A photosensitive material with blood vessel repair function, its preparation method and balloon dilation catheter

Abstract

This application relates to the technical field of medical materials, and discloses a photosensitive material with blood vessel repair function, its preparation method and a balloon dilatation catheter. The chemical structural formula of the photosensitive material includes a first functional group and a second functional group. The first functional group has the function of initiating cross-linking of amino acids in the blood vessel wall under light excitation, and the second functional group has the function of inhibiting cell proliferation. The photosensitive material of this application has good liposolubility, can accurately anchor to the lesion site, exert the blood vessel repair function, and can also exert the anti-cell proliferation effect, further reducing the risk of in-stent restenosis.

Description

Technical Field

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

[0002] Currently, the most commonly used treatment plan for cardiovascular diseases is percutaneous transluminal angioplasty. This surgery requires the use of an interventional treatment device, namely a drug balloon, which carries anti-proliferative drugs (such as paclitaxel, rapamycin, etc.) on the balloon. Through angioplasty, the anti-proliferative drugs are brought to the blood vessel wall and evenly released, inhibiting the proliferation of vascular endothelial cells, smooth muscle cells, and fibroblasts, and playing a role in reducing restenosis of blood vessels after balloon dilatation. However, clinical practice has confirmed that for severely stenotic blood vessels, the blood vessels may still rebound after the balloon is withdrawn, further forming severe stenosis or occlusion.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 balloon releases the drug, it cannot effectively solve the problem of blood vessel occlusion.

[0003] To solve the above problems, related technologies have proposed implanting a natural blood vessel stent in the blood vessel. This technology coats a photosensitive material such as 1,8-naphthalimide on the balloon. After the balloon is dilated, the photosensitive material is released onto the inner wall of the blood vessel and can trigger covalent cross-linking between amino acids in the blood vessel wall after being activated by light of a specific wavelength (such as 450 nm), providing a supporting effect on the blood vessel. In this way, on the one hand, blood vessel retraction can be avoided, and on the other hand, the body's proliferative reaction caused by the use of a metal stent can also be avoided, preventing restenosis within the blood vessel stent. Unfortunately, the photosensitive materials developed in the prior art 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 blood vessel repair function and a preparation method thereof. This material can accurately anchor to the lesion site, reducing the risk of restenosis within the blood vessel, and thus effectively solving the problems of blood vessel stenosis and occlusion.

[0005] According to an embodiment of the present application, in a first aspect, there is provided a photosensitive material with blood vessel repair function, the chemical structural formula of which includes a first functional group and a second functional group;

[0006] The first functional group has the function of triggering cross-linking of amino acids in the blood vessel wall under light excitation;

[0007] The second functional group has the function of inhibiting cell proliferation.

[0008] In some alternative embodiments, the first functional group includes a 1,8-naphthalimide skeleton and a substituent located at the 4-position carbon of the 1,8-naphthalimide skeleton.

[0009] In some alternative embodiments, the second functional group may be provided, for example, by a cell proliferation inhibitor capable of providing a reactive hydroxyl group (represented by R3-OH), that is, the second functional group is the group obtained by dehydrogenating the cell proliferation inhibitor capable of providing a reactive hydroxyl group, denoted as -O-R3.

[0010] In some alternative embodiments, 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 is connected to the second functional group;

[0011] The bridging structure is , where m is an integer selected from 2 to 7, and R1 and R2 are each independently selected from hydrogen, halogen, or C1-C10 alkyl.

[0012] Further, the halogen is selected from any one of fluorine, chlorine, bromine, and iodine.

[0013] Further, the C1-C10 alkyl includes any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0014] In some alternative 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.

[0015] In some alternative embodiments, the first functional group is connected to the bridging structure through the terminal amino group of the substituent.

[0016] In some alternative embodiments, the chemical structure of the photosensitive material is as shown in Formula I. In Formula I, n is an integer from 1 to 6, m is an integer selected from 2 to 7, and R1 and R2 are each independently selected from hydrogen, halogen, or C1-C10 alkyl.

[0017]

[0018] Formula I.

[0019] Further, the C1-C10 alkyl 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.

