Photosensitive material with vascular repair function, preparation method thereof and balloon dilatation catheter

Abstract

The invention relates to the technical field of medical materials, and discloses a photosensitive material with a vascular repair function, a preparation method of the photosensitive material and a balloon dilatation catheter. A chemical structural formula of the photosensitive material comprises a first functional group and a second functional group, the first functional group has a function of triggering amino acid in a blood vessel wall to be crosslinked under light excitation, and the second functional group has a function of inhibiting cell proliferation. The photosensitive material provided by the invention has good fat solubility, can accurately anchor a diseased region, exerts a vascular repair function, also can exert an anti-cell proliferation effect together, and further reduces the risk of intravascular restenosis.

Description

Technical Field

[0001] The present application relates to the technical field of medical materials, and in particular to a photosensitive material with a vascular repair function, a preparation method thereof, and a balloon dilatation catheter. Background Art

[0002] At present, the most commonly used treatment for cardiovascular diseases is percutaneous transluminal angioplasty, which requires the use of an interventional treatment device, namely a drug-eluting balloon, which carries antiproliferative drugs (such as paclitaxel, rapamycin, etc.) on the balloon, and brings the antiproliferative drugs to the blood vessel wall through angioplasty and releases them evenly, inhibiting the proliferation of endothelial cells, smooth muscle cells and fibroblasts, and reducing the restenosis of blood vessels after balloon dilation. However, clinical evidence shows that for severely narrowed blood vessels, the blood vessels may still rebound after the balloon is withdrawn, further forming severe stenosis or occlusion. In this case, although the drug-eluting balloon releases the drug, it cannot effectively solve the problem of vascular occlusion.

[0003] To solve the above problems, related technologies propose to implant natural vascular stents in blood vessels. This technology is to coat the balloon with photosensitive materials such as 1,8-naphthalimide. After the balloon is expanded, the photosensitive materials are released to the inner wall of the blood vessel. After being activated by light of a specific wavelength (such as 450nm), covalent cross-linking between amino acids in the blood vessel wall can be induced, which supports the blood vessels. On the one hand, this can prevent blood vessel retraction, and on the other hand, it can prevent the body from producing a proliferative reaction due to the use of metal stents, causing restenosis in the vascular stent. Unfortunately, this type of photosensitive material developed by existing technologies cannot accurately reach the lesion site, affecting the final treatment effect. Summary of the invention

[0004] In view of this, the present application provides a photosensitive material with vascular repair function and a preparation method thereof, which can accurately anchor the lesion site and reduce the risk of restenosis in the blood vessel, thereby effectively solving the problem of vascular stenosis and occlusion.

[0005] According to an embodiment of the present application, in a first aspect, a photosensitive material having a vascular repair function is provided, wherein the chemical structure thereof includes a first functional group and a second functional group; The first functional group has the function of inducing cross-linking of amino acids in the blood vessel wall under light excitation; The second functional group has the function of inhibiting cell proliferation.

[0006] In some optional embodiments, the first functional group includes a 1,8-naphthalene imide skeleton and a substituent located on the carbon 4 of the 1,8-naphthalene imide skeleton.

[0007] In some optional embodiments, the second functional group can be, for example, a cell proliferation inhibitor (with R 3 -OH represents), that is, the second functional group is a dehydrogenated group of a cell proliferation inhibitor that can provide a reactive hydroxyl group, denoted as -OR 3 .

[0008] In some optional embodiments, the chemical structure of the photosensitive material further includes a bridging structure, one end of the bridging structure is connected to the first functional group, and the other end is connected to the second functional group; The bridging structure is , m is an integer selected from 2 to 7, R 1 and R 2 Each is independently selected from hydrogen, halogen or C1-C10 alkyl.

[0009] Furthermore, the halogen is selected from any one of fluorine, chlorine, bromine and iodine.

[0010] Furthermore, the C1-C10 alkyl group includes any one of a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.

[0011] In some optional embodiments, the cell proliferation inhibitor includes any one of paclitaxel, docetaxel, cabazitaxel, vinorelbine, camptothecin, hydroxycamptothecin, rapamycin, tacrolimus, doxorubicin, epirubicin, pirarubicin, idarubicin, mitoxantrone, cytarabine, gemcitabine, and dexamethasone.

[0012] In some optional embodiments, the first functional group is connected to the bridging structure via the terminal amino group of the substituent.

[0013] In some optional embodiments, the chemical structure of the photosensitive material is as shown in Formula I, wherein n is an integer of 1-6, m is an integer selected from 2-7, and R 1 and R 2 Each is independently selected from hydrogen, halogen or C1-C10 alkyl.

[0014]

[0015] Formula I.

[0016] Furthermore, the C1-C10 alkyl group includes any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; the halogen is selected from any one of fluorine, chlorine, bromine and iodine; m can be 2, 3, 4, 5, 6 or 7; and n can be 1, 2, 3, 4, 5 or 6.

