CN112402620A - Nano-medicine with tumor microenvironment reduction responsiveness and preparation method thereof - Google Patents
Nano-medicine with tumor microenvironment reduction responsiveness and preparation method thereof Download PDFInfo
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6905—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
- A61K47/6907—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a microemulsion, nanoemulsion or micelle
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- A—HUMAN NECESSITIES
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Abstract
The invention relates to a nano-drug for tumor microenvironment reduction response and a preparation method thereof, wherein the drug is a nano-scale monomethoxy polyethylene glycol and tripterine compound (MPEG)2k-SS-Cel) drugs with safe and non-toxic monomethoxypolyethylene glycol (MPEG) with a molecular weight of about 20002k) Is hydrophilic material, and is chemically bonded with hydrophobic natural antitumor drug such as tripterine and MPEG via disulfide bond2kthe-SS-Cel can be self-assembled into nano micelles of about 140nm, and the monomethoxypolyethylene glycol is used as a hydrophilic segment to embed the tripterine outside the micelles. The medicine is prepared by bonding hydrophilic monomethoxypolyethylene glycol with tripterine to overcome its hydrophobicityThe nano-micelle has the defect of effective utilization in vivo, and has the characteristic that the nano-micelle is broken to respond under the condition of high-concentration Glutathione (GSH) in a tumor microenvironment to disintegrate and release the drug through an intermediate disulfide bond. The nano-drug is detected to have high-efficiency treatment effect through cell experiments.
Description
Technical Field
The invention relates to a tumor microenvironment reduction responsive nano-drug and a preparation method thereof, in particular to a preparation method of a reduction responsive anticancer nano-drug.
Background
According to statistics, approximately 430 million people per year are diagnosed with cancer, that is, more than 8 people per minute are diagnosed with cancer in china. In addition, cancer is also a disease with a very high mortality rate, more than 280 ten thousand per year, and on average 5 people die from cancer per minute. The main treatment modalities for cancer are surgical resection, chemotherapy and radiotherapy. Although these therapeutic means have clinically significant therapeutic effects, they have not been able to completely treat cancer. For example, although surgery can remove a large portion of tumor tissue, a small portion of tumor tissue that has not been removed may still recur. The chemotherapy drugs can generate toxic and side effects on normal cells of a human body, such as liver and kidney injury and cardiotoxicity, while treating cancers, and tumors can generate drug resistance on the chemotherapy drugs after the chemotherapy drugs are applied for a long time, so that the treatment effect of the chemotherapy drugs is reduced.
Celastrol (Celastrol, Cel), molecular formula C29H38O4The tripterygium wilfordii is an important active component of tripterygium wilfordii, also called celastrol, which is a triterpenoid, and is a red needle-shaped crystal, is insoluble in water and soluble in organic solvents such as methanol, ethanol, dichloromethane and the like. The tripterygium wilfordii extract mainly comes from the root bark of the tripterygium wilfordii, has various biological activities, and has important research value in the treatment of certain inflammations and tumors. The anticancer mechanism of Cel is that C2 and C6 on the aromatic ketone group have strong nucleophilic activity, can react with hydrogen at threonine-N terminal on proteasome 5 subunit to form covalent bond, and inhibit proteasome chymotrypsin-like activity of cancer cells, thereby inducing cancer cell apoptosis, and is called as an effective natural proteasome inhibitor. The research finds that Cel can block a PI 3K/Akt-NF-kB signal channel by down-regulating microRNA-21. Although Cel has better anticancer effect, Cel is an insoluble anticancer drug, has lower oral bioavailability and larger self toxicity, is easy to generate systemic toxic and side effects on organisms, and has limited clinical application due to physicochemical properties.
