CN115364215B - Platinum medicine carbon nano dot, preparation method thereof, carbon nano dot protein complex and application - Google Patents
Platinum medicine carbon nano dot, preparation method thereof, carbon nano dot protein complex and application Download PDFInfo
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 222
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 106
- 229910052799 carbon Inorganic materials 0.000 title claims abstract description 92
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 title claims abstract description 91
- 239000003814 drug Substances 0.000 title claims abstract description 91
- 239000002096 quantum dot Substances 0.000 title claims abstract description 51
- 102000004169 proteins and genes Human genes 0.000 title claims abstract description 22
- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 82
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims abstract description 46
- 150000001491 aromatic compounds Chemical class 0.000 claims abstract description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 150000003058 platinum compounds Chemical class 0.000 claims abstract description 17
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- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 10
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- 238000004729 solvothermal method Methods 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
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- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 8
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 8
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- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 7
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- 238000013329 compounding Methods 0.000 claims description 4
- 150000004985 diamines Chemical class 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
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- -1 hydroxyl free radical Chemical class 0.000 description 8
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- UJHBVMHOBZBWMX-UHFFFAOYSA-N ferrostatin-1 Chemical compound NC1=CC(C(=O)OCC)=CC=C1NC1CCCCC1 UJHBVMHOBZBWMX-UHFFFAOYSA-N 0.000 description 3
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- CBCKQZAAMUWICA-UHFFFAOYSA-N 1,4-phenylenediamine Chemical group NC1=CC=C(N)C=C1 CBCKQZAAMUWICA-UHFFFAOYSA-N 0.000 description 2
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- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- 230000003287 optical effect Effects 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0042—Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
The invention discloses a platinum medicine carbon nano dot, a preparation method thereof, a carbon nano dot protein compound and application thereof. The platinum carbon nano-dot comprises a carbon-based core with visible light absorption characteristic, wherein tetravalent platinum element is coordinately combined with the carbon-based core, and the platinum carbon nano-dot can be reduced under the condition of light irradiation to obtain bivalent platinum compounds and hydroxyl free radicals. The preparation method comprises the step of carrying out solvothermal reaction on the disubstituted aromatic compound and the tetravalent platinum compound to obtain the platinum carbon nano-dots. Under the irradiation of visible light, the carbon-based inner core generates a hole-electron pair, excited electrons are captured by platinum (IV) to generate a reduction reaction, a Pt (II) compound with high cytotoxicity and hydroxyl free radicals are rapidly generated, the pH value of cells and tumor parts is regulated down, so that cancer cells are subjected to immunogenic death, and the antitumor immune reaction of an organism is activated while the cancer cells are killed. The platinum drug carbon nano-dot and the protein complex thereof can be used as high-efficiency photoactive anticancer drugs and used for accurate tumor treatment.
Description
Technical Field
The invention relates to the technical field of platinum anti-cancer drugs, in particular to a platinum drug carbon nano dot, a preparation method thereof, a carbon nano dot protein complex and application thereof.
Background
The traditional chemotherapeutics such as cisplatin and the like are bivalent platinum complexes with anticancer activity, and are widely applied to cancer chemotherapy after being discovered by B.Rosenborg et al for the first time in 1965 that the growth of tumor cells can be inhibited, and occupy important positions in the chemotherapeutics (Nature 1965,205, 698). Then, there are carboplatin, oxaliplatin and other bivalent platinum compound and other anticancer drugs approved for market. However, general platinum-based compounds are not orally administered, and most of the methods of clinical use are by intravenous drip, and cisplatin and the like rapidly disappear in plasma after intravenous injection and rapidly spread throughout the body, especially in the liver, kidneys, large and small intestine and skin, so that toxic and side effects are large, such as nephrotoxicity, bone marrow suppression and gastrointestinal side effects are caused (chem. Rev.2014,114, 4470-4495). Meanwhile, the platinum compound such as cisplatin has short half-life in blood, so that the proportion of reaching focus parts is low and the drug effect is poor.
