CN110981918A - Modified platinum compound and preparation method and application thereof - Google Patents
Modified platinum compound and preparation method and application thereof Download PDFInfo
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- CN110981918A CN110981918A CN201911330674.7A CN201911330674A CN110981918A CN 110981918 A CN110981918 A CN 110981918A CN 201911330674 A CN201911330674 A CN 201911330674A CN 110981918 A CN110981918 A CN 110981918A
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- dichlorobenzyl
- carbohydrazide
- indazole
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- 229940079593 drug Drugs 0.000 claims abstract description 42
- -1 carboxyl modified 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide Chemical class 0.000 claims abstract description 16
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- 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
- A61P35/02—Antineoplastic agents specific for leukemia
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- General Health & Medical Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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Abstract
The invention relates to a modified platinum compound and a preparation method and application thereof, belonging to the technical field of anti-tumor drugs. Oxidizing a divalent platinum compound into a tetravalent platinum compound; carrying out condensation reaction on 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide and 4-formylbenzoic acid to obtain carboxyl modified 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide; adding carboxyl modified 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide into a tetravalent platinum compound to obtain an intermediate product; and reacting the intermediate product with isocyanate to obtain the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound. The compound has good self-assembly performance, can greatly reduce the using amount of a carrier, improves the encapsulation rate and the drug-loading rate of the drug, and has simple preparation, high controllability and good stability. Meanwhile, the compound and the nanoparticles show a remarkably enhanced anti-tumor effect, wherein the killing index of the compound and the nanoparticles can be enhanced by 266.4 times to the maximum in drug-resistant cells, so that the drug resistance problem of platinum drugs can be greatly reduced.
Description
Technical Field
The invention relates to the technical field of antitumor drugs, in particular to a modified platinum compound and a preparation method and application thereof, and especially relates to a 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound and a preparation method and application thereof.
Background
The platinum antineoplastic drugs comprise cisplatin, carboplatin, heptaplatin, lobaplatin, eptaplatin, leplatin, oxaliplatin, nedaplatin, episulfide platinum, satraplatin and the like, and the platinum antineoplastic drugs have wide application and can be used for treating various tumors such as testicular cancer, ovarian cancer, cervical cancer, head and neck tumor, non-small cell lung cancer and the like. However, with the progress of research, the clinical application of cisplatin is gradually limited, and the cisplatin mainly faces the following problems of great side effects, drug resistance and the like. Platinum compounds can cause tubular injury and dysfunction in a variety of ways. Meanwhile, the platinum compound is easy to generate inherent resistance and acquired resistance.
The nanometer medicine can reduce the toxicity of medicine in vivo and improve the treatment effect, but most of the nanometer medicine has the defects of low medicine-loading rate (< 10%), difficult degradation and metabolism of excipient, and the like.
Adjudin (ADD) is a derivative of the antitumor drug lonidamine. Studies show that ADD can also affect mitochondrial membrane potential, reduce the content of intracellular ATP, inhibit the discharge of an energy-dependent external pump to a medicament, improve the concentration of the intracellular medicament and have obvious inhibition effect on drug-resistant tumors. Therefore, the addition of ADD is expected to remarkably inhibit the drug resistance phenomenon of cisplatin and increase the treatment effect of cisplatin on drug-resistant tumors. Meanwhile, ADD is a hydrophobic drug, the structure of the ADD contains rich aromatic groups, and the platinum compound is a hydrophilic drug, so that the platinum compound modified by the adutant is an amphiphilic drug-drug conjugate, meets the basic characteristics of self-assembled nano-drugs, and is expected to solve the difficult problem of the traditional nano-drug preparation.
Disclosure of Invention
The invention aims to solve the problems of toxicity, drug resistance and the like of non-target organs in the prior tumor treatment and the technical problems of low drug-loading rate and difficult degradation and metabolism of excipients of nano-drugs. The invention provides a novel adutant modified platinum compound. The platinum compound modified by the addumidine can be self-assembled to form nanoparticles, a nano-drug system with high drug loading, less side effects and strong treatment effect is constructed by utilizing the low toxicity characteristic of the platinum prodrug, the synergistic killing characteristic of the platinum compound and ADD and the characteristic of inhibiting drug resistance of the ADD and combining the advantages of the self-assembled nanoparticles, so that the problems of the side effects and the drug resistance of the platinum compound are finally relieved, and the efficient killing of tumors is realized.
