Platinum drug ultra-carbon dot as well as preparation method and application thereof
Platinum-based supercarbon dots, formed by assembling platinum-based carbon nanodots with substituted aromatic compounds, solve the problems of short excitation wavelength and poor penetration of light in photocontrolled release of platinum-based drugs, achieving efficient tumor enrichment and immune response under near-infrared light, thus enhancing the therapeutic effect.
Patent Information
- Application Number
- CN202410309026.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-05-17
- Publication Date
- 2025-11-18
AI Technical Summary
Existing photocontrolled release platinum drugs suffer from problems such as short excitation wavelength, poor in vivo penetration, insufficient water solubility and tumor accumulation capacity, and short circulation time.
Platinum drug carbon nanodots are assembled with substituted aromatic compounds to form platinum drug supercarbon dots. Near-infrared light response is used to reduce and release divalent platinum compounds and hydroxyl radicals. Platinum drug supercarbon dots with J-type aggregate structure are formed through solvothermal reaction and ultrasonic self-assembly, and the excitation wavelength is redshifted to 600-1200 nm.
It improves the drug's penetration and tumor accumulation in vivo, enhances endocytosis efficiency, and can rapidly generate highly cytotoxic Pt(II) compounds and hydroxyl radicals under near-infrared light irradiation, thereby activating anti-tumor immune responses, reducing side effects, and improving therapeutic efficacy.
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Abstract
Description
Technical Field
[0001] This invention relates to the pharmaceutical field, specifically to a platinum drug supercarbon point, its preparation method, and its application. Background Technology
[0002] Photocontrolled release of platinum-based drugs is a personalized treatment approach that utilizes specific light conditions to precisely release drug molecules at the lesion site in both time and space. It has many advantages, such as high drug utilization and low toxicity, providing new ideas for the precision treatment of various major diseases, such as tumors. However, current photocontrolled release of platinum-based drugs generally have at least one of the following drawbacks: (1) The excitation light is of short wavelength, resulting in poor in vivo penetration and poor therapeutic effect; (2) As small molecule compounds, they have poor water solubility, poor tumor accumulation ability, and short circulation time. Summary of the Invention
[0003] In order to overcome the problems existing in the prior art, one of the objectives of the present invention is to provide a platinum drug supercarbon point.
[0004] The second objective of this invention is to provide a method for preparing platinum drug supercarbon dots.
[0005] A third objective of this invention is to provide a pharmaceutical composition for treating cancer.
[0006] The fourth objective of this invention is to provide an application of platinum drug supercarbon dots in the preparation of light-controlled release platinum drugs.
[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:
[0008] The first aspect of this invention provides a platinum-based supercarbon dot, which is assembled from platinum-based carbon nanodots; the platinum-based carbon nanodots are coordination compounds of a platinum-based drug and a substituted aromatic compound; the platinum-based drug is selected from at least one of carboplatin oxide, cisplatin oxide, cisplatin diacid, and oxaliplatin oxide; the substituted aromatic compound is selected from...
[0009]
[0010]
[0011] Each of R1, R2, R3, and R4 is independently selected from -(CH2). m NH2, -O(CH2) m NH2、-(CH2) m OH, -(CH2) m NO2, -O(CH2) m NO2、-(CH2) m COOH, -O(CH2) mCOOH, -(CH2) m CHO;
[0012] m is a natural number from 0 to 10.
[0013] The substituted aromatic compounds in this invention have visible light absorption properties. Their coordination compounds with platinum drugs can self-assemble to form platinum drug supercarbon dots with near-infrared light response. Under near-infrared light irradiation, they can be reduced to divalent platinum compounds and hydroxyl radicals with anti-cancer effects. The specific mechanism is as follows: Under near-infrared light irradiation, the substituted aromatic compounds generate hole-electron pairs. The excited electrons are captured by platinum (IV) in the platinum drug and undergo a reduction reaction, releasing platinum (II)-containing compounds. The holes formed by photoexcitation on the valence band react with hydroxide ions in aqueous solution on the surface of the platinum drug supercarbon dots to form hydroxyl radicals.
[0014] The structural formula of carboplatin oxide is The structural formula of oxaliplatin oxide is The structural formula of cisplatin oxide is
[0015] Preferably, the platinum drug supercarbon dots have a J-type aggregate structure.
[0016] Preferably, m is selected from natural numbers from 0 to 3.
[0017] Preferably, m is 0, that is, each R1, R2, R3, R4 is independently selected from -NH2, -ONH2, -OH, -NO2, -ONO2, -COOH, -OCOOH, and -CHO.
[0018] Preferably, the substituted aromatic compound is selected from...
[0019]
[0020] Preferably, when the substituted aromatic compound is When the platinum drug is cisplatin oxide, the reaction formula for preparing platinum drug carbon nanodots is:
[0021]
[0022] In the above reaction process, excess p-phenylenediamine forms a dimer and further coordinates with the hydroxyl groups of cisplatin oxide to form platinum-based carbon nanodots. It should be noted that aromatic compounds of diamines include, but are not limited to, p-phenylenediamine, and at least one of compounds with any two amino groups substituted with perylene, naphthalene, anthracene, phenanthrene, etc.
[0023] The substituted aromatic compounds in this invention can redshift the excitation wavelength and improve the in vivo penetration of platinum drug supercarbon dots.