[0020] In some alternative embodiments, the chemical structure of the photosensitive material is as shown in Formula I-1 or Formula I-2:

[0021]

[0022] Formula I-1

[0023]

[0024] Formula I-2.

[0025] It is understood that in Formula I-1 and Formula I-2, the meanings of R1, R2, m and n are the same as those in Formula I, which will not be elaborated here.

[0026] In some alternative embodiments, the chemical structure of the photosensitive material is as shown in Formula I-1a or Formula I-2a:

[0027]

[0028] Formula I-1a

[0029] Formula I-2a.

[0030] According to the embodiments of the present application, in a second aspect, there is provided a method for preparing the photosensitive material described in the first aspect, including the following steps:

[0031] S1. React a cell proliferation inhibitor with a substituted or unsubstituted cyclic anhydride to undergo a first condensation reaction to obtain an intermediate;

[0032] The chemical structure of the substituted or unsubstituted cyclic anhydride is as shown in Formula II. In Formula II, m is an integer selected from 2 to 7, and R1 and R2 are each independently selected from hydrogen, halogen or C1-C10 alkyl;

[0033]

[0034] Formula II

[0035] S2. React the intermediate with a 4-substituted 1,8-naphthalimide compound to undergo a second condensation reaction to obtain the product.

[0036] In some alternative embodiments, the chemical structure of the 4-substituted 1,8-naphthalimide compound is as shown in Formula III. In Formula III, n is an integer from 1 to 6;

[0037]

[0038] Formula III.

[0039] According to the embodiments of the present application, in a third aspect, the present application provides the use of the photosensitive material having a blood vessel 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.

[0040] According to an embodiment of the present application, in a fourth aspect, the present application further provides a balloon dilation catheter, including a balloon body; a coating is provided on the surface of the balloon body, and the coating includes the photosensitive material with blood vessel repair function described in the first aspect or the photosensitive material prepared by the method described in the second aspect.

[0041] The technical solution of the present application has the following advantages:

[0042] The photosensitive material with blood vessel repair function provided by the present application chemically stitches a first functional group capable of initiating amino acid crosslinking in the blood vessel wall with a second functional group having an inhibitory effect on cell proliferation, so that the photosensitive material of the present application has both photo-crosslinking characteristics and anti-cell proliferation characteristics. Under the activation of light with a specific wavelength, the photosensitive material of the present application can initiate covalent crosslinking 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, since this natural stent does not belong to a foreign body in the blood vessel, there will be no problem of in-stent restenosis.

[0043] Meanwhile, since the second functional group with an inhibitory effect on cell proliferation also has good lipophilicity, by introducing the second functional group into the photosensitive compound (i.e., the substance providing the first functional group), the hydrophobicity of the photosensitive material of the present application can be improved, preventing the photosensitive material from being washed away by blood after entering the blood vessel, enabling the photosensitive material of the present application to accurately anchor at the lesion site, thereby better exerting the blood vessel repair function and effectively solving the problems of blood vessel stenosis and occlusion. Moreover, the second functional group can also play a role in anti-cell proliferation, further reducing the risk of in-stent restenosis.

[0044] Additional aspects and advantages of the embodiments of the present application will be described and shown in part in the subsequent description, or will be explained through the implementation of the embodiments of the present application. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the following will briefly introduce the drawings required for use in the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present application. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0046] Figure 1 It is a contact angle test diagram of the balloon in Embodiment 3 of the present application;

[0047] Figure 2 It is a contact angle test diagram of the balloon in Embodiment 4 of the present application;

[0048] Figure 3 It is the contact angle test diagram of the balloon in Comparative Example 1 of the present application;

[0049] Figure 4 It is the contact angle test diagram of the balloon in Comparative Example 2 of the present application;

[0050] Figure 5 It is the contact angle test diagram of the balloon in Comparative Example 4 of the present application;

[0051] Figure 6 It is the anti - proliferation effect diagram of the paclitaxel photosensitive material prepared in Example 1 of the present application, the rapamycin photosensitive material prepared in Example 2, as well as paclitaxel and rapamycin. Detailed implementation manners

[0052] The following embodiments are provided to better further understand the present application. It is not limited to the described best implementation manner, and does not constitute a limitation to the content and protection scope of the present application. Any product that is the same as 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 existing technologies falls within the protection scope of the present application.