According to a first aspect of the present invention, there is provided a 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound having the general structural formula shown in formula i:
in the formula I, the compound has the following structure,
is a platinum compound; the value range of n is more than or equal to 0 and less than or equal to 19, and n is an integer.
Preferably, in the formula I,
is cisplatin, carboplatin, heptaplatin, nedaplatin, oxaliplatin, lobaplatin, miriplatin, eptaplatin, or picoplatin.
According to another aspect of the invention, 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound nanoparticles are provided, the nanoparticles are obtained by self-assembling 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compounds, 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide is gathered inside the nanoparticles due to hydrophobic interaction and pi-pi accumulation, and the platinum compounds form a hydrated layer outside the nanoparticles to stabilize the nanostructure.
According to another aspect of the present invention, there is provided a process for the preparation of any one of the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide-modified platinum compounds, comprising the steps of:
(1) oxidizing a divalent platinum compound into a tetravalent platinum compound; mixing 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide and 4-formylbenzoic acid, and carrying out condensation reaction to obtain carboxyl modified 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide;
(2) adding the carboxyl modified 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide into the tetravalent platinum compound obtained in the step (1), adding a catalyst and an anhydrous organic solvent, heating to enable the tetravalent platinum compound and the carboxyl modified 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide to perform esterification reaction, centrifuging to remove precipitates, recrystallizing, washing, and drying in vacuum to obtain an intermediate product;
(3) and (3) fully and uniformly mixing the intermediate product obtained in the step (2) with isocyanate, carrying out nucleophilic reaction on the intermediate product and the isocyanate, washing, and purifying and separating by using eluent through silica gel column chromatography to obtain the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound.
Preferably, the ratio of the amount of the tetravalent platinum compound and the amount of the substance of the carboxyl-modified 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide in the step (2) is 0.1 to 10.
The anhydrous organic solvent in the step (2) is anhydrous dimethyl sulfoxide or anhydrous N, N-dimethylformamide, and the solvent used in the recrystallization process is ethyl acetate, acetone, acetonitrile or ethanol;
the eluent in the step (3) is a mixture of halogenated hydrocarbon and alcohol organic matters;
preferably, the halogenated hydrocarbon is dichloromethane or trichloromethane, and the alcoholic organic substance is a mono-alcohol or a polyol.
According to another aspect of the invention, a preparation method of the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound nanoparticles is provided, wherein the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound is dissolved in an organic solvent, then the solution is dropwise added into deionized water, a surfactant is added, the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound is subjected to self-assembly, and the organic solvent is removed through dialysis, so that the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound nanoparticles can be obtained.
Preferably, the organic solvent is dimethyl sulfoxide, N-dimethylformamide or ethanol;
the surfactant is distearoyl phosphatidyl ethanolamine-polyethylene glycol or polyethylene glycol vitamin E succinate.
According to another aspect of the invention, the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound is provided for preparing an anti-tumor medicament.
According to another aspect of the invention, the application of the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound nanoparticles in preparing antitumor drugs is provided.
Preferably, the tumor is a drug-resistant tumor.
Generally, compared with the prior art, the above technical solution conceived by the present invention mainly has the following technical advantages:
(1) in the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound and the nanoparticles formed by the platinum compound, 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide can be gathered inside due to hydrophobic interaction and pi-pi accumulation, and the platinum compound forms a hydration layer outside to stabilize the nanostructure. In this process, a small amount of surfactant may be added to further stabilize the nanostructure.
(2) The 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound in the invention forms a nanoparticle system which is simple, most of the nanoparticle system is medicines, only contains a small amount of surfactant, can obviously reduce the complexity of the nanoparticle system, improves the uniformity and controllability, and is suitable for large-scale production.
(3) The nano-particle has high drug encapsulation efficiency and drug loading, the drug encapsulation efficiency is 78.8-92.6%, and the drug loading is 84.0-86.0%, which is far higher than that of most traditional nano-drugs at present (< 10%).
(4) The invention has low content of the nano particle carrier, and can avoid the safety concerns of production cost increase, metabolism, excretion, immunogenicity and the like caused by introducing a large amount of carriers in the preparation.
