CN108888600B - pH-sensitive nano-drug based on calcium carbonate coordination chelating drug, preparation method and application - Google Patents
pH-sensitive nano-drug based on calcium carbonate coordination chelating drug, preparation method and application Download PDFInfo
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Abstract
A pH sensitive nanometer medicine based on calcium carbonate coordination chelating medicine and its preparation method and application, dissolving calcium chloride in anhydrous alcohol, then adding additive solution, stirring well to obtain solution A; dropwise adding an ethanol solution of the antitumor drug into the solution A, and standing to obtain a mixed solution B; and putting the mixed solution B and ammonium bicarbonate into a vacuum drying oven for reaction, dissolving the mixed solution B and the ammonium bicarbonate into dichloromethane, adding a high molecular substance containing carboxyl, stirring the mixture evenly, adding 4-dimethylaminopyridine and dicyclohexylcarbodiimide, heating the mixture to room temperature, and continuing the light-shielding reaction to obtain the pH sensitive nano-drug based on the calcium carbonate coordination chelate drug. The preparation method has mild conditions, easy operation, controllable size of the nano-drug and good stability. The prepared drug carrier can selectively release the anti-tumor drug according to the difference of the pH environment of tumor tissues and can be applied to preparing the anti-tumor drug.
Description
Technical Field
The invention belongs to the technical field of biomedical application, and relates to a preparation method and application of a pH sensitive nano-drug based on a calcium carbonate coordination chelating drug.
Background
Malignant tumors are serious diseases seriously harming human life health, and the morbidity and mortality rate are on an increasing trend year by year. The operation treatment and the chemotherapy are the main means of the current clinical treatment, but have the problems of large trauma, large side effect and the like, and particularly, the chemotherapy is based on the group universal dose administration and has large side effect. In recent years, a nano drug delivery system brings new opportunities for treating tumors, and can be used for improving drug targeting, reducing drug side effects and the like.
In recent years, researchers have used pH-sensitive drug carriers loaded with anti-tumor drugs for the treatment of tumors. The purpose of controlled release of antitumor drugs is achieved by introducing pH sensitive units (amide bond, hydrazone bond, acetal, imine bond, etc.) into a stimulus response system by utilizing the difference between the pH value of most solid tumors (<6.5) and the pH value of normal tissues (pH 7.4), wherein the sensitive units can cause the structural structure of the whole system to be disassembled when encountering an acidic pH environment (Biomaterials,2017,113,266-278.International Journal of Molecular Sciences,2017,18, 2029.).
Calcium carbonate is one of the most abundant inorganic materials and biominerals in the nature, has excellent biocompatibility, pH sensitivity and low toxicity, and has certain application potential in the fields of drug delivery and biomedical engineering. In research, an organic matrix is usually adopted to regulate and control the reaction of calcium chloride and anhydrous sodium carbonate to generate a micron-sized mesoporous hollow sphere for loading an anti-tumor drug to obtain a micron-sized pH-sensitive drug carrier (Journal of Colloid & Interface Science,2017,502 and 59.), however, the micron-sized pH-sensitive calcium carbonate has certain problems in subsequent biomedical application, such as incapability of passing through the EPR effect of a tumor, incapability of endocytosis and the like. And the exterior of the product is not modified by high polymer, so the product has poor water solubility and is easy to decompose in systemic circulation.
Disclosure of Invention
In order to solve the existing problems, the invention aims to provide a pH sensitive nano-drug based on calcium carbonate coordination chelating drug, a preparation method and application thereof, wherein the drug carrier can selectively release anti-tumor drugs according to the difference of the pH environment of tumor tissues; the preparation method of the drug carrier has the advantages of mild conditions, controllable size of the nano-drug, good stability and easy operation.
In order to achieve the purpose, the invention is realized by the following technical scheme:
a preparation method of pH sensitive nano-drugs based on calcium carbonate coordinated chelating drugs comprises the following steps:
1) according to the weight ratio of absolute ethyl alcohol: ethanol solution of additive: calcium chloride 80 mL: (200-800) L: (50-150) mg, dissolving calcium chloride in absolute ethyl alcohol, adding the additive solution, and uniformly stirring to obtain a solution A; wherein the concentration of the ethanol solution of the additive is 0.4 mol/L;
2) dropwise adding an ethanol solution of the antitumor drug into the solution A obtained in the step 1), and standing to obtain a mixed solution B; wherein the mass ratio of the calcium chloride to the antitumor drug is (50-150): (3-10);
3) according to the weight ratio of ammonium bicarbonate: 5mg of antitumor drug: (3-10) putting the mixed solution B and ammonium bicarbonate into a vacuum drying oven together to react to obtain an antitumor drug-calcium carbonate crude product; purifying to obtain an anti-tumor drug-calcium drug carrier;
4) reducing the temperature of an anhydrous dichloromethane solution of an antitumor drug-calcium carbonate carrier to-2-0 ℃, then adding a carboxyl-containing high molecular substance, uniformly stirring, adding 4-dimethylaminopyridine and dicyclohexylcarbodiimide, uniformly mixing, heating to room temperature, continuously reacting in a dark place for 4-48 h, and freeze-drying to obtain the pH sensitive nano-drug based on the calcium carbonate coordination chelate drug.
