CN110302390B - Oxaliplatin precursor as phospholipid analogue, preparation method and application thereof - Google Patents
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Abstract
The invention discloses a phospholipid-like oxaliplatin precursor with a structure shown in the following formula 1, and a preparation method and application thereof. The phospholipid oxaliplatin-like precursor can be independently self-assembled into micelles in water. The micelle has the characteristic of environmental sensitivity, the PEG hydration layer can be removed under the stimulation of a slightly acidic environment, the cellular uptake is promoted, the tetravalent oxaliplatin precursor is reduced into bivalent oxaliplatin after the reduction of glutathione, the concentration of the medicament in the tumor cells is rapidly increased, and the tumor cells are killed, so that the tumor chemotherapy effect is effectively improved.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a phospholipid-like oxaliplatin precursor, a preparation method and application thereof.
Background
Chemotherapy is one of the main means of cancer treatment, and Oxaliplatin (Oxaliplatin) is a platinum drug commonly used in clinic. However, most of the platinum antineoplastic drugs are easy to cause serious toxic and side effects and cause acquired drug resistance in the clinical use process, and the clinical application of oxaliplatin is limited. In recent years, nanotechnology-based drug delivery strategies have provided new drug delivery systems for chemotherapy. The nano-drug delivery system can effectively prolong the blood clearance time of small molecules and reduce toxic and side effects; however, the nano-drug has the problems of poor tumor permeability, difficult drug release and poor treatment effect.
Disclosure of Invention
Based on the background, the invention aims to provide the oxaliplatin precursor as the phospholipid capable of forming the self-assembled micelle in water, wherein the micelle is effectively dissociated under the stimulation of a tumor microacid environment, and the tumor distribution and release of the medicament are efficiently promoted.
The invention also aims to provide a preparation method of the oxaliplatin precursor as the phospholipid.
It is also an object of the invention to provide the use of the phospholipid oxaliplatin-like precursor for the manufacture of a medicament for the treatment of cancer.
It is a further object of the invention to provide a micelle formed by self-assembly of the phospholipid oxaliplatin-like precursor in water.
It is still another object of the present invention to provide a method for preparing the above micelle.
It is still another object of the present invention to provide use of the above micelle for the preparation of a medicament for the treatment of cancer.
According to one aspect, the invention provides a phospholipid-like oxaliplatin precursor having the structure shown in formula 1 below:
wherein R1 is selected from C2-C16 saturated alkyl; n is the polymerization degree of PEG chain, and is 20-20000.
According to another aspect, the invention provides a method for preparing the oxaliplatin precursor as the phospholipid, which specifically comprises the following steps:
step a: preparation of double-alkylated oxaliplatin prodrug DiPt
Firstly, reacting monocarboxylated and alkylated oxaliplatin with a carboxyl activating agent to obtain activated monocarboxylated and alkylated oxaliplatin, then reacting with N- (2, 3-dihydroxypropyl) carbamic acid tert-butyl ester to obtain N- (2, 3-dihydroxypropyl) carbamic acid tert-butyl ester connected with two monocarboxylated and alkylated oxaliplatin, then removing the formic acid tert-butyl ester under the action of trifluoroacetic acid, and finally obtaining the dialkylated oxaliplatin prodrug DiPt.
Wherein R1 is as defined above.
Preferably, monocarboxylated and alkylated oxaliplatin is dissolved in an organic solvent, the carboxyl activator is added to the solution in a molar ratio of carboxyl activator to monocarboxylated and alkylated oxaliplatin of 1:1 to 10:1, and the reaction is carried out at a constant temperature between 0 and 40 ℃ for 1 to 5 h; adding N- (2, 3-dihydroxypropyl) tert-butyl carbamate into the reaction solution in a molar ratio of monocarboxylated and alkylated oxaliplatin to the N- (2, 3-dihydroxypropyl) tert-butyl carbamate of 2:1-10: 1; then stirring and reacting for 6-48h at any constant temperature between 0-40 ℃; and then adding trifluoroacetic acid to continue reacting for 4 hours to remove tert-butyl formate, performing rotary evaporation and concentration, precipitating with diethyl ether, and drying in vacuum to obtain the dialkylated oxaliplatin prodrug DiPt.