The light-operated platinum drug release is a personalized medical means, and can accurately release the entrapped drug molecules at the focus in time and space under the environment of specific illumination, thereby having the advantages of high drug utilization rate, low toxic and side effects and the like and providing a new idea for the accurate treatment of various serious diseases such as tumors. Traditional light-controlled drug release systems are divided into two modes of physical loading and chemical bond combination. The physical mounting mode has the problems of low drug loading rate, drug leakage in the conveying process and the like, and further application of the physical mounting mode is limited. This can be effectively overcome by means of covalent bonding. However, platinum drugs with light control are currently mainly small molecular compounds, and have the disadvantages of poor water solubility, poor tumor enrichment capability, short cycle time and the like (Nat. Rev. Cancer.3 (2003) 380-387).
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide a platinum drug carbon nano dot, a preparation method thereof, a carbon nano dot protein compound and application thereof, so as to solve the technical problems.
The invention is realized in the following way:
in a first aspect, the invention provides a platinum carbon nanodot, which comprises a carbon-based core with visible light absorption characteristic, wherein tetravalent platinum element is coordinately combined with the carbon-based core, the platinum carbon nanodot can be reduced to obtain bivalent platinum compound and hydroxyl free radical under the condition of light irradiation, and preferably, the light irradiation wavelength is 200nm-1200nm.
In a second aspect, the present invention provides a method for preparing platinum drug carbon nanodots, comprising performing a solvothermal reaction of a disubstituted aromatic compound with a tetravalent platinum compound to obtain platinum drug carbon nanodots.
Optionally, the disubstituted aromatic compound is a benzene, naphthalene, anthracene or phenanthrene disubstituted compound; and/or the tetravalent platinum compound is selected from at least one of cisplatin oxide and cisplatin diacid, and the chemical formula of the cisplatin oxide is
Alternatively, the disubstituted aromatic compound is an aromatic compound of a diamine.
Optionally, the disubstituted aromatic compound is a compound shown in a formula (I) or a formula (II);
in the formula (I) and the formula (II), R 1 、R 2 Each independently selected from- (CH) 2 ) m NH 2 、-O(CH 2 ) n NH 2 、-(CH 2 ) m OH、-O(CH 2 ) n OH、-(CH 2 ) m NO 2 、-O(CH 2 ) n NO 2 、-(CH 2 ) m COOH、-O(CH 2 ) n Any one of COOH; m and n are respectively 0 to 10.
Alternatively, R 1 、R 2 Each independently selected from the group consisting of-NH 2 、-ONH 2 、-OH、-NO 2 、-ONO 2 -COOH, -OCOOH; and/or the tetravalent platinum-based complex is cisplatin oxide.
Optionally, the disubstituted aromatic compound is at least one of the following compounds:
alternatively, the disubstituted aromatic compound is
In a third aspect, the invention also provides a carbon nanodot protein complex, which is obtained by compounding the platinum drug carbon nanodot and macromolecular protein.
In a fourth aspect, the invention also provides an application of the platinum carbon nanodots or the carbon nanodot protein complex in preparing antitumor drugs.