In a further improvement of the invention, in step 1), the additive is polyacrylic acid, phytic acid or polypeptide.
In a further development of the invention, in step 2), the reaction is carried out according to the following formula: 20mL of antitumor drug: (3-10) adding the antitumor drug into absolute ethyl alcohol according to the dosage ratio of mg, and uniformly stirring to obtain an ethanol solution of the antitumor drug; the antitumor drug is a hydroxyl-containing antitumor drug.
The further improvement of the invention is that in the step 2), the standing time is 2-4 h; the antitumor drug is curcumin, adriamycin, quercetin or resveratrol.
The further improvement of the invention is that in the step 3), the reaction temperature is 25-40 ℃ and the reaction time is 4-48 h.
The further improvement of the invention is that in the step 3), the specific process of purification is as follows: and centrifuging and washing the obtained crude antitumor drug-calcium carbonate product with absolute ethyl alcohol for 5-8 times, centrifuging at 6000-10000 rpm for 10min, and freeze-drying for 12-24 h after centrifugation is finished to obtain a yellow solid, namely the antitumor drug-calcium carbonate drug carrier.
The further improvement of the invention is that in the step 4), the following components are added according to an anti-tumor drug-calcium carbonate drug carrier: anhydrous dichloromethane ═ (0.05 to 0.2) g: 15mL, adding the anti-tumor drug-calcium carbonate carrier into anhydrous dichloromethane to obtain an anhydrous dichloromethane solution of the anti-tumor drug-calcium carbonate carrier; the stirring time is 3-10 min.
The further improvement of the invention is that in the step 4), the anti-tumor drug-calcium carbonate drug carrier: carboxyl group-containing high molecular substance: 4-dimethylaminopyridine: dicyclohexylcarbodiimide (0.05 to 0.2) g: (0.05-2) g: 50 mg: 50 mg; the carboxyl-containing polymer is hyaluronic acid, carboxyl-terminated polyethylene glycol, carboxymethyl chitosan or folic acid.
A pH sensitive nano-medicament based on calcium carbonate coordination chelate medicament prepared by the method.
An application of pH sensitive nano-drug based on calcium carbonate coordination chelating drug in preparing anti-tumor drug.
Compared with the prior art, the invention has the following beneficial effects: the invention firstly connects the antitumor drug and amorphous calcium carbonate through a coordination bond to obtain an antitumor drug-amorphous calcium carbonate drug carrier; then, the pH sensitive nano-medicament based on the calcium carbonate coordination chelate medicament is prepared by connecting a macromolecular substance containing carboxyl through esterification reaction. The invention takes calcium chloride in ethanol solution containing antitumor drugs and anhydrous calcium chloride as Ca2+Source of ammonium bicarbonate as CO3 2-Preparing amorphous calcium carbonate loaded with antitumor drugs, and performing macromolecular modification on the surface of an antitumor drug-amorphous calcium carbonate carrier by adopting a carboxyl-containing macromolecular substance. The additive is added in the preparation process, so that the absolute anhydrous environment is maintained, the problems of poor water solubility, easy decomposition and phase change of the amorphous calcium carbonate are solved, and the amorphous calcium carbonate with controllable particle size is obtained. The invention adopts the additive, which can inhibit crystallization, poison the surface active center of the nano-particles formed in the early stage and effectively control the nucleation and growth of the nano-particles. According to the invention, the anti-tumor drug and calcium ions are combined through coordination bonds, and the anti-tumor drug is bonded between calcium carbonate molecules in situ, so that the drug loading rate is high, the drug loading is stable, and the characteristics of acid sensitivity of amorphous calcium carbonate are combined, so that the drug has an acid sensitivity release behavior, the stability is improved, and the premature release of the drug in the blood circulation process is prevented. In the invention, amorphous calcium carbonate-antitumor drug surface is treatedThe polymer modification is carried out, the circulation stability of the anti-tumor drug-amorphous calcium carbonate drug carrier is improved, the drug is protected from being released in systemic circulation, and a large amount of acid-sensitive drugs are released when reaching the acidic part of the tumor, so that the aim of intelligent drug release is fulfilled. The antitumor medicine-amorphous calcium carbonate carrier is obtained by endogenous reaction of calcium ions in calcium chloride and carbon dioxide generated by thermal decomposition of ammonium bicarbonate at a certain temperature. The preparation method of the drug carrier has mild conditions, easy operation, controllable size of the nano-drug and good stability.
