Radiopaque hydrogel, and preparation method therefor and use thereof

Abstract

The present invention provides a radiopaque hydrogel, comprising a first component and a second component, wherein the first component is maleimide-terminated multi-arm polyethylene glycol; and the second component is a thiol-modified iodine-containing contrast agent. The components of the hydrogel of the present invention can be formulated into a neutral solution, which undergoes a mild reaction in a physiological environment and has a high safety, and the hydrogel formed therefrom has a good biocompatibility. The hydrogel of the present invention does not cause a hypertonic phenomenon in vivo, and degraded hydrophilic iodine molecule units can be easily metabolized and excreted from the body. The two components of the hydrogel of the present invention are used at low concentrations, thereby significantly reducing the concentration of raw materials and also reducing the amount thereof. Therefore, not only are the costs lowered, but the hydrogel is also more friendly to the human body and exhibits a better clinical safety. The hydrogel of the present invention allows for precise adjustment within a wide gelation time window of 2-120 s, the CT value can be quantitatively regulated and controlled within 80-400 Hu, and therefore the hydrogel is adaptive to application requirements of different tissues; and the degradation period of the hydrogel in vivo can be adjusted within 1-24 weeks.

Description

Developable hydrogel, preparation method and application thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of biomedical hydrogels. More specifically, it relates to a developable hydrogel and a preparation method thereof. BACKGROUND

[0002] Hydrogels have excellent performance in targeted drug delivery, tissue engineering, wound dressing and closure, tissue anti-adhesion, tissue isolation, cancer adjuvant therapy, etc. due to their biocompatibility, diversity of physicochemical properties and expandability of multifunction, and have shown great application potential and research value in the medical field.

[0003] Currently, the cross-linking principles of hydrogels on the market or under research are mainly the reaction between aldehyde groups and amino groups or the esterification reaction between active ester groups and amino groups. In order to achieve rapid gelation and obtain stable gel materials, the above two reaction mechanisms require that the two components are acidic (aldehyde component, active ester component usually pH<4) and alkaline (amino component usually pH>9) respectively. Although the mixture can maintain a neutral range, there may be a biological safety risk due to the deviation of pH value from the neutral due to uneven mixing. In addition, aldehyde groups or active ester groups may compete with the amino groups of a large number of amino acids present in the body, which may affect the stability and function of proteins and produce unpredictable results, and on the other hand, the reaction cannot be accurately quantified. The reaction conditions of this type of reaction are not conducive to the stability of the physiological environment and the safety of adjacent tissues and organs. In contrast, the hydrogel prepared by cross-linking between polymer chains using Michael addition reaction is safer. Michael addition reaction does not require the addition of any chemical catalyst or initiator that is harmful to cells, the reaction conditions are mild, it can react quickly under physiological conditions, and there is no other by-product. For example, thiol and maleimide groups undergo Michael addition reaction to form stable thioether bonds to achieve binding cross-linking, thereby forming a hydrogel (Fu Y, Kao WJ. In situ forming poly(ethylene glycol)-based hydrogels via thiol-maleimide Michael-type addition. J Biomed Mater Res A. 2011 Aug;98(2):201-11.). Chinese patent CN118685018A cross-links a thiol-terminated multi-arm polyethylene glycol derivative and a maleimide-terminated multi-arm polyethylene glycol derivative to form a hydrogel.

[0004] However, to achieve better mechanical properties, hydrogels prepared using the Michael addition reaction require the use of maleimide-terminated multi-arm polyethylene glycol precursors with high solids content, often at a mass-to-volume concentration of 15% (w / v) (e.g., Chinese patent CN118356534A). This means high raw material concentration and usage, resulting in relatively high costs and is not very suitable for materials intended for human use. Furthermore, existing methods for preparing hydrogels using the Michael addition reaction involve long gelation times, often exceeding 5 minutes, with a narrow adjustment window for gelation time, making it difficult to meet the diverse clinical requirements regarding processing time. Summary of the Invention

[0005] The present invention aims to provide a developable hydrogel with fast gelation speed, large gelation speed adjustment window, and higher safety.

[0006] The first objective of this invention is to provide a developable hydrogel composition and its application.

[0007] The second objective of this invention is to provide a method for preparing a hydrogel and the hydrogel prepared therefrom.

