Thermosensitive gel polymer and preparation method thereof, tracer and embolic agent

Abstract

The present invention relates to the field of biomedicine technology, and in particular, to a thermosensitive gel polymer and a preparation method thereof, a tracer and an embolic agent. The fluorescently labeled thermosensitive gel polymer is obtained by polymerization reaction of fluorescent molecules and monomers forming thermosensitive gels, and the binding force between the fluorescent molecules and the thermosensitive gel polymer in the thermosensitive gel polymer is significantly improved, thereby preventing the fluorescent molecules from falling off during transportation, storage and use of the fluorescently labeled thermosensitive gel polymer, improving its stability, and then helping to monitor the metabolic process of the fluorescently labeled thermosensitive gel polymer and the drug using the fluorescently labeled thermosensitive gel polymer in the body.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to a thermosensitive gel polymer and a preparation method thereof, a tracer and an embolic agent. Background Art

[0002] Thermosensitive nanogel is a temperature-sensitive material that has good fluidity and is in a liquid state at room temperature. However, under the human body temperature environment, it changes from a good flow state to a non-flowable gel state. It can be seen that it has both good fluidity and embolic properties. As an embolic material, it can overcome the contradiction between the fluidity and embolic properties of traditional embolic agents. At the same time, it also has drug-loaded sustained-release properties. Therefore, thermosensitive nanogel is expected to become a new generation of injectable interventional embolic materials.

[0003] For injectable interventional embolic materials, their systemic metabolic distribution in vivo is the basis of their toxicological research. Fluorescently labeling thermosensitive nanogels to study their concentration in the blood at different administration times is an effective way to study the metabolic distribution of such embolic materials.

[0004] At present, the method of fluorescent labeling thermosensitive nanogels is mainly to combine fluorescent molecules with thermosensitive nanogels by physical or chemical methods, that is, first synthesizing thermosensitive gel polymers, and then the thermosensitive gel polymers react with fluorescent molecules to form thermosensitive gels with fluorescent properties. However, in the thermosensitive gels with fluorescent properties formed in this way, the interaction between the fluorescent molecules and the thermosensitive gel polymers is weak and easy to fall off, which leads to a decrease in its fluorescent properties or insufficient fluorescence intensity.

[0005] In view of this, the present invention is proposed. Summary of the invention

[0006] The purpose of the present invention is to provide a thermosensitive gel polymer and a preparation method thereof, a tracer and an embolic agent. The embodiment of the present invention provides a new thermosensitive gel polymer, whose fluorescent molecules are strongly bound to the thermosensitive gel and are not easy to fall off. The thermosensitive gel polymer has a strong fluorescence intensity during transportation, storage and use, which is helpful to monitor the metabolic process of drugs in the body.

[0007] The present invention is achieved in that:

[0008] In a first aspect, the present invention provides a fluorescently labeled thermosensitive gel polymer, which is obtained by polymerization reaction of fluorescent molecules and monomers that form thermosensitive gel, wherein the fluorescent molecules meet the following five requirements: (1) having carbon-carbon unsaturated double bonds; (2) having a solid solubility greater than 0.1 g at 20°C; (3) having characteristic fluorescence in the ultraviolet-visible-near infrared region; (4) not failing or denaturing at temperatures above 50°C; and (5) not affecting the preparation process and performance of the thermosensitive gel, and the formed fluorescently labeled thermosensitive gel polymer can generate emission light intensity.

[0009] In an optional embodiment, the fluorescent molecule includes indocyanine green and its analogs;

[0010] Preferably, the fluorescent molecule is selected from any one of the compounds represented by the following structural formulas:

[0011]

[0012] In an optional embodiment, the temperature-sensitive gel comprises a poly (N-isopropylacrylamide) temperature-sensitive gel.