The invention has the following beneficial effects: the platinum drug carbon nano-dots and the protein complex thereof have adjustable light response release characteristics, and under the condition of illumination, bivalent platinum anti-cancer drugs can be obtained through reduction, hydroxyl free radicals with strong tumor killing property and acidification in tumor cells are caused, so that the problem of side effects of the platinum drugs is reduced, and the anti-cancer effect of the traditional cisplatin is improved; compared with the traditional single-drug cisplatin, the platinum-drug carbon nano-dot has various forms, and the circulation time and the enrichment of tumor parts in vivo can be improved after the protein is compounded.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic diagram of a platinum drug carbon nanodot illumination reaction;
FIG. 2 is a transmission electron microscope image of platinum drug carbon nanodots of example 1;
FIG. 3 is an EDS diagram of platinum drug carbon nanodots of example 1;
FIG. 4 is an XPS spectrum of platinum drug carbon nanodots of example 1;
FIG. 5 is a graph of Pt 4f energy spectrum of platinum drug carbon nanodots of example 1;
FIG. 6 is an O1s energy spectrum of platinum drug carbon nanodots of example 1;
FIG. 7 is an N1s energy spectrum of platinum drug carbon nanodots of example 1;
FIG. 8 is a hydrogen spectrum nuclear magnetic spectrum of platinum drug carbon nanodots of example 1;
FIG. 9 is an electron spin energy spectrum of platinum drug carbon nanodots of example 1;
fig. 10 is a flowchart of the illumination of platinum carbon quantum dots in experimental example three;
FIG. 11 is a transmission electron microscope image of platinum drug carbon nanodots @ BSA in experimental example four;
FIG. 12 is an ultraviolet and fluorescence spectrum of platinum drug carbon nanodot @ BSA in experimental example four;
FIG. 13 is a graph showing the slow release of platinum in the light or glutathione reducing environment at the platinum carbon nanodots in experiment example five;
fig. 14 is a graph showing the pH change of the platinum carbon quantum dots in experimental example six under light;
FIG. 15 shows intracellular platinum content of platinum drug carbon nanodots and platinum drug carbon nanodots @ BSA at different incubation times in experimental example seven;
FIG. 16 is a fluorescence microscope image of the platinum drug carbon quantum dots and platinum drug carbon nanodots @ BSA in experiment example seven after incubation for 4h with 4T1 cells, respectively;
FIG. 17 is a graph showing the inhibitory effect of platinum carbon nanodots on 4T1 breast cancer cells in experimental example eight;
FIG. 18 is a graph showing the effect of platinum carbon nanodot @ BSA on inhibiting 4T1 breast cancer cells in experimental example eight;
FIG. 19 is a molecular imprinting of phosphorylated histone H2AX (p-H2A.X) of 4T1 breast cancer cells before and after exposure to light of cisplatin, platinum drug carbon quantum dots @ BSA in experimental example nine;
FIG. 20 shows the effect of platinum drug carbon quantum dots @ BSA illumination before and after exposure to active oxygen of 4T1 breast cancer cells in experimental example nine;
FIG. 21 is a flow chart showing the apoptosis of 4T1 breast cancer cells under the inhibition of Fer-1 before and after illumination of platinum drug carbon quantum dots and platinum drug carbon quantum dots @ BSA in experimental example nine;
FIG. 22 is an immunofluorescence image of Calreticulin (CRT) and high mobility group box protein B1 (HMGB 1) in 4T1 breast cancer cells after illumination with cisplatin, platinum drug carbon quantum dots @ BSA in experimental example ten;
FIG. 23 is a schematic diagram showing the effect of the experimental example on inhibiting the growth of the tumor of the 4T1 mouse before and after the irradiation of the carbon quantum dots of the undeclatinum medicine;
FIG. 24 is a schematic diagram showing the effect of the experimental example of the inhibition of the remote tumor growth of 4T1 mice by the carbon quantum dots of the undeclatinum medicine before and after illumination;
FIG. 25 is a graph showing survival curves of the carbon quantum dots of the undecapelatinum drug of experimental example on 4T1 mice before and after irradiation;
fig. 26 is a photograph of lung metastasis of 4T1 mice before and after carbon quantum dot irradiation of experimental example undecapelatinum.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The platinum drug carbon nanodots, the preparation method thereof, the carbon nanodot protein complex and the application thereof provided by the invention are specifically described below.
Some embodiments of the present invention provide a platinum carbon nanodot, which includes a carbon-based core to which tetravalent platinum element is chemically bonded, the carbon-based core having a visible light absorbability, and the platinum carbon nanodot being reducible under light irradiation conditions to obtain a divalent platinum compound and a hydroxyl radical, preferably at a light irradiation wavelength of 200nm to 1200nm.
Referring to fig. 1, under irradiation of visible light, the carbon-based core generates hole-electron pairs, and electrons in an excited state are captured by platinum (IV) to undergo a reduction reaction, and a platinum (II) -containing compound is released; holes formed by photoexcitation on the valence band are subjected to an oxidation reaction with hydroxyl ions in the aqueous solution on the surface of the nano particles to form hydroxyl free radicals, and the pH value of the aqueous solution is reduced.