[0008] A third objective of this invention is to provide applications for the hydrogel prepared as described above.

[0009] The above-mentioned objective of this invention is achieved through the following technical solution:

[0010] The present invention provides a radioactive hydrogel composition comprising a first component and a second component; the first component is maleimide-terminated multi-arm polyethylene glycol; and the second component is a thiol-containing contrast agent modified with thiol groups.

[0011] As an alternative implementation, the method for preparing the thiol-modified iodine-containing contrast agent is as follows:

[0012] S1. Add sodium periodate solution to iodine-containing contrast agent solution and react at 0-10℃ for 5-120 min;

[0013] S2. After the reaction is complete, the powder is dried, washed and extracted with anhydrous ethanol, and the supernatant is collected and subjected to negative pressure rotary evaporation to obtain a developer precursor containing aldehyde active groups.

[0014] S3. Dissolve the contrast agent precursor in anhydrous ethanol, add mercaptoethylamine in anhydrous ethanol solution while stirring at room temperature, and react at 0-30℃ for 20-240 min. After the reaction is completed, extract, wash, dry and column chromatography to obtain the mercapto-modified iodine-containing contrast agent.

[0015] Specifically, the solvent for the iodine-containing contrast agent solution and the sodium periodate solution is water.

[0016] As an alternative implementation, the iodine-containing contrast agent is any one of iopromide, iopamidol, iofluoxetine, iohexol, iodine bismuth subcitrate, and iodixanol; the thiol-modified iodine-containing contrast agent has 2-4 thiol groups.

[0017] As an alternative implementation, the second component is a mercapto-modified oligomer of an iodine-containing contrast agent, wherein the number of monomers in the oligomer is 1-8.

[0018] As an alternative implementation, the maleimide-terminated multi-arm polyethylene glycol has 2-8 arms; in the maleimide-terminated multi-arm polyethylene glycol, the maleimide group and the polyethylene glycol are covalently linked by ester or amide bonds.

[0019] Preferably, the maleimide-terminated multi-arm polyethylene glycol has 4 or 8 arms and a molecular weight of 10,000-20,000 Da.

[0020] As an alternative implementation, the molar ratio of the double bond in the first component to the thiol group in the second component is (0.6-1.4):1. That is, the molar ratio of the double bond in the maleimide-terminated multi-arm polyethylene glycol to the thiol group in the thiol-modified iodine-containing compound is (0.6-1.4):1.

[0021] As an alternative preferred embodiment, the molar ratio of the double bond in the maleimide-terminated multi-arm polyethylene glycol to the thiol group in the thiol-modified iodine-containing compound is 1:1.

[0022] As an optional preferred embodiment, it further includes solvents for the first and second components; the ionic strength of the solvent is 1 to 343 mM.

[0023] Specifically, the solvent is physiological saline, phosphate buffer, or deionized water.

[0024] Furthermore, the ionic strengths of the solvents in solutions A and B are 1.6–160 mM.

[0025] Our research shows that the gelation time varies significantly when using solvents with different ionic strengths and different thiol-containing contrast agents with different thiol groups. Therefore, the gelation time window of the hydrogel can be controlled by adjusting the ionic strength of the solvent in this invention.

[0026] For example, if thiopromide is selected as the solute in solution B, and the gelation time needs to be no longer than 32 s, then the ionic strength of solutions A and B should be no less than 8 mM; otherwise, the ionic strength needs to be less than 8 mM.

[0027] The application of the above composition in the preparation of hydrogels should also be within the scope of protection of this invention.

[0028] This invention also provides a method for preparing a hydrogel, comprising the following steps:

[0029] S1. Dissolve the first and second components in a solvent to obtain solution A and solution B, respectively;

[0030] S2. Mixing solution A and solution B yields a developable hydrogel.

[0031] As an alternative implementation, the concentration of the first component in solution A is 0.015 g / mL (i.e., a mass-volume concentration of 3%); and the concentration of the second component in solution B is 0.01 g / mL (i.e., a mass-volume concentration of 2%).

[0032] As an alternative implementation, in step S2, solution A and solution B are mixed at a volume ratio of 1:1.

[0033] Specifically, the solvent is physiological saline, phosphate buffer, or deionized water.

[0034] Specifically, the pH value of the solvent is 6.5-7.5.

