyl-11-oxo-12-oxa-3,6,9-triazatetradecanoic acid 1-tert-butyl ester] and add them to 50 ml of dimethyl sulfoxide. Stir at 55 ± 5 °C and 300 rpm until the solution becomes clear.

[0094] b. Then, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.5) and 4-dimethylaminopyridine (0.4 g) to the above solution in sequence, and continue to stir while maintaining the temperature for 1 hour.

[0095] c. Take 0.2 ml of acrylic acid (n 20 is zero and R 20 is a terminal olefinic compound with a hydroxyl group) and add it to the above reaction solution. Stir at 50 - 60 °C for 2 h, and then cool to 20 - 30 °C.

[0096] d. Slowly pour the above solution into 100 ml of absolute ethanol and stir at 25 ± 5 °C for 1 hour.

[0097] e. Filter the precipitate, wash the filter cake with ethanol three times, and freeze-dry to obtain the intermediate Compound L for later use.

[0098] Preparation of Compound N

[0099] a. Weigh the freeze-dried functionalized Compound L (1 g) and dissolve it in 5 ml of absolute dimethyl sulfoxide, and stir until the solution becomes clear.

[0100] b. Add 0.5 mL of trifluoroacetic acid to the above solution and stir at 20 - 30 °C for 2 hours.

[0101] c. Adjust the pH of the above solution to 7 - 8 with saturated sodium carbonate solution, then pour it into ethanol (15 mL), stir at 25 ± 5 °C for 30 minutes, filter, wash the filter cake with ethanol, and freeze-dry the filter cake to obtain the intermediate Compound N for later use.

[0102] Preparation of Compound O

[0103] a. Add Compound N (1 g) to 5 ml of pure water and stir until it becomes clear;

[0104] b. Then, add NaHCO3 (35 mg) and GdCl3 (100 mg, metal ion M provided in the form of a salt) to the above solution in sequence. Heat the solution to 50 - 60 °C and stir for 2 hours.

[0105] c. Cool the reaction solution to 20 - 30 °C to obtain the intermediate product O for later use.

[0106] Preparation of Magnetic Resonance Microspheres

[0107] a. To the reaction solution containing the intermediate compound O in the previous step, add 2-acrylamido-2-methylpropanesulfonic acid monomer (50 mg; a small molecule monomer with n3 being zero and R4 being hydrogen) and potassium persulfate (30 mg) in sequence, and stir at 25 ± 5 °C until completely dissolved.

[0108] b. Weigh 50 mg of cellulose acetate and add it to 3 mL of ethyl acetate, heat to 62.5 ± 2.5 °C, and stir evenly.

[0109] c. Slowly add the solution from step b to the solution from step a to form an oil-water mixed system.

[0110] d. Take 0.3 mL of ethanol and add it to the solution from step c, continue to stir for 5 min, then add 0.3 mL of tetramethylethylenediamine, raise the temperature of the system to 60 - 65 °C, and keep stirring for 6 h.

[0111] e. Cool the reaction solution to 25 ± 5 °C, filter, and wash with ethyl acetate to obtain embolization microspheres with magnetic resonance imaging.

[0112] Example 2

[0113] Prepare embolization microspheres for magnetic resonance imaging - magnetic resonance hydrogel according to the foregoing third reaction equation. s

[0114] a. Weigh 1 g of polyvinyl alcohol (a hydrophilic polymer; compound A) and 1 g of compound K [6-(carboxymethyl)-3,9-bis[2-(1,1-dimethylethoxy)-2-oxoethyl]-13,13-dimethyl-11-oxo-12-oxa-3,6,9-triazatetradecanoic acid-1-tert-butyl ester] and add them to 50 mL of dimethyl sulfoxide, stir at 55 ± 5 °C and 300 rpm until the solution is clear.

[0115] b. Then, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.5) and 4-dimethylaminopyridine (0.4 g) to the above solution in sequence, and continue to stir while keeping warm for 1 hour.

[0116] c. Take 0.2 mL of acrylic acid (n 20 being zero and R 20 being a terminal olefinic bond compound with a hydroxyl group) and add it to the above reaction solution, stir at 50 - 60 °C for 2 h, and cool to 20 - 30 °C.

[0117] d. Slowly pour the above solution into 100 mL of absolute ethanol, and stir at 25 ± 5 °C for 1 hour.

[0118] e. Filter the precipitate, wash the filter cake with ethanol three times, and freeze-dry to obtain the intermediate compound L for later use.

[0119] Preparation of Compound N

[0120] a. Weigh 1 g of the freeze-dried functionalized compound L and dissolve it in 5 ml of anhydrous dimethyl sulfoxide, and stir until the solution becomes clear.

[0121] b. Add 0.5 mL of trifluoroacetic acid to the above solution and stir at 20 - 30 °C for 2 hours.

[0122] c. Adjust the pH of the above solution to 7 - 8 with saturated sodium carbonate solution, then pour it into 15 mL of ethanol, stir at 25 ± 5 °C for 30 minutes, filter, wash the filter cake with ethanol, and freeze-dry the filter cake to obtain the intermediate compound N for later use.