[0013] In an optional embodiment, the monomer forming the thermosensitive gel includes N-isopropylacrylamide;

[0014] Preferably, the monomers forming the thermosensitive gel further include acrylic compounds and methacrylic compounds;

[0015] Preferably, the monomers forming the thermosensitive gel further include acrylic acid, acrylic acid ester, methacrylic acid and methacrylic acid ester;

[0016] Preferably, the monomers forming the thermosensitive gel further include any one of acrylic acid, methyl acrylate, ethyl acrylate, methacrylic acid, butyl methacrylate, methyl methacrylate, ethyl methacrylate, lauryl methacrylate, octadecyl methacrylate, allyl methacrylate and benzyl methacrylate.

[0017] In an optional embodiment, the amount of the fluorescent molecule used is 0.2-1.0% of the mass of the monomers forming the thermosensitive gel.

[0018] In a second aspect, the present invention provides a method for preparing the fluorescently labeled thermosensitive gel polymer described in the aforementioned embodiment, comprising mixing fluorescent molecules and monomers forming thermosensitive gel to carry out polymerization reaction.

[0019] In an optional embodiment, the preparation process of forming the fluorescently labeled thermosensitive gel polymer is carried out in the dark;

[0020] Preferably, the amount of the fluorescent molecule is 0.2-1.0% of the mass of the monomers forming the thermosensitive gel.

[0021] In a third aspect, the present invention provides a gel labeling method, comprising: mixing fluorescent molecules and monomers for forming a thermosensitive gel to carry out a polymerization reaction, wherein the fluorescent molecules meet the following five requirements: (1) having a carbon-carbon unsaturated double bond; (2) having a solid solubility greater than 0.1 g at 20°C; (3) having characteristic fluorescence in the ultraviolet-visible-near infrared region; (4) not failing or denaturing at temperatures above 50°C; and (5) not affecting the preparation process and performance of the thermosensitive gel, and the fluorescently labeled thermosensitive gel polymer formed can generate an emission light intensity.

[0022] In a fourth aspect, the present invention provides a tracer, which includes the fluorescently labeled thermosensitive gel polymer described in the aforementioned embodiment.

[0023] In a fifth aspect, the present invention provides an embolic agent, which includes the fluorescently labeled thermosensitive gel polymer described in the aforementioned embodiment.

[0024] The present invention has the following beneficial effects: in the embodiments of the present invention, fluorescent molecules are involved as reaction monomers in the reaction of thermosensitive gel polymers, so that the binding force between the fluorescent molecules and the thermosensitive gel polymers is significantly improved, thereby preventing the fluorescent molecules from falling off during the transportation, storage and use of the fluorescently labeled thermosensitive gel polymers, thereby improving their stability, and then helping to monitor the metabolic process of drugs using the fluorescently labeled thermosensitive gel polymers in the body. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.

[0026] Figure 1 The result diagram provided for the detection example 1 of the present invention;

[0027] Figure 2 The result diagram provided for the detection example 2 of the present invention;

[0028] Figure 3 The result diagram provided for the detection example 3 of the present invention;

[0029] Figure 4-Figure 5 This is a result diagram provided for detection example 5 of the present invention. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0031] In the prior art, in order to study the metabolism of thermosensitive nanogels or drugs loaded as carriers in the body, they are often fluorescently labeled. However, the fluorescent labeling method is: first synthesizing thermosensitive gel polymers, and then the thermosensitive gel polymers react with fluorescent molecules to form thermosensitive gels with fluorescent properties. The fluorescent molecules in the thermosensitive gel obtained by this labeling method have low binding force and are easy to fall off, which leads to reduced fluorescence performance or insufficient fluorescence intensity.