[0053] In the description of the present application, it should be noted that the terms "first" and "second" are only used for descriptive purposes and cannot be understood as indicating or implying relative importance. In addition, the technical features involved in different embodiments of the present application described below can be combined with each other as long as they do not conflict with each other.

[0054] The related technology discloses a photosensitive material with blood vessel repair function, which uses polypeptide dendrimers to improve the distribution of photosensitive compounds, thereby enhancing the permeability of photosensitive compounds in the blood vessel wall. However, the photosensitive material synthesized in this way contains a large number of amino groups in its molecules, showing strong hydrophilicity, which makes the molecule easy to be washed away by blood when used in blood vessels and is not conducive to the precise reaction of the material with the blood vessel wall.

[0055] In response to this, another technology proposes to perform hydrophobic regulation on 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 the blood vessel transportation process. Using the material with the structure shown in Formula 2 for blood vessel repair experiments with a balloon dilatation catheter, the experimental results are still not very satisfactory.

[0056]

[0057] Formula 2

[0058] To solve the above problems existing in the prior art, according to the first aspect of the present application, a photosensitive material with blood vessel repair function is provided, and its chemical structural formula includes a first functional group and a second functional group;

[0059] The first functional group has the function of initiating crosslinking of amino acids in the blood vessel wall under light excitation;

[0060] The second functional group has the function of inhibiting cell proliferation.

[0061] In this application, by chemically splicing the first functional group that can initiate crosslinking of amino acids in the blood vessel wall with the second functional group that has the effect of inhibiting cell proliferation, the photosensitive material of this application simultaneously has the characteristics of photo-crosslinking and anti-cell proliferation. Under the activation of light with a specific wavelength, the photosensitive material of this application can initiate covalent crosslinking between amino acids in the blood vessel wall, thereby forming a natural and stable invisible scaffold to stably support the blood vessel. Compared with metal stents, since this natural stent does not belong to foreign substances in the blood vessel, the problem of in-stent restenosis will not occur. At the same time, the photosensitive material of this application can also play the role of anti-cell proliferation, further reducing the risk of in-stent restenosis.

[0062] It is worth mentioning that since the second functional group with the function of inhibiting cell proliferation also has good lipophilicity, by introducing the second functional group into the photosensitive compound (i.e., the substance providing the first functional group), the hydrophobicity of the photosensitive material can be improved, avoiding the photosensitive material from being washed away by blood after entering the blood vessel, enabling the photosensitive material of this application to accurately anchor at the lesion site, thereby better playing the blood vessel repair function and effectively solving the problems of blood vessel stenosis and occlusion.

[0063] A photosensitive compound, as the name implies, refers to a compound with photosensitive properties, that is, a substance that undergoes a chemical reaction 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, and 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 irradiation and are not prone to photobleaching.

[0064] Further research shows that 4-substituted 1,8-naphthalimide substances show good functions of promoting protein crosslinking, thereby constructing a natural blood vessel stent in the blood vessel, providing a supporting effect on the blood vessel, and avoiding blood vessel retraction. In some alternative embodiments, the first functional group can be provided, for example, by 4-substituted 1,8-naphthalimide compounds. Specifically, the first functional group includes a 1,8-naphthalimide skeleton and a substituent located at the 4-position carbon of the 1,8-naphthalimide skeleton.

[0065] Exemplarily, the first functional group has the structure shown in Formula III-1. In Formula III-1, n is an integer from 1 to 6, for example, it can be 1, 2, 3, 4, 5, or 6. Compared with the 1,8-naphthalimide monomer, the 1,8-naphthalimide dimer has higher stability and an extended conjugated structure, making it exhibit higher efficiency and stability in the photocrosslinking reaction. Moreover, the 1,8-naphthalimide dimer can absorb light with a longer wavelength, thereby having a deeper penetration depth in tissues.

[0066]

[0067] Formula III-1

[0068] It has been found that the proliferation of vascular smooth muscle cells 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 in-stent restenosis on the basis of forming a natural vascular scaffold to avoid vascular retraction.

[0069] In some alternative embodiments, the second functional group can be provided, for example, by a cell proliferation inhibitor that can provide a reactive hydroxyl group (represented by R3-OH), that is, the second functional group is the group after dehydrogenation of the cell proliferation inhibitor that can provide a reactive hydroxyl group, denoted as -O-R3.