(5) The invention has good curative effect on drug-resistant tumor, and the killing ability of the invention can be improved by 266.4 times to the maximum. Has good killing effect on breast cancer, ovarian cancer, colorectal cancer, liver cancer, prostatic cancer, testicular cancer, lung cancer, nasopharyngeal cancer, head and neck cancer, thyroid cancer, leukemia, malignant melanoma and other solid tumors and blood system tumors.
Drawings
FIG. 1 is a mechanism diagram of the self-assembly of the adotin-modified cisplatin prodrug into a nano-result.
Fig. 2 shows the particle size (n ═ 3) of different pt (iv) -ADD @ PEG nanoparticles.
Fig. 3 shows the potentials (n ═ 3) of different pt (iv) -ADD @ PEG nanoparticles.
Fig. 4 shows the encapsulation efficiency (n ═ 3) of different pt (iv) -ADD @ PEG nanoparticles.
Fig. 5 shows drug loading (n ═ 3) for different pt (iv) -ADD @ PEG nanoparticles.
FIG. 6 is an electron micrograph (without DSPE-PEG) of different Pt (IV) -ADD nanoparticles.
FIG. 7 is an electron micrograph of different Pt (IV) -ADD @ PEG nanoparticles (containing DSPE-PEG).
Fig. 8 shows the inhibition of tumor growth curves for each mouse after different drugs (n-8).
FIG. 9 is a graph of mean tumor growth in mice of each group after the effect of different drugs.
FIG. 10 shows the body weight change of mice in each group after different drugs.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1: synthesis of adutant-modified cisplatin (Pt (IV) -ADD) prodrugs
The specific synthesis steps are as follows:
(1) synthesis of tetravalent platinum compound
The specific synthesis steps are as follows: 1.2g of cisplatin (4.00mmol) was weighed into a 100mL round-bottomed flask, 60mL of 30% hydrogen peroxide solution was added, and the mixture was stirred vigorously at 70 ℃ for 5 hours in the absence of light. As the reaction proceeded, cisplatin slowly dissolved, eventually producing a clear yellow solution. After the reaction was completed, a small amount of insoluble matter was removed by filtration while it was hot, and after cooling at room temperature, it was left overnight at 4 ℃ to obtain a crystalline precipitate of platinum oxide. The product was centrifuged, washed once with deionized water and dried under vacuum overnight to give a pale yellow powder. Yield: 1.26g (93.3%).
(2) Synthesis of ADD-TPA
100mg of ADD (0.30mmol) and 44.95mg of TPA (0.30mmol) were added to 2mL of DMSO, and the mixture was stirred at room temperature overnight. After the reaction was complete, 20mL of deionized water was added to precipitate the product, which was centrifuged and washed once more, and the resulting precipitate was vacuum dried overnight to give an off-white powder. Yield: 124mg (89.2%). Of ADD-TPA1H-NMR、13The C-NMR and HRMS results are shown below:1H NMR(ppm,400MHz,DMSO-d6)δ13.09(s,1H,COOH),12.10(s,1H,CONHNCH),8.63(s,1H,CONHNCH),8.28(d,J＝8.1Hz,1H,ArH),8.02(d,J＝8.3Hz,2H,ArH),7.81(dd,J＝14.6,8.4Hz,3H,ArH),7.71(d,J＝2.1Hz,1H,ArH),7.52(m,1H,ArH),7.37(dt,J＝8.5,4.4Hz,2H,ArH),6.79(d,J＝8.4Hz,1H,ArH),5.89(s,2H,NCH2).13C NMR(ppm,101MHz,DMSO-d6)δ166.9,158.2,146.7,141.1,138.5,137.1,133.4,133.3,132.8,131.6,130.1,129.8,129.1,127.9,127.5,127.0,123.2,122.8,121.9,110.6,49.8.HRMS(negative mode)C23H16Cl2N4O3:[M-H]-,cald,(m/z)465.0526；found,465.0520.Purity(HPLC):98.6％at327nm。