The anticancer nano-drug utilizes a material with good biocompatibility to load the drug, and the obtained nano-scale drug can be taken by the tumor through the high permeability and retention effect of the solid tumor, so that the probability of releasing the drug in normal cells is reduced, and the damage to normal tissues is weakened. Moreover, the tumor cells have vigorous life activities, frequent proliferation and rapid metabolism, so that the microenvironment around the tumor cells is different from that of normal cells. For example, the concentration of Glutathione (GSH), a reducing substance in tumor cells, is 2-10 mM, which is about several thousand times the concentration of GSH (2-20. mu.M) in normal cells and blood. The reduction response type nano-drug can be designed by utilizing the huge difference of the reduction environment inside and outside the tumor cells. Common reduction-sensitive chemical bonds in the structure of the reduction-responsive nano-drug are mainly disulfide bonds (-SS-) and diselenide bonds (-SeSe-). The reduction response type polymer micelle is generally formed by respectively connecting hydrophilic chain ends and hydrophobic chain ends at two ends of-SS-or-SeSe-, an amphiphilic polymer is self-assembled into the micelle in water and then entraps a hydrophobic anti-tumor drug, and the-SS-or-SeSe-in a drug-carrying micelle structure can be broken under the stimulation of a reduction environment in a tumor cell to realize the rapid release of the drug.
Chinese patent CN202010047522.2 discloses a drug combination controlled release system of celecoxib micelles and honokiol micelles and a preparation method thereof. The carrier used by the medicine comprises a monomethoxypolyethylene glycol-racemic polylactic acid block copolymer, wherein the molecular weight of a polyethylene glycol block is 1000-2000. The monomethoxy polyethylene glycol-racemic polylactic acid block copolymer is an amphiphilic molecule, namely has an amphiphilic structure, can be self-assembled into nanoparticles in an aqueous solution, and improves the solubility of the anticancer drug. Although the monomethoxy polyethylene glycol-racemic polylactic acid block copolymer medical high molecular auxiliary material belongs to low toxic substances, the medical high molecular auxiliary material generally has a certain toxic effect when being used in a large amount. Therefore, when the compound is used as a medical polymer auxiliary material, the dosage and the toxicity of the compound are particularly considered so as to ensure the safety of a new preparation.
Disclosure of Invention
The invention aims to provide a tumor microenvironment reduction responsive nano-drug and a preparation method thereof, in particular to a method for constructing a reduction responsive anticancer nano-drug by self-assembly of monomethoxypolyethylene glycol-drug. The reduction response type anticancer nano particle provided by the invention has stronger response to a cancer cell microenvironment, can specifically kill cancer cells, and has wide applicability to cancer cells.
The invention provides a nano-drug with tumor microenvironment reduction responsiveness (a reduction-responsive nano-anticancer drug constructed by self-assembly of monomethoxypolyethylene glycol-drug), which is a nano-drug with the average particle diameter of 130-150nm prepared by a solvent evaporation method (or a thin film hydration method) by using monomethoxypolyethylene glycol (molecular weight is about 2000) as a carrier and bonding tripterine (Celastrol) as an anticancer drug by using a disulfide bond with reduction responsiveness. The reductive response type nano anticancer drug MPEG2KThe structure of SS-CEL is represented as:
the preparation method of the tumor microenvironment reduction responsive nano-drug provided by the invention comprises the following steps:
1) monomethoxypolyethylene glycol-succinimide carbonate (MPEG)2K-SC), cystamine dihydrochloride, triethylamine in a molar ratio of 1: 3: 7 was dissolved in a mixed solvent of dichloromethane/methanol (v/v =1: 1) and reacted at room temperature for 12 hours. After the reaction is finished, saturated NH is used4And (3) washing twice with a Cl solution, drying an organic phase by using anhydrous sodium sulfate, concentrating under reduced pressure, and pulping residual liquid by using methyl tertiary butyl ether. Vacuum drying to obtain monomethoxy polyethylene glycol-cystamine (MPEG)2k-SS-NH2）。
2) Tripterine (Cel), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 1-Hydroxybenzotriazole (HOBT) are mixed according to a molar ratio of 1: 3: 3, dissolving in N, N-Dimethylformamide (DMF), activating for 2 hours at zero centigrade degree, adding monomethoxypolyethylene glycol-cystamine with one third equivalent of tripterine, and reacting for 24 hours at room temperature in a dark place. After the reaction is finished, transferring the organic solution into a cellulose dialysis membrane with the molecular weight cutoff of 2000, dialyzing in DMF for 24 hours, and then transferring into distilled water for dialysis for 24 hours; after dialysis, the water solution in the dialysis bag is frozen at minus 80 ℃ for 4 hours and then dried by a freeze dryer for 24 hours, and the orange red flocculent monomethoxy polyethylene glycol-SS-tripterine prodrug product is obtained.