[0070] It can be understood that inhibiting cell proliferation means inhibiting cell division in a certain way so that it cannot grow and reproduce normally. A cell proliferation inhibitor refers to a compound with the function of inhibiting cell proliferation.

[0071] Exemplarily, the cell proliferation inhibitor includes any one of Paclitaxel, Docetaxel, Cabazitaxel, Vinorebine, Camptothecin, Hydroxycamptothecin, Rapamycin, Tacrolimus, Adriamycin, Epirubicin, Pirarubicin, Idarubicin, Mitoxantrone, Cytarabine, Gemcitabine, Dexamethasone. The structural formulas are as follows:

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079] Among them, taxane drugs can be rapidly and uniformly taken up by the blood vessel wall due to their strong lipophilicity, and can persistently inhibit the proliferation of smooth muscle cells, which is the main choice for the drug coating on the drug balloon at present. Compared with paclitaxel, rapamycin and its derivatives have less cytotoxicity and are safer in clinical application, but their lipophilicity is slightly inferior to that of paclitaxel.

[0080] In some embodiments, 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 is connected to the second functional group;

[0081] The bridging structure is , m is an integer selected from 2-7, and R1 and R2 are each independently selected from hydrogen, halogen or C1-C10 alkyl.

[0082] By adopting the bridging structure, the chemical splicing of the first functional group and the second functional group is realized. The photosensitive material formed thereby has good liposolubility, can accurately anchor the lesion site, play a blood vessel repair function, and can also play an anti-cell proliferation role, further reducing the risk of in-stent restenosis.

[0083] Compared with the balloon dilatation catheter obtained by directly physically mixing a photosensitive compound (such as the structure shown in III-1) with a cell proliferation inhibitor and then coating it on the surface of the balloon body, when the balloon is delivered and dilated, the photosensitive compound will still be washed away by the blood, and it is difficult to form a natural and stable invisible stent to stably support the blood vessel. The balloon dilatation catheter containing the photosensitive material of the present application can accurately anchor the lesion site, show a better blood vessel dilation effect, and thus effectively solve the problems of blood vessel stenosis and occlusion.

[0084] Further, the halogen is selected from any one of fluorine, chlorine, bromine and iodine.

[0085] Further, the C1-C10 alkyl group includes any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0086] It should be noted that the first functional group is connected to the bridging structure through the terminal amino group in the substituent on the 4-position carbon of the 1,8-naphthalimide skeleton, and the second functional group is connected to the bridging structure through the oxygen atom after dehydrogenation of the reactive hydroxyl group in the cell proliferation inhibitor.

[0087] Exemplarily, the chemical modification at the 2'-hydroxy position of paclitaxel has little effect on the activity of paclitaxel. Similarly, the chemical modification at the 40-hydroxy position of rapamycin also has little effect on its activity. Therefore, in the photosensitive material of the present application, the bridging structure is covalently linked to the 2'-hydroxy group in the paclitaxel molecule or the 40-hydroxy group in the rapamycin molecule.

[0088]

[0089] Further, the chemical structure of the photosensitive material is shown in Formula I. In Formula I, n is an integer from 1 to 6, m is selected from integers from 2 to 7, and R1 and R2 are each independently selected from hydrogen, halogen, or a C1-C10 alkyl group.

[0090]

[0091] Formula I.

[0092] 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.

[0093] In the structural design of the photosensitive material of the present application, by connecting the anti-cell proliferation drug molecule through the bridging structure in the symmetric 1,8-naphthalimide dimer structure, a symmetric photosensitive drug material is obtained. This makes it unnecessary to perform the steps of protecting and deprotecting the terminal amino group of the 1,8-naphthalimide dimer during the preparation process of the material. Therefore, it is easier to prepare the photosensitive material of the present application by chemical synthesis.

[0094] In some embodiments, the chemical structure of the photosensitive material is shown in Formula I-1 or Formula I-2:

[0095]

[0096] Formula I-1

[0097]

[0098] Formula I-2.

[0099] It can be understood that in Formula I-1 and Formula I-2, the meanings of R1, R2, m and n are the same as those in Formula I, and will not be elaborated here.