[0032] The best way to solve the above problems is to allow fluorescent molecules to participate in the polymerization process of thermosensitive gel polymers. However, there are several problems that are extremely difficult to solve when fluorescent molecules participate in the polymerization reaction: (1) The polymerization reaction of thermosensitive nanogels is carried out in the aqueous phase. Can the fluorescent molecules be dissolved and can they participate in the reaction? (2) The polymerization reaction of thermosensitive nanogels is a random copolymerization of "carbon-carbon" unsaturated double bonds. So what kind of reactive groups can the fluorescent molecules have to participate in the reaction, and can the properties of the fluorescent molecules and the properties of the thermosensitive gel still be preserved after the fluorescent molecules participate in the reaction? (3) The polymerization reaction of the thermosensitive gel needs to last for several hours at a temperature not lower than 50°C. So can the fluorescent molecules remain denatured at the reaction temperature and still maintain their fluorescent properties?

[0033] The embodiment of the present invention provides a fluorescent molecule that meets the above requirements, can undergo polymerization reaction with the monomers that form the thermosensitive gel, does not affect the preparation process and performance of the thermosensitive gel, and the formed fluorescently labeled thermosensitive gel polymer can generate emission light intensity. In addition, the fluorescent molecule can be significantly improved in the thermosensitive gel polymer formed by the fluorescent molecule as a reactive monomer, so as to avoid the fluorescent molecule from falling off during the transportation, storage and use of the fluorescently labeled thermosensitive gel polymer, thereby improving its stability, and then helping to monitor the metabolic process of the drug using the fluorescently labeled thermosensitive gel polymer in the body.

[0034] Specifically, the present invention provides a fluorescently labeled thermosensitive gel polymer, which is obtained by polymerization reaction of fluorescent molecules and monomers forming thermosensitive gel, wherein the fluorescent molecules meet the following five requirements: (1) having carbon-carbon unsaturated double bonds; (2) having a solid solubility greater than 0.1 g at 20°C; (3) having characteristic fluorescence in the ultraviolet-visible-near infrared region; (4) not failing or denaturing at temperatures above 50°C; and (5) not affecting the preparation process and performance of the thermosensitive gel, and the formed fluorescently labeled thermosensitive gel polymer can generate emission light intensity.

[0035] The inventors discovered that the fluorescent molecule has a specific functional group, namely a carbon-carbon unsaturated double bond, which enables the fluorescent molecule to participate in the random copolymerization of the "carbon-carbon" unsaturated double bonds of the monomer. If a fluorescent molecule that does not contain a carbon-carbon unsaturated double bond is used, it needs to be modified so that it has a "carbon-carbon" unsaturated double bond before it can participate in the polymerization reaction, which makes the preparation method more complicated and may destroy the fluorescent properties of the fluorescent molecule.

[0036] Among them, the fluorescent molecule can specifically be selected from indocyanine green and its analogs, for example,

[0037]

[0038] (available from Xi'an Kaixin Biotechnology Co., Ltd., number IR-808). It should be noted that the indocyanine green and its analogs shown in the above structural formula are merely examples of embodiments of the present invention, and other indocyanine green analogs may also be used, such as Sulfo-Cyanine 7.5, Cyanine 7.5 and Sulfo-Cyanine 7.5 NHS lactone.

[0039] Furthermore, the thermosensitive gel comprises a poly-N-isopropylacrylamide thermosensitive gel polymer, that is, the thermosensitive gel polymer without fluorescence labeling comprises a poly-N-isopropylacrylamide thermosensitive gel polymer. That is, the thermosensitive gel refers to a thermosensitive gel polymer without fluorescence labeling.

[0040] Specifically, the monomers forming the thermosensitive gel include N-isopropylacrylamide; they may also include acrylic compounds and methacrylic compounds, which may be selected from acrylic acid, acrylate, methacrylic acid and methacrylate; for example, any one of acrylic acid, methyl acrylate, ethyl acrylate, methacrylic acid, butyl methacrylate, methyl methacrylate, ethyl methacrylate, lauryl methacrylate, octadecyl methacrylate, allyl methacrylate and benzyl methacrylate.

[0041] It should be noted that: (1) the above-mentioned acrylic acid, acrylic acid ester, methacrylic acid and methacrylic acid ester are only examples, and other acrylic acid esters or methacrylic acid esters may also be used.

