A developable hydrogel and its preparation method and application

Abstract

The present invention provides a developable hydrogel, comprising a first component and a second component; the first component is a multi-arm polyethylene glycol terminated with a maleimide group; the second component is an iodine-containing contrast agent modified with a thiol group. The components of the hydrogel of the present invention can be formulated as a neutral solution, react mildly under a physiological environment, have high safety, and the formed hydrogel has good biocompatibility. The hydrogel of the present invention does not cause hyperosmotic phenomena in vivo, and the hydrophilic iodine molecular units after degradation are easily metabolized and excreted from the body. The two components of the hydrogel of the present invention are used at a low concentration, which greatly reduces the raw material concentration and the usage amount, which can not only reduce costs, but also be more friendly to the human body and have better clinical safety. The hydrogel of the present invention can achieve precise adjustment of a wide gel time window of 2-120s, and the development value can be quantitatively regulated at 80-400Hu, adapted to the application requirements of different tissues, and the degradation cycle of the gel in vivo can be adjusted from 1 week to 24 weeks.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedical hydrogels, and more specifically, relates to a developable hydrogel and a preparation method thereof. Background Art

[0002] Due to its biocompatibility, diverse physical and chemical properties, and multifunctional expandability, hydrogels have outstanding performance in targeted drug delivery, tissue engineering, wound dressing and closure, tissue anti-adhesion, tissue isolation, and cancer adjuvant therapy, showing great application potential and research value in the medical field.

[0003] The cross-linking principle of hydrogels currently on the market or under development is mostly the reaction between aldehyde groups and amino groups or the esterification reaction between active esters 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 and active ester component usually have a pH of less than 4) and alkaline (amino component usually has a pH of more than 9). Although the neutral range can be maintained after mixing, there may be biosafety risks caused by the deviation of the pH value from neutrality due to uneven mixing. In addition, aldehyde groups or active ester groups may compete with the amino groups of amino acids that exist in large quantities in the body. On the one hand, they may affect the stability and function of proteins and produce unpredictable results. On the other hand, they make it impossible to accurately and quantitatively carry out the reaction. 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 the Michael addition reaction is safer. The Michael addition reaction does not require the addition of any chemical catalysts or initiators that are harmful to cells. The reaction conditions are mild and can react quickly under human physiological conditions without other by-products. For example, a thiol group and a maleimide group undergo Michael addition reaction to form a stable thioether bond to achieve bonding and crosslinking, thereby forming a hydrogel (such as 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 forms a hydrogel by crosslinking a thiol-terminated multi-arm polyethylene glycol derivative and a maleimide-terminated multi-arm polyethylene glycol derivative.

[0004] However, in order to obtain better mechanical properties, hydrogels using Michael addition reactions need to use a high-solid content maleimide-terminated multi-arm polyethylene glycol precursor, and the mass-volume concentration is often 15% (w / v) (such as Chinese patent CN118356534A), that is, the raw material concentration and usage are high, which is not only relatively costly, but also not very friendly to materials used in the human body. At the same time, the gelation time of the existing hydrogels prepared by Michael addition reactions is relatively long, mostly more than 5 minutes, and the adjustment window of the gelation time is narrow, which is not convenient for meeting the diverse clinical requirements for operation 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 object of the present invention is to provide a developable hydrogel composition and its application.

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

[0008] The third object of the present invention is to provide the application of the hydrogel prepared as above.

[0009] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0010] The invention provides a developable hydrogel composition, comprising a first component and a second component; the first component is a multi-arm polyethylene glycol terminated with a maleimide group; and the second component is an iodine-containing contrast agent modified with a thiol group.

[0011] As an optional embodiment, the preparation method of the thiol-modified iodine-containing contrast agent is:

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

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

[0014] S3. Take the developer precursor and dissolve it in anhydrous ethanol. Add mercaptoethylamine anhydrous ethanol solution under stirring at room temperature, and react at 0-30°C for 20-240 min. After the reaction is completed, extract, wash, dry and column chromatography to obtain a thiol-modified iodine-containing contrast agent.