Among them, preferably, the organic solvent is at least one selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, acetone, N-dimethylformamide, N-dimethylacetamide, and dimethylsulfoxide.
Wherein, preferably, the carboxyl activating agent is selected from one or more of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and N-hydroxysuccinimide.
Wherein, the drying temperature is preferably 25-60 ℃, and the drying time is 12-48 h.
Wherein, the addition amount of the trifluoroacetic acid is preferably 10 to 80 percent of the volume of the original organic solvent.
Step b: preparation of functionalized polyethylene glycol (PEG) chain PEGn-CDM
Firstly, carrying out substitution reaction on 2, 5-dihydroxy-4-methyl-2, 5-dioxo-3-furanpropionic acid and oxalyl chloride to obtain 2, 5-dihydroxy-4-methyl-2, 5-dioxo-3-furanpropionic acid acyl chloride, and then adding methoxy polyethylene glycol (PEGn-OH) to obtain a functionalized polyethylene glycol (PEG) chain PEGn-CDM; wherein n is as defined above.
Preferably, 2, 5-dihydroxy-4-methyl-2, 5-dioxo-3-furanpropionic acid is weighed out and dissolved in an organic solvent, and oxalyl chloride is mixed with 2, 5-dihydroxy-4-methyl-2, 5-dioxo-3-furanpropionic acid 10: 1-1: 1, stirring and reacting at a constant temperature of between 0 and 40 ℃ for 1 to 4 hours, then stirring and reacting at a constant temperature of between 15 and 60 ℃ for 1 to 12 hours, concentrating by rotary evaporation to remove the oxalyl chloride, redissolving in 1 to 10ml of an organic solvent, and then reacting the mixture with monomethoxypolyethylene glycol (PEGn-OH) and 2, 5-dihydroxy-4-methyl-2, 5-dioxo-3-furanpropionic acid 10: 1-1: 1, adding monomethoxy polyethylene glycol (PEGn-OH), stirring and reacting at a constant temperature of between 15 and 40 ℃ for 12 to 48 hours, adding 1 to 10ml of saturated ammonium chloride aqueous solution to stop the reaction, extracting an organic layer, performing rotary evaporation and concentration, precipitating with diethyl ether, and performing vacuum drying to obtain the functionalized polyethylene glycol chain PEGn-CDM. Wherein n is as defined above.
Among them, preferably, the organic solvent is at least one selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, acetone, N-dimethylformamide, N-dimethylacetamide, and dimethylsulfoxide.
Wherein, the drying temperature is preferably 25-60 ℃, and the drying time is 12-48 h.
Step c: preparation of oxaliplatin precursor phospholipid
The double alkylated oxaliplatin prodrug DiPt obtained in the step a and the PEG obtained in the step b are reactedn-CDM reaction to obtain oxaliplatin precursor phospholipid, wherein R1And definition of nAs previously described.
Preferably, the double alkylated oxaliplatin prodrug DiPt obtained in the step a is dissolved in an organic solvent, PEGn-CDM obtained in the step b is added into a reaction liquid according to the molar ratio of PEGn-CDM to the double alkylated oxaliplatin prodrug DiPt2:1-10:1, and the mixture is stirred and reacted for 6-48h at any constant temperature of 0-40 ℃; rotary evaporation and concentration, ether precipitation and vacuum drying are carried out to obtain the phospholipid oxaliplatin precursor DiPt-CDM-PEGn。
Among them, preferably, the organic solvent is at least one selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, acetone, N-dimethylformamide, N-dimethylacetamide, and dimethylsulfoxide.
Wherein, the drying temperature is preferably 25-60 ℃, and the drying time is 12-48 h.