[0042] (2) The above-mentioned acrylic acid compounds and methacrylic acid compounds are merely examples of monomers that can be selected to form poly (N-isopropylacrylamide) thermosensitive gel polymers. Other types of monomers that can be used to form poly (N-isopropylacrylamide) thermosensitive gel polymers in the prior art can also be selected.

[0043] Further, the amount of the fluorescent molecule is 0.2-1.0% of the mass of the monomers forming the thermosensitive gel, such as 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% and 1.0%, etc., any value between 0.2-1.0% or a range value between any two values. The use of the above-mentioned amount of fluorescent molecules can ensure the smooth progress of the reaction and the performance of the fluorescently labeled thermosensitive gel polymer formed. If the amount of fluorescent molecules is too low, it may result in insufficient fluorescence intensity of the fluorescently labeled thermosensitive gel polymer. If the amount of fluorescent molecular weight is too large, it may affect the nanogel performance of the fluorescently labeled thermosensitive gel polymer, and may also cause self-quenching of the fluorescent substance, thereby resulting in insufficient fluorescence intensity.

[0044] In summary, the fluorescently labeled thermosensitive gel polymer provided in the embodiments of the present invention has high chemical stability, the fluorescently labeled thermosensitive gel polymer has the original physical and chemical properties of the thermosensitive gel, such as gelation temperature, particle size distribution, viscosity and embolic strength, and the fluorescently labeled thermosensitive gel polymer has a low minimum effective detection limit, which is conducive to exploring the systemic metabolism of the thermosensitive nanogel vascular embolic agent in the treatment of complete liver cancer.

[0045] Furthermore, an embodiment of the present invention also provides a method for preparing the above-mentioned fluorescently labeled thermosensitive gel polymer, comprising mixing fluorescent molecules and monomers for forming thermosensitive gel to carry out polymerization reaction.

[0046] Specifically, the fluorescent molecule is polymerized with N-isopropylacrylamide and at least one of an acrylic compound and a methacrylic compound or other types of monomers that form a poly-N-isopropylacrylamide-based thermosensitive gel polymer.

[0047] It should be noted that the conditions and method for the above-mentioned polymerization to form a fluorescently labeled thermosensitive gel polymer are basically the same as the conditions and method for polymerization to form an unlabeled thermosensitive gel polymer in the prior art, except that the fluorescent molecules are added as reaction monomers to the polymerization reaction, and the specific contents will not be described in detail in the embodiments of the present invention.

[0048] After the polymerization reaction is completed, conventionally known post-treatments such as dialysis, purification and freeze-drying are required.

[0049] Furthermore, the preparation process of the fluorescently labeled thermosensitive gel polymer is carried out in the dark. Since fluorescent molecules are generally photosensitivity and gradually lose effectiveness under light conditions, the preparation process is carried out in the dark.

[0050] The amount of fluorescent molecules used is 0.2-1.0% of the mass of the monomers forming the thermosensitive gel, such as 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% and 1.0%, etc., any value between 0.2-1.0% or a range between any two values.

[0051] The present invention provides a gel labeling method, comprising: mixing fluorescent molecules and monomers for forming a thermosensitive gel to carry out a polymerization reaction, wherein the fluorescent molecules meet the following five requirements: (1) having a carbon-carbon unsaturated double bond; (2) having a solid solubility greater than 0.1 g at 20° C.; (3) having characteristic fluorescence in the ultraviolet-visible-near infrared region; (4) not becoming ineffective and denatured at temperatures above 50° C.; and (5) not affecting the preparation process and performance of the thermosensitive gel, and the formed fluorescently labeled thermosensitive gel polymer can generate an emission light intensity.

[0052] The present invention provides a tracer, which comprises the fluorescently labeled thermosensitive gel polymer described in the above embodiments.

[0053] The present invention provides an embolic agent, which comprises the fluorescently labeled thermosensitive gel polymer described in the above embodiment.