[0100] Further exemplarily, the chemical structure of the photosensitive material is shown in Formula I-1a or Formula I-2a:

[0101]

[0102] Formula I-1a

[0103]

[0104] Formula I-2a.

[0105] According to an embodiment of the present application, in a second aspect, a method for preparing the photosensitive material described in the first aspect is provided, including the following steps:

[0106] S1. Perform a first condensation reaction between a cell proliferation inhibitor and a substituted or unsubstituted cyclic anhydride to obtain an intermediate;

[0107] The chemical structure of the substituted or unsubstituted cyclic anhydride is shown in Formula II. In Formula II, m is an integer selected from 2-7, and R1 and R2 are each independently selected from hydrogen, halogen, or a C1-C10 alkyl group;

[0108]

[0109] Formula II

[0110] S2. Perform a second condensation reaction between the intermediate and a 4-substituted 1,8-naphthalimide compound to obtain the product.

[0111] By utilizing the structural characteristics of cyclic anhydride compounds, they are respectively subjected to condensation reactions with a cell proliferation inhibitor and a 4-substituted 1,8-naphthalimide compound, so as to join the cell proliferation inhibitor and the 4-substituted 1,8-naphthalimide compound together to construct a photosensitive material with blood vessel 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.

[0112] In some alternative embodiments, S1 is a first condensation reaction carried out in a first organic solvent and in the presence of an organic base.

[0113] Further, 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.

[0114] Further, the molar ratio of the cell proliferation inhibitor, the substituted or unsubstituted cyclic anhydride, and the organic base is 1:5 to 20:20 to 200. This can ensure that the cell proliferation inhibitor reacts completely, thereby guaranteeing the yield of the target product, the photosensitive material.

[0115] In some alternative embodiments, S2 is a second condensation reaction carried out in a second organic solvent in the presence of a condensing agent.

[0116] Further, the condensing 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.

[0117] Further, the molar ratio of the intermediate, the 4-substituted 1,8-naphthalimide compound, and the condensing agent is 1:1 to 10:8 to 20. This can ensure that the intermediate reacts completely, thereby guaranteeing the yield of the target product, the photosensitive material.

[0118] In some alternative embodiments, the chemical structure of the 4-substituted 1,8-naphthalimide compound is shown in Formula III, where n is an integer from 1 to 6;

[0119]

[0120] Formula III.

[0121] It should be noted that the preparation of the 4-substituted 1,8-naphthalimide shown in Formula III refers to the literature by Kelly et al., "Solvent-Dependent Photophysics and Reactivity of Monomeric and Dimeric 4-Amino-1,8-Naphthalimides", J.Phys.Chem.A 2021, 125, 2294 - 2307. It includes the following steps:

[0122] Step 1: Dissolve 4-bromo-1,8-naphthalic 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, and wash the filter cake first with dimethylacetamide (1.5 volumes) and then with tert-butyl methyl ether (4 volumes). Then dry the collected solid material in a vacuum oven at 65 °C to constant weight to obtain purified 4-bromo-1,8-naphthalic anhydride.

[0123] 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 the substituted or unsubstituted cyclic anhydride shown in Formula II (1 equivalent) and dimethylacetamide (3 volumes) to maintain the temperature of the reaction system not exceeding 25 °C. After the addition is complete, stir the resulting mixture overnight at room temperature, then stir at 80 °C for 6 hours. Filter the resulting mixture while it is hot, and wash the filter cake first with dimethylacetamide (washed 4 times, 3 volumes each time) and then with tert-butyl methyl ether (washed 4 times, 3 volumes each time). Dry the collected solid material in a vacuum oven at 45 °C to constant weight to obtain the dimer.

[0124] Step 3: Stir a mixture of the dimer obtained in Step 2, toluene (20 volumes), and the substituted or unsubstituted cyclic anhydride shown in Formula II (20 volumes) at 80 °C for at least 24 hours, and continue to stir for at least 48 hours after cooling. Then filter the resulting suspension, and wash it first with toluene (washed 3 times, 7 volumes each time) and then with acetonitrile (washed 4 times, 7 volumes each time). Dry the separated filter cake with a nitrogen stream on the filter, and store the obtained product (i.e., the 4-substituted 1,8-naphthalimide shown in Formula III) away from light. The total yield of the above three steps is in the range of about 40.5% to about 44.5%.