[0035] As an alternative implementation, the method for preparing the hydrogel includes the following steps:

[0036] S1. Dissolve 0.15 g of the first component in 5 mL of PBS to obtain solution A, and dissolve 0.01 g of the second component in 5 mL of PBS (pH=7.4) to obtain solution B;

[0037] S2. Mix 0.5 mL of solution A and 0.5 mL of solution B to obtain a developable hydrogel.

[0038] The present invention also provides a developable hydrogel obtained by the above preparation method.

[0039] The application of the above-described hydrogel composition or the above-described radiopaque hydrogel in the preparation of products for radiotherapy isolation and protection, tissue reference marking, medical sealing, tumor embolization, drug delivery or tissue filling should also be within the scope of protection of this invention.

[0040] The present invention has the following beneficial effects:

[0041] 1. The components of the hydrogel of this invention can be formulated into a neutral solution, allowing for a mild reaction under physiological conditions, resulting in high safety and good biocompatibility. Furthermore, the components used in preparing the hydrogel of this invention do not contain aldehyde groups, thus avoiding adverse reactions caused by the large amount of amino groups in tissue proteins.

[0042] 2. This invention uses a hydrophilic iodine-containing contrast agent that has been modified with thiol groups and introduced into a gel network. The gel does not cause hyperosmolarity in vivo, and the degraded hydrophilic iodine molecules are easily metabolized and excreted from the body, resulting in better clinical safety.

[0043] 3. The hydrogel of the present invention uses two components with low concentrations (mass-volume concentration can be controlled at 2%-3%), which greatly reduces the concentration of raw materials and the amount used. This not only reduces costs, but more importantly, it is very friendly to materials used in the human body.

[0044] 4. This invention can achieve precise adjustment of a wide gelation time window of 2-120s by controlling the type of iodine-containing contrast agent and the ionic strength of the solvent.

[0045] 5. The introduction of thiol-modified imaging molecules in this invention enables long-term imaging of the gel in vivo, with the imaging value quantitatively adjustable from 80 to 400 HU, adapting to the application needs of different tissues. The degradation cycle of the gel in vivo can be adjusted from 1 week to 24 weeks. Attached Figure Description

[0046] Figure 1 shows the structural formula of maleimide-terminated multi-arm polyethylene glycol (Figure a shows the structural formula of maleimide-terminated multi-arm polyethylene glycol with ester bond linkage; Figure b shows the structural formula of maleimide-terminated multi-arm polyethylene glycol with amide bond linkage; where m is a positive integer from 2 to 10).

[0047] Figure 2 shows the molecular structure of multi-arm polyethylene glycols with maleimide-terminated linkages via ester or amide bonds (Figure a shows the molecular structure of four-arm polyethylene glycol; Figure b shows the molecular structure of eight-arm polyethylene glycol).

[0048] Figure 3 shows the structural formulas of hydrophilic iodine-containing contrast agents with different thiol modifications (in the structural formulas, R=H or COOH, n=1-4; Figure a shows the structural formula of thiolized iopromide, Figure b shows the structural formula of thiolized iopamidol, Figure c shows the structural formula of thiolized iodofol, Figure d shows the structural formula of thiolized iohexol, Figure e shows the structural formula of thiolized iodopamidol, and Figure f shows the structural formula of thiolized iodixanol).

[0049] Figure 4 shows the structural formula of the hydrophilic iodine-containing contrast agent oligomer modified with thiol; in the structural formula, R1=H or COOH, R2=H or COOH, (m=2-8), (n1, n2=1-4); Figure a shows the thiolized iopromide oligomer, Figure b shows the thiolized iopamidol oligomer, and Figure c shows the thiolized iodofol oligomer.

[0050] Figure 5 shows the appearance of the samples of the dual syringe, solution A, and solution B.

[0051] Figure 6 shows the actual gel and its CT image (Figure a is the actual gel image, and Figure b is the CT image of the gel when it is implanted subcutaneously).

[0052] Figure 7 is a schematic diagram of the crosslinking of the developable hydrogel.

[0053] Figure 8 shows the imaging results of the gel formed by the thiolized iodoproamine oligomer and maleimide-terminated 8-arm polyethylene glycol (Figure a is the gel CT scan, Figure b is the imaging value on the day of gel preparation and 10 days later).