[0054] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0055] Example 1

[0056] The embodiment of the present invention provides a method for preparing a fluorescently labeled thermosensitive gel polymer, comprising:

[0057] 2.2632g N-isopropylacrylamide, 0.0108g indocyanine green, 0.032g sodium dodecyl sulfate and 0.0324g N,N'-methylenebisacrylamide were added to a three-necked flask equipped with a reflux condenser and a gas guide, and dissolved with ultrapure water under magnetic stirring, and then high-purity nitrogen was introduced into the above reaction system for 30 minutes, and the reaction system was heated to 65°C, and 0.0952g potassium persulfate was added, and the reaction was continued for 1 hour at 75°C in a N2 atmosphere, and 0.168mL butyl methacrylate was added to continue the reaction for 4 hours, and the reaction solution was dialyzed and purified in ultrapure water and then freeze-dried, and the freeze-dried powder was the target product. The above reaction, purification, and freeze-drying processes must be carried out in the dark.

[0058] Example 2

[0059] The embodiment of the present invention provides a method for preparing a fluorescently labeled thermosensitive gel polymer, comprising:

[0060] 2.2632g N-isopropylacrylamide, 0.0054g indocyanine green, 0.032g sodium dodecyl sulfate and 0.0324g N, N'-methylenebisacrylamide were added to a three-necked bottle equipped with a reflux condenser and a gas guide, and dissolved with ultrapure water under magnetic stirring, and then high-purity nitrogen was introduced into the above reaction system for 45 minutes, and the reaction system was heated to 80°C, 0.0952g potassium persulfate was added, and the reaction was carried out at 85°C in a N2 atmosphere for 30 minutes, and then 0.455mL acrylic acid was added to continue the reaction for 5 hours, and the reaction solution was dialyzed and purified in ultrapure water and then freeze-dried, and the freeze-dried powder was the target product. The above reaction, purification, and freeze-drying processes must be carried out in the dark.

[0061] Example 3

[0062] The embodiment of the present invention provides a method for preparing a fluorescently labeled thermosensitive gel polymer, comprising:

[0063] 2.2632g N-isopropylacrylamide, 0.027g indocyanine green, 0.032g sodium dodecyl sulfate and 0.0324g N, N'-methylenebisacrylamide were added to a three-necked flask equipped with a reflux condenser and a gas guide, and dissolved with ultrapure water under magnetic stirring, and then high-purity nitrogen was introduced into the above reaction system for 30 minutes, and the reaction system was heated to 70°C, 0.0952g potassium persulfate was added, and the reaction was continued for 20 minutes at 75°C in a N2 atmosphere, and 0.326mL methyl acrylate was added to continue the reaction for 4.5 hours, and the reaction solution was dialyzed and purified in ultrapure water and then freeze-dried, and the freeze-dried powder was the target product. The above reaction, purification, and freeze-drying processes must be carried out in the dark.

[0064] Example 4

[0065] The embodiment of the present invention provides a method for preparing a fluorescently labeled thermosensitive gel polymer, comprising:

[0066] 2.2632g N-isopropylacrylamide, 0.0135g neoindocyanine green, 0.032g sodium dodecyl sulfate and 0.0324g N,N'-methylenebisacrylamide were added to a three-necked flask equipped with a reflux condenser and a gas guide, and dissolved with ultrapure water under magnetic stirring, and then high-purity nitrogen was introduced into the above reaction system for 30 minutes, and the reaction system was heated to 73°C, and 0.0952g potassium persulfate was added, and the reaction was continued for 30 minutes at 75°C in a N2 atmosphere, and 0.208mL methacrylic acid was added to continue the reaction for 4 hours, and the reaction solution was dialyzed and purified in ultrapure water and then freeze-dried, and the freeze-dried powder was the target product. The above reaction, purification, and freeze-drying processes must be carried out in the dark.