Some embodiments of the present invention provide a method for preparing platinum drug carbon nanodots, which comprises solvothermal reaction of a disubstituted aromatic compound and a tetravalent platinum compound to obtain platinum drug carbon nanodots.
Specifically, in some embodiments, the disubstituted aromatic compound is a disubstituted compound of benzene, naphthalene, anthracene, or phenanthrene; and/or the tetravalent platinum compound is selected from at least one of cisplatin oxide and cisplatin diacid, and the chemical formula of the cisplatin oxide is
In some embodiments, the disubstituted aromatic compound is an aromatic compound of a diamine.
In some embodiments, the disubstituted aromatic compound is a compound of formula (I) or formula (ii);
in the formula (I) and the formula (II), R 1 、R 2 Each independently selected from- (CH) 2 ) m NH 2 、-O(CH 2 ) n NH 2 、-(CH 2 ) m OH、-O(CH 2 ) n OH、-(CH 2 ) m NO 2 、-O(CH 2 ) n NO 2 、-(CH 2 ) m COOH、-O(CH 2 ) n Any one of COOH; m and n are respectively 0 to 10.
For example, the equation may be:
in some preferred embodiments, R 1 、R 2 Each independently selected from the group consisting of-NH 2 、-ONH 2 、-OH、-NO 2 、-ONO 2 -COOH, -OCOOH; and/or the tetravalent platinum-based complex is cisplatin oxide.
Further, the disubstituted aromatic compound is at least one of the following compounds:
preferably, the disubstituted aromatic compound isAt this time, the reaction process is:
in the reaction process, hydroxyl and amino of the oxidized cisplatin are coordinated and combined so as to load the oxidized cisplatin on the carbon-based core. The aromatic compound of diamine includes, but is not limited to, one of any two amine groups such as o-phenylenediamine, p-phenylenediamine, m-phenylenediamine, and naphthalene anthracene phenanthrene.
In some embodiments, to enable better formation of carbon nanodots, the molar ratio of the disubstituted aromatic compound to tetravalent platinum complex is 1 to 1000:1 to 1000, preferably 1 to 100:1 to 100, more preferably 1 to 3:1 to 3, for example, the disubstituted aromatic compound and tetravalent platinum compound may be 1:1.
Specifically, in the solvothermal reaction process, in order to enable the reactants to be fully mixed and reacted, the reaction process needs to be performed in a solvent system, and the reaction solvent for dissolving the disubstituted aromatic compound and the tetravalent platinum compound includes, but is not limited to, at least one of dimethyl sulfoxide, N' -dimethylformamide, water, formic acid, ethanol, diethyl ether, tetrahydrofuran, folic acid and acetone. That is, the reaction solvent may be selected from dimethyl sulfoxide, N' -dimethylformamide, water, formic acid, ethanol, diethyl ether, tetrahydrofuran, folic acid and acetone, or may be selected from a mixture of two or more of these, and the mixing ratio is not limited.
Further, in some embodiments, the ratio of the disubstituted aromatic compound to the reaction solvent is from 0.001g to 1g/mL.
Further, in some embodiments, the solvothermal reaction temperature is 100 to 250 ℃, for example, 100 ℃, 110 ℃, 120 ℃, 130 ℃, 140 ℃, 150 ℃, 160 ℃, 170 ℃, 180 ℃, 190 ℃, 200 ℃, 210 ℃, 220 ℃, 230 ℃, 240 ℃, or 250 ℃, and the like, and the reaction time is 1 to 10 hours, for example, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, and the like.
Some embodiments of the invention also provide a carbon nanodot protein complex, which is obtained by compounding the platinum drug carbon nanodot and macromolecular protein.
The carbon nano dot protein complex has high cell endocytosis efficiency and tumor enrichment efficiency. The platinum carbon nanodots can rapidly generate high-cytotoxicity Pt (II) compound and hydroxyl free radical under irradiation of visible light wave band, and can reduce pH value of intracellular and tumor parts, so that cancer cells can generate immunogenic death, and the anti-tumor immune response of the organism is activated while the cancer cells are killed.