[0017] In some optional embodiments, the chemical structure of the photosensitive material is as shown in Formula I-1 or Formula I-2:

[0018] Formula I-1

[0019] Formula I-2.

[0020] It is understood that in Formula I-1 and Formula I-2, R 1 , R 2 The meanings of m and n are the same as those in Formula I and are not repeated here.

[0021] In some optional embodiments, the chemical structure of the photosensitive material is as shown in Formula I-1a or Formula I-2a:

[0022] Formula I-1a

[0023] Formula I-2a.

[0024] According to an embodiment of the present application, in a second aspect, a method for preparing the photosensitive material according to the first aspect is provided, comprising the following steps: S1, subjecting the cell proliferation inhibitor to a first condensation reaction with a substituted or unsubstituted cyclic anhydride to obtain an intermediate; The chemical structure of the substituted or unsubstituted cyclic anhydride is shown in Formula II, wherein m is selected from an integer of 2-7, and R 1 and R 2 Each is independently selected from hydrogen, halogen or C1-C10 alkyl;

[0025] Formula II S2, allowing the intermediate to undergo a second condensation reaction with a 4-substituted 1,8-naphthaleneimide compound to obtain.

[0026] In some optional embodiments, the chemical structure of the 4-substituted 1,8-naphthalene imide compound is as shown in Formula III, wherein n is an integer of 1-6;

[0027] Formula III.

[0028] According to the embodiments of the present application, in a third aspect, the present application provides the use of the photosensitive material with vascular repair function described in the first aspect or the photosensitive material prepared by the method described in the second aspect in the preparation of a drug for treating vascular stenosis or occlusion.

[0029] According to an embodiment of the present application, in a fourth aspect, the present application also provides a balloon dilatation catheter, comprising a balloon body; the surface of the balloon body has a coating, and the coating comprises the photosensitive material with vascular repair function described in the first aspect or the photosensitive material prepared by the method described in the second aspect.

[0030] The technical solution of this application has the following advantages: The photosensitive material with vascular repair function provided by the present application is chemically spliced ​​with a first functional group that can induce amino acid cross-linking in the blood vessel wall and a second functional group that has the effect of inhibiting cell proliferation, so that the photosensitive material of the present application has both photo-cross-linking properties and anti-cell proliferation properties. Under the activation of light of a specific wavelength, the photosensitive material of the present application can induce covalent cross-linking between amino acids in the blood vessel wall, thereby forming a natural and stable invisible stent to stably support the blood vessel. Compared with a metal stent, this natural stent is not a foreign body in the blood vessel, so the problem of restenosis within the stent will not occur.

[0031] At the same time, since the second functional group that inhibits cell proliferation also has good fat solubility, by introducing the second functional group into the photosensitive compound (i.e., the substance that provides the first functional group), the hydrophobicity of the photosensitive material of the present application can be improved, and the photosensitive material can be prevented from being washed away by blood after entering the blood vessel, so that the photosensitive material of the present application can accurately anchor the lesion site, thereby better exerting the vascular repair function, and effectively solving the problem of vascular stenosis and occlusion. In addition, the second functional group can also play an anti-cell proliferation role, further reducing the risk of restenosis in the blood vessel.

[0032] Additional aspects and advantages of the embodiments of the present application will be described and shown in part in the subsequent description, or explained through the implementation of the embodiments of the present application. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0034] Figure 1 This is a contact angle test diagram of the balloon in Example 3 of the present application; Figure 2 This is a contact angle test diagram of the balloon in Example 4 of the present application; Figure 3 This is a contact angle test diagram of the balloon in Comparative Example 1 of the present application; Figure 4 This is a contact angle test diagram of the balloon in Comparative Example 2 of the present application; Figure 5 This is a contact angle test diagram of the balloon in Comparative Example 4 of the present application; Figure 6 It is a diagram showing the anti-proliferative effects of the paclitaxel photosensitizer prepared in Example 1 of the present application and the rapamycin photosensitizer prepared in Example 2, as well as paclitaxel and rapamycin. DETAILED DESCRIPTION

[0035] The following examples are provided for a better understanding of the present application, but are not limited to the best implementation mode described, and do not limit the content and protection scope of the present application. Any product identical or similar to the present application obtained by anyone under the inspiration of the present application or by combining the features of the present application with other prior arts shall fall within the protection scope of the present application.

[0036] It should be noted that the terms "first" and "second" are used for descriptive purposes only and cannot be understood as indicating or implying relative importance. In addition, the technical features involved in the different embodiments of the present application described below can be combined with each other as long as they do not conflict with each other.