[0067] Comparative Example 1: In this comparative example, poly(NIP-co-BMA) not labeled with indocyanine green was synthesized by referring to the method of Example 1. The difference between the synthesis method and that of Example 1 is that indocyanine green was not added in the polymerization reaction. The synthesized product is regarded as the thermosensitive nanogel before labeling.

[0068] Comparative Example 2: In this comparative example, acrylrhodamine B labeled indocyanine green labeled p(NIP-co-BMA) was synthesized by referring to the method of Example 1. The difference between its synthesis method and that of Example 1 is that the fluorescent molecule indocyanine green is replaced by acrylrhodamine B.

[0069] Comparative Example 3: In this comparative example, rhodamine B-labeled indocyanine green-labeled p(NIP-co-BMA) was synthesized by referring to the method of Example 1. The difference between its synthesis method and that of Example 1 is that the fluorescent molecule indocyanine green is replaced by rhodamine B.

[0070] Test Example 1

[0071] The thermosensitive nanogels obtained in Example 1 and Comparative Example 1 were subjected to infrared detection. The detection results are shown in Figure 1 .

[0072] Figure 1 Where PIB represents the thermosensitive nanogel obtained in Comparative Example 1, and PIB-ICG represents the thermosensitive gel polymer prepared in Example 1. Figure 1 It can be seen that due to the low feed ratio of the fluorescent substance, its characteristic absorption peak is completely covered by the absorption peak of the gel. At the same time, the experimental phenomena / data of the following detection examples can indirectly confirm that the fluorescent substance participates in the polymerization reaction rather than a simple physical mixture.

[0073] Test Example 2

[0074] The thermosensitive nanogels obtained in Example 1 and Comparative Example 1 (i.e., the thermosensitive gels before and after fluorescent labeling) were tested for their particle size, PDI, viscosity, complex shear modulus, gelation temperature, and macroscopic state. Figure 2 and Table 1.

[0075] Table 1 Performance indicators of thermosensitive nanogels before and after fluorescence labeling

[0076] Performance Indicators Comparative Example 1 Example 1 25℃ Particle size (nm) 273 274 25℃, PDI 0.158 0.204 37℃ Particle size (nm) 154 152 37℃, PDI 0.177 0.216 25℃ viscosity (mPas) 30.17 32.80 Gelation temperature (℃) 33.0 32.81 37℃ Complex shear modulus (Pa) 107 119

[0077] According to the above results, the use of fluorescent labeling does not affect the original physical and chemical properties of the thermosensitive gel, such as gelation temperature, particle size distribution, viscosity and embolic strength, but only makes it have fluorescent properties. This shows that the fluorescently labeled thermosensitive gel polymer has the properties of the original thermosensitive gel and fluorescent properties, which can be used to explore the systemic metabolism of thermosensitive nanogel vascular embolic agents in the treatment of complete liver cancer.

[0078] Test Example 3

[0079] The fluorescently labeled thermosensitive gel polymer prepared in Example 1 was diluted by multiples, and the linear relationship between its concentration and fluorescence intensity was detected within the concentration range of 0.50-1000 mg / L under the conditions of Em=550 nm and Ex=830 nm.

[0080] Results Figure 3 ,according to Figure 3 It can be seen that the concentration of the fluorescently labeled thermosensitive gel polymer has a good linear relationship with the fluorescence intensity in the range of 0.5 to 750 mg / L. When the concentration exceeds the upper limit, the fluorescent molecules will be self-quenched. At the same time, after the polymerization reaction, the reaction solution was dialyzed, purified, freeze-dried, and re-dissolved, and the fluorescence intensity did not change significantly, indicating that the fluorescent substance was not lost; indicating that the fluorescent molecules participated in the polymerization reaction, rather than a simple physical mixture.