3) Dissolving 10mg of monomethoxy polyethylene glycol-SS-tripterine prodrug in 1.5ml of tetrahydrofuran, and oscillating for 2 min by ultrasound to fully dissolve the monomethoxy polyethylene glycol-SS-tripterine prodrug; then dropwise adding the solution into 10mL of distilled water by using a 1 mL syringe under the condition of vigorous stirring, stirring at room temperature for 30 min, and then carrying out reduced pressure rotary evaporation to remove tetrahydrofuran in the system; passing the solution through a 0.22 μm filter to obtain MPEG with particle size of 130-150nm2K-SS-Cel micellar solution.
The invention utilizes covalent bonding between monomethoxy polyethylene glycol and anticancer drug molecules, and then forms the nano micelle with the particle size of 130-150nm through self-assembly. In a reducing environment, the disulfide bond in the nano-drug is broken, the nano-micelle is decomposed, and the anticancer drug is released. In vivo, due to EPR effect, the nano-drug is easy to be enriched in tumor tissues, and simultaneously, under the action of tumor cell over-expression GSH, the disulfide bond is broken, the nano-micelle is decomposed, the drug is quickly released and is accumulated in the tumor cells in large quantity, so that the cancer cells are killed, and the purpose of treatment is achieved. The anticancer drugs used in the invention are anti-inflammatory broad-spectrum anticancer drugs, and the applicable cancers comprise breast cancer, cervical cancer, lung cancer and the like.
The invention has the following outstanding substantive features:
1) the monomethoxy polyethylene glycol used in the invention has good biocompatibility and low biotoxicity, and is easy to degrade in vivo.
2) The disulfide bond in the medicine disclosed by the invention is sensitive to GSH response, so that the medicine can be quickly released at a tumor part, and the utilization efficiency of the medicine is improved.
3) Compared with the traditional chemotherapy drugs, the drug provided by the invention has stronger anticancer effect, can effectively kill and inhibit cancer cells, and has a good chemotherapy effect.
4) The drug carrier only contains monomethoxy polyethylene glycol, does not need to introduce a hydrophobic group, and has the advantages of simple synthesis, convenient operation, higher yield, controllable quality and easy amplification preparation.
Drawings
FIG. 1 shows the NMR spectrum of the prodrug of the drug: (1HNMR）。
Fig. 2 is a morphology image of nano-micelles under a Transmission Electron Microscope (TEM).
Figure 3 shows the particle size and potential of the nanomicelle measured in a malvern nanomicelle potentiostat.
FIG. 4 shows the results of the cytotoxicity (MTT) assay for human breast cancer (MCF-7) using the prodrug and nanomicelle.
Detailed Description
In order to clearly illustrate the technical solutions of the present invention, the following detailed description of the present invention is provided with reference to specific embodiments. The experimental methods used in the examples are all conventional methods unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1 (the whole course of the operation is dark)
1) Accurately weighing monomethoxypolyethylene glycol-succinimide carbonate (MPEG)2K-SC) 10.00g and 3.36g of cystamine dihydrochloride were dissolved in 200ml of a methylene chloride/methanol (100 ml/100 ml) mixed solvent, and after complete dissolution, 3.54g of triethylamine was added to the solution to carry out a reaction at room temperature for 12 hours.
