CN111840574A - Preparation and application of 5-aminolevulinic acid-camptothecin small-molecule prodrug - Google Patents
Preparation and application of 5-aminolevulinic acid-camptothecin small-molecule prodrug Download PDFInfo
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Abstract
The invention discloses a preparation method and application of a 5-aminolevulinic acid-camptothecin small molecule prodrug, wherein the preparation method comprises the following steps: (1) preparation of camptothecin monomer BHD-CPT containing disulfide bond (2) preparation of CPT-SS-NPC (3) reaction of photosensitizer ALA and CPT-SS-NPC to prepare CPT-SS-ALA. Due to the amphiphilic structure, the drug conjugate can be self-assembled in water to form nanoparticles, and has the advantages of high micelle stability, controllable micelle shape, high drug loading capacity, low toxic and side effects, good drug controlled release and the like. In a reductive tumor microenvironment, disulfide bonds in the drug nanoparticles are broken to release a chemotherapeutic drug CPT, and meanwhile, the photosensitizer ALA continuously generates singlet oxygen under laser irradiation to kill cancer cells, so that the multi-modal synergistic treatment of tumors is realized.
Description
Technical Field
The invention relates to the field of high-molecular chemical drugs, in particular to a preparation method and application of a 5-aminolevulinic acid-camptothecin small-molecule prodrug nano micelle.
Background
Camptothecin (CPT, chemical structural formula: C)20H16N2O4CAS number: 7689-03-4, relative molecular weight: 348.43) is a plant anticancer drug extracted from Camptotheca acuminata in south and southwest of China. Has good curative effect on gastrointestinal tract cancer, head and neck cancer and the like. Camptothecin belongs to the class of cytotoxic quinoline alkaloids, and inhibits DNA Topoisomerase (TOPOI).
5-aminolevulinic acid (ALA, CAS number: 5451-09-6), which is a second-generation photosensitizer, is a Photodynamic Therapy (PDT) medicine. ALA is an endogenous biochemical substance, and protoporphyrin IX (PP IX) with strong photosensitivity is generated through ALA dehydratase and a series of enzymatic actions. Irradiating the cancer tissue containing PP IX with 420-640 nm light to generate singlet oxygen (-O) in the energy transfer process2) This oxygen state, when present at a certain concentration, can destroy cancer cells. The other is that the excited PP IX directly reacts with the biological molecule after light irradiation or transfers energy to oxygen and water to form free radicals, and a series of chain reactions of the biological molecule are caused by the free radicals to cause the death of cancer cells.
Due to the small molecular size and extremely low solubility in water of camptothecin drugs, problems of nonspecific selectivity, low drug utilization rate, high renal clearance, strong toxic and side effects and the like are faced in the drug delivery process and need to be solved, so that the improvement of the water solubility and the protection of the biological activity of the camptothecin drugs have important scientific significance. By introducing a disulfide bond into a camptothecin molecule and linking a photosensitizer ALA through the disulfide bond, the cleavage of the disulfide bond requires high GSH concentration, when the drug is delivered to a tumor part, the disulfide bond is cleaved by the high GSH concentration, the drug CPT and the photosensitizer ALA are released from a carrier to exert drug effect, and meanwhile, singlet oxygen is continuously generated under laser irradiation to kill cancer cells, so that the multi-modal synergistic treatment of the tumor is realized. The drug-loaded system increases the solubility and stability of the drug, forms micelle in water and also shows good cell permeation and retention Effects (EPR), so that the uptake of the drug by tumor cells is greatly increased, meanwhile, the photosensitizer ALA can be used for dynamically detecting the aggregation amount of the drug and PDT treatment, overcomes the defects of great toxic and side effects on normal tissues and the like of camptothecin and ALA, and realizes the targeting property and excellent controllable release of the drug-loaded micelle.
Disclosure of Invention
Aiming at the defects that the existing single-molecule polymeric prodrug has poor selectivity, the loading capacity of the drug is low, the selective controllable release of the drug is difficult to ensure, and the like, and the curative effect of single chemotherapy is low. The invention aims to provide a preparation method of a 5-aminolevulinic acid-camptothecin small molecule prodrug and application of the prodrug in the field of cancer treatment by medicines.
The technical scheme of the invention is as follows:
a preparation method of 5-aminolevulinic acid-camptothecin small molecule prodrug nano-micelle is characterized by comprising the following steps:
(1) the preparation method of the camptothecin CPT precursor BHD-CPT with the disulfide bond has the following synthetic route and comprises the following steps: dissolving camptothecin CPT and 4-dimethylpyridine DMAP in anhydrous dichloromethane DCM at 25 ℃ and 2-10Pa in argon atmosphere; dissolving triphosgene BTC in anhydrous DCM, then dropwise adding the BTC solution dissolved in the anhydrous DCM into a reaction system, and reacting for 0.5-1h in a dark place; dissolving 2-hydroxyethyl disulfide BHD in anhydrous tetrahydrofuran THF, then slowly dropwise adding BHD solution dissolved in anhydrous THF into the reaction system under stirring, reacting for 12-24h in a dark place, and obtaining a CPT precursor BHD-CPT with a disulfide bond through multiple extraction and column purification.