[0037] Related art discloses a photosensitive material with vascular repair function, which uses polypeptide dendrimers to improve the distribution of photosensitive compounds, thereby increasing the permeability of photosensitive compounds in the blood vessel wall. However, the photosensitive material molecules synthesized in this way contain a large number of amino groups, showing strong hydrophilicity, making the molecules easily washed away by blood when used in blood vessels, which is not conducive to the precise reaction between the material and the blood vessel wall.

[0038] In this regard, another technology proposes to hydrophobically regulate the molecular structure of the photosensitive material to form a repair material shown in Formula 2, which can prevent the material from being washed away by blood during intravascular delivery. The material with the structure shown in Formula 2 was used in a balloon dilatation catheter for vascular repair experiments, but the experimental results were still not ideal.

[0039]

[0040] Formula 2 In order to solve the above problems existing in the prior art, according to the first aspect of the present application, a photosensitive material having a vascular repair function is provided, wherein the chemical structure thereof includes a first functional group and a second functional group; The first functional group has the function of inducing cross-linking of amino acids in the blood vessel wall under light excitation; The second functional group has the function of inhibiting cell proliferation.

[0041] The present application chemically splices a first functional group that can induce amino acid cross-linking in the blood vessel wall with a second functional group that has the effect of inhibiting cell proliferation, so that the photosensitive material of the present application has both photo-cross-linking properties and anti-cell proliferation properties. Under the activation of light of a specific wavelength, the photosensitive material of the present application can induce covalent cross-linking between amino acids in the blood vessel wall, thereby forming a natural and stable invisible stent to stably support the blood vessel. Compared with metal stents, this natural stent is not a foreign body in the blood vessel, so there will be no problem of restenosis in the stent; at the same time, the photosensitive material of the present application can also play an anti-cell proliferation role, further reducing the risk of restenosis in the blood vessel.

[0042] It is worth mentioning that since the second functional group that has the effect of inhibiting cell proliferation also has good lipid solubility, by introducing the second functional group into the photosensitive compound (i.e., the substance that provides the first functional group), the hydrophobicity of the photosensitive material can be improved, and the photosensitive material can be prevented from being washed away by the blood after entering the blood vessels. The photosensitive material of the present application can be accurately anchored to the lesion site, thereby better exerting the vascular repair function, and effectively solving the problem of vascular stenosis and occlusion.

[0043] Photosensitizing compounds, as the name implies, refer to compounds with photosensitivity, that is, substances that undergo chemical reactions under light. Naphthalimide compounds are a class of fluorescent dyes with excellent optical properties and chemical stability. Their typical structure includes a naphthalene ring and an imide group. Their fluorescence properties and solubility can be adjusted by introducing different substituents. Naphthalimide substances exhibit high fluorescence quantum yields in both solution and solid state, have strong luminescence intensity, and can remain stable under long-term light exposure and are not prone to photobleaching.

[0044] Further studies have shown that 4-substituted 1,8-naphthalene imide substances show good function of promoting protein cross-linking, thereby constructing a natural vascular stent in the blood vessel, supporting the blood vessel and preventing blood vessel retraction. In some optional embodiments, the first functional group can be provided by a 4-substituted 1,8-naphthalene imide compound. Specifically, the first functional group includes a 1,8-naphthalene imide skeleton and a substituent located on the 4-carbon of the 1,8-naphthalene imide skeleton.

[0045] Exemplarily, the first functional group has a structure shown in formula III-1, in which n is an integer of 1-6, for example, 1, 2, 3, 4, 5 or 6. Compared with 1,8-naphthaleneimide monomer, 1,8-naphthaleneimide dimer has higher stability and extended conjugated structure, so that it exhibits higher efficiency and stability in photocrosslinking reaction, and 1,8-naphthaleneimide dimer can absorb longer wavelength light, so that the penetration depth in tissue is deeper.

[0046]

[0047] Formula III-1 Studies have found that vascular smooth muscle cell proliferation is the core pathological process of cardiovascular diseases such as restenosis after angioplasty. Therefore, introducing a second functional group with the function of inhibiting cell proliferation into the photosensitive compound can further reduce the risk of restenosis in the blood vessel on the basis of forming a natural vascular scaffold to avoid vascular retraction.

[0048] In some optional embodiments, the second functional group can be, for example, a cell proliferation inhibitor (with R 3 -OH represents), that is, the second functional group is a dehydrogenated group of a cell proliferation inhibitor that can provide a reactive hydroxyl group, denoted as -OR 3 .

[0049] It is understood that inhibiting cell proliferation refers to inhibiting cell division in a certain way so that it cannot grow and reproduce normally. Cell proliferation inhibitors refer to compounds that have the function of inhibiting cell proliferation.