According to a further aspect, the invention provides the use of the phospholipid oxaliplatin-like precursor for the manufacture of a medicament for the treatment of cancer.
Preferably, the cancer comprises breast cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, liver cancer, head and neck cancer, gastric cancer, or the like.
According to a further aspect, the invention provides a micelle formed by self-assembly of the oxaliplatin-like precursor phospholipid in water. And the average hydrodynamic particle size of the micelle is preferably 10 to 300 nm.
According to still another aspect, the present invention provides a method for preparing the above micelle, comprising: the oxaliplatin precursor as phospholipid is added into water according to the solid-to-liquid ratio of 3-30mg/ml under the stirring speed of 300-1000rpm, and the micelle can be obtained after the reaction for 5-30 min.
According to a further aspect, the present invention provides the use of the above-described micelle for the preparation of a medicament for the treatment of cancer. The micelle has the characteristic of environmental sensitivity, the PEG hydration layer can be removed under the stimulation of a slightly acidic environment, the cellular uptake is promoted, the tetravalent oxaliplatin precursor is reduced into bivalent oxaliplatin after the reduction of glutathione, the concentration of the medicament in the tumor cells is rapidly increased, and the tumor cells are killed, so that the tumor chemotherapy effect is effectively improved.
Preferably, the cancer comprises breast cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, liver cancer, head and neck cancer, gastric cancer, or the like.
Drawings
Fig. 1 is a nuclear magnetic resonance hydrogen spectrum (a) and a mass spectrum (B) of a bis-alkylated oxaliplatin precursor prepared in example 1 of the present invention. As shown in a nuclear magnetic resonance hydrogen spectrum A, peaks a and B are characteristic peaks of N- (2, 3-dihydroxypropyl) amino, peaks c and d are characteristic peaks of hexadecyl isocyanate, and a mass spectrum B shows that the molecular weight of a synthesized product is 1653, which is consistent with the theoretical molecular weight, so that the method proves that the double-alkylated oxaliplatin precursor is successfully prepared.
FIG. 2 shows a functionalized polyethylene glycol chain PEG prepared in example 2 of the present invention2kNuclear magnetic resonance hydrogen spectrum of CDM. As shown by hydrogen nuclear magnetic resonance spectroscopy, the peak a is the characteristic peak of methyl of polyethylene glycol, the peak b is the characteristic peak of methylene of polyethylene glycol, and the peak c is the characteristic peak of methyl of 2, 5-dihydroxy-4-methyl-2, 5-dioxo-3-furanpropionic acid, which proves that the functionalized polyethylene glycol chain PEG is successfully prepared2k-CDM。
Fig. 3 shows the nmr hydrogen spectrum of oxaliplatin-like precursor as a phospholipid prepared in example 3 of the present invention. As shown in a nuclear magnetic resonance hydrogen spectrum, peaks a, b, c and d are characteristic peaks of polyethylene glycol, and peaks e, f, g and h are characteristic peaks of the double-alkylated oxaliplatin precursor, so that the acid-sensitive amphipathic oxaliplatin precursor is successfully prepared.
FIG. 4 is a hydrodynamic particle size distribution of oxaliplatin-like precursor micelles as the phospholipid in example 4 of the present invention. The hydrodynamic particle size of the oxaliplatin-like precursor micelle of the phospholipid is measured by a MALVERN NANO SIZER type laser particle size tester, and the result shows that the diameter of the oxaliplatin-like precursor micelle of the phospholipid is 10-70nm, and the average particle size is 30 nm.
Fig. 5 shows MTT toxicity test data of oxaliplatin bulk drug and oxaliplatin-like precursor micelle, which is a phospholipid prepared in example 4 of the present invention, on 4T1 breast cancer cells after treatment with buffers of pH7.4 and pH 6.5. The result shows that when the concentration of the drug is 2.5 mu M, the cell survival rate of the oxaliplatin precursor drug group is 43%, the cell survival rate of the phospholipid oxaliplatin precursor micelle group after being treated at pH7.4 is 44%, and the cell survival rate of the phospholipid oxaliplatin precursor micelle group after being treated at pH6.5 is 24%, which indicates that the phospholipid oxaliplatin precursor micelle with acid sensitivity can obviously inhibit the growth of tumor cells.