(3) synthesis of HO-Pt-ADD
500mg of platinum oxide (1.50mmol), 726mg of ADD-TPA (1.50mmol), 314.8mg of EDC. HCl (1.65mmol) and 189.4mg of NHS (1.65mmol) were weighed into a 50mL round-bottomed flask, 15mL of anhydrous DMSO was added, and vigorous stirring was carried out at 50 ℃ for 24 h. After completion of the reaction, the reaction mixture was returned to room temperature, and unreacted platinum oxide was removed by centrifugation to obtain a dark yellow solution, which was then added dropwise to ethyl acetate (150mL) to obtain a precipitate. The crude product was filtered, washed twice with 5mL of deionized water and dried under vacuum to give the final product. Yield: 368mg (31.4%). Of HO-Pt-ADD1H-NMR、13The C-NMR and HRMS results are shown below:1HNMR(ppm,400MHz,DMSO-d6)δ12.04(s,1H,CONHNCH),8.61(s,1H,CONHNCH),8.28(d,J＝8.1Hz,1H,ArH),7.96(d,J＝8.2Hz,2H,ArH),7.75(m,5H,ArH),7.53(m,1H,ArH),7.38(m,2H,ArH),6.80(d,J＝8.4Hz,1H,ArH),6.06(overlap,6H,2×NH3,2H,NCH2).13C NMR(ppm,101MHz,DMSO-d6)δ172.9,158.2,147.2,141.0,136.9,135.9,133.4,133.3,132.8,130.1,129.8,129.1,127.9,127.5,126.4,123.1,122.8,121.9,110.6,49.8.HRMS(positivemode)C23H22Cl4N6O4Pt:[M+H]+,cald,(m/z)784.0148；found,784.0136.Purity(HPLC):96.7％at 327nm。
(4)Cnsynthesis of (E) -Pt-ADD
a.C2Synthesis of (E) -Pt-ADD
100mg of HO-Pt-ADD (0.13mmol) were dissolved in 2mL of anhydrous DMF, and ethyl isocyanate (0.26mmol) was added. The reaction solution was stirred at room temperature for 12h, then precipitated with 20mL of deionized water and centrifuged to obtain crude productA compound (I) is provided. Purifying and separating by silica gel column chromatography to obtain light yellow solid. The eluent is a mixed system of dichloromethane and methanol. Yield: 37mg (34.2%). C2of-Pt-ADD1H-NMR、13The C-NMR and HRMS results are shown below:1H NMR(ppm,400MHz,DMSO-d6)δ12.06(s,1H,CONHNCH),8.60(s,1H,CONHNCH),8.27(d,J＝8.14Hz,1H,ArH),7.97(d,J＝8.23Hz,2H,ArH),7.76(m,4H,ArH),7.52(m,1H,ArH),7.37(m,2H,ArH),6.73(overlap,6H,2×NH3,1H,ArH,1H,OCONH),5.90(s,2H,NCH2),2.97(m,2H,NHCH2CH3),0.98(t,J＝7.03,3H,NHCH2CH3).13C NMR(ppm,101MHz,DMSO-d6)δ158.2,147.1,141.1,137.3,137.2,133.4,133.3,132.8,130.1,129.9,129.7,129.1,127.9,127.5,126.8,126.5,123.1,122.8,121.9,110.6,49.8,34.1,15.5.HRMS(positive mode)C26H27Cl4N7O5Pt:[M+H]+,cald,(m/z)855.0519；found,855.0499.Purity(HPLC):98.5％at 327nm。
b.C4synthesis of (E) -Pt-ADD
100mg of HO-Pt-ADD (0.13mmol) was dissolved in 2mL of anhydrous DMF, followed by addition of n-butyl isocyanate (0.26mmol), and stirring at room temperature for 12 hours. Purification method and C2-Pt-ADD are the same. Yield: 76mg (67.8%). C4of-Pt-ADD1H-NMR、13The C-NMR and HRMS results are shown below:1H NMR(ppm,400MHz,DMSO-d6)δ12.06(s,1H,CONHNCH),8.60(s,1H,CONHNCH),8.27(d,J＝8.15Hz,1H,ArH),7.94(d,J＝8.26Hz,2H,ArH),7.76(m,4H,ArH),7.52(m,1H,ArH),7.37(m,2H,ArH),6.73(overlap,6H,2×NH3,1H,ArH,1H,OCONH),5.90(s,2H,NCH2),2.92(d,J＝6.03,2H,NHCH2CH2CH2CH3),1.29(m,4H,NHCH2CH2CH2CH3),0.96(t,J＝7.22,3H,NHCH2CH2CH2CH3).13C NMR(ppm,101MHz,DMSO-d6)δ158.2,158.2,147.1,141.1,137.3,137.2,133.4,133.3,132.8,130.1,129.8,129.7,129.1,127.9,127.5,126.7,126.5,123.1,122.8,121.9,110.6,49.8,32.0,29.1,19.6,13.8.HRMS(positive mode)C28H31Cl4N7O5Pt:[M+H]+,cald,(m/z)883.0832；found,883.0859.Purity(HPLC):99.6％at 327nm。
c.C6synthesis of (E) -Pt-ADD