[0050] Exemplarily, the cell proliferation inhibitor includes any one of paclitaxel, docetaxel, cabazitaxel, vinorebine, camptothecin, hydroxycamptothecin, rapamycin, tacrolimus, adriamycin, epirubicin, pirarubicin, idarubicin, mitoxantrone, cytarabine, gemcitabine, and dexamethasone. The structural formula is as follows:

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057] Among them, paclitaxel molecules are the main choice for drug coating in drug balloons because of their strong lipophilicity, which enables them to be quickly and evenly absorbed by the blood vessel wall and permanently inhibit the proliferation of smooth muscle cells. Compared with paclitaxel, rapamycin and its derivatives are less cytotoxic and safer in clinical application, but their lipophilicity is slightly inferior to paclitaxel.

[0058] In some embodiments, the chemical structure of the photosensitive material further includes a bridging structure, one end of the bridging structure is connected to the first functional group, and the other end is connected to the second functional group; The bridging structure is , m is an integer selected from 2 to 7, R 1 and R 2 Each is independently selected from hydrogen, halogen or C1-C10 alkyl.

[0059] By adopting the bridging structure, the chemical splicing of the first functional group and the second functional group is achieved. The photosensitive material thus formed has good fat solubility, can accurately anchor the lesion site, play a vascular repair function, and can also play an anti-cell proliferation effect, further reducing the risk of restenosis in the blood vessel.

[0060] Compared with the balloon dilatation catheter obtained by directly physically mixing the photosensitive compound (such as the structure shown in III-1) with the cell proliferation inhibitor and then coating it on the surface of the balloon body, the photosensitive compound will still be washed away by the blood during balloon delivery and expansion, making it difficult to form a natural and stable invisible stent to stably support the blood vessels. The balloon dilatation catheter containing the photosensitive material described in the present application can accurately anchor the lesion site, show a better vascular dilation effect, and effectively solve the problem of vascular stenosis and occlusion.

[0061] Furthermore, the halogen is selected from any one of fluorine, chlorine, bromine and iodine.

[0062] Furthermore, the C1-C10 alkyl group includes any one of a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.

[0063] It should be noted that the first functional group is connected to the bridge structure through the terminal amino group in the substituent on the carbon at position 4 of the 1,8-naphthalimide skeleton, and the second functional group is connected to the bridge structure through the oxygen atom after the reactive hydroxyl group in the cell proliferation inhibitor is dehydrogenated.

[0064] For example, chemical modification at the 2'-hydroxyl position of paclitaxel has little effect on the activity of paclitaxel, and similarly, chemical modification at the 40-hydroxyl position of rapamycin has little effect on its activity. Therefore, in the photosensitive material of the present application, the bridging structure is covalently linked to the 2'-hydroxyl group in the paclitaxel molecule or the 40-hydroxyl group in the rapamycin molecule.

[0065]

[0066] Furthermore, the chemical structure of the photosensitive material is as shown in Formula I, wherein n is an integer of 1-6, m is an integer selected from 2-7, and R 1 and R 2 Each is independently selected from hydrogen, halogen or C1-C10 alkyl.

[0067]

[0068] Formula I.

[0069] Exemplarily, the C1-C10 alkyl group includes any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; the halogen is selected from any one of fluorine, chlorine, bromine and iodine; m can be 2, 3, 4, 5, 6 or 7; and n can be 1, 2, 3, 4, 5 or 6.

[0070] The structural design of the photosensitive material in the present application is to obtain a photosensitive drug material with a symmetrical structure by connecting anti-cell proliferation drug molecules through a bridging structure in a symmetrical 1,8-naphthalimide dimer structure. This makes it unnecessary to protect and deprotect the terminal amino group of the 1,8-naphthalimide dimer during the preparation of the material, so it is easier to prepare the photosensitive material of the present application by chemical synthesis.

[0071] In some embodiments, the chemical structure of the photosensitive material is as shown in Formula I-1 or Formula I-2:

[0072] Formula I-1

[0073] Formula I-2.

[0074] It is understood that in Formula I-1 and Formula I-2, R 1 , R 2 The meanings of m and n are the same as those in Formula I and are not repeated here.

[0075] Further exemplary, the chemical structure of the photosensitive material is shown in Formula I-1a or Formula I-2a:

[0076] Formula I-1a

[0077] Formula I-2a.

[0078] According to an embodiment of the present application, in a second aspect, a method for preparing the photosensitive material according to the first aspect is provided, comprising the following steps: S1, subjecting the cell proliferation inhibitor to a first condensation reaction with a substituted or unsubstituted cyclic anhydride to obtain an intermediate; The chemical structure of the substituted or unsubstituted cyclic anhydride is shown in Formula II, wherein m is selected from an integer of 2-7, and R 1 and R 2 Each is independently selected from hydrogen, halogen or C1-C10 alkyl;

[0079] Formula II S2, allowing the intermediate to undergo a second condensation reaction with a 4-substituted 1,8-naphthaleneimide compound to obtain.