[0024] Preferably, the particle size of the platinum drug supercarbon dots is 80–250 nm.
[0025] Preferably, the particle size of the platinum drug carbon nanodots is 1–20 nm.
[0026] Preferably, the excitation wavelength of the platinum drug supercarbon dots is redshifted by 100 to 500 nm compared to the excitation wavelength of the platinum drug carbon nanodots.
[0027] Preferably, the excitation wavelength of the platinum supercarbon point is 600–1200 nm.
[0028] The second aspect of the present invention provides a method for preparing platinum drug supercarbon dots as provided in the first aspect of the present invention, comprising the following steps:
[0029] S1: Platinum-based drugs and substituted aromatic compounds are subjected to a solvothermal reaction to obtain platinum-based carbon nanodots;
[0030] S2: The platinum drug carbon nanodots are self-assembled to obtain the platinum drug supercarbon dots.
[0031] Preferably, the molar ratio of the platinum drug to the substituted aromatic compound is 1:(0.0001 to 10000); more preferably, the molar ratio of the platinum drug to the substituted aromatic compound is 1:(0.01 to 100); even more preferably, the molar ratio of the platinum drug to the substituted aromatic compound is 1:(0.3 to 3).
[0032] Preferably, the solvent used in the solvothermal reaction in step S1 is selected from at least one of dimethyl sulfoxide, N,N'-dimethylformamide, water, formic acid, ethanol, diethyl ether, tetrahydrofuran, folic acid, and acetone. That is, the reaction solvent can be selected individually from dimethyl sulfoxide, N,N'-dimethylformamide, water, formic acid, ethanol, diethyl ether, tetrahydrofuran, folic acid, or acetone, or a mixture of two or more of these substances can be selected, and the mixing ratio is not limited.
[0033] Preferably, the mass-to-volume ratio of the substituted aromatic compound to the reaction solvent is (0.001-1) g: 1 mL.
[0034] Preferably, the self-assembly step involves mixing the platinum drug carbon nanodots with a solvent and then sonicating them.
[0035] Preferably, the ultrasonic power is 0.1-100 W / cm². 3 .
[0036] Preferably, the ultrasound time is 0.01 to 100 min.
[0037] Preferably, the self-assembly step involves mixing the platinum drug carbon nanodots with a solvent and then heating the mixture.
[0038] Preferably, the solvent in the self-assembly step is a mixture of polar and non-polar solvents.
[0039] Preferably, the polar solvent is selected from at least one of dimethyl sulfoxide, water, dimethylformamide, ethanol, and methanol.
[0040] Preferably, the nonpolar solvent is selected from at least one of tetrahydrofuran, toluene, dichloromethane, ethyl acetate, acetone, and diethyl ether.
[0041] Preferably, the volume ratio of the polar solvent to the non-polar solvent is (0.01–100):1. The mixing of the polar and non-polar solvents can promote the self-assembly of platinum-doped carbon nanodots into platinum-doped supercarbon dots.
[0042] A third aspect of the invention provides a pharmaceutical composition for treating cancer, comprising a therapeutically effective amount of the platinum supercarbonate provided in the first aspect of the invention and pharmaceutically acceptable excipients.
[0043] Preferably, the pharmaceutical composition is a photoactive anticancer drug.
[0044] The fourth aspect of the present invention provides the application of the platinum drug supercarbon dots provided in the first aspect of the present invention in the preparation of light-controlled release platinum drugs.
[0045] In this invention, platinum drug supercarbon dots refer to regular platinum drug supercarbon dots assembled by non-chemical bond interactions between platinum drug carbon nanodots, similar to supramolecular compounds, and their English name is supra-CDs.
[0046] The beneficial effects of this invention are as follows: the platinum drug supercarbon dots in this invention have a longer laser wavelength, and the excitation light has better penetration in the body, which can further improve the circulation of platinum drug supercarbon dots in the body, and have high efficiency in cell endocytosis and tumor accumulation. In addition, the platinum drug supercarbon dots in this invention can accumulate in cancer cells or tumor cells. Under near-infrared light irradiation, they can rapidly produce highly cytotoxic Pt(II) compounds and hydroxyl radicals, causing cancer cells to undergo immunogenic death. While killing cancer cells, they also activate the body's anti-tumor immune response.
[0047] The platinum drug supercarbon dots in this invention are formed by the self-assembly of platinum drug carbon nanodots coordinated with platinum drug and substituted aromatic compounds, thereby forming J-type aggregates. The platinum drug carbon nanodots are orderly stacked into a regular structure. The excitation wavelength of the assembled platinum drug supercarbon dots is red-shifted, thereby obtaining platinum drug supercarbon dots with a long wavelength window stimulation response (excitation wavelength of 600-1200 nm).
[0048] The preparation method of platinum drug supercarbon points in this invention is simple. It can be obtained by direct ultrasonic or heating mixing after solvothermal reaction. It is easy to operate, requires no special equipment, does not pollute the environment, and is suitable for large-scale industrial production. Attached Figure Description
[0049] Figure 1 This is a TEM image of the platinum drug carbon nanodots in Example 1.
[0050] Figure 2 This is a TEM image of the supercarbon dots of the platinum drug in Example 1.
[0051] Figure 3 This is a TEM image of the supercarbon dots of the platinum drug in Example 3.
[0052] Figure 4 This is a TEM image of the supercarbon dots of the platinum drug in Example 4.