2) The solution after the reaction was saturated with 100ml of NH4The Cl solution was washed twice, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was slurried with 200ml of methyl-tert-butyl ether. Drying at 50 deg.C under vacuum to obtain MPEG2k-SS-NH2。
Example 2 (the whole course of the operation is dark)
1) 135mg of tripterine, 172.5mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 121.5mg of 1-Hydroxybenzotriazole (HOBT) are accurately weighed, dissolved in 3ml of anhydrous DMF, and after complete dissolution, the solution is protected from light and reacted for 2 hours at zero centigrade.
2) Accurately weighing MPEG2k-SS-NH2 210 mg, adding into the reaction system in the step 1), keeping out of the light,the reaction was continued at room temperature for 24 hours.
3) After the reaction, the organic solution was transferred to a cellulose dialysis membrane having a molecular weight cut-off of 2000, dialyzed in 2L DMF for 24 hours (dialysate was changed every 4 hours), and then transferred to distilled water for dialysis for 24 hours (distilled water was changed every 2 hours).
4) After dialysis, the water solution in the dialysis bag is transferred to a glass culture dish, the mouth of the dish is covered by a preservative film, and the needle tip is placed at minus 80 ℃ for freezing for 4 hours after a plurality of air holes are punched.
5) And drying the frozen sample in the culture dish for 24 hours by using a freeze dryer to obtain an orange red flocculent monomethoxy polyethylene glycol-SS-tripterine prodrug product.
Example 3
1) Accurately weighing 10mg of the monomethoxy polyethylene glycol-SS-tripterine prodrug, dissolving in 1.5ml of tetrahydrofuran, and ultrasonically oscillating for 2 min to fully dissolve.
2) The solution was then added to 10ml of distilled water with vigorous stirring and stirred at room temperature for 30 min.
3) The tetrahydrofuran in the system is removed by reduced pressure rotary evaporation.
4) Passing the solution through a 0.22 μm filter to obtain MPEG with particle size of 130-150nm2K-SS-Cel micellar solution
Application effect test results:
the nano-drugs obtained in examples 1 to 3 were subjected to application effect test and evaluation:
FIG. 1 shows that the drug is detected by 400MHz liquid nuclear magnetic resonance spectrometer, and with deuterated chloroform as a solution, characteristic peaks of related structures of monomethoxypolyethylene glycol, tripterine and cystamine can be correspondingly found in the spectrum, which indicates that the drug compound is successfully synthesized.
FIG. 2 is a transmission electron microscope detection of the prepared nano-drug, which shows that monomethoxy polyethylene glycol and tripterine form a nano-micelle with an average diameter of about 130-150nm after self-assembly, indicating that the nano-drug meets the requirement of the EPR effect of solid tumors on the particle size of the nano-drug.
FIG. 3 shows the particle size and potential of the nanomicelle measured by Malvern nanometer particle size potentiometer, the average particle size was 142nm, the results were consistent with those of the particle size measured by transmission electron microscope, and the zeta potential was-9.47 mV measured in aqueous solution.
FIG. 4 is a graph showing the anticancer activity of the nano-drugs of examples 1 to 3 measured using MCF-7 cells (human breast cancer cells). Cells in logarithmic growth phase are inoculated in a sterile 96-well plate, about 10000 cells/well, cultured in 1640 culture medium containing 10% FBS for 24 hours, after the cells reach a good adherence state, the culture medium is changed into culture solution containing prodrug and micelle drugs with different concentrations (the prodrug and micelle concentrations are 0, 1, 2, 4, 8, 16, 20, 24, 32, 40 and 50 mu g/mL respectively according to Cel content concentration), and 5 wells are respectively arranged in each group. After 24 hours of incubation, 10. mu.L of 5. mu.g/mL MTT was added to each well, incubation was continued for 4 hours, the medium was removed, 150. mu.L DMSO was added to dissolve the crystals formed, and shaking was carried out for 10 minutes to ensure that the crystals were sufficiently dissolved to form a homogeneous solution. The absorbance of the sample was measured at 490 nm using a multifunctional microplate reader. It can be seen that the drug has obvious toxicity to MCF-7 cells, when the prodrug is used for treating the cells, the survival rate of the tumor cells is only 9% after the tripterine concentration of the anticancer drug reaches 50 mug/mL, and when the nano-micelle is used for treating the cells, the survival rate of the tumor cells is reduced to 2% when the tripterine concentration of the anticancer drug is only 8 mug/mL, which indicates that the nano-micelle is easier to be endocytosed by the cells, so as to achieve better anticancer effect.