[0125] According to an embodiment of the present application, in a third aspect, the present application provides the use of the photosensitive material having a blood vessel 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 blood vessel stenosis or occlusion.

[0126] According to an embodiment of the present application, in a fourth aspect, the present application further provides a balloon dilatation catheter, including a balloon body; the surface of the balloon body has a coating, and the coating includes the photosensitive material having a blood vessel repair function described in the first aspect or the photosensitive material prepared by the method described in the second aspect.

[0127] In some alternative 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 to 5 mg / ml, and forming a coating on the surface of the balloon body by means of brushing, spraying, or immersing the balloon body.

[0128] Further, the volatile organic solvent includes at least one of absolute ethanol, ethyl acetate, acetone, isopropanol, and cyclohexane, and the spraying can be carried out by means of ultrasonic atomization or pneumatic atomization.

[0129] After the balloon dilatation catheter provided by the present application is dilated in a blood vessel and activated by an optical fiber with a specific wavelength (450 nm), it can cause covalent bonds to form between amino acids in the blood vessel wall, play a supporting role for the blood vessel, and thus avoid restenosis of the blood vessel.

[0130] The following further describes the present application in detail with specific examples, and these examples should not be construed as limiting the scope claimed by the present application. For those without specific experimental steps or conditions indicated in the examples and comparative examples, the operations or conditions of the conventional experimental steps described in the literature in the art can be followed. For reagents or instruments without the manufacturer indicated, they are all conventional reagent products that can be obtained through commercial purchase.

[0131] In all the examples and comparative examples of the present application, the unit % represents mass percentage.

[0132] Example 1

[0133] The reaction route is as follows:

[0134]

[0135] Add 50 mg (0.060 mmol) of paclitaxel and 74 mg (0.74 mmol) of succinic anhydride (molar ratio 1 / 12.3) to a round-bottom flask, add 2 mL of dichloromethane to dissolve, and add 0.6 mL of pyridine to dissolve it. Stir at room temperature for 3 hours. Detect the reaction progress by thin-layer chromatography. After all the paclitaxel has reacted, remove the solvent by vacuum concentration at room temperature, add 5 mL of deionized water and stir for 20 min. After stirring, filter, wash the precipitate with water, and finally vacuum-dry the precipitate for 12 hours to obtain Intermediate 1 (yield 90%).

[0136] Dissolve the intermediate 1 (36 mg, 0.038 mmol) prepared in the previous step, N-hydroxysuccinimide (NHS, 80 mg, 0.70 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl, 80 mg, 0.42 mmol) in 2 mL of N,N-dimethylformamide, stir at room temperature for 2 hours, then dissolve the 4-substituted 1,8-naphthalimide dimer shown in Formula 1 (36 mg, 0.044 mmol) in 1 mL of N,N-dimethylformamide and add it to the above system. Stir the mixture at room temperature overnight. After the reaction is completed, extract with water and dichloromethane. Take the organic phase, add anhydrous magnesium sulfate for drying and filter, concentrate, and separate by column chromatography to obtain the paclitaxel photosensitive material shown in Formula I-1a (yield 48%). Its mass spectrometry data is: HRMS (ESI) m / z [M+H] + C 144 H 159 N8O 42 Calculated value: 2672.0552, Found value: 2672.0547.

[0137] Example 2

[0138] The reaction route is as follows:

[0139]

[0140] Add 50 mg (0.055 mmol) of rapamycin and 69 mg (0.69 mmol) of succinic anhydride (molar ratio 1 / 12.5) to a round-bottom flask, add 2 mL of N,N-dimethylformamide to dissolve, and add 0.6 mL of pyridine to dissolve it. Stir at 60 °C for 4 hours. Detect the reaction progress by thin-layer chromatography. After all the rapamycin has reacted, remove the solvent by vacuum concentration at room temperature, add 5 mL of deionized water and stir for 20 min. After stirring, filter, wash the precipitate with water, and then vacuum-dry the precipitate for 12 hours to obtain intermediate 2 (yield 82%).