[0123] Preparation of Compound S

[0124] a. Add 1 g of compound N to 5 ml of pure water and stir until it becomes clear;

[0125] b. Sequentially add 50 mg of 2-acrylamido-2-methylpropanesulfonic acid monomer and 30 mg of potassium persulfate, and stir at 25 ± 5 °C until completely dissolved;

[0126] c. Weigh 50 mg of cellulose acetate and add it to 3 mL of ethyl acetate, heat to 62.5 ± 2.5 °C, and stir evenly;

[0127] d. Take 0.3 ml of ethanol and add it to the solution in step c, continue to stir for 5 min, then add 0.3 ml of tetramethylethylenediamine, raise the temperature of the system to 62.5 ± 2.5 °C, and keep stirring for 6 h;

[0128] e. Cool the reaction solution to 25 ± 5 °C, filter, wash with ethyl acetate to obtain embolization microspheres, and freeze-dry for later use.

[0129] Preparation of Magnetic Resonance Microspheres (MRI Microspheres)

[0130] a. Take 1 g of the freeze-dried microspheres obtained in the previous step, add 20 mL of purified water, and stir evenly;

[0131] b. Add 35 mg of NaHCO3 and 100 mg of GdCl3 to the above mixture, raise the temperature of the solution to 55 ± 5 °C, and stir for 2 hours

[0132] c. Cool the reaction system to 25 ± 5 °C, filter, wash the filter cake with pure water to obtain magnetic resonance microspheres.

[0133] Test Example 1

[0134] Figure 1 The first performance diagram of the embolic microspheres provided in Example 1 of the present application is shown in FIG. Figure 1 It can be seen that the particles of the embolic microspheres provided in the examples of the present application are relatively round.

[0135] Figure 2 This is the appearance diagram of the embolic microspheres provided in Example 1 of the present application before pressurization; Figure 3 This is a diagram of the appearance of the embolic microspheres after pressurization provided in Example 1 of the present application. In this test example, the embolic microspheres were pressurized for 30 minutes and then released, and their appearance did not change, indicating that the embolic microspheres were highly elastic microspheres.

[0136] Take the microspheres provided in Example 1 and the microspheres currently used clinically respectively, dry the water, and weigh the microspheres as M1; add doxorubicin aqueous solution at a ratio of 1 ml (1 mg / ml) to 1 g of microspheres, gently shake, resuspend the microspheres, let stand at room temperature for 5 minutes, then absorb the supernatant, wash three times with water, measure the absorbance of the supernatant solution, and calculate the amount of doxorubicin remaining in the supernatant as M2. The mass of the microspheres after drug loading is measured as M2, and the test drug loading amount M0=M1-M2. Figure 4 Schematic diagram of the drug loading of the microspheres provided in Example 1 of the present application and the microspheres of Hengrui, from Figure 4 It can be seen that the drug loading capacity of the microspheres provided in Example 1 of the present application is higher.

[0137] Test Example 2

[0138] Figure 5 The nuclear resonance imaging (MRI) images after adding different concentrations of DOTA-Gd to the embolic microspheres provided in Example 1 of the present application. Figure 5 In the figure, 1 means that the concentration of DOTA-Gd is 0 mg / mL, 2 means that the concentration of DOTA-Gd is 12.5 mg / mL, 3 means that the concentration of DOTA-Gd is 25 mg / mL, T1 means the nuclear resonance imaging of T1-weighted imaging, and T2 means the nuclear resonance imaging of T2-weighted imaging. The results show that these embolic microspheres have a significant enhancement effect in T1-weighted MRI imaging, and as the concentration of DOTA-Gd in the microspheres increases, the T1-weighted signal intensity is significantly enhanced. However, the signals of the embolic microspheres containing different concentrations of DOTA-Gd in T2-weighted imaging are not significantly different from those of the control group, indicating that they do not have the enhancement effect of T2-weighted imaging. It is shown that the embolic microspheres provided in this application have nuclear resonance imaging capabilities.

[0139] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A hydrogel, characterized in that: The hydrogel comprises a metal complex and a high molecular polymer which are combined via functional groups, wherein the functional groups comprise acyloxy groups, acetal groups or ether groups.

2. The hydrogel according to claim 1, characterized in that The hydrogel has a structure shown in the following formula 1 or formula 2: Wherein, Z represents a carbon atom or a nitrogen atom; n1 represents the number of carbons in the carbon chain connected to Z; M is a metal that provides a source of central bodies in the metal complex; H represents the functional group; G represents the high molecular polymer; Optionally, the functional group represented by H is produced by reacting the structure shown in the following formula 3, formula 4, formula 5 or formula 6; Among them, P w represents a carboxyl group, an ester group, an aldehyde group, an acetal group or a halogen, and P w The group represented by forms the functional group represented by H through reaction.