[0054] Figure 9 shows the gelation time of different types of thiolized developers with maleimide-terminated 8-arm polyethylene glycol.

[0055] Figure 10 shows the effect of solvents with different ionic strengths on the gelation time of hydrogels.

[0056] Figure 11 shows the hydrogel degradation curves for different treatment groups. Embodiments of the present invention

[0057] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0058] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0059] The 8-arm maleimide ester bond-terminated PEG was purchased from Xiamen Sinobond Biotechnology Co., Ltd., product number 06021801812.

[0060] The 4-arm maleimide ester bond-terminated PEG was purchased from Xiamen Sinobond Biotechnology Co., Ltd., product number 06020701812.

[0061] The 8-arm maleimide amide bond-terminated PEG was purchased from Xiamen Sinobond Biotechnology Co., Ltd., product number 06022001912.

[0062] The 4-arm maleimide amide bond-terminated PEG was purchased from Xiamen Sinobond Biotechnology Co., Ltd., product number 06021801912.

[0063] Example 1

[0064] A hydrogel, the preparation method of which includes the following steps:

[0065] S1. Dissolve 0.15 g of 8-arm maleimide ester-terminated PEG in 5 mL of PBS (pH=7.4) to obtain solution A, and dissolve 0.01 g of thiopromide thiodide in 5 mL of PBS (pH=7.4) to obtain solution B;

[0066] S2. Mix 0.5 mL of solution A and 0.5 mL of solution B to obtain a developable hydrogel.

[0067] The structure of maleimide-terminated multi-arm polyethylene glycol is shown in Figure 1. The specific structure of 8-arm maleimide ester-terminated PEG is shown in Figure 2b. The structure of thiopromide is shown in Figure 3a.

[0068] Example 2

[0069] A hydrogel, the preparation method of which includes the following steps:

[0070] S1. Dissolve 0.15 g of 8-arm maleimide ester-terminated PEG in 5 mL of PBS (pH=7.4) to obtain solution A, and dissolve 0.01 g of thiophanate-methyl in 5 mL of PBS (pH=7.4) to obtain solution B;

[0071] S2. Mix 0.5 mL of solution A and 0.5 mL of solution B to obtain a developable hydrogel.

[0072] The structural formula of the 8-arm maleimide ester-terminated PEG is shown in Figure 2b, and the structural formula of the thiophanate-methyl is shown in Figure 3b.

[0073] Example 3

[0074] A hydrogel, the preparation method of which includes the following steps:

[0075] S1. Dissolve 0.3 g of 4-arm maleimide amide bond-capped PEG in 5 mL of PBS (pH=7.4) to obtain solution A, and dissolve 0.01 g of thiophanate-methyl in 5 mL of PBS (pH=7.4) to obtain solution B;

[0076] S2. Mix 0.5 mL of solution A and 0.5 mL of solution B to obtain a developable hydrogel.

[0077] The structural formula of the 8-arm maleimide ester bond-terminated PEG is shown in Figure 2b, and the structural formula of the thiolated iodofol is shown in Figure 3c.

[0078] Example 4

[0079] A hydrogel, the preparation method of which includes the following steps:

[0080] S1. Dissolve 0.15 g of 8-arm maleimide ester-terminated PEG in 5 mL of PBS (pH=7.4) to obtain solution A, and dissolve 0.01 g of mercapto-iodinated iohexol in 5 mL of PBS (pH=7.4) to obtain solution B;

[0081] S2. Mix 0.5 mL of solution A and 0.5 mL of solution B to obtain a developable hydrogel.

[0082] The structural formula of the 8-arm maleimide ester-terminated PEG is shown in Figure 2b, and the structural formula of the mercapto-iodinated iohexol is shown in Figure 3d.

[0083] Example 5

[0084] A hydrogel, the preparation method of which includes the following steps:

[0085] S1. Dissolve 0.3 g of 4-arm maleimide ester-terminated PEG in 5 mL of PBS (pH=7.4) to obtain solution A, and dissolve 0.01 g of mercaptoiodinated iodide in 5 mL of PBS (pH=7.4) to obtain solution B;

[0086] S2. Mix 0.5 mL of solution A and 0.5 mL of solution B to obtain a developable hydrogel.

[0087] The structural formula of the 8-arm maleimide ester-terminated PEG is shown in Figure 2b, and the structural formula of the thiodiol iodide is shown in Figure 3e.