100mg of HO-Pt-ADD (0.13mmol) were dissolved in 2mL of anhydrous DMF, and n-hexyl isocyanate (0.26mmol) was added and stirred at room temperature for 12 h. Purification method and C2-Pt-ADD are the same. Yield: 64mg (55.2%). C6of-Pt-ADD1H-NMR、13The C-NMR and HRMS results are shown below:1H NMR(ppm,400MHz,DMSO-d6)δ12.06(s,1H,CONHNCH),8.61(s,1H,CONHNCH),8.28(d,J＝8.1Hz,1H,ArH),7.95(d,J＝8.2Hz,2H,ArH),7.76(m,4H,ArH),7.53(m,1H,ArH),7.38(m,2H,ArH),6.77(overlap,6H,2×NH3,1H,ArH,1H,OCONH),5.90(s,2H,NCH2),2.92(d,J＝6.2Hz,2H,NHCH2(CH2)4CH3),1.29(m,8H,NHCH2(CH2)4CH3),0.87(t,J＝6.8Hz,3H,NHCH2(CH2)4CH3).13C NMR(ppm,101MHz,DMSO-d6)δ158.18,147.07,141.06,137.32,137.15,133.37,133.27,132.79,130.10,129.84,129.07,127.87,127.49,126.49,123.14,122.84,121.89,110.56,49.76,31.12,29.80,26.12,22.11,13.96.HRMS(positive mode)C30H35Cl4N7O5Pt:[M+H]+,cald,(m/z)911.1145；found,911.1161.Purity(HPLC):99.4％at 327nm。
d.C8synthesis of (E) -Pt-ADD
100mg of HO-Pt-ADD (0.13mmol) were dissolvedIn 2mL of anhydrous DMF was added n-butyloctyl isocyanate (0.26mmol) and the mixture was stirred at room temperature for 12 hours. Purification method and C2-Pt-ADD are the same. Yield: 80mg (66.7%). C8of-Pt-ADD1H-NMR、13The C-NMR and HRMS results are shown below:1H NMR(ppm,400MHz,DMSO-d6)δ12.06(s,1H,CONHNCH),8.60(s,1H,CONHNCH),8.27(d,J＝8.13Hz,1H,ArH),7.94(d,J＝8.26Hz,2H,ArH),7.76(m,4H,ArH),7.52(m,1H,ArH),7.37(m,2H,ArH),6.73(overlap,6H,2×NH3,1H,ArH,1H,OCONH),5.90(s,2H,NCH2),2.91(d,J＝5.94,2H,NHCH2(CH2)6CH3),1.29(m,12H,NHCH2(CH2)6CH3),0.86(t,J＝6.80,3H,NHCH2(CH2)6CH3).13C NMR(ppm,101MHz,DMSO-d6)δ158.2,158.2,147.1,141.1,137.3,137.2,133.4,133.3,132.8,130.1,129.8,129.7,129.1,127.9,127.5,126.7,126.5,123.1,122.8,121.9,110.5,49.8,31.3,29.8,28.9,28.7,28.5,26.5,22.1,14.0.HRMS(positive mode)C32H39Cl4N7O5Pt:[M+H]+,cald,(m/z)939.1458；found,939.1448.Purity(HPLC):99.4％at 327nm。
e.C12synthesis of (E) -Pt-ADD
100mg of HO-Pt-ADD (0.13mmol) were dissolved in 2mL of anhydrous DMF, followed by addition of 1-dodecylisocyanate (0.26mmol) and stirring at room temperature for 12 h. Purification method and C2-Pt-ADD are the same. Yield: 81mg (63.8%). C12of-Pt-ADD1H-NMR、13The C-NMR and HRMS results are shown below:1H NMR(ppm,400MHz,DMSO-d6)δ12.06(s,1H,CONHNCH),8.60(s,1H,CONHNCH),8.27(d,J＝8.11Hz,1H,ArH),7.94(d,J＝8.23Hz,2H,ArH),7.75(m,4H,ArH),7.52(m,1H,ArH),7.37(m,2H,ArH),6.73(overlap,6H,2×NH3,1H,ArH,1H,OCONH),5.90(s,2H,NCH2),2.90(d,J＝6.11,2H,NHCH2(CH2)10CH3),1.29(m,20H,NHCH2(CH2)10CH3),0.85(t,J＝6.81,3H,NHCH2(CH2)10CH3).13C NMR(ppm,101MHz,DMSO-d6)δ158.2,158.2,147.1,141.1,137.3,137.2,133.4,133.3,132.8,130.1,129.8,129.7,129.1,127.9,127.5,126.7,126.5,123.1,122.8,121.9,110.6,49.7,31.3,29.9,29.1,29.1,29.0,28.9,28.7,26.5,22.1,14.0.HRMS(positive mode)C36H47Cl4N7O5Pt:[M+H]+,cald,(m/z)995.2084；found,995.2091.Purity(HPLC):99.6％at 327nm。
example 2: preparation and characterization of self-assembled nanoparticles of adutant-modified cisplatin (Pt (IV) -ADD) prodrug