Detailed Description
The present invention will be described with reference to the following specific examples, but the present invention is not limited to these specific examples.
The monocarboxylated and alkylated oxaliplatin used in the examples was prepared by the method of example 3 of patent application No. 201610514832.4. T-butyl N- (2, 3-dihydroxypropyl) carbamate, monomethoxypolyethylene glycol, was purchased from Sigma Aldrich (China). 2, 5-dihydroxy-4-methyl-2, 5-dioxo-3-furanpropionic acid, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 4-dimethylaminopyridine were purchased from Secoid (Shanghai) chemical industry development Co., Ltd. The solvents dichloromethane, trifluoroacetic acid, oxalyl chloride, pyridine, N-dimethylformamide, dimethyl sulfoxide were purchased from Shanghai Bailingwei science and technology Co. 4T1 breast cancer cells were purchased from ATCC cell bank, and RPIM1640 medium and fetal bovine serum were purchased from Gibco.
In the present application, the rest of the reagents and solvents used are purchased from the national pharmaceutical group (Shanghai) Chemicals, Inc., unless otherwise specified.
In this application, the equipment and the test methods are conventional in the art unless otherwise specified. Transmission electron micrographs were obtained with a Transmission Electron microscope model Tecnai G2F 20S-TWIN. The hydrodynamic particle size of the micelles was measured by a MALVERN NANO size laser particle size meter.
Example 1 preparation of DiPt as precursor for Bialkylated oxaliplatin
Weighing 700mg of monocarboxylated and alkylated oxaliplatin, dissolving the monocarboxylated and alkylated oxaliplatin in 5ml of dichloromethane solution, adding 191mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 140mg of 4-dimethylaminopyridine, stirring the solution at 25 ℃ for reaction and activation for 2h, adding 30mg of N- (2, 3-dihydroxypropyl) carbamic acid tert-butyl ester, reacting for 48h, performing rotary evaporation and concentration, dissolving the solution in a trifluoroacetic acid/dichloromethane (volume ratio of 1/1) mixed solvent again, continuing the reaction for 4h, performing rotary evaporation and concentration, precipitating with diethyl ether, and drying in vacuum to obtain the dialkylated oxaliplatin precursor DiPt. The obtained material was characterized by hydrogen nuclear magnetic resonance spectroscopy and mass spectrometry, and the results are shown in FIG. 1.
Example 2 functionalized polyethylene glycol chain PEG2kPreparation of CDM
Weighing 138mg of 2, 5-dihydroxy-4-methyl-2, 5-dioxo-3-furanpropionic acid, dissolving in 5ml of dichloromethane solution, adding 504. mu.l of oxalyl chloride and 40. mu.l of DMF equivalent to catalyst, stirring at 15 deg.C for reaction for 1h, stirring at 25 deg.C for reaction for 3h, rotary evaporating for concentration to remove oxalyl chloride, dissolving in 3ml of dichloromethane again, adding monomethoxypolyethylene glycol (PEG)2k-OH)300mg, reacting at room temperature for 24h, adding 5ml of saturated ammonium chloride aqueous solution to terminate the reaction, extracting an organic layer, performing rotary evaporation and concentration, precipitating with diethyl ether, and drying in vacuum to obtain the functionalized polyethylene glycol chain PEG2k-CDM. The obtained material was characterized by NMR spectrum, and the results are shown in FIG. 2.
Example 3 preparation of oxaliplatin precursor Phospholipids
200mg of the double alkylated oxaliplatin precursor DiPt prepared in example 1 was weighed, dissolved in 5ml of dimethyl sulfoxide solution, and the functionalized polyethylene glycol chain PEG prepared in example 2 was added2k-CDM 240mg, reacting at 45 ℃ for 24h, precipitating with diethyl ether, and vacuum drying to obtain the oxaliplatin prodrug as phospholipid. The obtained material was characterized by NMR spectrum, and the results are shown in FIG. 3.