[0053] Figure 5 This is a TEM image of the supercarbon dots of the platinum drug in Example 5.
[0054] Figure 6 The image shows the two-dimensional fluorescence spectra of platinum drug carbon nanodots and platinum drug supercarbon dots in Example 1.
[0055] Figure 7 The images show the ultraviolet spectra of platinum drug carbon nanodots and platinum drug supercarbon dots in Example 1.
[0056] Figure 8 This is a fluorescence lifetime test diagram of the platinum drug supercarbon dots in Example 1.
[0057] Figure 9 The image shows the two-dimensional fluorescence spectra of platinum drug carbon nanodots and platinum drug supercarbon dots in Example 4.
[0058] Figure 10 The image shows the two-dimensional fluorescence spectra of platinum drug carbon nanodots and platinum drug supercarbon dots in Example 5.
[0059] Figure 11 This is an EDS diagram of the supercarbon dots of the platinum drug in Example 1.
[0060] Figure 12 The particle size distribution test diagrams are for platinum drug carbon nanodots and platinum drug supercarbon dots in Example 1.
[0061] Figure 13 XPS spectra of platinum drug carbon nanodots in Example 1 before, after, and after light exposure, as well as the released products.
[0062] Figure 14 The image shows the N-spectrum XPS spectra of the platinum drug carbon nanodots in Example 1 before and after illumination.
[0063] Figure 15 The image shows the O spectrum of the XPS energy distribution of the platinum drug carbon nanodots in Example 1 before and after light irradiation.
[0064] Figure 16 The images show XPS Pt spectra of the platinum drug carbon nanodots before and after irradiation and the sustained-release product in Example 1.
[0065] Figure 17 This is a test diagram of the photothermal conversion effect of the platinum drug supercarbon dots in Example 1.
[0066] Figure 18 This is a test diagram of the photothermal conversion effect of the platinum drug supercarbon dots in Example 1.
[0067] Figure 19 The image shows a laser confocal test pattern of platinum-doped carbon nanodots and platinum-doped supercarbon dots from Example 1.
[0068] Figure 20 The image shows the cytotoxicity test results of platinum drug carbon nanodots and platinum drug supercarbon dots in Example 1.
[0069] Figure 21 This is a test diagram showing the effect of platinum drug carbon nanodots and platinum drug supercarbon dots on ATPase in Example 1.
[0070] Figure 22 This is a graph showing the effect of platinum drug carbon nanodots and platinum drug supercarbon dots on the expression of calreticulin and high-mobility group group B1 in Example 1.
[0071] Figure 23 This is a small animal imaging test image of platinum drug carbon nanodots and platinum drug supercarbon dots from Example 1.
[0072] Figure 24 The image shows thermal imaging test results of platinum drug carbon nanodots and platinum drug supercarbon dots from Example 1.
[0073] Figure 25 This is a tissue imaging test image of platinum drug carbon nanodots and platinum drug supercarbon dots from Example 1.
[0074] Figure 26 This is a tumor volume test image of platinum drug carbon nanodots and platinum drug supercarbon dots under non-light illumination, as shown in Example 1.
[0075] Figure 27 The image shows the tumor volume test results of platinum drug carbon nanodots and platinum drug supercarbon dots under light irradiation in Example 1.
[0076] Figure 28 The image shows the lung tissue of mice treated with platinum-based carbon nanodots and platinum-based supercarbon dots as described in Example 1. Detailed Implementation
[0077] The specific implementation of the present invention will be further described in detail below with reference to the accompanying drawings and examples, but the implementation and protection of the present invention are not limited thereto. It should be noted that any processes not specifically described in detail below are those that can be implemented or understood by those skilled in the art by referring to the prior art. Reagents or instruments used without specified manufacturers are all conventional products that can be purchased commercially.
[0078] In this invention, Pt-CDs refer to unassembled platinum drug carbon nanoparticles in specific embodiments; Hagg-CDs refer to self-assembled platinum drug supercarbon dots in specific embodiments; Pt-CDs in sonication refers to the intermediate state during the sonication process, in which both platinum drug carbon nanoparticles and platinum drug supercarbon dots exist.
[0079] Example 1
[0080] This example provides a self-assembled platinum drug supercarbon dot solid, which is prepared by the following method, the specific steps of which are as follows:
[0081] Weigh 0.1 g of cisplatin oxide and 0.1 g of p-phenylenediamine, add 30 mL of N,N-dimethylformamide to a polytetrafluoroethylene reactor, and then place it in an oven at 200 °C for 6 h. Remove the solution and dialyze it with ultrapure water. The molecular weight of the dialysis bag is 1000-3000 Da. After dialysis filtration, freeze-dry to obtain platinum drug carbon nanodot solid.
[0082] Weigh 0.5g of platinum drug carbon nanodot solid and dissolve it in 0.1mL of DMF. Add 5mL of water and then sonicate for 20 minutes to obtain the self-assembled platinum drug supercarbon dot solid in this example.
[0083] Example 2
[0084] This example provides a self-assembled platinum drug supercarbon dot solid, which is prepared by the following method, the specific steps of which are as follows:
[0085] Weigh 0.1 g of oxaliplatin oxide and 0.1 g of tetraaminophenylporphyrin (TCCP), add 20 mL of N,N-dimethylformamide to a polytetrafluoroethylene reactor, and then place it in an oven at 250 °C for 4 h. After that, take out the solution and dialyze it with ultrapure water. The molecular weight of the dialysis bag is 1000-3000 Da. After dialysis filtration, freeze-dry to obtain platinum drug carbon nanodot solid.