Some embodiments of the invention also provide application of the platinum carbon nanodots or the carbon nanodot protein complex in preparing antitumor drugs. The platinum drug carbon nanodots and the protein complex thereof in the embodiment can be used as high-efficiency photoactive anticancer drugs and applied to accurate tumor treatment.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
The embodiment improves the preparation method of the platinum drug carbon nano-dots, which comprises the following specific operations:
0.1g of cisplatin oxide and 0.1g of o-phenylenediamine were weighed. Then 30mLN, N-dimethylformamide was added to the polytetrafluoroethylene reaction vessel, followed by reaction in an oven at 200℃for 6 hours. And then taking out the solution, dialyzing, filtering, and freeze-drying to obtain the platinum carbon nano dot solid.
Example 2
The embodiment improves the preparation method of the platinum drug carbon nano-dots, which comprises the following specific operations:
1g of cisplatin oxide and 0.1g of m-phenylenediamine were weighed. Then 20mL of N, N-dimethylformamide was added to the polytetrafluoroethylene reaction vessel, and the mixture was then placed in an oven to react at 250℃for 4 hours. And then taking out the solution, dialyzing, filtering, and freeze-drying to obtain the platinum carbon nano dot solid.
Example 3
The embodiment improves the preparation method of the platinum drug carbon nano-dots, which comprises the following specific operations:
0.1g of cisplatin oxide and 1g of p-phenylenediamine were weighed. 40mL of dimethyl sulfoxide was then added to the polytetrafluoroethylene reaction vessel, and the mixture was then placed in an oven and reacted at 180℃for 9 hours. And then taking out the solution, dialyzing, filtering, and freeze-drying to obtain the platinum carbon nano dot solid.
Example 4
The embodiment improves the preparation method of the platinum drug carbon nano-dots, which comprises the following specific operations:
0.5g of cisplatin diacid and 1g of o-phenylenediamine are weighed. Then 30mL of N, N-dimethylformamide was added to the polytetrafluoroethylene reaction vessel, and the mixture was then placed in an oven to react at 210℃for 8 hours. And then taking out the solution, dialyzing, filtering, and freeze-drying to obtain the platinum carbon nano dot solid.
Experimental example 1
Ultraviolet analysis, fluorescence spectrum analysis and xps spectrum analysis were performed on the structure of the platinum drug carbon nanodot compound obtained in example 1. The transmission electron microscope image is shown in figure 2, the size of the carbon nano dot is about 5nm, and the lattice fringe spacing is 0.21nm under high power, which proves that the platinum carbon nano dot is successfully prepared. The results of EDS and XPS analysis of the platinum carbon nanodot elements are shown in fig. 3 and 4, respectively, and it is known that the platinum has a C, N, O, cl, pt signal, which indicates that platinum is successfully involved in the formation of carbon nanodots. The XPS spectrum result of Pt shows that the electron binding energy of Pt 4f is 75.5eV and 78.8eV, and the compound is a Pt (IV) structural compound (shown in figure 5).
Example two
XPS light was performed on the photoactivation properties of the platinum drug carbon nanodot compound obtained in example 1A spectrum (spectrum), 1 H NMR and ESR spectroscopy. XPS energy spectrum before and after illumination shows Pt (NH) in N1s 3 ) 2 The fit peaks and Pt-O fit peaks in O1s decreased, demonstrating platinum drug release under light (fig. 6 and 7). And XPS energy spectrum of the slow release product collected after illumination shows that the electron binding energy of Pt 4f is 76.0eV and 72.8eV, and the slow release product is a Pt (II) structural compound (shown in figure 5), and the released platinum substance is proved to be a bivalent high-toxicity platinum drug. Meanwhile, XPS energy spectrum of the platinum drug carbon nano dot compound after illumination shows that the COOH fitting peak in O1s is obviously increased, and the result is also that 1 Obtained from the H NMR spectrum (shown in fig. 8). And then the platinum-containing carbon nano-dots are combined with an electron spin capturing agent DMPO, and the active oxygen generated by the platinum-containing carbon nano-dots is detected before and after illumination. Electron spin spectroscopy (ESR) results prove that no hydroxyl radical is generated under the condition of no illumination, and obvious hydroxyl radicals can be obviously generated after illumination (as shown in fig. 9), so that the platinum carbon nanodot compound has the capability of reducing the pH value of the surrounding environment.