The drug carrier prepared by the invention can selectively release the anti-tumor drug according to the difference of the pH environment of tumor tissues. The medicine prepared by the invention can be applied to preparing antitumor medicines.
Drawings
FIG. 1 is a structural formula of Ca-CCM;
FIG. 2 is a graph showing a particle size distribution and a degree of dispersion (PDI) of an ACC-CCM drug carrier measured by a dynamic scattering light analyzer;
FIG. 3 is a Scanning Electron Microscope (SEM) image of an ACC-CCM drug carrier;
FIG. 4 is a Transmission Electron Microscope (TEM) image of an ACC-CCM drug carrier;
FIG. 5 is a fluorescence spectrum of ACC-CCM solution prepared by the present invention;
FIG. 6 is a graph of the fluorescence spectra of ACC-CCM prepared according to the present invention at different time points after the addition of hydrochloric acid having a pH of 5.0;
FIG. 7 is a UV absorption spectrum of an ACC-CCM solution prepared according to the present invention;
fig. 8 is a graph of the uv absorption spectrum of ACC-CCM prepared according to the present invention at various time points after the addition of hydrochloric acid having a pH of 5.0.
Detailed Description
The present invention is further illustrated by the following specific examples, which are intended to be illustrative, but not limiting, of the invention.
Because the drug carrier with smaller grain diameter is easier to enter the tumor cells and play a role, the invention adds proper additives in the preparation process to keep absolute anhydrous environment, thereby solving the problem of amorphous carbonThe calcium carbonate has poor water solubility and is easy to decompose and change phase, and the amorphous calcium carbonate with controllable particle size is obtained. Antitumor drug and Ca in nano-drug2+The anti-tumor drugs are bonded between the amorphous calcium carbonate molecules in situ through coordination bonds, so that the anti-tumor drugs are high in drug loading rate and stable in drug loading, and have acid-sensitive release behavior by combining the characteristics of acid sensitivity of the amorphous calcium carbonate. In the preparation process, the anti-tumor drug-amorphous calcium carbonate surface is subjected to macromolecular modification, such as polyethylene glycol (PEG) modification, so that the circulation stability of the anti-tumor drug-amorphous calcium carbonate drug carrier is improved, the drug is protected from being released in systemic circulation, and a large amount of acid-sensitive drugs are released when reaching an acidic tumor part, thereby achieving the purpose of intelligent drug release.
The preparation process of the invention is as follows:
1) according to the weight ratio of absolute ethyl alcohol: ethanol solution of additive: calcium chloride 80 mL: (200-800) L: (50-150) mg, dissolving calcium chloride in absolute ethyl alcohol, adding the additive solution, and uniformly stirring to obtain a solution A; wherein the concentration of the ethanol solution of the additive is 0.4 mol/L; wherein the additive is polyacrylic acid, phytic acid or polypeptide.
2) According to the weight ratio of absolute ethyl alcohol: 20mL of antitumor drug: (3-10) adding the antitumor drug into absolute ethyl alcohol according to the dosage ratio of mg, and uniformly stirring to obtain an ethanol solution of the antitumor drug; dropwise adding an ethanol solution of an antitumor drug into the solution A obtained in the step 1), and standing for 2-4 h after the dropwise adding is finished to obtain a mixed solution B; wherein the mass ratio of the calcium chloride to the antitumor drug is (50-150): (3-10); the antitumor drug is curcumin, adriamycin, quercetin or resveratrol.
3) According to the weight ratio of ammonium bicarbonate: 5mg of antitumor drug: (3-10) mg, putting the mixed solution B and ammonium bicarbonate into a vacuum drying oven to react for 4-48 h at 25-40 ℃ to obtain an antitumor drug-amorphous calcium carbonate crude product; and (3) centrifugally washing the antitumor drug-amorphous calcium carbonate crude product with absolute ethyl alcohol for 5-8 times, centrifuging at 6000-10000 rpm for 10min, and freeze-drying for 12-24 h after centrifugation is finished to obtain a yellow solid, namely the antitumor drug-amorphous calcium carbonate drug carrier.