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

[0016] As an optional embodiment, the iodine-containing contrast agent is any one of iopromide, iopamidol, ioversol, iohexol, iobitrol, and iodixanol; and the number of thiol groups in the thiol-modified iodine-containing contrast agent is 2-4.

[0017] As an optional embodiment, the second component is a thiol-modified iodine-containing contrast agent oligomer, and the number of monomers of the oligomer is 1-8.

[0018] As an optional embodiment, the number of arms of the maleimide-terminated multi-arm polyethylene glycol is 2-8; in the maleimide-terminated multi-arm polyethylene glycol, the maleimide group and the polyethylene glycol are covalently linked via an ester bond or an amide bond.

[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 optional embodiment, 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. That is, the molar ratio of the double bonds in the maleimide-terminated multi-arm polyethylene glycol to the thiol groups in the thiol-modified iodine-containing compound is (0.6-1.4):1.

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

[0022] As an optional preferred embodiment, a solvent for the first component and the second component is further included; 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 strength of the solvents of solution A and solution B is 1.6 to 160 mM.

[0025] Our research shows that when solvents with different ionic strengths and different thiol-modified iodine-containing contrast agents are selected, the gelation time will be significantly different. Therefore, in the scheme of the present invention, the gelation time window of the hydrogel can be regulated by regulating the ionic strength of the solvent.

[0026] For example, when iopromide thiosulfate is selected as the solute in solution B, if the gelation time needs to be no longer than 32 s, the ionic strength of solution A and solution 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 preparing hydrogel should also be within the protection scope of the present invention.

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

[0029] S1. The first component and the second component are dissolved in a solvent to obtain a solution A and a solution B;

[0030] S2. Solution A and solution B are mixed to obtain a developable hydrogel.

[0031] As an optional embodiment, the concentration of the first component in solution A is 0.015 g / mL (ie, the mass-volume concentration is 3%); the concentration of the second component in solution B is 0.01 g / mL (ie, the mass-volume concentration is 2%).

[0032] As an optional embodiment, in step S2, solution A and solution B are mixed in 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 optional embodiment, the method for preparing the hydrogel comprises 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 invention also provides a developable hydrogel obtained by the above preparation method.

[0039] The use of the above hydrogel composition or the above developable hydrogel in the preparation of products for radiotherapy isolation protection, tissue reference marking, medical sealing, tumor embolization, drug loading or tissue filling should also be within the scope of protection of the present invention.

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

[0041] 1. The components of the hydrogel of the present invention can be prepared as a neutral solution, which reacts mildly under physiological conditions, is highly safe, and the formed hydrogel has good biocompatibility. In addition, the components for preparing the hydrogel of the present invention do not contain aldehyde groups, thus avoiding adverse reactions caused by reactions with a large number of amino groups in tissue proteins.

[0042] 2. The present invention uses a hydrophilic iodine-containing contrast agent to carry out thiol functionalization modification and introduce it into the gel network. The gel will not cause hyperosmotic phenomenon in the body, and the degraded hydrophilic iodine molecular units are easily metabolized and excreted from the body, which has better clinical safety.

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

[0044] 4. The present invention can achieve precise adjustment of a wide gel time window of 2-120 s by regulating the type of iodine-containing contrast agent and the solvent ion strength.

[0045] 5. The introduction of the thiol-modified developing molecules of the present invention realizes the long-term development of the gel in vivo. The development value can be quantitatively controlled at 80-400Hu to adapt to the application requirements of different tissues. The degradation period of the gel in vivo can be adjusted from 1 week to 24 weeks. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 is the structural formula of maleimide-terminated multi-arm polyethylene glycol (Figure a is the structural formula of maleimide-terminated multi-arm polyethylene glycol connected by ester bonds; Figure b is the structural formula of maleimide-terminated multi-arm polyethylene glycol connected by amide bonds; wherein m is a positive integer from 2 to 10).

[0047] Figure 2 The molecular structure formula of multi-arm polyethylene glycol capped with maleimide connected by ester bonds or amide bonds (Figure a is the molecular structure formula of four-arm polyethylene glycol; Figure b is the molecular structure formula of eight-arm polyethylene glycol).