Experimental example III
Dissolving the platinum drug carbon nanodots of example 1 in one of water, physiological saline, buffer solution, tissue culture solution or body fluid, wherein the excitation light may be selected from 300nm to 1200nm (e.g., 589nm laser in fig. 10); the photodynamic irradiation time may be selected from 0-10 hours; the photodynamic irradiation device can be selected from laser or LED lamplight; the photodynamic power can be selected from 0-5w/cm 2 Between them. Preparing into solution, and then applying laser with wavelength of 400-650nm and power of 0.1-1.0w/cm 2 The platinum carbon nano-dots are reduced under light irradiation to obtain bivalent cisplatin anticancer drug.
Experimental example four
In order to improve the optical performance and the endocytosis of the carbon nanodots, the platinum drug carbon nanodots of example 1 were compounded with bovine serum albumin in a ratio of 0.5:10 mass ratio. The composite nanodots were observed by transmission electron microscopy, and it was found that the size was increased from about 5nm to about 50nm after the bovine serum albumin was composited (as shown in FIG. 11). And then ultraviolet-visible absorption and fluorescence tests are carried out on the platinum drug carbon nano-dots before and after the bovine serum albumin is compounded, the result is shown in figure 12, the absorption peak of the ultraviolet absorption spectrum is not changed greatly, but the fluorescence spectrum curve shows that the fluorescence of the platinum drug carbon nano-dots can be obviously improved through the bovine serum albumin compounding.
Experimental example five
Drug release testing was performed using a 1000 molecular weight cut-off dialysis bag loaded with 2mL of the platinum drug carbon nanodots of example 1 at a concentration of 0.5mg/mL followed by 50mL of a different PBS buffer solution containing 10mM glutathione or 589nm laser (5 min interval, 0.5W/cm) 2 ). As shown in fig. 13, the platinum drug carbon nanodots of example 1 released rapidly after illumination, and the release rate reached 40% after five illumination times within 4 hours, while the release rate in glutathione environment at the same time was only about 10%, indicating good light-operated release rate. The release rate is obviously superior to that of reducing mediums such as glutathione and the like.
Experimental example six
The pH value is then measured using a pH meter as a pH value measuring means. Illuminating with platinum drug carbon nanodot solutions with different solubilities, and laser power of 0.1-1.0W/cm 2 The irradiation time is 1-30min, and the laser wavelength is 380-650nm. As shown in FIG. 14, the platinum drug carbon nanodots of example 1 have a pH value of 0.25mg/mL, for example, 0.5W/cm, reduced under 589nm irradiation 2 The final pH can be reduced to below 6.5 under illumination for 10 minutes.
Example seven
Subsequently, an endocytic assay was performed, and the platinum drug carbon nanodots of example 1 and the platinum drug carbon nanodots @ BSA of example four were studied for intracellular platinum content at the same concentration. The solubility used was 10. Mu.M Pt. By ICP-MS means, as shown in fig. 15, the platinum drug carbon nanodot @ BSA increased significantly in the enrichment of cells with increasing co-culture time with cells, and decreased after 12 hours of maximum enrichment. Compared with platinum medicine carbon nano-dots, the enrichment capacity of the platinum medicine carbon nano-dots coated with BSA reaches 19 times. Fluorescence microscopy pictures also demonstrate this trend (as shown in figure 16).
Experimental example eight
Followed by light attenuationCytotoxicity test platinum drug carbon nanodots of example 1 and platinum drug carbon nanodot @ BSA of example 1 were co-cultured with 4T1 cells at platinum concentrations of 1.0, 2.5, 5.0, 10, 20, 40. Mu.M, respectively, and after 6 hours of culture, a 589nm laser was used at 0.5W/cm 2 For 10min, followed by further incubation for 48h. As shown in fig. 17 and 18, the platinum drug carbon nanodots of example 1 have a rapid increase in toxicity after irradiation with light, and compared with pure carbon dots, the concentration of BSA-coated carbon dots has a significant inhibitory effect at 10 μm, whereas pure carbon dots require 40 μm.