[0086] Weigh 0.5g of platinum drug carbon nanodots and dissolve them in 0.1mL of DMF. Add 5mL of water and then sonicate for 20 minutes to obtain the self-assembled platinum drug supercarbon dot solid in this example.
[0087] Example 3
[0088] This example provides a self-assembled platinum drug supercarbon dot solid, which is prepared by the following method, the specific steps of which are as follows:
[0089] Weigh 0.1 g of oxaliplatin oxide and 0.1 g of dihydroporphyrin E6, then add 40 mL of dimethyl sulfoxide to a polytetrafluoroethylene reactor, and then place it in an oven at 180 °C for 9 h. Remove the solution and dialyze it with ultrapure water. The molecular weight of the dialysis bag is 1000-3000 Da. After dialysis filtration, freeze-dry to obtain the platinum drug carbon nanodot solid in this example.
[0090] Weigh 0.5g of platinum drug carbon nanodots and dissolve them in 0.1mL of DMF. Add 5mL of water and then sonicate for 20 minutes to obtain the self-assembled platinum drug supercarbon dot solid in this example.
[0091] Example 4
[0092] This example provides a self-assembled platinum drug supercarbon dot solid, which is prepared by the following method, the specific steps of which are as follows:
[0093] Weigh 0.1 g of oxaliplatin oxide and 0.1 g of trimesin, add 30 mL of N,N-dimethylformamide to a polytetrafluoroethylene reactor, and then place it in an oven at 200 °C for 6 h. Remove the solution and dialyze it with ultrapure water. The molecular weight of the dialysis bag is 1000-3000 Da. After dialysis filtration, freeze-dry to obtain platinum drug carbon nanodot solids.
[0094] Weigh 0.5g of platinum drug carbon nanodots and dissolve them in 0.1mL of DMF. Add 5mL of water and then sonicate for 20 minutes to obtain the self-assembled platinum drug supercarbon dot solid in this example.
[0095] Example 5
[0096] This example provides a self-assembled platinum drug supercarbon dot solid, which is prepared by the following method, the specific steps of which are as follows:
[0097] 0.1 g of oxaliplatin oxide and 0.5 g of tetrachloroperyltetracarboxylic acid dianhydride were weighed and added to 30 mL of N,N-dimethylformamide in a polytetrafluoroethylene reactor. The reactor was placed in an oven and reacted at 200 °C for 6 h. The solution was then removed and dialyzed with ultrapure water. The molecular weight of the dialysis bag was 1000–3000 Da. After dialysis filtration, the solution was freeze-dried to obtain platinum drug carbon nanoparticles. These nanoparticles were then assembled using ultrasound to obtain the self-assembled platinum drug supercarbon nanoparticles with a particle size of 100–150 nm.
[0098] Example 6
[0099] This example provides a self-assembled platinum drug supercarbon dot solid, which is prepared by the following method, the specific steps of which are as follows:
[0100] 0.1 g of carboplatin oxide and 0.1 g of dihydroporphyrin E6 (Ce6) were weighed and added to 30 mL of N,N-dimethylformamide in a polytetrafluoroethylene reactor. The reactor was placed in an oven and reacted at 200 °C for 6 h. The solution was then removed and dialyzed with ultrapure water. The molecular weight of the dialysis bag was 1000–3000 Da. After dialysis filtration, the solution was freeze-dried to obtain platinum drug carbon nanodot solids. These were then assembled by ultrasound to obtain the self-assembled platinum drug supercarbon dot solids in this example.
[0101] Example 7
[0102] This example provides a self-assembled platinum drug supercarbon dot solid, which is prepared by the following method, the specific steps of which are as follows:
[0103] Weigh 0.5g of the platinum drug carbon nanodots from Example 1 and dissolve them in 0.1mL of DMF. Add 5mL of water and stir at 60°C for one hour to obtain the self-assembled platinum drug supercarbon dot solid in this example.
[0104] Example 8
[0105] This example provides a self-assembled platinum drug supercarbon dot solid, which is prepared by the following method, the specific steps of which are as follows:
[0106] Weigh 0.5g of the platinum drug carbon nanodots from Example 2 and dissolve them in 0.1mL of DMF. Add 5mL of water and stir at 60°C for one hour to obtain the self-assembled platinum drug supercarbon dot solid in this example.
[0107] Example 9
[0108] This example provides a self-assembled platinum drug supercarbon dot solid, which is prepared by the following method, the specific steps of which are as follows:
[0109] Weigh 0.5g of the platinum drug carbon nanodots from Example 3 and dissolve them in 0.1mL of DMF. Add 5mL of water and stir at 60°C for one hour to obtain the self-assembled platinum drug supercarbon dot solid in this example.
[0110] Example 10
[0111] This example provides a self-assembled platinum drug supercarbon dot solid, which is prepared by the following method, the specific steps of which are as follows:
[0112] Weigh 0.5g of the platinum drug carbon nanodots from Example 4 and dissolve them in 0.1mL of DMF. Add 5mL of water and stir at 60°C for one hour to obtain the self-assembled platinum drug supercarbon dot solid in this example.