[0048] Figure 3 are the structural formulas of hydrophilic iodine-containing contrast agents modified with different thiol groups (in the structural formulas, R=H or COOH, n=1-4; Figure a is the structural formula of thiolated iopromide, Figure b is the structural formula of thiolated iopamidol, Figure c is the structural formula of thiolated ioforamol, Figure d is the structural formula of thiolated iohexol, Figure e is the structural formula of thiolated iobitrinol, and Figure f is the structural formula of thiolated iodixanol).

[0049] Figure 4 It is 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 is the thiolated iopromide oligomer, Figure b is the thiolated iopamidol oligomer, and Figure c is the thiolated iodineforsol oligomer.

[0050] Figure 5 The following are the appearance pictures of the double syringe, solution A and solution B samples.

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

[0052] Figure 7 Schematic diagram of the cross-linking of the developable hydrogel.

[0053] Figure 8 The results of gel development detection of thiolated iopromide oligomers and maleimide-terminated 8-arm polyethylene glycol (Figure a is the gel CT scan, and Figure b is the development value on the day of gel preparation and 10 days later).

[0054] Fig. 9 is the gelation time of different types of thiol developers and maleimide-terminated 8-arm polyethylene glycol.

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

[0056] Fig.11 Shown are the degradation curves of hydrogels in different treatment groups. DETAILED DESCRIPTION

[0057] The present invention is further described below in conjunction with the accompanying drawings and specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

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

[0059] 8-arm maleimide ester-terminated PEG was purchased from Xiamen Sinopang Biotechnology Co., Ltd. with the catalog number 06021801812.

[0060] 4-arm maleimide ester-terminated PEG was purchased from Xiamen Sinobond Biotechnology Co., Ltd. with the catalog number 06020701812.

[0061] 8-arm maleimide amide bond-terminated PEG was purchased from Xiamen Sinopang Biotechnology Co., Ltd. with the catalog number 06022001912.

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

[0063] Example 1

[0064] A hydrogel, the preparation method of which comprises 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 iopromide thiolate 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 as follows Figure 1 As shown, the specific structural formula of 8-arm maleimide ester bond-terminated PEG is as follows Figure 2 As shown in Figure b, the structural formula of thiopromide is as follows Figure 3 As shown in Figure a.

[0068] Example 2

[0069] A hydrogel, the preparation method of which comprises 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 thiolated iopamidol 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 8-arm maleimide ester-terminated PEG is as follows Figure 2 As shown in Figure b, the structural formula of thiolated iopamidol is as follows Figure 3 As shown in Figure b.

[0073] Example 3

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

[0075] S1. Dissolve 0.3 g of 4-arm maleimide amide-terminated PEG in 5 mL of PBS (pH=7.4) to obtain solution A, and dissolve 0.01 g of thiolated iodoversol 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 8-arm maleimide ester-terminated PEG is as follows Figure 2 As shown in Figure b, the structural formula of iodophor is as follows: Figure 3 As shown in Figure c.

[0078] Example 4

[0079] A hydrogel, the preparation method of which comprises 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 thiolated 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 8-arm maleimide ester-terminated PEG is as follows Figure 2 As shown in Figure b, the structural formula of thiolated iodine hexanol is as follows Figure 3 As shown in Figure d.

[0083] Example 5

[0084] A hydrogel, the preparation method of which comprises 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 thiolated iodine bis(hydryl) alcohol 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 8-arm maleimide ester-terminated PEG is as follows Figure 2 As shown in Figure b, the structure of iodine thiolate is as follows: Figure 3 As shown in Figure e.

[0088] Example 6

[0089] A hydrogel, the preparation method of which comprises 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. Dissolve 0.01 g of thiolated 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 8-arm maleimide ester-terminated PEG is as follows Figure 2As shown in Figure b, the structural formula of thiolated iodixanol is as follows Figure 3 As shown in the figure f.

[0093] Example 7

[0094] A hydrogel, the preparation method of which comprises 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 thiolated iopromide 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 8-arm maleimide ester-terminated PEG is as follows Figure 2 As shown in Figure b, the structure of the thiolated iopromide oligomer is as follows Figure 4 As shown in Figure a.