Experimental example nine
The mode of death and active oxygen expression at the cellular level were then studied, using cisplatin at a platinum concentration of 10 μm, the platinum drug carbon quantum dot of example 1, the platinum drug carbon quantum dot @ BSA of example 1, respectively, for the ability of phosphorylated histone H2AX (p-h2a.x) expression in 4T1 breast cancer cells under 589nm laser irradiation. As shown in fig. 19, p-h2a.x generated by the platinum drug carbon quantum dot @ BSA after illumination was lower than cisplatin at the same concentration, indicating that the toxicity of the platinum drug carbon quantum dot @ BSA to cells was not derived from the damage of the platinum drug to DNA. Therefore, the mode of cell death is further studied through the expression of active oxygen, and as shown in fig. 20, under the action of an iron death inhibitor Fer-1, the ROS generated by the platinum carbon quantum dot@BSA on 4T1 cells is partially inhibited, which indicates that the active oxygen generated after the irradiation of the platinum carbon quantum dot@BSA participates in the death of cell iron. As shown in FIG. 21, further investigation of death of 4T1 cells after illumination with platinum drug carbon quantum dots @ BSA by flow cytometry inhibited cell death after addition of Fer-1, further demonstrating that the cells had iron death characteristics.
Examples ten
Subsequent studies of Immune Cell Death (ICD) were performed using cisplatin at a platinum concentration of 10 μm, the platinum drug carbon quantum dots of example 1 @ BSA to immune-related factors of 4T1 breast cancer cells under 589nm laser irradiation: calreticulin (CRT) and high mobility group protein B1 (HMGB 1) expression. As shown in fig. 22, calreticulin expression of the drug carbon quantum dot @ BSA on the surface of 4T1 cell membrane under 589nm laser irradiation and disappearance of high mobility group protein B1 in the nucleus indicated induction of immune cell death.
Example eleven
Animal experiments show that BABL/c mice with in-situ 4T1 tumor grow to 80mm in tumor 3 At this time, a tail vein injection was carried out, and 200. Mu.L of cisplatin at a concentration of 2mg/kg, the platinum drug carbon quantum dot of example 1, the platinum drug carbon quantum dot @ BSA of example 1, and a 589nm laser light of 0.5W/cm was used for the light irradiation group 2 Power and 10min irradiation time. As shown in fig. 23, the platinum carbon nanodot @ BSA group has a remarkable inhibitory effect after illumination, indicating that it has a remarkable light control treatment effect. In addition, the platinum carbon nanodot@BSA group also has obvious inhibition effect on the far-end tumor after illumination, which shows that the platinum carbon nanodot@BSA group has obvious immunotherapy effect (figure 24).
Example twelve
All tumors of the BABL/c mice with 4T1 tumors were subsequently resected 14 days after treatment and the mice were observed continuously. The survival curves are shown in FIG. 25, and mice treated with the platinum drug carbon quantum dot @ BSA light group of example 1 survived after 30 days, while other control groups all died. The mice were then dissected to obtain different lungs. As shown in fig. 26, the lung of mice treated with platinum carbon quantum dot @ BSA light group had no obvious tumor production, while the other control groups had a large number of tumor metastases to the lung, indicating that the platinum carbon quantum dot @ BSA light control treatment could generate significant immunity, thereby inhibiting lung metastases.
In summary, the platinum carbon nanodots and the protein complex thereof in the embodiment of the invention have adjustable light response release characteristics, and under the condition of illumination, bivalent platinum anticancer drugs can be obtained through reduction, hydroxyl free radicals with strong tumor killing property and acidification in tumor cells are caused, so that the problem of side effects of the platinum drugs is reduced, and the anticancer effect of the traditional cisplatin is improved. In addition, compared with the traditional single-drug cisplatin, the platinum drug carbon nanodots in the embodiment of the invention have various forms, and the circulation time and the enrichment of tumor parts in vivo can be improved after the protein is compounded.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (14)
1. The platinum medicine carbon nano-dot is characterized by comprising a carbon-based inner core with visible light absorption characteristic, wherein tetravalent platinum element is coordinately combined with the carbon-based inner core, the carbon-based inner core has visible light absorption property, and the platinum medicine carbon nano-dot can be reduced under the condition of light irradiation to obtain bivalent platinum compounds and hydroxyl free radicals;
the preparation of the platinum carbon nano-dots comprises the steps of carrying out solvothermal reaction on a disubstituted aromatic compound and a tetravalent platinum compound so as to obtain the platinum carbon nano-dots;
the disubstituted aromatic compound is a disubstituted compound of benzene, naphthalene, anthracene or phenanthrene; and/or the tetravalent platinum compound is selected from at least one of cisplatin oxide and cisplatin diacid, and the chemical formula of the cisplatin oxide is。