Example 4 preparation of oxaliplatin precursor micelles, a phospholipid
Weighing 5mg of the oxaliplatin precursor as the phospholipid prepared in the embodiment 3, dissolving the oxaliplatin precursor in 2ml of methanol solution, slowly rotating and evaporating to remove the solvent, and adding 5ml of deionized water for dissolving to obtain the amphipathic oxaliplatin precursor micelle. The micelle size distribution is shown in fig. 4.
Example 5 evaluation of cytotoxicity of oxaliplatin precursor micelles, Phospholipids
After the micelles prepared in example 4 were placed in a buffer salt of pH7.4 or pH6.5 for 6 hours, they were then prepared at an equimolar concentration of 10. mu. mol/ml, and 7 gradients of concentrations, i.e., 10, 5, 2.5, 1.25, 0.625, 0.3 and 0.15. mu. mol/ml, were prepared in this order by the two-fold dilution method. 4T1 breast cancer cells were seeded in 96-well cell culture plates (3000 cells/well) with 0.1ml of RPIM1640 medium (10% serum) per well. After 24h of incubation, the medium was changed and supplemented (190. mu.l/well). mu.L of the diluted solution was added to a cell culture plate, and the cell activity was measured by MTT method after incubation for 48 hours with cancer cells. The results are shown in FIG. 5.
Claims (15)
1. A phospholipid-like oxaliplatin precursor, wherein the phospholipid-like oxaliplatin precursor has a structure represented by the following formula 1:
wherein R1 is selected from C2-C16 saturated alkyl; n is the polymerization degree of PEG chain, and is 20-20000.
2. A method of preparing the oxaliplatin-like precursor phospholipid as defined in claim 1, which comprises the steps of:
step a: preparation of double-alkylated oxaliplatin prodrug DiPt
Firstly, reacting monocarboxylated and alkylated oxaliplatin with a carboxyl activating agent to obtain activated monocarboxylated and alkylated oxaliplatin, then reacting with N- (2, 3-dihydroxypropyl) carbamic acid tert-butyl ester to obtain N- (2, 3-dihydroxypropyl) carbamic acid tert-butyl ester connected with two monocarboxylated and alkylated oxaliplatin, then removing the formic acid tert-butyl ester under the action of trifluoroacetic acid, and finally obtaining a double alkylated oxaliplatin prodrug DiPt; wherein R1 is as defined in claim 1;
step b: preparation of functionalized polyethylene glycol chain PEGn-CDM
Firstly, carrying out substitution reaction on 2, 5-dihydroxy-4-methyl-2, 5-dioxo-3-furylpropionic acid and oxalyl chloride to obtain 2, 5-dihydroxy-4-methyl-2, 5-dioxo-3-furylpropionic acid acyl chloride, and then adding methoxy polyethylene glycol PEGn-OH to obtain a functionalized polyethylene glycol chain PEGn-CDM; wherein n is as defined in claim 1;
step c: preparation of oxaliplatin precursor phospholipid
The double alkylated oxaliplatin prodrug DiPt obtained in the step a and the PEG obtained in the step b are reactedn-CDM reaction to obtain oxaliplatin precursor phospholipid, wherein R1And n is as defined in claim 1.
3. The method of claim 2, wherein: the specific steps of the step a are as follows: dissolving monocarboxylated and alkylated oxaliplatin in an organic solvent, adding a carboxyl activator to the solution in a molar ratio of the carboxyl activator to monocarboxylated and alkylated oxaliplatin of 1:1-10:1, and reacting at a constant temperature of between 0 and 40 ℃ for 1 to 5 hours; adding N- (2, 3-dihydroxypropyl) tert-butyl carbamate into the reaction solution in a molar ratio of monocarboxylated and alkylated oxaliplatin to the N- (2, 3-dihydroxypropyl) tert-butyl carbamate of 2:1-10: 1; then stirring and reacting for 6-48h at any constant temperature between 0-40 ℃; and then adding trifluoroacetic acid to continue reacting for 4 hours to remove tert-butyl formate, performing rotary evaporation and concentration, precipitating with diethyl ether, and drying in vacuum to obtain the dialkylated oxaliplatin prodrug DiPt.