[0098] Example 8

[0099] A hydrogel, the preparation method of which comprises 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, and dissolve 0.048 g of thiolated iopromide 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 comprises 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 thiolated iopromide 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 comprises the following steps:

[0108] S1. Dissolve 0.15 g of 8-arm maleimide ester-terminated PEG in 5 mL PBS (pH=7.4) to obtain solution A, and dissolve 0.120 g of thiolated iopromide oligomer (m=5) in 5 mL 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] Embodiment 11

[0111] A hydrogel, the preparation method of which comprises 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, and dissolve 0.192 g of thiolated iopromide 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] After mixing through a double syringe, a gel is formed. The double syringe looks like Figure 5 The hydrogel was obtained by the preparation method of Example 1. Figure 6 As shown in Figure a.

[0116] Solution A (0.5 mL) and solution B (0.5 mL) in Example 1 were co-injected subcutaneously using a double syringe to form a gel. The CT image of the gel formed by subcutaneous injection is as follows: Figure 6 As shown in Figure b, it can be seen from the figure that the gel has a certain mechanical strength and three-dimensional supporting effect, and subcutaneous experiments and observations can effectively support a certain physical space distance.

[0117] Schematic diagram of cross-linking of developable hydrogels Figure 7 As shown, the thiol-modified iodine-containing contrast agent is chemically bonded into a three-dimensional molecular network, and its developing properties will be stable and lasting, matching the material degradation behavior.

[0118] Embodiment 13

[0119] Multi-arm polyethylene glycol terminated with different functional groups was reacted with dithiothreitol (DTT) and the reaction results were observed.

[0120] The following 4 treatment groups were set up:

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

[0122] 2. Acrylate group: Dissolve 8-arm acrylate ester-terminated PEG in PBS (pH=7.4) to obtain 0.1 g / mL solution A, and dissolve DTT in PBS (pH=7.4) to obtain 6.16×10 -3 g / mL solution B, take 1 mL of solution A and 1 mL of solution B and mix them at 37℃ for reaction.

[0123] 3. Vinyl sulfone group: Dissolve 8-arm vinyl sulfone ester-terminated PEG in PBS (pH=7.4) to obtain 0.1 g / mL solution A, and dissolve DTT in PBS (pH=7.4) to obtain 6.16×10 -3 g / mL solution B, take 1 mL of solution A and 1 mL of solution B and mix them at 37℃ for reaction.

[0124] 4. Allyl group: Dissolve 8-arm allyl ester-terminated PEG in PBS (pH=7.4) to obtain 0.1 g / mL solution A. Dissolve DTT in PBS (pH=7.4) to obtain 6.16×10 -3 g / mL solution B, take 1 mL of solution A and 1 mL of solution B and mix them at 37℃ for reaction.

[0125] The time of gelation of each group was recorded and counted from the time when solution A and solution B were mixed in each group, to the time when the gel was inverted and did not flow. The test results are shown in Table 1, which shows that only multi-arm polyethylene glycol terminated with maleimide and acrylate can form gel, and the gelation speed of maleimide group is significantly faster than that of acrylate group, and it only takes 5 seconds to gel successfully.

[0126] Table 1 Gel status of different treatment groups

[0127]

[0128] Embodiment 14

[0129] Accurately measure 100 mL of phosphate buffer solution (pH = 6.5) at 25°C and place it in a container. Gradually add an excess of m1 of thiolated iodinated contrast agent oligomer to the phosphate buffer solution (PBS) and stir or oscillate at a constant temperature 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 and calculate the solubility of the thiolated iodinated contrast agent oligomer.

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

[0131] The hydrophilicity test results of thiolated iodine-containing contrast agent oligomers with different numbers of monomer units are shown in Table 2. The results show that as the number of monomer units increases, the water solubility gradually decreases. The monomer units are 2-8, which have a suitable solubility window. Among them, for applications requiring high development values, it is appropriate to use oligomers with high monomer units (6 or 8); for applications requiring low development values, it is appropriate to use oligomers with low monomer units (2 or 4). Among the three thiolated iodine-containing contrast agent oligomers, the oligomers of thiolated iodine-containing contrast agents have the best hydrophilicity, followed by thiolated iopamidol oligomers, and finally thiolated iopromide oligomers.