2. The platinum carbon nanodot according to claim 1, wherein the light irradiation wavelength is 200nm to 1200nm.
3. The preparation method of the platinum drug carbon nano-dots is characterized by comprising the following steps: carrying out solvothermal reaction on the disubstituted aromatic compound and the tetravalent platinum compound to obtain the platinum carbon nano-dots;
the disubstituted aromatic compound is a disubstituted compound of benzene, naphthalene, anthracene or phenanthrene; and/or the tetravalent platinum compound is selected from at least one of cisplatin oxide and cisplatin diacid, and the chemical formula of the cisplatin oxide is。
4. The method for preparing platinum carbon nanodots according to claim 3, wherein the disubstituted aromatic compound is an aromatic compound of diamine.
5. The method for preparing platinum carbon nanodots according to claim 3, wherein the disubstituted aromatic compound is a compound represented by formula (I) or formula (ii);
（I）（Ⅱ）
in the formula (I) and the formula (II), R 1 、R 2 Each independently selected from- (CH) 2 ) m NH 2 、-O(CH 2 ) n NH 2 、-(CH 2 ) m OH、-O(CH 2 ) n OH、-(CH 2 ) m NO 2 、-O(CH 2 ) n NO 2 、-(CH 2 ) m COOH、-O(CH 2 ) n Any one of COOH; m and n are respectively 0 to 10.
6. The method for preparing platinum carbon nanodots according to claim 5, wherein R 1 、R 2 Each independently selected from the group consisting of-NH 2 、-ONH 2 、-OH、-NO 2、 -ONO 2 -COOH, -OCOOH;
and/or the tetravalent platinum complex is the cisplatin oxide.
7. The method for preparing platinum carbon nanodots according to claim 6, wherein the disubstituted aromatic compound is at least one of the following compounds:
、/>、/>、/>、/>、、/>、/>。
8. the method for preparing platinum carbon nanodots according to claim 6, wherein said disubstituted aromatic compound is。
9. The method for preparing platinum carbon nanodots according to claim 3, wherein the molar ratio of the disubstituted aromatic compound to the tetravalent platinum complex is 1-1000:1-1000.
10. The method for preparing platinum carbon nanodots according to claim 3, wherein the molar ratio of the disubstituted aromatic compound to the tetravalent platinum complex is 1-100: 1-100.
11. The method for preparing platinum carbon nanodots according to claim 3, wherein the molar ratio of the disubstituted aromatic compound to the tetravalent platinum complex is 1-3:1-3.
12. The method for preparing platinum carbon nanodots according to any one of claims 9 to 11, wherein the solvent for the reaction is at least one selected from dimethyl sulfoxide, N' -dimethylformamide, water, formic acid, ethanol, diethyl ether, tetrahydrofuran and acetone;
and/or the ratio of the disubstituted aromatic compound to the solvent is 0.001 g-1 g/mL;
the temperature of the solvothermal reaction is 100-250 ℃, and the reaction time is 1-10 hours.
13. The carbon nanodot protein complex is characterized in that the carbon nanodot is obtained by compounding the platinum drug carbon nanodot in claim 1 or 2 or the platinum drug carbon nanodot prepared by the preparation method in any one of claims 3-12 with macromolecular protein.
14. The platinum carbon nanodots according to claim 1 or 2 or the platinum carbon nanodots prepared by the preparation method according to any one of claims 3 to 12 or the carbon nanodot protein complex according to claim 13, and the application thereof in preparing antitumor drugs.
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