[0088] Example 6

[0089] A hydrogel, the preparation method of which includes the following steps:

[0090] S1. Dissolve 0.15 g of 8-arm maleimide ester-terminated PEG in 5 mL of PBS (pH=7.4) to obtain solution A, and dissolve 0.01 g of thiodilated iodixanol in 5 mL of PBS (pH=7.4) to obtain solution B;

[0091] S2. Mix 0.5 mL of solution A and 0.5 mL of solution B to obtain a developable hydrogel.

[0092] The structural formula of the 8-arm maleimide ester-terminated PEG is shown in Figure 2b, and the structural formula of the mercapto-iodixanol is shown in Figure 3f.

[0093] Example 7

[0094] A hydrogel, the preparation method of which includes the following steps:

[0095] S1. Dissolve 0.15 g of 8-arm maleimide ester-terminated PEG in 5 mL of PBS (pH=7.4) to obtain solution A, and dissolve 0.024 g of thiopromide oligomer (m=1) in 5 mL of PBS (pH=7.4) to obtain solution B;

[0096] S2. Mix 0.5 mL of solution A and 0.5 mL of solution B to obtain a developable hydrogel.

[0097] The structural formula of the 8-arm maleimide ester-terminated PEG is shown in Figure 2b, and the structural formula of the thiopromide oligomer is shown in Figure 4a.

[0098] Example 8

[0099] A hydrogel, the preparation method of which includes the following steps:

[0100] S1. Dissolve 0.15 g of 8-arm maleimide ester-terminated PEG in 5 mL of PBS (pH=7.4) to obtain solution A. Dissolve 0.048 g of thiopromide oligomer (m=2) in 5 mL of PBS (pH=7.4) to obtain solution B.

[0101] S2. Mix 0.5 mL of solution A and 0.5 mL of solution B to obtain a developable hydrogel.

[0102] Example 9

[0103] A hydrogel, the preparation method of which includes the following steps:

[0104] S1. Dissolve 0.15 g of 8-arm maleimide ester-terminated PEG in 5 mL of PBS (pH=7.4) to obtain solution A, and dissolve 0.072 g of thiopromide oligomer (m=3) in 5 mL of PBS (pH=7.4) to obtain solution B;

[0105] S2. Mix 0.5 mL of solution A and 0.5 mL of solution B to obtain a developable hydrogel.

[0106] Example 10

[0107] A hydrogel, the preparation method of which includes the following steps:

[0108] S1. Dissolve 0.15 g of 8-arm maleimide ester-terminated PEG in 5 mL of PBS (pH=7.4) to obtain solution A. Dissolve 0.120 g of thiopromide oligomer (m=5) in 5 mL of PBS (pH=7.4) to obtain solution B.

[0109] S2. Mix 0.5 mL of solution A and 0.5 mL of solution B to obtain a developable hydrogel.

[0110] Example 11

[0111] A hydrogel, the preparation method of which includes the following steps:

[0112] S1. Dissolve 0.15 g of 8-arm maleimide ester-terminated PEG in 5 mL of PBS (pH=7.4) to obtain solution A. Dissolve 0.192 g of thiopromide oligomer (m=8) in 5 mL of PBS (pH=7.4) to obtain solution B.

[0113] S2. Mix 0.5 mL of solution A and 0.5 mL of solution B to obtain a developable hydrogel.

[0114] Example 12

[0115] The mixture was stirred using a dual syringe to form a gel, the appearance of which is shown in Figure 5. The hydrogel was obtained according to the preparation method of Example 1, and the actual hydrogel is shown in Figure 6a.

[0116] Using a dual syringe, 0.5 mL of solution A and 0.5 mL of solution B from Example 1 were injected subcutaneously to form a gel. The CT image of the gel formed by subcutaneous injection is shown in Figure 6b. As can be seen from the figure, the gel exhibits a certain mechanical strength and three-dimensional support, and the subcutaneous experiment and observation can effectively support a certain physical space distance.

[0117] Figure 7 shows a schematic diagram of the crosslinking of the radioactive hydrogel. The thiol-containing contrast agent modified with thiol is chemically bonded to the three-dimensional molecular network, which will ensure stable and long-lasting radioactivity, matching the material degradation behavior.