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

[0133]

[0134] Embodiment 15

[0135] The iodine-containing contrast agents (iopromide, iopamidol, ioversol, iohexol, iobitrol, iodixanol) were modified with different numbers of thiol functional groups (2, 3, 4, 6, and 12 thiols were modified on the iodine-containing contrast agents, respectively). The water solubility of the thiol-containing contrast agent was determined by the method of Reference Example 7. The results are shown in Table 3. The results show that as the number of thiol functional groups increases, the water solubility of the thiol-containing contrast agent decreases significantly, and the water-insoluble thiol-modified iodine-containing contrast agent is not suitable for the injectable hydrogel of the present 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 gel prepared in Example 7-11 was 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 as follows: Figure 8The results of the development value determination on the day of hydrogel preparation and 10 days after preparation are shown in Figure a. Figure 8 As shown in Figure b, the results show that as the number of monomer units of the thiolated iopromide oligomer increases, the development value also increases, and has a certain positive proportional increase trend. The development value of the hydrogel changed little after 10 days of preparation, indicating that the iodine molecular unit is grafted onto the molecular network through chemical bonds, and the development function can be stably and continuously exerted. The development value is slightly reduced, which may be caused by scanning errors. The swelling of the gel itself causes a slight increase in volume and may also reduce the density of iodine to a certain extent, resulting in a slight decrease in the development value.

[0140] The development value of the hydrogel is positively correlated with the iodine content. In the past clinical applications and research, the concentration of the bulk material was increased to increase the number of reactive functional groups, so that the iodine content could be increased by grafting more iodine molecules. However, this approach will undoubtedly increase the amount of implanted materials in the body, which may bring potential risks. The present invention can conveniently adjust the point development value without changing the amount of active double bonds and thiol groups used in the body by regulating the number of monomer units of the thiolated iopromide oligomer, and the method is simpler and safer.

[0141] Embodiment 17

[0142] Different clinical applications have different requirements for gelation time. For open body cavities, hydrogels need to gel quickly after injection to prevent loss from the intended location. For applications injected into closed cavities, hydrogels with slightly longer gelation times can be selected to more completely fill irregular areas.

[0143] The gel time of the hydrogels of Example 1, Example 4, and Example 6 was measured. The starting point of the timing was the mixing of solution A and solution B, and the end point of the timing was the gel time when the gel was inverted and did not flow. The gel time of each group was recorded and counted. The gel time measurement results are shown in Table 1. Fig. 9 As shown, the results show that the gelation time of the hydrogel in which the solute of solution B is thiolated iopromide is 20s, the gelation time of the hydrogel in which the solute of solution B is thiolated iohexanol is 7s, and the gelation time of the hydrogel in which the solute of solution B is thiolated iodixanol is 4s. This indicates that the hydrogel of the present invention can obtain a gelation window with a certain range by adjusting different thiolated iodine-containing contrast agents.

[0144] Embodiment 18

[0145] 1. Solution preparation

[0146] 1. Prepare a sodium chloride solution with an ionic strength of 160 mM. The formula is as follows:

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

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

[0149] The 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 80 mM, 16 mM, 160 mM, 8 mM and 1.6 mM sodium chloride solutions.

[0150] 2. Preparation of Solution A and Solution B

[0151] Sodium chloride solutions with different ionic strengths were used as solvents (160 mM, 80 mM, 16 mM, 160 mM, 8 mM and 1.6 mM). 1.5×10 -6 mol / mL 8-arm maleimide-terminated PEG (average molecular weight 20,000) solution A and 6×10 -6 mol / mL solution B of iopromide thiolate.

[0152] 3. Preparation of hydrogel

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

[0154] 4. Determination of gelation time

[0155] The starting point of the timing was the mixing of solution A and solution B in each group, and the end point of the timing was the stoppage of the gel when it was inverted. The gelation time of each group was recorded and counted.