(2) The synthesis route of preparing CPT-SS-NPC is shown as follows, and comprises the following steps: under the conditions of ice bath and argon atmosphere of 2-10Pa, dissolving the product BHD-CPT obtained in the step (1) in anhydrous dichloromethane DCM, dissolving chlorate 4-NPC in anhydrous dichloromethane DCM, mixing and stirring the two for 10 minutes, adding anhydrous pyridine into a reaction system by using an injector, reacting for 24 hours at room temperature, filtering the product by using a filter head, concentrating by rotary evaporation, washing twice by using ether to obtain dark yellow mucus, and drying in vacuum.
(3) The CPT-SS-ALA is prepared by reacting a photosensitizer ALA with CPT-SS-NPC, and the synthetic route of the reaction is shown as follows, and comprises the following steps: dissolving the product CPT-SS-NPC obtained in the step (2) and a photosensitizer ALA in anhydrous dichloromethane DCM at 25 ℃ and 2-10Pa in an argon atmosphere, adding triethylamine TEA, adding 1mL of anhydrous DMSO, and stirring for 24h to change the solution from a clear yellow solution to a turbid yellow solution. Filtering with a filter head, and performing rotary evaporation and concentration to obtain the final product CPT-SS-ALA.
(4) The preparation method of the camptothecin prodrug CPT-SS-ALA nano micelle comprises the following steps: and (2) dissolving a certain amount of the CPT-SS-ALA material obtained in the step (3) in a proper amount of organic solvent at 25 ℃, wherein the organic solvent is one of DMF (dimethyl formamide) or DMSO (dimethyl sulfoxide), slowly dropwise adding the mixture into a certain amount of deionized water under stirring, stirring for 10-30 min, and dialyzing with the deionized water to remove the organic solvent to obtain the prodrug nano micelle aqueous solution.
Further, in the step (1), the molar concentrations of CPT, DMAP and BTC dissolved in the anhydrous DCM are respectively 0.05-0.1 mol.L-1、0.1-0.5 mol· L-1And 0.02 to 0.04 mol. L-1(ii) a BHD is dissolved in THF solution with a molar concentration of 1.2-1.5 mol.L-1。
Further, in the step (2), the molar concentrations of BHD-CPT and 4-NPC dissolved in the anhydrous DCM are respectively 0.125-0.25 mol.L-1And 0.1 to 0.3 mol. L-1(ii) a The volume of the anhydrous pyridine is 60-65 mu L.
Further, the molar ratio of CPT-SS-NPC, ALA and TEA in the step (3) is 1: 1: 1; the volume ratio of the mixed solution of the anhydrous DCM and the anhydrous DMSO is 3: 1.
Further, the diameter of the camptothecin prodrug CPT-SS-ALA nano-micelle prepared in the step (4) is about 120-150 nm.
The main advantages of the invention are:
1. aiming at the problems of the existing single-molecule prodrug delivery system, the project creatively provides the delivery system of the preparation method of the small molecule of the GSH-responsive camptothecin prodrug combined photodynamic therapy, which can effectively improve the loading quantity and selective release of the drug, solve the problems of the micelle stability and the selective controllable release of the drug of the existing single-molecule prodrug delivery system and promote the accurate diagnosis and the high-efficiency treatment of the tumor.
2. In a reductive tumor microenvironment, disulfide bonds in the drug nanoparticles are broken to release chemotherapeutic drugs, and meanwhile, the photosensitizer ALA can be used for dynamically detecting the aggregation amount of the drugs and PDT treatment under laser irradiation to continuously generate singlet oxygen to kill cancer cells, thereby realizing the multi-modal synergistic treatment of tumors.
Drawings
In order to make the purpose, technical scheme and beneficial effect of the invention more clear, the invention provides the following drawings:
FIG. 1 is a schematic diagram of the synthesis of the small molecule prodrug CPT-SS-ALA of 5-aminolevulinic acid-camptothecin in example 1.
FIG. 2 is a nuclear magnetic representation of the small molecule prodrug of 5-aminolevulinic acid-camptothecin CPT-SS-ALA from example 1.
FIG. 3 is a UV spectrum of the small molecule prodrug CPT-SS-ALA of 5-aminolevulinic acid-camptothecin in example 1.
FIG. 4 is a graph of the hydrated particle size of 5-aminolevulinic acid-camptothecin small molecule prodrug CPT-SS-ALA nanomicelle in example 1.