[0118] Example 13

[0119] Multi-arm polyethylene glycols with different functional group ends were reacted with dithiothreitol (DTT), and the reaction results were observed.

[0120] Configure the following 4 processing groups:

[0121] 1. Maleimide group: 8-arm maleimide ester-terminated PEG was dissolved in PBS (pH=7.4) to obtain solution A of 0.1 g / mL. DTT was dissolved in PBS (pH=7.4) to obtain 6.16 × 10⁻⁶ g / mL solution. -3 Take 1 mL of solution A and 1 mL of solution B with a concentration of g / mL, and mix them at 37℃ for reaction.

[0122] 2. Acrylate group: PEG with 8-arm acrylate ester bonds capped was dissolved in PBS (pH=7.4) to obtain solution A at 0.1 g / mL. DTT was dissolved in PBS (pH=7.4) to obtain 6.16 × 10⁻⁶ g / mL solution. -3 Take 1 mL of solution A and 1 mL of solution B with g / mL and mix them at 37℃ to react.

[0123] 3. Vinyl sulfone group: PEG with 8-arm vinyl sulfone ester bond capping was dissolved in PBS (pH=7.4) to obtain solution A of 0.1 g / mL. DTT was dissolved in PBS (pH=7.4) to obtain 6.16 × 10⁻⁶ g / mL solution. -3 Take 1 mL of solution A and 1 mL of solution B with g / mL and mix them at 37℃ to react.

[0124] 4. Allyl group: PEG with an 8-arm allyl ester bond capped was dissolved in PBS (pH=7.4) to obtain solution A at 0.1 g / mL. DTT was dissolved in PBS (pH=7.4) to obtain 6.16 × 10⁻⁶ g / mL solution. -3 Take 1 mL of solution A and 1 mL of solution B with g / mL and mix them at 37℃ to react.

[0125] The gelation time for each group was recorded and statistically analyzed, starting from the mixing of solutions A and B and ending when the gel stopped flowing after inversion. The experimental results are shown in Table 1. The results show that only maleimide and acrylate-terminated multi-arm polyethylene glycol can form gels, and the gelation speed of the maleimide group is significantly faster than that of the acrylate group, requiring only 5 seconds to successfully gel.

[0126] Table 1. Gel properties of different treatment groups

[0127]

[0128] Example 14

[0129] Accurately measure 100 mL of phosphate buffer solution (pH = 6.5) maintained at 25°C and place it in a container. Gradually add an excess of mercapto-modified iodine-containing contrast agent oligomer (m1) to the phosphate buffer solution (PBS), stirring or shaking under constant temperature conditions until the solute no longer dissolves. After reaching equilibrium, filter or centrifuge the solution, collect the undissolved solute, dry and weigh it (m2), and obtain a saturated solution. Calculate the solubility of the mercapto-modified iodine-containing contrast agent oligomer.

[0130] The formula for calculating solubility is: S = (m1 - m2).

[0131] Table 2 shows the hydrophilicity determination results of thiolated iodine-containing contrast agent oligomers with different monomer unit numbers. The results indicate that water solubility gradually decreases with increasing monomer unit number, and a monomer unit number of 2-8 provides a suitable solubility window. For applications requiring high imaging values, oligomers with high monomer unit numbers (6 or 8) are preferred; for applications requiring low imaging values, oligomers with low monomer unit numbers (2 or 4) are preferred. Among the three thiolated iodine-containing contrast agent oligomers, the thiolated iodofol oligomer exhibits the best hydrophilicity, followed by the thiolated iopamidol oligomer, and finally the thiolated iopromide oligomer.

[0132] Table 2. Solubility of thiolated iodine-containing contrast agent oligomers with different numbers of monomer units (g / 100g)

[0133]

[0134] Example 15

[0135] Iodine-containing contrast agents (iopromide, iopamidol, iofluoxetine, iohexol, iodine bismuth subtilis, and iodixanol) were modified with different numbers of thiol functional groups (2, 3, 4, 6, and 12 thiol groups were added to the iodine-containing contrast agents, respectively). The water solubility of the thiolized iodine-containing contrast agents was determined according to the method in Example 7. The results are shown in Table 3. The results show that the water solubility of the thiolized iodine-containing contrast agents decreased significantly with the increase of the number of thiol functional groups. The thiol-modified iodine-containing contrast agents that are insoluble in water are not suitable for the injectable hydrogel of this invention.