In the step, the mixed solution B and ammonium bicarbonate are put into a vacuum drying oven, specifically, a container filled with the mixed solution B and a container filled with the ammonium bicarbonate are both put into the vacuum drying oven, when the mixed solution B and the container filled with the ammonium bicarbonate are heated to 25-40 ℃, the ammonium bicarbonate is decomposed, and the generated carbon dioxide gas reacts with calcium chloride in the mixed solution B to generate amorphous calcium carbonate.
4) According to the antineoplastic drug-amorphous calcium carbonate drug carrier: anhydrous dichloromethane ═ (0.05 to 0.2) g: 15mL, adding the antitumor drug amorphous calcium carbonate carrier into anhydrous dichloromethane to obtain an anhydrous dichloromethane solution of the antitumor drug amorphous calcium carbonate carrier; reducing the temperature of an anhydrous dichloromethane solution of an antitumor drug, namely an amorphous calcium carbonate carrier, to-2-0 ℃, then adding a carboxyl-containing high molecular substance, stirring and stirring for 3-10 min, then adding 4-dimethylaminopyridine and dicyclohexylcarbodiimide, uniformly mixing, naturally heating to room temperature, continuing to react in a dark place for 4-48 h, and freeze-drying to obtain the pH sensitive nano-drug based on the calcium carbonate coordination chelate drug. Wherein, the anti-tumor drug-amorphous calcium carbonate drug carrier: carboxyl group-containing high molecular substance: 4-dimethylaminopyridine: dicyclohexylcarbodiimide (0.05 to 0.2) g: (0.05-2) g: 50 mg: 50 mg; the carboxyl-containing polymer is hyaluronic acid, carboxyl-terminated polyethylene glycol, carboxymethyl chitosan or folic acid.
The pH sensitive nano-medicament based on the calcium carbonate coordination chelate medicament prepared by the method can be applied to preparing anti-tumor medicaments.
Example 1
A preparation method of a pH sensitive nano-drug based on calcium carbonate coordination chelating drugs comprises the following steps:
1) 5g of ammonium bicarbonate (2 beakers, 2.5g each) were placed into two clean, dry beakers;
2) two beakers (250mL and 100mL) were taken, and 80mL of absolute ethanol and 150mg of CaCl were added to one 250mL beaker2Stirring with 500L PAA (polyacrylic acid) to dissolve, adding 20mL anhydrous ethanol into another 100mL beaker, adding 5mg curcumin (CCM), stirring to dissolve,after substances in each beaker are completely dissolved, dropwise adding the solution in the small beaker into the large beaker, standing and chelating for 2-4 h to obtain a mixed solution, and then placing the mixed solution in a vacuum drying oven (30 ℃) to react for 48h to obtain amorphous calcium carbonate-curcumin;
3) and (3) centrifuging and washing the obtained amorphous calcium carbonate-curcumin by using ethanol and water respectively for 6 times at 8000rpm for 10min, and freeze-drying at (-50 ℃) for 12h after the centrifugation is finished to obtain a yellow solid, namely the amorphous calcium carbonate-curcumin drug carrier, wherein the yield is 11.4%.
4) Mixing the obtained amorphous calcium carbonate-curcumin drug carrier (0.1g) and anhydrous dichloromethane (15mL), and carrying out ice salt bath to 0 ℃; then adding carboxyl-terminated polyethylene glycol 2000(1.9g) into the reaction system, stirring for 5min, adding 50mg of DMAP (4-dimethylaminopyridine) and 50mg of DCC (dicyclohexylcarbodiimide), performing ultrasonic treatment to completely dissolve the DMAP and the DCC, uniformly mixing, naturally heating to room temperature, continuing to react in a dark place for 24h, centrifuging for 6 times by using water to remove unreacted substances, and freeze-drying to obtain the pH sensitive medicine based on the calcium carbonate coordination chelate medicine.
A scattered light dynamic analyzer is used for measuring the particle size distribution diagram and the dispersity (PDI) of the amorphous calcium carbonate-curcumin (ACC-CCM) drug carrier, and the result is shown in figure 2, the hydrated particle size of the ACC-CCM drug carrier is 599nm, the PDI is 0.204, and the ACC-CCM drug carrier is single in component, uniform in distribution, free of aggregation and good in monodispersion property. The morphology structure of the nanoparticles is observed under a scanning electron microscope and a transmission electron microscope, and the results are shown in fig. 3 and 4, so that the nanoparticles are spherical, the particle size is about 150nm, the surface is smooth, the morphology is round, and the particle size is relatively uniform.