[0113] Example 11
[0114] This example provides a self-assembled platinum drug supercarbon dot solid, which is prepared by the following method, the specific steps of which are as follows:
[0115] Weigh 0.5g of the platinum drug carbon nanodots from Example 5 and dissolve them in 0.1mL of DMF. Add 5mL of water and stir at 60°C for one hour to obtain the self-assembled platinum drug supercarbon dot solid in this example.
[0116] Performance testing:
[0117] Tests showed that the platinum-based supercarbon dots in Examples 1-11 of this invention have essentially the same performance. For ease of explanation, only the test results of some examples are listed below:
[0118] (1) Morphological test
[0119] The surface structure of the platinum-doped carbon nanodots in Example 1 was tested using transmission electron microscopy. Specific test results are as follows: Figure 1 As shown in (a), the surface structure of the platinum-doped carbon nanodots in Example 1 was then tested using a high-power transmission electron microscope. The specific test results are as follows: Figure 1 As shown in (b), by Figure 1 (a) and Figure 1 (b) It can be seen that the particle size of the platinum-doped carbon nanodots in Example 1 is about 5 nm; the lattice fringe spacing under high magnification is 0.21 nm, proving that the platinum-doped carbon nanodots were successfully prepared. Then, the TEM image of the platinum-doped carbon nanodots in Example 1 was tested using transmission electron microscopy, as shown in the figure below. Figure 2 As shown, where, Figure 2 (a) Figure 2 (b) and Figure 2 (c) TEM images of the platinum-based supercarbon dots at scale bars of 100 nm, 20 nm, and 2 nm, respectively. Figure 2 It is known that the particle size of the platinum drug supercarbon dots is about 200 nm, and they are assembled into platinum drug supercarbon dots with a hollow structure. It can be observed that the hollow structure of the platinum drug supercarbon dots is constructed from platinum drug carbon nanodots of about 5 nm, and the lattice fringe spacing is 0.21 nm.
[0120] The surface structure of the platinum-based supercarbon dots in Example 3 was tested using transmission electron microscopy. Specific test results are as follows: Figure 3 As shown, where, Figure 3 (a) Figure 3 (b) and Figure 3 (c) TEM images of the platinum-based supercarbon dots at scale bars of 100 nm, 20 nm, and 2 nm, respectively. Figure 3 (a) It can be seen that the platinum drug supercarbon dots in Example 3 are nanocluster structures with a particle size of about 100 nm; Figure 3(b) It can be seen that the platinum drug supercarbon dots of the nanocluster structure are constructed from platinum drug carbon nanodots of about 5 nm, and the lattice fringe spacing is 0.21 nm.
[0121] The surface structure of the platinum-based supercarbon dots in Example 4 was tested using transmission electron microscopy. Specific test results are as follows: Figure 4 As shown in (a), by Figure 4 (a) It can be seen that the platinum supercarbon dots in Example 4 are hollow spherical structures with a particle size of about 50 nm; then, the surface structure of the platinum supercarbon dots in Example 4 was tested using a high-power transmission electron microscope, and the specific test results are as follows. Figure 4 As shown in (b), by Figure 4 (b) It can be seen that the arc-shaped lattice fringes are monodisperse carbon dots that curl up under ultrasonic action and self-assemble into hollow spheres with a particle size of about 50 nm.
[0122] The surface structure of the platinum-based supercarbon dots in Example 5 was tested using transmission electron microscopy. Specific test results are as follows: Figure 5 As shown, by Figure 5 It can be seen that the platinum drug supercarbon dots in Example 5 are cluster structures with a particle size of 100-150 nm, which are assembled from individual platinum drug carbon nanodots.
[0123] (2) Optical performance testing
[0124] The platinum drug carbon nanodots and platinum drug supercarbon dots in Example 1 were subjected to ultraviolet and fluorescence spectroscopy analysis. The specific test results are as follows: Figures 6-7 As shown, the two-dimensional fluorescence spectra of platinum drug carbon nanodots and platinum drug supercarbon dots are as follows. Figure 6 (a) and Figure 6 As shown in (b), the ultraviolet spectra of platinum drug carbon nanodots and platinum drug supercarbon dots are as follows. Figure 7 As shown. By Figure 6 It can be seen that the excitation and emission spectral ranges of the platinum-doped carbon nanodots obtained in Example 1 are 380-580 nm and 550-700 nm, respectively. The platinum-doped supercarbon nanodots formed through ultrasonic self-assembly exhibit a red shift in their spectra, with excitation and emission spectral ranges of 550-680 nm and 600-800 nm, respectively. Figure 7 It can be seen that platinum drug carbon nanodots (corresponding to Figure 7 The main absorption peak of Pt-CDs is at 420 nm, which is achieved through self-assembly of platinum drug supercarbon dots (corresponding to Figure 7 The main absorption of Hagg-CDs in the sample is at 600 nm, further demonstrating that red-shifted platinum drug supercarbon dots can be obtained through ultrasonic assembly. Then, fluorescence lifetime tests were performed on the platinum drug supercarbon dots from Example 1, and the specific test results are as follows: Figure 8 As shown. By Figure 8It can be seen that once platinum drug carbon nanodots self-assemble into platinum drug supercarbon dots, their fluorescence lifetime increases significantly, from 7.9 ns for Pt-CDs to 19.8 ns for Hagg-CDs, indicating that energy transfer occurs.