[0136] Table 3. Water solubility of iodine-containing contrast agents modified with different numbers of thiol functional groups

[0137]

[0138] Example 16

[0139] Using PBS solution (pH=7.4) as a control, the gels prepared in Examples 7-11 were scanned under CT on the day of preparation and 10 days after preparation. The PBS solution was also scanned under CT. The CT scan results are shown in Figure 8a. The development value of the hydrogel on the day of preparation and 10 days after preparation is shown in Figure 8b. The results show that as the number of monomer units of the thiopromidine oligomer increases, the development value also increases, showing a certain positive proportional upward trend. The development value of the hydrogel after 10 days of preparation changed little, indicating that the development function can be stably and continuously performed by grafting iodine molecular units onto the molecular network through chemical bonds. The slight decrease in development value may be due to scanning error; the swelling of the gel itself may cause a slight increase in volume, which may also reduce the density of iodine to some extent, resulting in a slight decrease in development value.

[0140] The radioactivity of hydrogels is positively correlated with iodine content. Previous clinical applications and research have primarily focused on increasing the concentration of the bulk material and the number of reactive functional groups, thereby increasing the iodine content by grafting more iodine molecules. However, this approach undoubtedly increases the amount of implantable material used, potentially posing risks. This invention, by controlling the number of monomer units in the thiopropylamine oligomer, allows for convenient control of radioactivity without altering the amount of active double bonds and thiol groups used in vivo. This method is simpler and safer.

[0141] Example 17

[0142] Different clinical applications have different requirements for gelation time. Open body cavities require hydrogels to gel rapidly after injection to prevent loss from the intended location. However, for applications involving closed cavities, hydrogels with a slightly longer gelation time can be used to more completely fill irregular areas.

[0143] The gelation time of the hydrogels in Examples 1, 4, and 6 was determined. The timing started when solutions A and B were mixed and ended when the gel stopped flowing after inversion. The gelation time for each group was recorded and statistically analyzed. The gelation time measurement results are shown in Figure 9. The results show that the gelation time of the hydrogel with mercapto-iopromide as the solute in solution B was 20 s, the gelation time of the hydrogel with mercapto-iohexol as the solute in solution B was 7 s, and the gelation time of the hydrogel with mercapto-iodixanol as the solute in solution B was 4 s. This indicates that the hydrogel of the present invention can achieve a gelation window within a certain range by adjusting different mercapto-containing iodine contrast agents.

[0144] Example 18

[0145] I. Solution Preparation

[0146] 1. Prepare a sodium chloride solution with an ionic strength of 160 mM using the following formula:

[0147] Weigh 9.35g of sodium chloride solid, dissolve the sodium chloride solid completely in distilled water, and bring the volume to 1L to prepare a 160 mM sodium chloride solution.

[0148] 2. Prepare sodium chloride solutions with different ionic strengths.

[0149] A 160 mM sodium chloride solution was diluted with distilled water to 80 mM, 16 mM, 160 mM, 8 mM and 1.6 mM, respectively, to obtain sodium chloride solutions of 80 mM, 16 mM, 160 mM, 8 mM and 1.6 mM.

[0150] II. Preparation of Solution A and Solution B

[0151] Using sodium chloride solutions of different ionic strengths as solvents (160 mM, 80 mM, 16 mM, 160 mM, 8 mM, and 1.6 mM), 1.5 × 10⁻⁶ ppm sodium chloride solutions were prepared respectively. -6 8-arm maleimide-terminated PEG (average molecular weight 20000) solution A and 6×10 -6 Solution B of 1 mol / mL thiopromide.

[0152] III. Preparation of Hydrogels

[0153] Mix 0.5 mL of solution A and 0.5 mL of solution B to react and obtain hydrogels prepared with sodium chloride solutions of different ionic strengths.

[0154] IV. Gelation Time Measurement

[0155] The gelation time for each group was recorded and statistically analyzed, starting from the mixing of solutions A and B and ending when the gel stopped flowing when inverted.