3. The hydrogel according to claim 1 or 2, characterized in that In the metal complex, the coordination bond is formed by the dehydrogenated carboxylic hydroxyl oxygen atom bonding to the metal; Alternatively, in the metal complex, the ligand is monodentate or polydentate; Alternatively, the metal complex is a chelate and the chelator molecule has a plurality of heteroatoms, two to six nitrogen atoms and four to eight oxygen atoms, some of which are coordinated with the metal; Alternatively, the metal complex is a chelate and the chelator molecule comprises EDTA, EGTA, DTPA, BOPTA, DTPA-BMA, NOTA, DO3A, DOTA, TETA or HP-DO3A; Alternatively, in the metal complex, the central body is a metal ion and is derived from an oxide, hydroxide, hydrochloride, sulfate, nitrate or triflate; and / or, in the metal complex, the central body is Fe 3+ , Mn 2+ , Gd 3+ 、Dy 3+ Or Ho 3+ ; Alternatively, the metal complex includes Gd-DTPA, Gd-DTPA-BMA, Gd-EOB-DTPA, Gd-DOTA, Gd-BOPTA, Gd-DO3A, Mn-DPDP or Dy-DTPA.

4. The hydrogel according to claim 1, 2 or 3, characterized in that: The high molecular polymer is hydrophilic.

5. The hydrogel according to claim 1, 2 or 3, characterized in that: The high molecular polymer is formed by cross-linking copolymer monomers and small molecular monomers, wherein the copolymer monomers are formed by covalently linking a hydrophilic macromolecule and a terminal olefinic compound; Optionally, the high molecular weight polymer has any of the following limitations: The first limitation is that the hydrophilic polymer has one or more hydrophilic groups, and the hydrophilic groups include hydroxyl, amino, amine, carboxyl, amide, sulfonic acid, sulfonyl or sulfate; optionally, the hydrophilic polymer has 1,2-dihydroxy or 1,3-dihydroxy; optionally, the hydrophilic polymer includes one or more of polyvinyl alcohol, polyethylene glycol, fucoidan, methyl cellulose, ethyl cellulose, amylose and polysaccharide macromolecules, wherein the polysaccharide macromolecule includes chitosan; The second limitation is that the terminal olefinic compound has the following structure: Among them, n 10 is the number of carbon atoms in the carbon chain, and n 10 The value of is 1 to 20; Among them, n 20 is the number of carbon atoms in the carbon chain, and n 20 The value of is 0 to 20; R1 is a first group and includes Cl, Br, I, COOH, CHO, acetal, ester or acyl halide; When n 20 ≠0, R2 is a second group and includes Cl, Br, I, COOH, CHO, acetal, ester or acyl halide; n 20 =0, R2 is a substituent and includes Cl, Br or OH; The third limitation is that the small molecule monomer has the following structure: Where n3 is the number of carbon atoms and has a value of 1 to 20; R4 is an ion or a third substituent, and the ion includes Na + , K + or NH4 + , the third substituent includes H, Me, Et, i Pr or n Bu.

6. Use of the hydrogel according to any one of claims 1 to 5 in the preparation of a drug carrier, an embolic agent, a medical filling material or a medical tissue scaffold; Optionally, the hydrogel is a porous particle or sphere having elasticity and magnetic resonance imaging properties; Optionally, the hydrogel is a porous spherical object having elasticity and magnetic resonance imaging properties, and the diameter of the spherical object is 50 microns to 1000 microns.

7. A method for preparing an embolic material capable of magnetic resonance imaging, characterized in that: The embolic material is a hydrogel, and the preparation method is carried out by the following reaction formula: or wherein Pj represents a carboxyl group, an ester group, an aldehyde group, an acetal group or a halogen; Wherein, W represents a hydrophilic polymer monomer, which is formed by the reaction of the hydrophilic polymer represented by A with a terminal olefinic compound, and the optional reaction equation is as follows: wherein H represents a functional group residue formed by reaction of Pj with W and is an acyloxy group, acetal or ether; Wherein, Y represents the copolymer monomer residue formed by W and Pj; Wherein, G represents a high molecular polymer formed by copolymerization, and is formed by the reaction of the Y group and the small molecular monomer; Wherein, acid represents a protonic acid or a Lewis acid; Wherein, M represents a metal ion and is provided in the form of a salt, an oxide or a hydroxide.

8. The method for preparing a magnetic resonance imaging embolic material according to claim 7, characterized in that: In the reaction of forming the G group from the Y group through copolymerization, the reaction temperature is 20° C. to 100° C., and the reaction solution system includes an emulsifier, potassium persulfate and tetramethylethylenediamine.

9. The method for preparing a magnetic resonance imaging embolic material according to claim 7 or 8, characterized in that: The above reaction process is carried out in a polar aprotic solvent; Optionally, the polar aprotic solvent comprises one or more mixtures of dioxane, tetrahydrofuran, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and N,N-dimethylformamide.

10. The method for preparing a magnetic resonance imaging embolic material according to claim 8, characterized in that: The emulsifier includes anionic and / or nonionic surfactants; Alternatively, the emulsifier includes carboxylates, sulfates and sulfonates, sodium stearate, sodium dodecyl sulfate, sodium dodecylbenzene sulfonate, Tween 20, Tween 60, Tween 80 or Span.

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