The specific operation steps for preparing the nanoparticles are as follows: c is to be2-Pt-ADD、C4-Pt-ADD、C6-Pt-ADD、C8-Pt-ADD or C12-Pt-ADD was dissolved in DMSO at a concentration of 10 mM. 100 μ L of the drug solution was slowly added dropwise to 2mL of deionized water under magnetic stirring at 300rpm, to obtain a self-assembled nanoparticle solution (Pt (IV) -ADD NPs). Adding DSPE-PEG, wherein the mass ratio is as follows: DSPE-PEG ═ 1: 0.15 (w/w). After mixing well, the above solution was transferred to a dialysis bag (MWCO1000) with the dialysis external phase being deionized water to remove the organic solvent DMSO. After dialysis, the nanoparticles are centrifuged at low speed to remove large particles and precipitates, and the DSPE-PEG-coated nanoparticle solution (Pt (IV) -ADD @ PEG NPs) can be obtained. The schematic diagram of the preparation of nanoparticles is shown in figure 1.
The particle size and potential of the nanoparticles were analyzed by a dynamic light scattering particle sizer, and the spectra thereof are shown in fig. 2 and 3. With the increase of the length of the carbon chain of the substituent group at the opposite side, the particle size of the nanoparticle is gradually increased, and the potential is not obviously changed. The encapsulation efficiency and the drug loading capacity of the drug in the nanoparticles are determined by an HPLC method, and the encapsulation efficiency and the drug loading capacity of each Pt (IV) -ADD prodrug in the self-assembled nanoparticles are shown in FIGS. 4 and 5. The entrapment rate of the medicine is between 78.8% and 92.6%, and the drug loading rate is between 84.0% and 86.0%. The encapsulation efficiency and drug loading capacity of the self-assembled nano-particle of the cisplatin prodrug are higher than that of the majority of the nano-particles at present (generally DLC is less than 10%). The high EE can greatly reduce the waste of the medicine in the preparation process of the nanoparticles, the high DLC can reduce the using amount of the carrier, and the safety and worries of metabolism/excretion problems, immunogenicity, toxic and side effects and the like brought by the carrier are reduced.
C is to be2-Pt-ADD、C4-Pt-ADD、C6-Pt-ADD、C8-Pt-ADD and C12Dropwise adding a nanoparticle solution of-Pt-ADD (comprising two nanoparticles containing DSPE-PEG and not containing DSPE-PEG) on a copper mesh, standing at room temperature for 1h, sucking the residual liquid by using filter paper, volatilizing the residual water, loading and observing, and comparing the particle size and the morphology of nanoparticles formed by self-assembly of different compounds (fig. 6 and 7). The particle diameters of the nanoparticles coated by the DSPE-PEG have no obvious difference, but the adhesion condition of the nanoparticles is obviously reduced, and the dispersibility is enhanced. The amphiphilic structure of the DSPE-PEG can increase the hydrophilicity of the surface of the nanoparticle, reduce the mutual aggregation of the nanoparticle in an aqueous solution due to the weak hydrophilicity, increase the contact between the surface of the nanoparticle and water molecules, and improve the stability of the nanoparticle. C2-Pt-ADD@DSPE-PEG NPs、C4-Pt-ADD@DSPE-PEG NPs、C6-Pt-ADD@DSPE-PEGNPs、C8-Pt-ADD @ DSPE-PEG NPs and C12The average particle diameters of the-Pt-ADD @ DSPE-PEG NPs under an electron microscope are respectively 50.5nm, 68.9nm, 67.8nm, 79.0nm and 120.0nm, and the average particle diameters are about 10-20nm smaller than the average particle diameter measured by DLS. The DLS measurement result shows that the hydrated particle size of the nanoparticles contains a hydrated layer on the surface of the nanoparticles, so the particle size is larger.