FIG. 5 is a schematic diagram of the in vitro drug release of 5-aminolevulinic acid-camptothecin small molecule prodrug CPT-SS-ALA nano-micelle in example 1.
FIG. 6 is a graph comparing the toxicity of CPT-SS-ALA nanomicelles, a small molecule prodrug of 5-aminolevulinic acid-camptothecin, in example 1, on 4T1 cells.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example 1 preparation of a 5-Aminolevulinic acid-camptothecin Small molecule prodrug
The general synthesis scheme of a 5-aminolevulinic acid-camptothecin small molecule prodrug is shown in figure 1, and mainly comprises the following steps:
(1) the preparation method of the camptothecin CPT precursor BHD-CPT with the disulfide bond has the following synthetic route and comprises the following steps: camptothecin CPT (376.2 mg, 1.08 mmol) and 4-dimethylpyridine DMAP (420.6 mg, 3.42 mmol) were dissolved in anhydrous dichloromethane DCM (15 mL) at 25 ℃ under an argon atmosphere of 2-10 Pa; dissolving triphosgene BTC (123 mg,0.396 mmol) in anhydrous DCM (15 mL), then dropwise adding the BTC solution dissolved in the anhydrous DCM into the reaction system, and reacting for 0.5-1h in the dark; dissolving 2-hydroxyethyl disulfide BHD (830 mg, 5.4 mmol) in anhydrous tetrahydrofuran THF (4 mL), then slowly dropwise adding the BHD solution dissolved in the anhydrous THF into the reaction system under stirring, reacting for 12-24h in a dark place, and obtaining a CPT precursor BHD-CPT with a disulfide bond through multiple extractions and column purification.
(2) The synthesis route of preparing CPT-SS-NPC is shown as follows, and comprises the following steps: under the conditions of ice bath and argon atmosphere of 2-10Pa, the product BHD-CPT (134.7 mg, 0.25 mmol) obtained in the step (1) is dissolved in anhydrous dichloromethane DCM (2 mL), chlorate 4-NPC (77.1 mg, 0.375 mmol) is dissolved in anhydrous dichloromethane DCM (3 mL), the two are mixed and stirred for 10 minutes, anhydrous pyridine (63.24 muL) is added into the reaction system by a syringe, the reaction system is reacted for 24 hours at room temperature, the product is filtered by a filter head, and after rotary evaporation concentration, the product is washed twice by diethyl ether to obtain dark yellow mucus which is dried in vacuum.
(3) The CPT-SS-ALA is prepared by reacting a photosensitizer ALA with CPT-SS-NPC, and the synthetic route of the reaction is shown as follows, and comprises the following steps: the product CPT-SS-NPC (100 mg, 0.145 mmol) obtained in step (2) and the photosensitizer ALA (24.21 mg, 0.145 mmol) were dissolved in anhydrous dichloromethane DCM (3 mL) at 25 ℃ under an argon atmosphere of 2-10Pa, triethylamine TEA (14.65 mg, 0.145 mmol) was added, 1mL of anhydrous DMSO was added, and stirring was carried out for 24h, the solution changed from a clear yellow solution to a cloudy yellow solution. Filtering with a filter head, and performing rotary evaporation and concentration to obtain the final product CPT-SS-ALA. FIG. 2 is a nuclear magnetic hydrogen spectrum of CPT-SS-ALA and FIG. 3 is an ultraviolet spectrum of CPT-SS-ALA, which shows the successful synthesis of the prodrug.