[0125] The two-dimensional fluorescence spectra of platinum drug carbon nanodots and platinum drug supercarbon dots in Example 4 were tested, and the test results are as follows: Figure 9 (a) and Figure 9 As shown in (b). Figure 9 It can be seen that, compared with platinum drug carbon nanodots, the fluorescence emission of platinum drug supercarbon dots assembled by ultrasound is extended from the original 400nm (emission wavelength of platinum drug carbon nanodots) to 750nm, which confirms that ultrasound can induce the assembly of individual platinum drug carbon nanodots into hollow platinum drug supercarbon dots, and will cause a spectral redshift.
[0126] The two-dimensional fluorescence spectra of platinum drug carbon nanodots and platinum drug supercarbon dots in Example 5 were tested, and the test results are as follows: Figure 10 (a) and Figure 10 As shown in (b). Figure 10 It can be seen that, compared with platinum drug carbon nanodots, the fluorescence emission of platinum drug supercarbon dots assembled by ultrasound is extended from the original 600nm (emission wavelength of platinum drug carbon nanodots) to 700nm, which confirms that ultrasound can induce the assembly of individual platinum drug carbon nanodots into platinum drug supercarbon dots and cause a spectral redshift.
[0127] The excitation wavelength of the platinum drug supercarbon dots in this invention is redshifted compared to platinum drug carbon nanodots. A higher excitation wavelength will result in a greater penetration depth, thereby improving the tumor enrichment ability and therapeutic effect of platinum drug supercarbon dots, especially in terms of cellular efficacy and animal efficacy, which is significantly better than platinum drug carbon nanodots.
[0128] (3) EDS analysis
[0129] EDS analysis was performed on the elemental composition of the platinum supercarbon point in Example 1. The specific test results are as follows: Figure 11 As shown. By Figure 11 It can be seen that the platinum-based supercarbon dots in Example 1 have C, N, O, Cl, and Pt signals, indicating that platinum successfully participated in the formation of carbon nanodots.
[0130] (4) Particle size distribution test
[0131] The particle size distribution of platinum drug carbon nanodots and platinum drug supercarbon dots in Example 1 were tested respectively, and the specific test results are as follows: Figure 12 As shown, by Figure 12 It can be seen that platinum drug carbon nanodots with a particle size of approximately 5 nm (corresponding to...) Figure 12 Pt-CDs in the medium self-assemble into platinum-based supercarbon dots (corresponding to...) Figure 12The particle size of Hagg-CDs increases to about 200 nm.
[0132] (5) Energy spectroscopy analysis
[0133] XPS energy dispersive spectroscopy analysis was performed on the photoactivation properties of the platinum drug supercarbon dots in Example 1. The specific test results are as follows: Figures 13 to 16 As shown, where, Figure 13 XPS spectra of the platinum drug supercarbon dots in Example 1 before and after light exposure, and the release products. Figures 14 to 15 The XPS N and O spectra of the platinum supercarbon dots in Example 1 before and after light irradiation are shown. Figure 16 The images show XPS Pt spectra of the platinum drug supercarbon points in Example 1 before and after light exposure, as well as the sustained-release product. Figure 13 It can be seen that the ratio of Pt and N elements in the platinum drug supercarbon point in Example 1 decreased before and after light irradiation, while the Pt signal of the released product was significant, indicating platinum drug release. From Figure 14 and Figure 15 It can be seen that the XPS spectra of the platinum drug supercarbon points in Example 1 show a decrease in the Pt(NH3)2 fitting peak in N1s and the Pt-O fitting peak in O1s before and after illumination, proving that platinum drug is released under illumination. Figure 16 The XPS spectra of the sustained-release products collected after illumination showed that the electron binding energies of Pt 4f were 76.0 eV and 72.8 eV, indicating a Pt(II) structure compound, thus proving that the released platinum substance was a divalent, highly toxic platinum drug. Figure 15 It can be seen that the XPS energy spectrum of platinum drug carbon nanodots after illumination shows a significant increase in the COOH fitting peak in O1s.
[0134] (5) Photothermal performance test
[0135] To verify the photothermal conversion effect of the near-infrared responsive platinum-based supercarbon dot in Example 1, thermal imaging was used for characterization. Specific test results are as follows: Figure 17 and Figure 18 As shown. By Figure 17 and Figure 18 The results show that the platinum-based supercarbon dots in Example 1 have the highest photothermal efficiency, rapidly raising the temperature of the aqueous solution to over 50°C within 3 minutes, significantly exceeding the death temperature of cancer cells. This further demonstrates that the platinum-based supercarbon dots in this invention have a good photothermal effect, providing a foundation for subsequent photothermal therapy using platinum-based supercarbon dots. In contrast, the photothermal effect of unassembled platinum-based carbon nanodots can only be increased to 37°C. Tests revealed that the platinum-based supercarbon dots in Examples 2 to 11 of this invention have essentially the same photothermal effect as those in Example 1.
[0136] (6) Cell endocytosis test
[0137] The platinum-doped carbon nanodots and platinum-doped supercarbon dots from Example 1 were subjected to endocytosis tests to investigate intracellular platinum content at different time points under the same concentration. A 10 μmol / L Pt solution was used, and the tests were performed using laser confocal microscopy. Specific test results are as follows: Figure 19 As shown, by Figure 19 It can be seen that as the co-culture time with cells increases, the enrichment of platinum drug supercarbon dots in cells increases significantly, and the enrichment gradually decreases after reaching its maximum at 12 hours.