Example 3: research on in-vitro anti-tumor activity of cisplatin-adutant self-assembled nanoparticles
In order to investigate the cell killing effect of the compounds and the self-assembled nanoparticles, MTT experiments are carried out on cisplatin-resistant cells (triple negative breast cancer MDA-MB-231) and sensitive cells (liver cancer HepG2 and non-small cell lung cancer A549), and IC (integrated circuit) is carried out under the action of various free drugs and nanoparticles50The values are shown in Table 1, where Table 1 shows the half Inhibitory Concentrations (IC) of various adutant-modified cisplatin prodrugs on triple-negative breast cancer MDA-MB-231, liver cancer HepG2 and non-small cell lung cancer A54950) Wherein the enhancement index (FI) is defined as IC50(cisplatin)/IC50(drug).
TABLE 1
From table 1, the following conclusions can be drawn initially: (1) the tumor killing effect of the self-assembled nanoparticles is better than that of corresponding free drugs. (2) The self-assembled nano-drug can produce enhanced tumor treatment effect in cisplatin-resistant and sensitive tumor cells. IC of cisplatin in drug-resistant cells MDA-MB-23150319.7 mu M, the minimum self-assembly nano-particle is 1.2 mu M, the FI can reach 266.4, the drug resistance problem of cisplatin can be greatly reduced, and the tumor treatment effect is enhanced; in sensitive cells HepG2 and A549, the FI value can reach 7.0 and 5.0 times to the maximum compared with cisplatin, and the tumor treatment effect can also be improved. (3) Whether free drugs or self-assembled nanoparticles are adopted, the tumor killing effect is C4-Pt-ADD>C6-Pt-ADD>C2-Pt-ADD>C8-Pt-ADD>C12Pt-ADD, of which only C in HepG2 cells8-Pt-ADD>C2-Pt-ADD。C4-Pt-ADD and C6The killing effect of the-Pt-ADD is stronger.
Example 4: research on in vivo anti-tumor activity of the cisplatin-adutane self-assembled nanoparticles.
In order to further investigate the in vivo kangzhongl effect of the nano-drug, a mouse subcutaneous tumor model of MDA-MB-231 was established. In the axillary region of BALB/C nude mice, 100. mu.L of PBS (containing 5X 10)6Individual cells), 6 days later, mice were randomly grouped into four groups: PBS, Cisplatin + ADD, C2-Pt-ADD@PEG NPs、C4-Pt-ADD @ PEG NPs and C6-Pt-ADD @ PENGNPs, 8 mice per group. Wherein the cisplatin is administered at a dose of 3mg/kg once every three days for four times. The change of the tumor volume and the body weight of the mice is measured during the administration period, and the tumor inhibition capability and the in vivo safety of different medicines are judged. Fig. 8 and 9 show the results of tumor suppression in mice. FIG. 10 shows the body weight change of mice. Compared with PBS and Cisplatin + ADD group, the nanoparticle has obviously enhanced tumor inhibition capability, wherein C4-Pt-ADD @ PEG NPs and C6Tumor suppression efficacy of-Pt-ADD @ PEG NPsThe fruit is better.
In conclusion, the platinum prodrug modified by the adutant has good self-assembly performance, the nano structure formed by self-assembly is simple to prepare and high in drug loading capacity, can obviously inhibit drug-resistant tumors and relieve the problems of drug resistance and toxic and side effects of the cisplatin, and is a potential anti-tumor drug.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound, which is characterized by having a general structural formula shown in a formula I:
in the formula I, the compound has the following structure,
is a platinum compound; the value range of n is more than or equal to 0 and less than or equal to 19, and n is an integer.
2. The 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified compound according to claim 1, wherein in said formula I,
is cisplatin, carboplatin, heptaplatin, nedaplatin, oxaliplatin, lobaplatin, miriplatin, eptaplatin, or picoplatin.
3. 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound nanoparticles, which are obtained by self-assembly of the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound according to claim 1 or 2, wherein 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide is accumulated in the nanoparticles due to hydrophobic interaction and pi-pi stacking interaction, and the platinum compound is hydrated outside the nanoparticles to stabilize the nanostructure.