[0080] By utilizing the structural characteristics of cyclic anhydride compounds, condensation reactions are performed with cell proliferation inhibitors and 4-substituted 1,8-naphthalene imide compounds respectively, thereby splicing the cell proliferation inhibitors and 4-substituted 1,8-naphthalene imide compounds together to construct a photosensitive material with vascular repair function. The preparation method of the present application has a short synthesis route, simple operation, high product yield, and is suitable for industrial production.

[0081] In some optional embodiments, S1 is a first condensation reaction carried out in a first organic solvent and in the presence of an organic base.

[0082] Furthermore, the organic base includes at least one of pyridine, N-methylpyridine, and triethylamine, and the first organic solvent includes at least one of N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, toluene, dichloromethane, chloroform, dimethyl sulfoxide, ethylene glycol monoethyl ether, ethylene glycol monoether, ethylene glycol dimethyl ether, and ethylene glycol diethyl ether.

[0083] Furthermore, the molar ratio of the cell proliferation inhibitor to the substituted or unsubstituted cyclic anhydride and the organic base is 1:5-20:20-200. This ensures that the cell proliferation inhibitor can react completely, thereby ensuring the yield of the target product photosensitive material.

[0084] In some optional embodiments, S2 is a second condensation reaction carried out in a second organic solvent in the presence of a condensation agent.

[0085] Furthermore, the condensation agent includes at least one of N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and the second organic solvent includes at least one of N,N-dimethylacetamide, tetrahydrofuran, toluene, dichloromethane, chloroform, dimethyl sulfoxide, ethylene glycol monoethyl ether, ethylene glycol monoether, ethylene glycol dimethyl ether, and ethylene glycol diethyl ether.

[0086] Furthermore, the molar ratio of the intermediate to the 4-substituted 1,8-naphthalimide compound and the condensing agent is 1:1-10:8-20. This ensures that the intermediate can react completely, thereby ensuring the yield of the target product photosensitive material.

[0087] In some optional embodiments, the chemical structure of the 4-substituted 1,8-naphthalene imide compound is as shown in Formula III, wherein n is an integer of 1-6;

[0088] Formula III.

[0089] It should be noted that the preparation of the 4-substituted 1,8-naphthalimide shown in formula III can be found in the literature “Solvent-Dependent Photophysics and Reactivity of Monomeric and Dimeric 4-Amino-1,8-Naphthalimides” by Kelly et al. J.Phys.Chem.A 2021,125,2294-2307. The method includes the following steps: Step 1: Dissolve 4-bromo-1,8-naphthalene dicarboxylic anhydride (1 equivalent) in dimethylacetamide (5 volumes), heat to 70°C and stir for about 1 hour, then cool the mixture to room temperature and stir overnight. Filter the resulting mixture, wash the filter cake with dimethylacetamide (1.5 volumes) and then with tert-butyl methyl ether (4 volumes). The collected solid material is then dried in a vacuum oven at 65°C to constant weight to obtain purified 4-bromo-1,8-naphthalene dicarboxylic anhydride.

[0090] Step 2: Add N,N-diisopropylethylamine (2.5 equivalents) to a mixture of purified 4-bromo-1,8-naphthalic anhydride (2.5 equivalents) and dimethylacetamide (8 volumes), then cool to 5±5°C, and slowly dropwise add a mixture of substituted or unsubstituted cyclic anhydride (1 equivalent) and dimethylacetamide (3 volumes) shown in formula II to maintain the temperature of the reaction system at no more than 25°C. After the addition is completed, the resulting mixture is stirred at room temperature overnight, then stirred at 80°C for 6 hours, and the resulting mixture is filtered while hot, and the filter cake is first washed with dimethylacetamide (4 times, 3 volumes each time) and then with tert-butyl methyl ether (4 times, 3 volumes each time). The collected solid material is dried in a vacuum oven at 45°C to constant weight to obtain a dimer.

[0091] Step 3: Stir the mixture of the dimer obtained in step 2, toluene (20 times the volume) and the substituted or unsubstituted cyclic anhydride shown in formula II (20 times the volume) at 80°C for at least 24 hours, and continue stirring for at least 48 hours after cooling. Then filter the obtained suspension, wash it with toluene (3 times, 7 times the volume each time), and then with acetonitrile (4 times, 7 times the volume each time). The separated filter cake is blown dry on the filter with a nitrogen stream, and the obtained product (i.e., 4-substituted 1,8-naphthaleneimide shown in formula III) is stored in the dark. The total yield of the above three steps is in the range of about 40.5% to about 44.5%.

[0092] According to the embodiments of the present application, in a third aspect, the present application provides the use of the photosensitive material with vascular repair function described in the first aspect or the photosensitive material prepared by the method described in the second aspect in the preparation of a drug for treating vascular stenosis or occlusion.

[0093] According to an embodiment of the present application, in a fourth aspect, the present application also provides a balloon dilatation catheter, comprising a balloon body; the surface of the balloon body has a coating, and the coating comprises the photosensitive material with vascular repair function described in the first aspect or the photosensitive material prepared by the method described in the second aspect.