[0138] (7) Cytotoxicity test
[0139] The platinum-based supercarbon dots from Example 1 are dissolved in a solvent, which can be water, physiological saline, buffer solution, tissue culture medium, or body fluid. The excitation light wavelength is selected from 500nm to 1200nm; the photodynamic irradiation time is selected from 0 to 10 hours; the photodynamic irradiation device can be a laser or an LED light; and the photodynamic power is selected from 0 to 5 W / cm². 2 Between. The platinum-based supercarbon dots from Example 1 were prepared into a solution, and then a laser with a wavelength of 660 nm and a power of 0.1-1.0 W / cm² was applied. 2 Tests revealed that the platinum drug supercarbon dots in Example 1 could be reduced to divalent cisplatin anticancer drugs under light irradiation.
[0140] The photocytotoxicity test of platinum-treated carbon nanodots and platinum-treated supercarbon dots in Example 1 was conducted as follows: Platinum-treated carbon nanodots or platinum-treated supercarbon dots were co-cultured with 4T1 cells at platinum concentrations of 1.0 μmol / L, 2.5 μmol / L, 5.0 μmol / L, 10 μmol / L, 20 μmol / L, and 40 μmol / L, respectively. After 6 hours of culture, a 660 nm laser was used at 0.5 W / cm². 2 The cells were irradiated with the specified power for 10 minutes, followed by incubation for a full 48 hours. For comparison, a blank control experiment and a control experiment using cisplatin as the control group were performed. The cytotoxicity results obtained according to the above testing method are as follows: Figure 20 As shown, where, Figure 20 (a) shows the cytotoxicity test results for the blank control group. Figure 20 (b) shows the cytotoxicity test results of the platinum drug carbon nanodots in Example 1. Figure 20 (c) shows the cytotoxicity test results of cisplatin; Figure 20 (d) shows the cytotoxicity test results of the platinum drug supercarbon dots in Example 1. Figure 20 It can be seen that in the illuminated area, the supercarbon dots of the platinum drug in Example 1 mainly exhibit red fluorescence, indicating that its toxicity increases rapidly after illumination. Figure 20 As shown in (b), there is no difference in cell viability between the illuminated and unilluminated areas of the platinum drug carbon nanodots, indicating that they do not produce toxicity after illumination.
[0141] (8) Immune cell death test
[0142] The immune cell death assay using platinum-based carbon nanodots and platinum-based supercarbon dots in Example 1 was conducted as follows: Cisplatin (10 μmol / L), platinum-based carbon nanodots (Pt-CDs), and platinum-based supercarbon dots (Hagg-CDs) were used under 660 nm laser irradiation to investigate the effects of cisplatin (10 μmol / L), platinum-based carbon nanodots (Pt-CDs), and Hagg-CDs on the expression of immune-related factors calreticulin (CRT) and high-mobility group box 1 (HMGB1) in 4T1 breast cancer cells, as well as the effect on ATPase. Specific test results are shown below. Figure 21 and Figure 22 As shown, where, Figure 22 (a) Figure 22 (b) and Figure 22 (c) These are test graphs showing the effects of cisplatin, platinum drug carbon nanodots, and platinum drug supercarbon dots on CRT expression; Figure 22 (d) Figure 22 (e) and Figure 22 (f) These are test graphs showing the effects of cisplatin, platinum-based carbon nanodots, and platinum-based supercarbon dots on the expression of high-mobility group box 1 (HMP) proteins. Figure 21 and Figure 22 It can be seen that the platinum drug supercarbon dots in Example 1 showed the expression of calreticulin on the surface of 4T1 cell membrane and the disappearance of high-mobility group B1 in the cell nucleus under 660nm laser irradiation, and produced a large amount of ATP, indicating that immune cell death was induced.
[0143] (7) Animal experimental testing
[0144] Small animal imaging, tissue imaging, and thermal imaging analyses were performed on the platinum-doped carbon nanodots and platinum-doped supercarbon dots from Example 1. The small animal imaging test images are shown below. Figure 23 As shown, where, Figure 23 In the image, (1) represents small animal imaging of platinum-doped carbon nanodots. Figure 23 (2) represents small animal imaging of platinum-based supercarbon dots; thermal imaging test image as shown. Figure 24 As shown, the tissue imaging test image is as follows. Figure 25 As shown. By Figure 23 It is evident that platinum-based drug supercarbon dots exhibit significant tumor accumulation capacity, maintaining signal intensity at the tumor site even after 12 hours, while the signal intensity of platinum-based drug carbon nanodots essentially disappears after 12 hours. Figure 24 The tissue imaging also demonstrated the significant enrichment ability of platinum-based supercarbon dots in tumors, with the strongest signal observed in the tumor region after 6 hours, superior to platinum-based carbon nanodots. For example... Figure 25 As shown, platinum-based supercarbon dots exhibit the best photothermal effect at the tumor site, raising the tumor temperature to 50°C after 7 minutes of light irradiation.