[0156] The results of the test are as follows Fig.10 As shown, the results show that as the ionic strength decreases, the gelation time tends to lengthen. The ionic strength is 8mM as the dividing point. When it is greater than 8mM, the gelation time is less than 32s, and when it is less than 8mM, the gelation time increases significantly. This result shows that the gel of the present invention can flexibly adjust the gelation time by regulating the ionic strength of the solution. Clinically, a solution with an ionic strength of less than 8mM can be preferably used for a closed cavity, and a solution with an ionic strength of greater than 8mM can be preferably used for an open cavity.

[0157] Embodiment 19

[0158] The duration of the developable hydrogel after implantation in vivo is closely related to its degradation behavior.

[0159] The following three treatment groups were set up:

[0160] 1. Ester-DTT group: 8-arm maleimide ester-terminated PEG (molecular weight: 20,000) was dissolved in PBS (pH = 7.4) to obtain 0.1 g / mL solution A, and DTT was dissolved in PBS (pH = 7.4) to obtain 6.16 × 10 -3 g / mL solution B, take 1 mL of solution A and 1 mL of solution B and mix them to form a gel.

[0161] 2. Ester-thiolated iodine hexol group: 0.15 g of 8-arm maleimide ester-terminated PEG (molecular weight: 20,000) was dissolved in 5 mL of PBS (pH = 7.4) to obtain solution A, 0.01 g of thiolated iodine hexol was dissolved in 5 mL of PBS (pH = 7.4) to obtain solution B, 1 mL of solution A and 1 mL of solution B were mixed to form a gel.

[0162] 3. Amide bond-thiolated iodine hexol: Dissolve 0.15 g of 8-arm maleimide amide bond-terminated PEG (molecular weight: 20,000) in 5 mL PBS (pH = 7.4) to obtain solution A. Dissolve 0.01 g of thiolated iodine hexol 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 in 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 weighed at set time points and degradation curves were drawn.

[0164] The degradation curves of hydrogels in different treatment groups are shown in Figure 2. Fig.11 As shown, the results show that the degradation stability of the hydrogels of the ester bond-thiolated iohexol group and the amide bond-thiolated iohexol group is significantly stronger than that of the ester bond-DTT group. It can be seen that the hydrogel prepared by the thiolated iodine-containing contrast agent of the present invention has a good clinical application prospect.

[0165] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A developable hydrogel composition, characterized in that: The invention comprises a first component and a second component; the first component is a maleimide-terminated multi-arm polyethylene glycol; the second component is a thiol-modified iodine-containing contrast agent; the molar ratio of the double bond in the first component to the thiol in the second component is (0.6-1.4):1; the iodine-containing contrast agent is any one of iopromide, iohexol and iodixanol; the number of thiol groups in the thiol-modified iodine-containing contrast agent is 2-4; and the invention also comprises a solvent for the first component and the second component, the ionic strength of the solvent being 1.6 to 160 mM.

2. The hydrogel composition according to claim 1, characterized in that: The second component is a thiol-modified oligomer of an iodine-containing contrast agent, and the number of monomers of the oligomer is 1-8.

3. The hydrogel composition according to claim 1, characterized in that: The number of arms of the maleimide-terminated multi-arm polyethylene glycol is 2-8; in the maleimide-terminated multi-arm polyethylene glycol, the maleimide group and the polyethylene glycol are covalently connected via an ester bond or an amide bond.

4. Use of the composition according to any one of claims 1 to 3 in preparing hydrogel.

5. A method for preparing a hydrogel, characterized in that: The following steps are involved: S1. The first component and the second component according to any one of claims 1-3 are dissolved in a solvent to obtain a solution A and a solution B; S2. Solution A and solution B are mixed to obtain a developable hydrogel.

6. The developable hydrogel obtained according to the preparation method of claim 5.

7. Use of the hydrogel composition according to any one of claims 1 to 3 or the developable hydrogel according to claim 6 in preparing products for radiotherapy isolation protection, tissue reference marking, medical sealing, tumor embolization, drug loading or tissue filling.

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