4. The production method according to claim 3, characterized in that: the organic solvent is at least one selected from dichloromethane, acetonitrile, tetrahydrofuran, acetone, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide.
5. The production method according to claim 3, characterized in that:
the carboxyl activating agent is one or more selected from 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and N-hydroxysuccinimide.
6. The method of claim 2, wherein: the concrete steps of the step b are as follows: weighing 2, 5-dihydroxy-4-methyl-2, 5-dioxo-3-furanpropionic acid, dissolving in an organic solvent, reacting oxalyl chloride with 2, 5-dihydroxy-4-methyl-2, 5-dioxo-3-furanpropionic acid 10: 1-1: 1, stirring and reacting at a constant temperature of between 0 and 40 ℃ for 1 to 4 hours, then stirring and reacting at a constant temperature of between 15 and 60 ℃ for 1 to 12 hours, concentrating by rotary evaporation to remove the oxalyl chloride, redissolving in 1 to 10ml of organic solvent, and then reacting the mixture with monomethoxypolyethylene glycol PEGn-OH and 2, 5-dihydroxy-4-methyl-2, 5-dioxo-3-furanpropionic acid 10: 1-1: 1, adding monomethoxy polyethylene glycol PEGn-OH, stirring and reacting at a constant temperature of between 15 and 40 ℃ for 12 to 48 hours, adding 1 to 10ml of saturated ammonium chloride aqueous solution to stop the reaction, extracting an organic layer, performing rotary evaporation and concentration, precipitating with diethyl ether, and performing vacuum drying to obtain the functionalized polyethylene glycol chain PEGn-CDM.
7. The method of claim 6, wherein:
the organic solvent is at least one selected from dichloromethane, acetonitrile, tetrahydrofuran, acetone, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide.
8. The method of claim 2, wherein: the concrete steps of the step c are as follows: b, dissolving the double-alkylated oxaliplatin prodrug DiPt obtained in the step a in an organic solvent, adding the PEGn-CDM obtained in the step b into a reaction liquid according to the molar ratio of PEGn-CDM to the double-alkylated oxaliplatin prodrug DiPt2:1-10:1, and stirring and reacting at any constant temperature of 0-40 ℃ for 6-48 h; rotary evaporation and concentration, ether precipitation and vacuum drying are carried out to obtain the phospholipid oxaliplatin precursor DiPt-CDM-PEGn。
9. The method of claim 8, wherein: the organic solvent is at least one selected from dichloromethane, acetonitrile, tetrahydrofuran, acetone, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide.
10. Use of the phospholipid oxaliplatin precursor of claim 1 in the manufacture of a medicament for the treatment of cancer.
11. Use according to claim 10, characterized in that: the cancer is breast cancer, lung cancer, ovarian cancer, prostatic cancer, pancreatic cancer, liver cancer, head and neck cancer or gastric cancer.
12. A micelle formed by self-assembly of the phospholipid-like oxaliplatin precursor of claim 1 in water.
13. A plurality of micelles of claim 12, wherein: the average hydrodynamic particle size of the micelle is 10-300 nm.
14. A method of preparing the micelle of claim 12 which comprises: the oxaliplatin precursor as phospholipid of claim 1 is added into water according to the solid-to-liquid ratio of 3-30mg/ml under the stirring speed of 300-1000rpm, and the micelle can be obtained after 5-30min of reaction.
15. Use of the micelle of claim 12 or 13 for the preparation of a medicament for the treatment of cancer.
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