[0094] In some optional embodiments, the method for preparing the coating includes: dissolving the photosensitive material in a volatile organic solvent to form a solution with a concentration of 0.5~5 mg / ml, and using brushing, spraying or immersing the balloon body to form a coating on the surface of the balloon body.

[0095] Furthermore, the volatile organic solvent includes at least one of anhydrous ethanol, ethyl acetate, acetone, isopropanol, and cyclohexane, and the spraying can be performed by ultrasonic atomization or air pressure atomization.

[0096] After the balloon dilatation catheter provided in the present application is expanded in a blood vessel, it is activated by an optical fiber of a specific wavelength (450nm), which can induce the formation of covalent bonds between amino acids in the blood vessel wall, thereby supporting the blood vessel and preventing restenosis of the blood vessel.

[0097] The present application is further described in detail below in conjunction with specific examples, and these examples should not be construed as limiting the scope of protection claimed in the present application. Where specific experimental steps or conditions are not specified in the examples and comparative examples, the conventional experimental steps or conditions described in the literature in the art can be used. Where the manufacturer of the reagents or instruments used is not specified, they are all conventional reagent products that can be obtained commercially.

[0098] In all the examples and comparative examples of the present application, the unit % represents the mass percentage.

[0099] Example 1 The reaction route is as follows:

[0100] 50 mg (0.060 mmol) of paclitaxel and 74 mg (0.74 mmol) of succinic anhydride (molar ratio 1 / 12.3) were added to a round-bottom flask, 2 mL of dichloromethane was added to dissolve, and 0.6 mL of pyridine was added to dissolve, and stirred at room temperature for 3 hours. The reaction progress was detected by thin layer chromatography. After all the paclitaxel was reacted, the solvent was removed by vacuum concentration at room temperature, 5 mL of deionized water was added and stirred for 20 minutes, and after the stirring was completed, it was filtered and the precipitate was washed with water. After the completion, the precipitate was vacuum dried for 12 hours to obtain intermediate 1 (yield 90%).

[0101] The intermediate 1 (36 mg, 0.038 mmol), N-hydroxysuccinimide (NHS, 80 mg, 0.70 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl, 80 mg, 0.42 mmol) prepared in the previous step were dissolved in 2 mL N,N-dimethylformamide and stirred at room temperature for 2 hours. Then, the 4-substituted 1,8-naphthaleneimide dimer (36 mg, 0.044 mmol) shown in Formula 1 was dissolved in 1 mL N,N-dimethylformamide and added to the above system. The mixture was stirred at room temperature overnight. After the reaction was completed, it was extracted with water and dichloromethane. The organic phase was dried with anhydrous magnesium sulfate and filtered, concentrated, and separated by column chromatography to obtain the paclitaxel photosensitive material shown in Formula I-1a (yield 48%). Its mass spectrum data is: HRMS (ESI) m / z [M+H] + C 144 H 159 N 8 O 42 Calculated value 2672.0552, measured value 2672.0547.

[0102] Example 2 The reaction route is as follows:

[0103] 50 mg (0.055 mmol) of rapamycin and 69 mg (0.69 mmol) of succinic anhydride (molar ratio 1 / 12.5) were added to a round-bottom flask, 2 mL of N,N-dimethylformamide was added to dissolve, and 0.6 mL of pyridine was added to dissolve, and stirred at 60°C for 4 hours. The reaction progress was monitored by thin layer chromatography. After all the rapamycin was reacted, the solvent was removed by vacuum concentration at room temperature, 5 mL of deionized water was added and stirred for 20 minutes, and after the stirring was completed, it was filtered and the precipitate was washed with water. After the completion, the precipitate was vacuum dried for 12 hours to obtain intermediate 2 (yield 82%).

[0104] The intermediate 2 (45 mg, 0.044 mmol), N-hydroxysuccinimide (NHS, 80 mg, 0.70 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC·HCl, 80 mg, 0.42 mmol) prepared in the previous step were dissolved in 2 mL N, N-dimethylformamide and stirred at room temperature for 2 hours. Then, the 4-substituted 1,8-naphthaleneimide dimer (53 mg, 0.066 mmol) shown in Formula 1 was dissolved in 1 mL N, N-dimethylformamide and added to the above system. The mixture was stirred at room temperature overnight. After the reaction was completed, it was extracted with water and dichloromethane. The organic phase was added with anhydrous magnesium sulfate to dry and filter, concentrated, and separated by column chromatography to obtain the rapamycin photosensitive material shown in Formula I-2a (yield 53%). Its mass spectrum data is: HRMS (ESI) m / z [M+H] + C 152 H 215 N 8 O 40 Calculated value 2792.5036, measured value 2792.5030.