Finally, it should be noted that: although the present invention has been described in detail with reference to the above embodiments, those skilled in the art can make modifications and equivalents to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.
Claims (6)
1. A tumor microenvironment reduction responsive nano-drug characterized by the structural representation as:
the preparation method is characterized in that monomethoxypolyethylene glycol is used as a carrier, the molecular weight is 2000, an anti-cancer drug tripterine (Celastrol) is bonded by a disulfide bond with reduction responsiveness, and the nano-drug with the average particle size of 130-150nm is prepared by a solvent evaporation method or a film hydration method.
2. The method for preparing nano-drug according to claim 1, characterized by comprising the steps of:
1) monomethoxypolyethylene glycol-succinimide carbonate (MPEG)2K-SC), cystamine dihydrochloride and triethylamine are dissolved in a dichloromethane/methanol mixed solvent with the volume =1:1, and the mixture is reacted for 12 hours at room temperature; after the reaction is finished, saturated NH is used4Washing with Cl solution twice, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and pulping the residual liquid with methyl tert-butyl ether; vacuum drying to obtain monomethoxy polyethylene glycol-cystamine (MPEG)2k-SS-NH2）；
2) Dissolving tripterine (Cel), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 1-Hydroxybenzotriazole (HOBT) in N, N-Dimethylformamide (DMF), activating at zero degree centigrade for 2 hours, adding monomethoxypolyethylene glycol-cystamine with one third equivalent of tripterine, and reacting at room temperature in dark for 24 hours; after the reaction is finished, transferring the organic solution into a cellulose dialysis membrane with the molecular weight cutoff of 2000, dialyzing in DMF for 24 hours, and then transferring into distilled water for dialysis for 24 hours; after dialysis, putting the water solution in the dialysis bag at-80 ℃ for freezing for 4 hours, and drying for 24 hours by using a freeze dryer to obtain an orange red flocculent monomethoxy polyethylene glycol-SS-tripterine prodrug product;
3) dissolving 10mg of monomethoxy polyethylene glycol-SS-tripterine prodrug in 1.5ml of tetrahydrofuran, and oscillating for 2 min by ultrasound to fully dissolve the monomethoxy polyethylene glycol-SS-tripterine prodrug; then, the solution was dropwise added to 10mL of distilled water using a 1 mL syringe under vigorous stirring, and after stirring at room temperature for 30 min, the solution was subjected to reduced pressure rotary evaporation to remove the tetrad in the systemHydrogen furan; passing the solution through a 0.22 μm filter to obtain MPEG with particle size of 130-150nm2K-SS-Cel micellar solution.
3. The method of claim 1, wherein said monomethoxypolyethylene glycol-succinimide carbonate (MPEG) is used as a starting material2K-SC), cystamine dihydrochloride, triethylamine in a molar ratio of 1: 3: 7.
4. the method according to claim 1, wherein the molar ratio of celastrol (Cel), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 1-Hydroxybenzotriazole (HOBT) is 1: 3: 3.
5. the method of claim 1, wherein the vacuum drying temperature is 50 ℃.
6. The tumor microenvironment reduction responsive nano-drug of claim 1, for use in treating breast cancer, cervical cancer, and lung cancer.
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