[0145] BABL / c mice with orthotopic 4T1 tumors were induced to develop tumors that reached 80 mm in size. 3 One tail vein injection was administered, consisting of 200 μL of cisplatin at a concentration of 2 mg / kg, the platinum drug supercarbonate of Example 1, and the platinum drug supercarbonate of Example 1, respectively. Patients were then divided into a light-illuminated group and a non-light-illuminated group. The light-illuminated group used a 660 nm laser at 0.5 W / cm². 2 Light power and 10-minute irradiation time. The results obtained according to the above test method are as follows: Figure 26 and Figure 27 As shown. By Figure 26 and Figure 27 It can be seen that the platinum-based supercarbon dots in Example 1 have a significant inhibitory effect after light irradiation, indicating that they have a significant photocontrolled therapeutic effect. Moreover, the platinum-based supercarbon dots also have a significant inhibitory effect on distant tumors after light irradiation, indicating that they have a significant immunotherapeutic effect.
[0146] After treating mice for 14 days as described above, all tumors in BABL / c mice with 4T1 tumors were removed, and the mice were continuously observed. Subsequently, the mice were dissected to obtain different lungs, and tissue imaging was performed, specifically as follows: Figure 28 As shown. By Figure 28 It is known that the mice treated with the platinum drug supercarbon dot light irradiation group in Example 1 did not develop obvious tumors in their lungs, while the other control groups showed a large number of tumors metastasizing to the lungs. That is, platinum drug carbon nanodots will cause a large number of tumors to metastasize to the lungs regardless of whether they are exposed to light. Platinum drug supercarbon dots also showed tumor metastasis to the lungs under non-light irradiation, but under light irradiation, platinum drug supercarbon dots did not show tumor metastasis to the lungs. This further illustrates that the platinum drug supercarbon dot light-controlled therapy of the present invention can generate significant immunity, thereby inhibiting lung metastasis.
[0147] In summary, the platinum-based supercarbon dots in this invention possess tunable near-infrared light-responsive release characteristics. Under light irradiation, they can be reduced to divalent platinum-based anticancer drugs, which contain potent tumor-killing hydroxyl radicals. Therefore, this reduces the side effects associated with direct administration of platinum-based drugs while improving the anticancer efficacy of traditional cisplatin. Furthermore, compared to traditional monotherapy cisplatin, the platinum-based supercarbon dots of this invention exhibit diverse morphologies, with hollow spherical shapes enhancing circulation time and tumor accumulation. Moreover, this invention is the first to utilize the self-assembly of platinum-based carbon nanoparticles into platinum-based supercarbon dots, thereby enabling the control of the excitation wavelength of the platinum-based photocontrolled drug release system. The morphology of the platinum-based supercarbon dot aggregates is controlled through particle interactions. J-shaped aggregations of platinum-based carbon nanoparticles are induced through ultrasound, heat, and solvents, resulting in longer excitation wavelengths, placing the excitation wavelength range within the red light or even the near-infrared II region. This enhances the penetration of laser light within the human body and improves therapeutic efficacy.
[0148] The embodiments of the present invention have been described in detail above. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof can be combined with each other unless otherwise specified.
Claims
1. A platinum drug supercarbon point, characterized in that: The platinum-based supercarbon dots are assembled from platinum-based carbon nanodots; the platinum-based carbon nanodots are coordination compounds of platinum and substituted aromatic compounds; the platinum-based drug is selected from at least one of carboplatin oxide, cisplatin oxide, cisplatin dicarboxylate, and oxaliplatin oxide; the substituted aromatic compounds are selected from... Each of R1, R2, R3, and R4 is independently selected from -(CH2). m NH2, -O(CH2) m NH2、-(CH2) m OH, -(CH2) m NO2, -O(CH2) m NO2、-(CH2) m COOH, -O(CH2) m COOH, -(CH2) m CHO; m is selected from natural numbers from 0 to 10.
2. The platinum drug supercarbon point according to claim 1, characterized in that: The number m is selected from natural numbers from 0 to 3.
3. The platinum drug supercarbon point according to claim 1, characterized in that: The value of m is 0.
4. The platinum drug supercarbon point according to claim 1, characterized in that: The substituted aromatic compound is selected from...
5. The platinum drug supercarbon point according to claim 1, characterized in that: The particle size of the platinum drug supercarbon dots is 80–250 nm. And / or, the particle size of the platinum drug carbon nanodots is 1–20 nm.
6. The platinum drug supercarbon point according to claim 1, characterized in that: The excitation wavelength of the platinum drug supercarbon dots is redshifted by 100–500 nm compared to the excitation wavelength of the platinum drug carbon nanodots, and / or the excitation wavelength of the platinum drug supercarbon dots is 600–1200 nm.
7. The method for preparing platinum-based supercarbon dots according to any one of claims 1 to 6, characterized in that: Includes the following steps: S1: Platinum-based drugs and substituted aromatic compounds are subjected to a solvothermal reaction to obtain platinum-based carbon nanodots; S2: The platinum drug carbon nanodots are self-assembled to obtain the platinum drug supercarbon dots.
8. The method for preparing platinum drug supercarbon dots according to claim 7, characterized in that: The self-assembly step is to mix the platinum drug carbon nanodots with a solvent and then sonicate; or, the self-assembly step is to mix the platinum drug carbon nanodots with a solvent and then heat them together.
9. A pharmaceutical composition for treating cancer, characterized in that: Includes a therapeutically effective amount of the platinum drug supercarbonate as described in any one of claims 1 to 6 and pharmaceutically acceptable excipients.
10. The use of the platinum drug supercarbon point according to any one of claims 1 to 6 in the preparation of light-controlled release platinum drugs.