[0141] The intermediate 2 (45 mg, 0.044 mmol) prepared in the previous step, N-hydroxysuccinimide (NHS, 80 mg, 0.70 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl, 80 mg, 0.42 mmol) were dissolved in 2 mL of N,N-dimethylformamide and stirred at room temperature for 2 hours. Then, the 4-substituted 1,8-naphthalimide dimer shown in Formula 1 (53 mg, 0.066 mmol) was dissolved in 1 mL of N,N-dimethylformamide and added to the above system. The mixture was stirred overnight at room temperature. After the reaction was completed, it was extracted with water and dichloromethane. The organic phase was taken, dried over anhydrous magnesium sulfate, filtered, concentrated, and separated by column chromatography to obtain the rapamycin photosensitive material shown in Formula I-2a (yield 53%). Its mass spectrometry data was: HRMS (ESI) m / z [M+H] + C 152 H 215 N8O 40 Calculated value: 2792.5036, measured value: 2792.5030.

[0142] Example 3

[0143] The paclitaxel photosensitive material prepared in Example 1 was dissolved in absolute 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 by an ultrasonic spraying machine to form a coating.

[0144] Example 4

[0145] The rapamycin photosensitive material prepared in Example 2 was dissolved in absolute 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 by an ultrasonic spraying machine to form a coating.

[0146] Comparative Example 1

[0147] It was different from Example 3 only in that the compound shown in Formula 1, i.e., (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)), was used to replace the paclitaxel photosensitive material in Example 3.

[0148]

[0149] Formula 1

[0150] Comparative Example 2

[0151] It was different from Example 3 only in that the compound shown in Formula 2 was used to replace the paclitaxel photosensitive material in Example 3.

[0152]

[0153] Formula 2

[0154] Comparative Example 3

[0155] It is different from Example 3 only in that the substance obtained by physically mixing the compound having the structure shown in Formula 1 and paclitaxel at a molar ratio of 1:2 is used to replace the paclitaxel photosensitive material in Example 3.

[0156]

[0157] Formula 1

[0158] Comparative Example 4

[0159] It is different from Example 3 only in that no coating is provided on the surface of the balloon body in this comparative example.

[0160] Experimental Example 1: Vasodilation experiment

[0161] The redundant tissues around the blood vessel were dissected, a section was cut and opened to measure the blood vessel circumference, denoted as a, and the initial diameter was obtained, denoted as d, d = a / π; according to the blood vessel diameter, a balloon dilation catheter of appropriate size was selected, and the blood vessels were dilated with a balloon dilation catheter containing a photosensitive material coating (Examples 3-4, Comparative Examples 1-3) and a common balloon dilation catheter without any coating (Comparative Example 4) respectively. After pressurizing to the specified pressure, the blood vessels were irradiated with a 450 nm optical fiber for 1 minute; after the blood vessels were irradiated, the optical fiber and the balloon dilation catheter were withdrawn, and the dilated blood vessels were cut open and measured for the circumference, denoted as A, and the dilated diameter was calculated and denoted as D, D = A / π; the blood vessel gain was calculated, denoted as X%, X% = (D - d) / d * 100%.

[0162] Table 1 Results of vasodilation experiment

[0163]

[0164] As can be seen from Table 1, compared with Comparative Example 4 without the photosensitive material coating, the balloon dilatation catheters using the photosensitive material coating (Comparative Examples 1-3 and Examples 3-4) can all achieve the effect of blood vessel dilation to a certain extent. And compared with Comparative Example 1 coated with the structural compound shown in Formula 1, Comparative Example 2 coated with the structural compound shown in Formula 2, and Comparative Example 3 coated with the physical mixture of the structural compound shown in Formula 1 and paclitaxel, the blood vessel dilation effect of Examples 3-4 is more obvious. This shows that introducing a functional group with the function of inhibiting cell proliferation into the chemical structure of the naphthalimide dimer can improve the hydrophobicity of the photosensitive material, avoid the photosensitive material being washed away by blood after entering the blood vessel, enable the photosensitive material of the present application to accurately anchor at the lesion site, thereby better exerting the blood vessel repair function and effectively solving the problems of blood vessel stenosis and occlusion.