(4) The preparation method of the camptothecin prodrug CPT-SS-ALA nano micelle comprises the following steps: and (2) dissolving a certain amount of the CPT-SS-ALA material obtained in the step (3) in a proper amount of organic solvent at 25 ℃, wherein the organic solvent is one of DMF (dimethyl formamide) or DMSO (dimethyl sulfoxide), slowly dropwise adding the mixture into a certain amount of deionized water under stirring, stirring for 10-30 min, and dialyzing with the deionized water to remove the organic solvent to obtain the prodrug nano micelle aqueous solution. The particle size distribution and size of the micelles are shown in FIG. 4. FIG. 5 is a schematic diagram of in vitro release of CPT-SS-ALA nano-micelle, and it can be seen that the drug release effect in the DTT simulated tumor site in vitro is excellent. FIG. 6 is a comparison of toxicity of CPT-SS-ALA nanomicelle 4T1 tumor cells, which shows that CPT-SS-ALA drug has strong toxicity to tumor cells under laser irradiation.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (5)
1. A preparation method of 5-aminolevulinic acid-camptothecin small molecule prodrug nano-micelle is characterized by comprising the following steps:
(1) the preparation method of the camptothecin CPT precursor BHD-CPT with the disulfide bond has the following synthetic route and comprises the following steps: dissolving camptothecin CPT and 4-dimethylpyridine DMAP in anhydrous dichloromethane DCM at 25 ℃ and 2-10Pa in argon atmosphere; dissolving triphosgene BTC in anhydrous DCM, then dropwise adding the BTC solution dissolved in the anhydrous DCM into a reaction system, and reacting for 0.5-1h in a dark place; dissolving 2-hydroxyethyl disulfide BHD in anhydrous tetrahydrofuran THF, then slowly dropwise adding BHD solution dissolved in anhydrous THF into the reaction system under stirring, reacting for 12-24h in a dark place, and obtaining a CPT precursor BHD-CPT with a disulfide bond through multiple extraction and column purification;
(2) the synthesis route of preparing CPT-SS-NPC is shown as follows, and comprises the following steps: under the conditions of ice bath and argon atmosphere of 2-10Pa, dissolving the product BHD-CPT obtained in the step (1) in anhydrous dichloromethane DCM, dissolving chlorate 4-NPC in anhydrous dichloromethane DCM, mixing and stirring the two for 10 minutes, adding anhydrous pyridine into a reaction system by using an injector, reacting for 24 hours at room temperature, filtering the product by using a filter head, carrying out rotary evaporation concentration, washing twice by using diethyl ether to obtain dark yellow mucus, and drying in vacuum to obtain CPT-SS-NPC;
(3) the CPT-SS-ALA is prepared by reacting a photosensitizer ALA with CPT-SS-NPC, and the synthetic route of the reaction is shown as follows, and comprises the following steps: dissolving the product CPT-SS-NPC obtained in the step (2) and a photosensitizer ALA in anhydrous dichloromethane DCM at 25 ℃ and under the argon atmosphere of 2-10Pa, adding triethylamine TEA, adding 1mL of anhydrous DMSO, stirring for 24h, and changing the solution from a clear yellow solution to a turbid yellow solution; filtering with a filter head, and performing rotary evaporation and concentration to obtain a final product CPT-SS-ALA;
(4) the preparation method of the camptothecin prodrug CPT-SS-ALA nano micelle comprises the following steps: and (2) dissolving a certain amount of the CPT-SS-ALA material obtained in the step (3) in a proper amount of organic solvent at 25 ℃, wherein the organic solvent is one of DMF or DMSO, slowly dripping the mixture into a certain amount of deionized water under stirring, stirring for 10-30 min, and dialyzing with the deionized water to remove the organic solvent to obtain the camptothecin prodrug CPT-SS-ALA nano micelle aqueous solution.
2. The method for preparing the 5-aminolevulinic acid-camptothecin small molecule prodrug nanomicelle according to claim 1, wherein the method comprises the following steps: in the step (1), the molar concentrations of CPT, DMAP and BTC dissolved in the anhydrous DCM are respectively 0.05-0.1 mol.L-1、0.1-0.5 mol· L-1And 0.02-0.04 mol· L-1(ii) a BHD is dissolved in THF solution with a molar concentration of 1.2-1.5 mol.L-1。
3. The method for preparing the 5-aminolevulinic acid-camptothecin small molecule prodrug nanomicelle according to claim 1, wherein the method comprises the following steps: in the step (2), the molar concentrations of BHD-CPT and 4-NPC dissolved in the anhydrous DCM are respectively 0.125-0.25 mol.L-1And 0.1 to 0.3 mol. L-1(ii) a The volume of the anhydrous pyridine is 60-65 mu L.
4. The method for preparing the 5-aminolevulinic acid-camptothecin small molecule prodrug nanomicelle according to claim 1, wherein the method comprises the following steps: the mol ratio of CPT-SS-NPC, ALA and TEA in the step (3) is 1: 1: 1; the volume ratio of the mixed solution of the anhydrous DCM and the anhydrous DMSO is 3: 1.
5. The method for preparing the 5-aminolevulinic acid-camptothecin small molecule prodrug nanomicelle according to claim 1, wherein the method comprises the following steps: the diameter range of the camptothecin prodrug CPT-SS-ALA nano-micelle prepared in the step (4) is 120-150 nm.
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| CN115154420A (en) * | 2022-07-10 | 2022-10-11 | 西南大学 | Preparation of 7-ethyl-10 hydroxycamptothecin/chlorin e6 nano micelle |
| CN115154420B (en) * | 2022-07-10 | 2023-08-04 | 西南大学 | Preparation of 7-ethyl-10 hydroxycamptothecin/chlorin e6 nano micelle |
| CN116196436A (en) * | 2022-12-07 | 2023-06-02 | 大连理工大学 | JQ1 prodrug nano-particle capable of reversing tumor microenvironment in cooperation with chemotherapy and preparation method and application thereof |
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Application publication date: 20201030 |