[0105] Example 3 The paclitaxel photosensitive material prepared in Example 1 was dissolved in anhydrous ethanol to obtain a solution with a concentration of 2 mg / ml. The solution was evenly sprayed on the surface of the balloon body of the balloon dilatation catheter using an ultrasonic sprayer to form a coating.

[0106] Example 4 The rapamycin photosensitive material prepared in Example 2 was dissolved in anhydrous ethanol to obtain a solution with a concentration of 2 mg / ml. The solution was evenly sprayed on the surface of the balloon body of the balloon dilatation catheter using an ultrasonic sprayer to form a coating.

[0107] Comparative Example 1 The only difference from Example 3 is that (2,2'-((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(6-((2-(2-(2-aminoethoxy)ethoxy)amino)-1H-benzo[de]isoquinoline-1,3(2H)-dione)), i.e., the compound with the structure shown in Formula 1, is used instead of the paclitaxel photosensitive material in Example 3.

[0108]

[0109] Formula 1 Comparative Example 2 The only difference from Example 3 is that the paclitaxel photosensitizer in Example 3 is replaced by the compound represented by Formula 2.

[0110]

[0111] Formula 2 Comparative Example 3 The only difference from Example 3 is that the paclitaxel photosensitive material in Example 3 is replaced by a material obtained by physically mixing the compound of the structure represented by Formula 1 and paclitaxel in a molar ratio of 1:2.

[0112]

[0113] Formula 1 Comparative Example 4 The only difference from Example 3 is that no coating is provided on the surface of the balloon body in this comparative example.

[0114] Experimental Example 1: Vascular dilation experiment Excess tissue around the blood vessel is peeled off, a section is cut and cut open to measure the circumference of the blood vessel, denoted as a, and the initial diameter is denoted as d, d=a / π; a balloon dilatation catheter of appropriate size is selected according to the diameter of the blood vessel, and the blood vessel is dilated using a balloon dilatation catheter containing a photosensitive material coating (Examples 3-4, Comparative Examples 1-3) and an ordinary balloon dilatation catheter without any coating (Comparative Example 4), and after the blood vessel is pressurized to a specified pressure, it is irradiated with a 450nm optical fiber for 1 min; after the blood vessel is irradiated, the optical fiber and the balloon dilatation catheter are withdrawn, and the circumference of the dilated blood vessel is cut open and measured, denoted as A, and the diameter after expansion is calculated and denoted as D, D=A / π; the blood vessel gain is calculated and denoted as X%, and X%=(Dd) / d*100%.

[0115] Table 1 Results of vasodilation experiment

[0116] As can be seen from Table 1, compared with Comparative Example 4 which does not use a photosensitive material coating, the balloon dilatation catheters (Comparative Examples 1-3 and Examples 3-4) using a photosensitive material coating can achieve the effect of vasodilation to a certain extent, and compared with Comparative Example 1 which is only coated with the structural compound shown in Formula 1, Comparative Example 2 which is coated with the structural compound shown in Formula 2, and Comparative Example 3 which is coated with a substance physically mixed with the structural compound shown in Formula 1 and paclitaxel, the vasodilation effect of Examples 3-4 is more obvious. This shows that the introduction of a functional group having an inhibitory effect on cell proliferation into the chemical structure of the naphthylimide dimer can improve the hydrophobicity of the photosensitive material, prevent the photosensitive material from being washed away by blood after entering the blood vessel, so that the photosensitive material of the present application can accurately anchor the lesion site, thereby better exerting the vascular repair function, and effectively solving the problem of vascular stenosis and occlusion.

[0117] Experimental Example 2: Contact Angle Test The contact angle test was performed on the balloons in Example 3, Example 4, Comparative Example 1, Comparative Example 2, and Comparative Example 4. The results are as follows: Figure 1-Figure 5As shown in the figure, it can be seen that the contact angle of Example 3 is 60.50°, the contact angle of Example 4 is 58.54°, the contact angle of Comparative Example 1 is 17.19°, the contact angle of Comparative Example 2 is 55.66°, and the contact angle of Comparative Example 4 is 22.74°. The smaller the contact angle, the easier it is to be washed by blood flow. Therefore, compared with Comparative Examples 1, 2 and 4, Examples 3-4 are less likely to be washed by blood flow.

[0118] It can be seen that the balloon dilatation catheter provided in the present application can reduce the loss of photosensitive materials caused by blood flow during intravascular delivery, allowing more photosensitive materials to reach the lesion site and achieve the effect of repairing blood vessels. Experimental Example 3: Antiproliferative Activity Test Digest, centrifuge and count the cells that have been cultured in advance. Inoculate 100uL of 3k-7k / well (human embryonic kidney cell 293) HEK293T cells on a 96-well plate and incubate at 37°C and 5% CO 2 After culturing for 24 hours under 90% humidity conditions, the cell growth status and density were observed under a microscope, and the wells with good growth status and uniform cell distribution and density were selected for the experiment.