Fig. 5 and 6 are graphs of fluorescence spectra of ACC-CCM solutions prepared according to the present invention at various time points after addition of hydrochloric acid having a pH of 5.0. As can be seen from FIG. 5, the prepared ACC-CCM only shows weak fluorescence when dissolved in ethanol, which indicates that the ACC-CCM drug carrier prepared by the invention can well wrap CCM in ACC, and effectively prevents CCM from being prematurely released in the blood circulation process. Fig. 6 shows the fluorescence result, the ethanol solution of ACC-CCM added with hydrochloric acid with pH 5.0 for 10min to 30min has obvious fluorescence enhancement, which indicates that the ACC-CCM prepared by the invention has good pH sensitivity and is a slow drug release process under acidic stimulation.
The release condition of the CCM in hydrochloric acid with the pH value of 5.0 of the ACC-CCM drug carrier is measured by an ultraviolet spectrophotometer, and as can be seen from figures 7 and 8, the ACC-CCM drug carrier prepared by the invention can well wrap the CCM in the ACC, thereby effectively preventing the CCM from leaking too early and having good pH sensitivity.
Example 2
1) According to the weight ratio of absolute ethyl alcohol: ethanol solution of additive: calcium chloride 80 mL: 200L: dissolving calcium chloride in absolute ethyl alcohol according to the dosage ratio of 50mg, then adding the additive solution, and uniformly stirring to obtain a solution A; wherein the concentration of the ethanol solution of the additive is 0.4 mol/L; wherein the additive is polyacrylic acid.
2) According to the weight ratio of absolute ethyl alcohol: 20mL of antitumor drug: 3mg, adding the antitumor drug into absolute ethyl alcohol, and uniformly stirring to obtain an ethanol solution of the antitumor drug; dropwise adding an ethanol solution of the antitumor drug into the solution A obtained in the step 1), and standing for 2h after the dropwise adding is finished to obtain a mixed solution B; wherein the mass ratio of the calcium chloride to the antitumor drug is 150: 3; the antitumor drug is curcumin.
3) According to the weight ratio of ammonium bicarbonate: 5mg of antitumor drug: 3mg, putting the mixed solution B and ammonium bicarbonate into a vacuum drying oven to react for 48 hours at 25 ℃ to obtain an antitumor drug-amorphous calcium carbonate crude product; and (3) centrifuging and washing the antitumor drug-amorphous calcium carbonate crude product with absolute ethyl alcohol for 5 times, centrifuging at 6000rpm for 10min, and freeze-drying for 12h after the centrifugation is finished to obtain a yellow solid, namely the antitumor drug-amorphous calcium carbonate drug carrier.
4) According to the antineoplastic drug-amorphous calcium carbonate drug carrier: anhydrous dichloromethane ═ 0.05 g: 15mL, adding the antitumor drug amorphous calcium carbonate carrier into anhydrous dichloromethane to obtain an anhydrous dichloromethane solution of the antitumor drug amorphous calcium carbonate carrier; reducing the temperature of an anhydrous dichloromethane solution of an antitumor drug-amorphous calcium carbonate carrier to-2-0 ℃, then adding a carboxyl-containing high molecular substance, stirring and stirring for 3-10 min, adding 4-dimethylaminopyridine and dicyclohexylcarbodiimide, uniformly mixing, naturally heating to room temperature, continuing to react in a dark place for 4h, and freeze-drying to obtain the pH sensitive nano-drug based on the calcium carbonate coordination chelate drug. Wherein, the anti-tumor drug-amorphous calcium carbonate drug carrier: carboxyl group-containing high molecular substance: 4-dimethylaminopyridine: dicyclohexylcarbodiimide ═ 0.05 g: 2 g: 50 mg: 50 mg; the carboxyl-containing polymer is hyaluronic acid.
Example 3
1) According to the weight ratio of absolute ethyl alcohol: ethanol solution of additive: calcium chloride 80 mL: 500L: dissolving calcium chloride in absolute ethyl alcohol at the dosage ratio of 120mg, then adding the additive solution, and uniformly stirring to obtain a solution A; wherein the concentration of the ethanol solution of the additive is 0.4 mol/L; wherein the additive is phytic acid.
2) According to the weight ratio of absolute ethyl alcohol: 20mL of antitumor drug: adding the antitumor drug into absolute ethyl alcohol according to the dosage ratio of 5mg, and uniformly stirring to obtain an ethanol solution of the antitumor drug; dropwise adding an ethanol solution of the antitumor drug into the solution A obtained in the step 1), and standing for 3h after the dropwise adding is finished to obtain a mixed solution B; wherein the mass ratio of the calcium chloride to the antitumor drug is 100: 7; the antineoplastic agent is adriamycin.