[0156] The measurement results are shown in Figure 10. The results indicate that the gelation time increases with decreasing ionic strength. An ionic strength of 8 mM serves as the dividing point. Above 8 mM, the gelation time is less than 32 seconds; below 8 mM, the gelation time increases significantly. This result demonstrates that the gel of this invention can be flexibly adjusted in terms of gelation time by regulating the solution's ionic strength. Clinically, for closed cavities, solutions with an ionic strength less than 8 mM are preferred, while for open cavities, solutions with an ionic strength greater than 8 mM are preferred.

[0157] Example 19

[0158] The duration of action of radiopaque hydrogels after implantation is closely related to their degradation behavior.

[0159] Configure the following 3 processing groups.

[0160] 1. Ester-DTT group: 8-arm maleimide ester-terminated PEG (molecular weight: 20000) was dissolved in PBS (pH=7.4) to obtain a 0.1 g / mL solution A. DTT was dissolved in PBS (pH=7.4) to obtain 6.16 × 10⁻⁶ DTT. -3 A solution B with a concentration of g / mL is mixed with 1 mL of solution A and 1 mL of solution B to form a gel.

[0161] 2. Ester bond-thiol-mercaptolated iohexol group: 0.15 g of 8-arm maleimide ester bond-terminated PEG (molecular weight: 20000) was dissolved in 5 mL PBS (pH=7.4) to obtain solution A. 0.01 g of thiol-mercaptolated iohexol was dissolved in 5 mL PBS (pH=7.4) to obtain solution B. 1 mL of solution A and 1 mL of solution B were mixed and reacted to form a gel.

[0162] 3. Amide bond-thiol-methyl-iohexol: Dissolve 0.15 g of 8-arm maleimide amide bond-terminated PEG (molecular weight: 20000) in 5 mL PBS (pH=7.4) to obtain solution A. Dissolve 0.01 g of methyl-methyl-iohexol in 5 mL PBS (pH=7.4) to obtain solution B. Mix 1 mL of solution A and 1 mL of solution B to form a gel.

[0163] The gels formed from the three treatment groups were placed in a phosphate buffer solution (pH=7.4) at 37°C and observed continuously. The weight of the gels was measured at the set time points, and degradation curves were plotted.

[0164] The hydrogel degradation curves of different treatment groups are shown in Figure 11. The results show that the hydrogels of the ester-mercapto-iohexol group and the amide-mercapto-iohexol group have significantly stronger degradation stability than those of the ester-DTT group. Therefore, the hydrogels prepared from the mercapto-containing iodine contrast agent of this invention have excellent clinical application prospects.

[0165] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A developable hydrogel composition, characterized in that, It includes a first component and a second component; the first component is maleimide-terminated multi-arm polyethylene glycol; the second component is a thiol-containing contrast agent modified with mercapto groups.

2. The hydrogel composition according to claim 1, characterized in that, The iodine-containing contrast agent is any one of iopromide, iopamidol, ioflufenicol, iohexol, iodiphenol, and iodixanol; the thiol-modified iodine-containing contrast agent has 2-4 thiol groups.

3. The hydrogel composition according to claim 1, characterized in that, The second component is a mercapto-modified iodine-containing contrast agent oligomer, wherein the number of monomers in the oligomer is 1-8.

4. The hydrogel composition according to claim 1, characterized in that, The maleimide-terminated multi-arm polyethylene glycol has 2-8 arms; in the maleimide-terminated multi-arm polyethylene glycol, the maleimide group and the polyethylene glycol are covalently linked by ester or amide bonds.

5. The hydrogel composition according to claim 1, characterized in that, The molar ratio of the double bonds in the first component to the thiol groups in the second component is (0.6-1.4):

1.

6. The hydrogel composition according to any one of claims 1-5, characterized in that, It also includes solvents for the first and second components; the ionic strength of the solvent is 1 to 343 mM.

7. Use of the composition according to any one of claims 1-6 in the preparation of hydrogels.

8. A method for preparing a hydrogel, characterized in that, Includes the following steps: S1. Dissolve the first component and the second component as described in any one of claims 1-6 in a solvent to obtain solution A and solution B, respectively; S2. Mixing solution A and solution B yields a developable hydrogel.

9. The developable hydrogel obtained by the preparation method according to claim 8.

10. The use of the hydrogel composition of any one of claims 1-6 or the radiopaque hydrogel of claim 9 in the preparation of products for radiotherapy isolation and protection, tissue reference marking, medical sealing, tumor embolization, drug delivery, or tissue filling.

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