[0081] Test Example 4

[0082] The fluorescently labeled thermosensitive gel polymer prepared in Example 1 was eluted with physiological saline at a constant temperature of 37°C, and the eluate was collected at different time periods. The elution instrument was a four-channel peristaltic pump, and the mobile phase injection rate was 0.5 ml / min. Then, under the conditions of Em=550nm, Ex=830nm, the fluorescence intensity of the eluate collected at different time points was detected, and the results are shown in Table 2.

[0083] Table 2 Elution results

[0084]

[0085] According to the above results, no fluorescent substances were detected in the eluent, which proves that no fluorescent substances were eluted out of the gel network during the experiment. It also shows that the fluorescent molecules participated in the polymerization reaction, rather than a simple physical mixture.

[0086] Test Example 5

[0087] 200 μl of the fluorescently labeled thermosensitive gel polymer of Example 1 or Comparative Example 2 was injected into the tail vein of different mice for 1 hour, and then infrared in vivo imaging detection was performed. Figure 4 and Figure 5 ,in Figure 4 This is an infrared image of the fluorescently labeled thermosensitive gel polymer of Example 1. Figure 5 This is the fluorescently labeled thermosensitive gel polymer of Comparative Example 2.

[0088] according to Figure 4 and Figure 5It can be seen that the fluorescence intensity of the thermosensitive gel labeled with acrylrhodamine B is insufficient, and it cannot penetrate the body surface from the blood or organs, and cannot achieve active tracing. However, the fluorescence intensity of the thermosensitive gel provided in the embodiment of the present invention is sufficient to achieve in vivo imaging, and can then be used to explore the systemic metabolism of the thermosensitive nanogel vascular embolic agent in the treatment of liver cancer.

[0089] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A fluorescently labeled thermosensitive gel polymer, characterized in that: It is obtained by polymerization reaction between fluorescent molecules and monomers that form thermosensitive gels, wherein: The fluorescent molecule is selected from any one of the compounds represented by the following structural formulas: , and The amount of the fluorescent molecule used is 0.2-1.0% of the mass of the monomer forming the thermosensitive gel.

2. The fluorescently labeled thermosensitive gel polymer according to claim 1, characterized in that: The temperature-sensitive gel includes poly-N-isopropylacrylamide temperature-sensitive gel.

3. The fluorescently labeled thermosensitive gel polymer according to claim 1, characterized in that: The monomer forming the thermosensitive gel includes N-isopropylacrylamide.

4. The fluorescently labeled thermosensitive gel polymer according to claim 3, characterized in that: The monomers forming the thermosensitive gel further include acrylic compounds and methacrylic compounds.

5. The fluorescently labeled thermosensitive gel polymer according to claim 3, characterized in that: The monomers forming the thermosensitive gel also include acrylic acid, acrylic acid ester, methacrylic acid and methacrylic acid ester.

6. The fluorescently labeled thermosensitive gel polymer according to claim 3, characterized in that: The monomers forming the thermosensitive gel further include any one of acrylic acid, methyl acrylate, ethyl acrylate, methacrylic acid, butyl methacrylate, methyl methacrylate, ethyl methacrylate, lauryl methacrylate, octadecyl methacrylate, allyl methacrylate and benzyl methacrylate.

7. A method for preparing the fluorescently labeled thermosensitive gel polymer according to claim 1, characterized in that: The method comprises mixing fluorescent molecules and monomers for forming a thermosensitive gel and performing a polymerization reaction.

8. The preparation method according to claim 7, characterized in that: The preparation process of forming the fluorescently labeled thermosensitive gel polymer is carried out in the dark.

9. A gel labeling method, characterized in that: include: The method comprises mixing fluorescent molecules and monomers for forming thermosensitive gel to carry out polymerization reaction to form the fluorescently labeled thermosensitive gel polymer according to claim 1.

10. A tracer, characterized in that: The invention comprises the fluorescently labeled thermosensitive gel polymer according to claim 1.

11. An embolic agent, characterized in that: The invention comprises the fluorescently labeled thermosensitive gel polymer according to claim 1.

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