3) According to the weight ratio of ammonium bicarbonate: 5mg of antitumor drug: 10mg, putting the mixed solution B and ammonium bicarbonate into a vacuum drying oven to react for 40 hours at 30 ℃ to obtain an antitumor drug-amorphous calcium carbonate crude product; and (3) centrifuging and washing the antitumor drug-amorphous calcium carbonate crude product with absolute ethyl alcohol for 8 times, centrifuging at 10000rpm for 10min, and freeze-drying for 24h after the centrifugation is finished to obtain a yellow solid, namely the antitumor drug-amorphous calcium carbonate drug carrier.
4) According to the antineoplastic drug-amorphous calcium carbonate drug carrier: anhydrous dichloromethane ═ 0.2 g: 15mL, adding the antitumor drug amorphous calcium carbonate carrier into anhydrous dichloromethane to obtain an anhydrous dichloromethane solution of the antitumor drug amorphous calcium carbonate carrier; reducing the temperature of an anhydrous dichloromethane solution of an antitumor drug-amorphous calcium carbonate carrier to-2-0 ℃, then adding a carboxyl-containing high molecular substance, stirring and stirring for 3-10 min, adding 4-dimethylaminopyridine and dicyclohexylcarbodiimide, uniformly mixing, naturally heating to room temperature, continuing to react in a dark place for 20h, and freeze-drying to obtain the pH sensitive nano-drug based on the calcium carbonate coordination chelate drug. Wherein, the anti-tumor drug-amorphous calcium carbonate drug carrier: carboxyl group-containing high molecular substance: 4-dimethylaminopyridine: dicyclohexylcarbodiimide ═ 0.2 g: 0.05 g: 50 mg: 50 mg; the carboxyl-containing high molecular substance is double-end carboxyl polyethylene glycol.
Example 4
1) According to the weight ratio of absolute ethyl alcohol: ethanol solution of additive: calcium chloride 80 mL: 800L: dissolving calcium chloride in absolute ethyl alcohol according to the dosage ratio of 80mg, then adding the additive solution, and uniformly stirring to obtain a solution A; wherein the concentration of the ethanol solution of the additive is 0.4 mol/L; wherein the additive is polypeptide.
2) According to the weight ratio of absolute ethyl alcohol: 20mL of antitumor drug: adding the antitumor drug into absolute ethyl alcohol according to the dosage ratio of 10mg, and uniformly stirring to obtain an ethanol solution of the antitumor drug; dropwise adding an ethanol solution of the antitumor drug into the solution A obtained in the step 1), and standing for 4h after the dropwise adding is finished to obtain a mixed solution B; wherein the mass ratio of the calcium chloride to the antitumor drug is 50: 5; the antitumor drug is quercetin.
3) According to the weight ratio of ammonium bicarbonate: 5mg of antitumor drug: 5mg, putting the mixed solution B and ammonium bicarbonate into a vacuum drying oven to react for 4 hours at 40 ℃ to obtain an antitumor drug-amorphous calcium carbonate crude product; and (3) centrifuging and washing the antitumor drug-amorphous calcium carbonate crude product by using absolute ethyl alcohol for 6 times, centrifuging at 8000rpm for 10min, and freeze-drying for 20h after the centrifugation is finished to obtain a yellow solid, namely the antitumor drug-amorphous calcium carbonate drug carrier.
4) According to the antineoplastic drug-amorphous calcium carbonate drug carrier: anhydrous dichloromethane ═ 0.1 g: 15mL, adding the antitumor drug amorphous calcium carbonate carrier into anhydrous dichloromethane to obtain an anhydrous dichloromethane solution of the antitumor drug amorphous calcium carbonate carrier; reducing the temperature of an anhydrous dichloromethane solution of an antitumor drug-amorphous calcium carbonate carrier to-2-0 ℃, then adding a carboxyl-containing high molecular substance, stirring and stirring for 3-10 min, adding 4-dimethylaminopyridine and dicyclohexylcarbodiimide, uniformly mixing, naturally heating to room temperature, continuing to react in a dark place for 35h, and freeze-drying to obtain the pH sensitive nano-drug based on the calcium carbonate coordination chelate drug. Wherein, the anti-tumor drug-amorphous calcium carbonate drug carrier: carboxyl group-containing high molecular substance: 4-dimethylaminopyridine: dicyclohexylcarbodiimide ═ 0.1 g: 1 g: 50 mg: 50 mg; the carboxyl-containing high molecular substance is carboxymethyl chitosan.
Example 5
1) According to the weight ratio of absolute ethyl alcohol: ethanol solution of additive: calcium chloride 80 mL: 300L: dissolving calcium chloride in absolute ethyl alcohol according to the dosage ratio of 150mg, then adding the additive solution, and uniformly stirring to obtain a solution A; wherein the concentration of the ethanol solution of the additive is 0.4 mol/L; wherein the additive is polyacrylic acid.