4. The process for the preparation of 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide-modified platinum-based compound according to claim 1 or 2, comprising the steps of:
(1) oxidizing a divalent platinum compound into a tetravalent platinum compound; mixing 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide and 4-formylbenzoic acid, and carrying out condensation reaction to obtain carboxyl modified 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide;
(2) adding the carboxyl modified 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide obtained in the step (1) into a tetravalent platinum compound, adding a catalyst and an anhydrous organic solvent, heating to enable the tetravalent platinum compound and the carboxyl modified 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide to perform esterification reaction, centrifuging to remove precipitates, recrystallizing, washing, and performing vacuum drying to obtain an intermediate product;
(3) and (3) fully and uniformly mixing the intermediate product obtained in the step (2) with isocyanate, carrying out nucleophilic reaction on the intermediate product and the isocyanate, washing, and purifying and separating by using eluent through silica gel column chromatography to obtain the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound.
5. The method for preparing a 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide-modified platinum compound according to claim 4, wherein in the step (2), the ratio of the amounts of the tetravalent platinum compound and the carboxyl-modified 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide is 0.1 to 10, the anhydrous organic solvent is anhydrous dimethylsulfoxide or anhydrous N, N-dimethylformamide, and the solvent used in the recrystallization is ethyl acetate, acetone, acetonitrile or ethanol;
the eluent in the step (3) is a mixture of halogenated hydrocarbon and alcohol organic matters;
preferably, the halogenated hydrocarbon is dichloromethane or trichloromethane, and the alcoholic organic substance is a mono-alcohol or a polyol.
6. The preparation method of 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound nanoparticles as claimed in claim 3, characterized in that the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound as claimed in claim 1 or 2 is dissolved in an organic solvent, then is dripped into deionized water, a surfactant is added, the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound is self-assembled, and the organic solvent is removed by dialysis, so that 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound nanoparticles can be obtained.
7. The preparation method of the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound nanoparticles as claimed in claim 6, wherein the organic solvent is dimethyl sulfoxide, N-dimethylformamide or ethanol;
the surfactant is distearoyl phosphatidyl ethanolamine-polyethylene glycol or polyethylene glycol vitamin E succinate.
8. Use of the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide-modified platinum compound according to claim 1 or 2, for the preparation of an antitumor drug.
9. The application of the 1- (2, 4-dichlorobenzyl) -1H indazole-3-carbohydrazide modified platinum compound nanoparticles as claimed in claim 3 in preparing antitumor drugs.
10. The use of claim 8 or 9, wherein the tumor is a drug resistant tumor.
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| CN112608397A (en) * | 2020-11-30 | 2021-04-06 | 西安交通大学 | Platinum antitumor drug-polysaccharide polymer nano prodrug and preparation method and application thereof |
| CN113648423A (en) * | 2021-07-22 | 2021-11-16 | 南方医科大学 | Amphiphilic conjugate anti-tumor nano-drug, preparation method thereof, nano-assembly and application |
| CN116410234A (en) * | 2023-04-14 | 2023-07-11 | 吉林大学 | Preparation and application of cisplatin prodrug self-assembled nanoparticles for overcoming cisplatin resistance |
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| CN108743963A (en) * | 2018-06-14 | 2018-11-06 | 华中科技大学 | One kind containing platinic anticancer conjugate and its preparation method and application |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112608397A (en) * | 2020-11-30 | 2021-04-06 | 西安交通大学 | Platinum antitumor drug-polysaccharide polymer nano prodrug and preparation method and application thereof |
| CN113648423A (en) * | 2021-07-22 | 2021-11-16 | 南方医科大学 | Amphiphilic conjugate anti-tumor nano-drug, preparation method thereof, nano-assembly and application |
| CN113648423B (en) * | 2021-07-22 | 2022-11-22 | 南方医科大学 | Amphiphilic conjugate anti-tumor nano-drug, preparation method thereof, nano-assembly and application |
| CN116410234A (en) * | 2023-04-14 | 2023-07-11 | 吉林大学 | Preparation and application of cisplatin prodrug self-assembled nanoparticles for overcoming cisplatin resistance |
| CN116410234B (en) * | 2023-04-14 | 2024-04-19 | 吉林大学 | Preparation and application of cisplatin prodrug self-assembled nanoparticles for overcoming cisplatin resistance |
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