[0165] Experimental Example 2: Contact Angle Test

[0166] The balloon catheters in Example 3, Example 4, Comparative Example 1, Comparative Example 2, and Comparative Example 4 were subjected to contact angle tests, and the results are as Figures 1 - 5 shown. As can be seen from the figure, 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 away by blood flow. Therefore, compared with Comparative Examples 1, 2, and 4, Examples 3-4 are less likely to be washed away by blood flow.

[0167] Thus, it can be seen that during the intravascular delivery process of the balloon dilatation catheter provided by the present application, the loss of the photosensitive material caused by blood flow scouring can be reduced, so that more photosensitive materials can reach the lesion site and play the role of repairing blood vessels.

[0168] Experimental Example 3: Anti-Proliferation Activity Test

[0169] The pre-cultured cells were digested, centrifuged, and counted. 100 μL of HEK293T cells (human embryonic kidney cells 293) at 3k-7k / well were inoculated on a 96-well plate and cultured at 37 °C, 5% CO2, and 90% humidity for 24 hours. Then, the cell growth state and density were observed under a microscope, and wells with good growth state, uniform cell distribution and density were selected for the experiment.

[0170] The paclitaxel photosensitive material prepared in Example 1, the rapamycin photosensitive material prepared in Example 2, paclitaxel, and rapamycin were respectively formulated into sample solutions with different concentration gradients (0 μM, 25 μM, 50 μM, 100 μM, 250 μM, 500 μM). Three replicate wells of each concentration were added to a 96-well plate and cultured for 24 hours under the conditions of 37 °C, 5% CO2, and 90% humidity. The cell growth status was detected using an inverted microscope, and wells with good growth status, uniform cell distribution, and density were photographed and recorded at 4X / 10X magnification. 10 μL of CCK-8 solution was added to each well and cultured for 2 hours under the conditions of 37 °C, 5% CO2, and 90% humidity. The absorbance was measured at 450 nm using an enzyme-linked immunosorbent assay (ELISA) reader, and the analysis results were processed as Figure 6 shown.

[0171] As can be seen from Figure 6 , 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 by introducing a functional group with an inhibitory effect on cell proliferation into the chemical structure of the naphthalimide dimer, the photosensitive material of the present application can, on the basis of accurately anchoring the lesion site to play a role in blood vessel repair, simultaneously exert an anti-cell proliferation effect, thereby further reducing the risk of in-stent restenosis.

[0172] Obviously, the above examples are only for clear illustration and not a limitation of the implementation mode. For those of ordinary skill in the art, other different forms of changes or modifications can be made on the basis of the above description. It is not necessary and impossible to list all the implementation modes here. The obvious changes or modifications derived therefrom are still within the protection scope of the present invention.

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 a function of inhibiting cell proliferation, and the second functional group is selected from a dehydrogenated group of a cell proliferation inhibitor that can provide a reactive hydroxyl group, which is denoted as -O-R3; the cell proliferation inhibitor is selected from any one of paclitaxel, docetaxel, cabazitaxel, vinorelbine, camptothecin, hydroxycamptothecin, rapamycin, tacrolimus, doxorubicin, epirubicin, pirarubicin, idarubicin, mitoxantrone, cytarabine, gemcitabine, and dexamethasone; The chemical structure of the photosensitive material is shown in Formula I: Formula I In formula I, n is an integer of 1-6; m is an integer selected from 2-7, and R1 and R2 are independently selected from hydrogen, halogen or C1-C10 alkyl.

2. The photosensitive material with vascular repair function according to claim 1, characterized in that: The halogen is selected from any one of fluorine, chlorine, bromine and iodine; And / or, the C1-C10 alkyl group is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

3. The photosensitive material with vascular repair function according to claim 1 or 2, 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.

4. The photosensitive material with vascular repair function according to claim 3, 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.

5. The method for preparing the photosensitive material with vascular repair function according to any one of claims 1 to 4, 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; 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.

6. Use of the photosensitive material with vascular repair function as claimed in any one of claims 1 to 4 or the photosensitive material prepared by the method as claimed in claim 5 in the preparation of a drug for treating vascular stenosis or occlusion.

7. 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 according to any one of claims 1 to 4 or the photosensitive material prepared by the method according to claim 5.

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