2) According to the weight ratio of absolute ethyl alcohol: 20mL of antitumor drug: adding the antitumor drug into absolute ethyl alcohol according to the dosage ratio of 7mg, and uniformly stirring to obtain an ethanol solution of the antitumor drug; dropwise adding an ethanol solution of the antitumor drug into the solution A obtained in the step 1), and standing for 2h after the dropwise adding is finished to obtain a mixed solution B; wherein the mass ratio of the calcium chloride to the antitumor drug is 120: 10; the antineoplastic agent is resveratrol.
3) According to the weight ratio of ammonium bicarbonate: 5mg of antitumor drug: 8mg, putting the mixed solution B and ammonium bicarbonate into a vacuum drying oven to react for 20 hours at 35 ℃ to obtain an antitumor drug-amorphous calcium carbonate crude product; and (3) centrifuging and washing the antitumor drug-amorphous calcium carbonate crude product by using absolute ethyl alcohol for 7 times, centrifuging at 9000rpm for 10min, and freeze-drying for 15h after the centrifugation is finished to obtain a yellow solid, namely the antitumor drug-amorphous calcium carbonate drug carrier.
4) According to the antineoplastic drug-amorphous calcium carbonate drug carrier: anhydrous dichloromethane ═ 0.15 g: 15mL, adding the antitumor drug amorphous calcium carbonate carrier into anhydrous dichloromethane to obtain an anhydrous dichloromethane solution of the antitumor drug amorphous calcium carbonate carrier; reducing the temperature of an anhydrous dichloromethane solution of an antitumor drug-amorphous calcium carbonate carrier to-2-0 ℃, then adding a carboxyl-containing high molecular substance, stirring and stirring for 3-10 min, adding 4-dimethylaminopyridine and dicyclohexylcarbodiimide, uniformly mixing, naturally heating to room temperature, continuing to react in a dark place for 48h, and freeze-drying to obtain the pH sensitive nano-drug based on the calcium carbonate coordination chelate drug. Wherein, the anti-tumor drug-amorphous calcium carbonate drug carrier: carboxyl group-containing high molecular substance: 4-dimethylaminopyridine: dicyclohexylcarbodiimide ═ 0.5 g: 0.5 g: 50 mg: 50 mg; the carboxyl-containing polymer is folic acid.
The invention has three innovative points, firstly, the additive is added in the preparation process, the absolute anhydrous environment is kept, the problems of poor water solubility, easy decomposition and phase change of the amorphous calcium carbonate are solved, and the amorphous calcium carbonate with controllable particle size is obtained. The second innovation point of the invention is that the anti-tumor drug is combined with calcium ions through coordination bonds, and the anti-tumor drug is bonded between calcium carbonate molecules in situ, so that the drug has high drug loading rate and stable drug loading, and has acid-sensitive release behavior by combining the characteristics of amorphous calcium carbonate acid sensitivity. The third advantage of the method is that the surface of the antitumor drug amorphous calcium carbonate is modified by macromolecules, such as polyethylene glycol (PEG), so that the circulation stability of the antitumor drug amorphous calcium carbonate drug carrier is improved, the drug is protected from being released in systemic circulation, and a large amount of acid-sensitive drugs are released when reaching the acidic part of the tumor, thereby achieving the purpose of intelligent drug release.
The invention discloses a pH sensitive nano-medicament based on calcium carbonate coordination chelating medicament, which is prepared from antitumor medicaments curcumin and Ca2+The curcumin is bonded between amorphous calcium carbonate molecules in situ through coordination bond combination, so that the medicine has high medicine carrying rate and stable medicine carrying, and has acid sensitive release behavior by combining the characteristic of acid sensitivity of amorphous calcium carbonate; in the preparation process, the surface of the ACC-CCM drug carrier is subjected to macromolecular modification, such as polyethylene glycol (PEG) modification, so that the circulation stability of the amorphous calcium carbonate drug carrier is improved, the drug is protected from being released in systemic circulation, and a large amount of acid-sensitive drugs are released when reaching the acidic part of the tumor, thereby achieving the purpose of intelligent drug release. Compared with the conventional nanoparticles containing pH sensitive units, the system overcomes the problem of burst release of the medicine, and the medicine is controllably released, so that the medicine dosage and the medicine administration frequency in the clinical treatment process are reduced, and the toxic and side effects are relieved.