[0119] The paclitaxel photosensitizer prepared in Example 1, the rapamycin photosensitizer prepared in Example 2, paclitaxel and rapamycin were prepared into sample solutions with different concentration gradients (0 μM, 25 μM, 50 μM, 100 μM, 250 μM, 500 μM), and three replicate wells of each concentration were added to a 96-well plate and incubated at 37°C and 5% CO 2 , 90% humidity for 24 hours. Use an inverted microscope to detect the cell growth status, and use 4X / 10X to take photos of wells with good growth status and uniform cell distribution and density. Add 10uL of CCK-8 solution to each well and incubate at 37℃, 5% CO 2 , 90% humidity for 2 hours. Measure the absorbance at 450nm with an enzyme reader and process the analysis results as follows: Figure 6 shown.

[0120] from Figure 6 It can be seen that the paclitaxel photosensitive material prepared in Example 1 can still maintain the anti-proliferative effect of paclitaxel, and the rapamycin photosensitive material prepared in Example 2 can still maintain the anti-proliferative effect of rapamycin. This shows that the photosensitive material of the present application can accurately anchor the lesion site to play a role in vascular repair, while playing an anti-cell proliferation effect, thereby further reducing the risk of restenosis in the blood vessel by introducing a functional group with an inhibitory cell proliferation effect into the chemical structure of the naphthalimide dimer.

[0121] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection created by this application.

Claims

1. A photosensitive material with vascular repair function, characterized in that: Its chemical structure includes a first functional group and a second functional group; The first functional group has the function of inducing cross-linking of amino acids in the blood vessel wall under light excitation; The second functional group has the function of inhibiting cell proliferation.

2. The photosensitive material with vascular repair function according to claim 1, characterized in that: The first functional group includes a 1,8-naphthalimide skeleton and a substituent located on the carbon 4 of the 1,8-naphthalimide skeleton; and / or, the second functional group is selected from the group after dehydrogenation of the cell proliferation inhibitor that can provide reactive hydroxyl groups, denoted as -O-R3; And / or, the chemical structural formula of the photosensitive material further includes a bridging structure, one end of the bridging structure is connected to the first functional group, and the other end of the bridging structure is connected to the second functional group; The bridging structure is , m is an integer selected from 2-7, and R1 and R2 are independently selected from hydrogen, halogen or C1-C10 alkyl.

3. The photosensitive material with vascular repair function according to claim 2, characterized in that: The cell proliferation inhibitor includes any one of paclitaxel, docetaxel, cabazitaxel, vinorelbine, camptothecin, hydroxycamptothecin, rapamycin, tacrolimus, doxorubicin, epirubicin, pirarubicin, idarubicin, mitoxantrone, cytarabine, gemcitabine, and dexamethasone; and / or, the first functional group is connected to the bridging structure via the substituent; And / or, the halogen is selected from any one of fluorine, chlorine, bromine and iodine; And / or, the C1-C10 alkyl group includes any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

4. The photosensitive material with vascular repair function according to claim 2, characterized in that: The chemical structure of the photosensitive material is shown in Formula I, where n is an integer of 1-6; Formula I.

5. The photosensitive material with vascular repair function according to claim 3 or 4, characterized in that: The chemical structure of the photosensitive material is shown in Formula I-1 or Formula I-2: Formula I-1 Formula I-2.

6. The photosensitive material with vascular repair function according to claim 5, characterized in that: The chemical structure of the photosensitive material is shown in Formula I-1a or Formula I-2a: Formula I-1a Formula I-2a.

7. The method for preparing the photosensitive material with vascular repair function according to any one of claims 1 to 6, characterized in that: The steps include: S1, subjecting the cell proliferation inhibitor to a first condensation reaction with a substituted or unsubstituted cyclic anhydride to obtain an intermediate; The chemical structure of the substituted or unsubstituted cyclic anhydride is shown in Formula II, wherein m is selected from an integer of 2-7, and R1 and R2 are independently selected from hydrogen, halogen or C1-C10 alkyl; Formula II S2, allowing the intermediate to undergo a second condensation reaction with a 4-substituted 1,8-naphthaleneimide compound to obtain.

8. The method for preparing a photosensitive material having a vascular repair function according to claim 7, characterized in that: The chemical structure of the 4-substituted 1,8-naphthaleneimide compound is shown in Formula III, wherein n is an integer of 1-6; Formula III.

9. Use of the photosensitive material with vascular repair function as claimed in any one of claims 1 to 6 or the photosensitive material prepared by the method as claimed in any one of claims 7 to 8 in the preparation of a drug for treating vascular stenosis or occlusion.

10. A balloon dilatation catheter, comprising a balloon body; characterized in that: The surface of the balloon body has a coating, and the coating includes the photosensitive material with vascular repair function described in any one of claims 1-6 or a photosensitive material prepared by the method described in any one of claims 7-8.

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