The pH sensitive nano-medicament based on the calcium carbonate coordination chelate medicament prepared by the invention has good water solubility, good stability and high bioavailability, and more importantly, the pH sensitive nano-medicament has good pH sensitive characteristic; the whole preparation process has mild conditions, is easy to operate and has good application prospect in the field of biomedicine. The nano-drug prepared by the invention has the functions of antioxidation, anti-inflammation, anticoagulation, lipid reduction, anti-atherosclerosis, anti-aging, free radical elimination, tumor growth inhibition and the like, and can be widely applied to the fields of medicines, biomedical materials and the like.
The medicine can be used for preparing anti-tumor medicines, and tumors comprise breast cancer, liver cancer, bladder cancer, prostatic cancer, intestinal cancer and the like.
Claims (9)
1. A preparation method of pH sensitive nano-drug based on calcium carbonate coordination chelating drug is characterized by comprising the following steps:
1) according to the weight ratio of absolute ethyl alcohol: ethanol solution of additive: calcium chloride 80 mL: (200-800) μ L: (50-150) mg, dissolving calcium chloride in absolute ethyl alcohol, adding the additive solution, and uniformly stirring to obtain a solution A; wherein the concentration of the ethanol solution of the additive is 0.4 mol/L; the additive is polyacrylic acid;
2) dropwise adding an ethanol solution of the antitumor drug into the solution A obtained in the step 1), and standing to obtain a mixed solution B; wherein the mass ratio of the calcium chloride to the antitumor drug is (50-150): (3-10); the antitumor drug is curcumin;
3) according to the weight ratio of ammonium bicarbonate: 5mg of antitumor drug: (3-10) putting the mixed solution B and ammonium bicarbonate into a vacuum drying oven together to react to obtain an antitumor drug-calcium carbonate crude product; purifying to obtain the anti-tumor drug-calcium carbonate drug carrier;
4) reducing the temperature of an anhydrous dichloromethane solution of an antitumor drug-calcium carbonate drug carrier to-2-0 ℃, then adding a carboxyl-containing high molecular substance, uniformly stirring, adding 4-dimethylaminopyridine and dicyclohexylcarbodiimide, uniformly mixing, heating to room temperature, continuously reacting in a dark place for 4-48 h, and freeze-drying to obtain the pH sensitive nano-drug based on the calcium carbonate coordination chelate drug, wherein the carboxyl-containing high molecular substance is carboxyl-terminated polyethylene glycol.
2. The method for preparing pH-sensitive nano-drug based on calcium carbonate coordinated chelating drug according to claim 1, characterized in that, in the step 2), the ratio of absolute ethyl alcohol: 20mL of antitumor drug: (3-10) mg, adding the antitumor drug into absolute ethyl alcohol, and uniformly stirring to obtain an ethanol solution of the antitumor drug.
3. The method for preparing the pH sensitive nano-drug based on the calcium carbonate coordinated chelating drug according to claim 2, wherein the standing time in the step 2) is 2-4 h.
4. The method for preparing pH sensitive nano-drug based on calcium carbonate coordinated chelated drug according to claim 1, wherein in step 3), the reaction temperature is 25-40 ℃ and the reaction time is 4-48 h.
5. The method for preparing pH-sensitive nano-drug based on calcium carbonate coordinated chelated drug according to claim 1, wherein in step 3), the specific process of purification is: and centrifuging and washing the obtained crude antitumor drug-calcium carbonate product with absolute ethyl alcohol for 5-8 times, centrifuging at 6000-10000 rpm for 10min, and freeze-drying for 12-24 h after centrifugation is finished to obtain a yellow solid, namely the antitumor drug-calcium carbonate drug carrier.
6. The method for preparing pH-sensitive nano-drug based on calcium carbonate coordinated chelated drug according to claim 1, characterized in that in step 4), according to the anti-tumor drug-calcium carbonate drug carrier: anhydrous dichloromethane ═ (0.05 to 0.2) g: 15mL, adding the anti-tumor drug-calcium carbonate carrier into anhydrous dichloromethane to obtain an anhydrous dichloromethane solution of the anti-tumor drug-calcium carbonate carrier; the stirring time is 3-10 min.
7. The method for preparing pH-sensitive nano-drug based on calcium carbonate coordinated chelated drug according to claim 1, wherein in step 4), the anti-tumor drug-calcium carbonate drug carrier: carboxyl group-containing high molecular substance: 4-dimethylaminopyridine: dicyclohexylcarbodiimide (0.05 to 0.2) g: (0.05-2) g: 50 mg: 50 mg.
8. A pH sensitive nano-drug based on a calcium carbonate coordinated chelated drug prepared by the method of any one of claims 1-7.
9. The application of the pH-sensitive nano-drug based on the calcium carbonate coordination chelate drug prepared by the method of any one of claims 1 to 7 in preparing an anti-tumor drug.
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