CN115463110A - Cholic acid modified oral paclitaxel nanoparticles, and preparation method and application thereof - Google Patents

Cholic acid modified oral paclitaxel nanoparticles, and preparation method and application thereof Download PDF

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CN115463110A
CN115463110A CN202110647637.XA CN202110647637A CN115463110A CN 115463110 A CN115463110 A CN 115463110A CN 202110647637 A CN202110647637 A CN 202110647637A CN 115463110 A CN115463110 A CN 115463110A
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paclitaxel
cholic acid
cholesterol
modified oral
oral
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高钟镐
刘薇
黄伟
金明姬
陈丽青
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Abstract

The invention relates to the field of pharmaceutical preparations, discloses cholic acid modified oral paclitaxel nanoparticles, a preparation method and application thereof, and particularly relates to cholic acid modified oral paclitaxel nanoparticles, which comprise total lipid, chitosan-glycocholic acid polymer and glucose, wherein the total lipid comprises: paclitaxel cholesterol complex, phospholipid, cholesterol, phospholipid-polyethylene glycol-quercetin polymer; the weight ratio of the paclitaxel to the cholesterol in the paclitaxel cholesterol complex is 1:0.1-1:1. The oral paclitaxel nanoparticles modified by cholic acid are combined with the ASBT transporter overexpressed at the tail end of the ileum by surface modification of cholic acid, so that the intestinal trans-transport efficiency of the medicine is remarkably improved, and the purposes of improving the oral bioavailability and the oral antitumor effect of paclitaxel are realized.

Description

Cholic acid-modified oral paclitaxel nanoparticles as well as preparation method and application thereof
Technical Field
The invention relates to cholic acid modified oral paclitaxel nanoparticles and a preparation method thereof, and also relates to application of the oral paclitaxel nanoparticles, belonging to the technical field of pharmaceutical preparations.
Background
Chemotherapy is a systemic treatment, and the medicine is distributed in most organs and tissues along with blood circulation, so that the chemotherapy is more suitable for middle and late-stage tumors which are prone to systemic dissemination or have already metastasized. Traditional chemotherapy regimens mostly adopt a Maximum Tolerated Dose (MTD) regimen once in three weeks, and a high-dose administration mode is accompanied by serious adverse reactions, and tumor resistance is generated after multiple administrations. Most of the drugs except for a few antitumor drugs such as cyclophosphamide, cisplatin and the like are clinically administered by intravenous administration, which is determined by the drug property, however, patients need to endure the problems of poor compliance, blood toxicity, infection and the like caused by long-term intravenous administration, and bear high hospitalization cost. Compared with the traditional MTD, the oral administration scheme has the advantages of low toxicity, low drug resistance and the like. Oral chemotherapy drugs have attracted the attention of researchers in recent years due to their advantages of safety, convenience, low cost, good compliance, etc. Compared with intravenous injection, the oral delivery system has the great advantages of maintaining stable blood concentration, prolonging the half life of the drug by controlled release of the drug and the like. However, the presence of multiple gastrointestinal physicochemical barriers has limited the development of oral chemotherapeutic drugs, including: the complicated environment of the gastrointestinal tract can damage the structure of the chemical drugs, and the intestinal tract of the chemical drugs has low permeability. Therefore, overcoming the absorption limitation caused by the above barrier through elaborate design is of great significance for improving the oral bioavailability of chemotherapeutic drugs.
Bile Salts (BS) are an endogenous substance which is secreted by bile into the small intestine and enters the blood circulation via the bile salt transporter (ASBT) of the epithelium of the ileum of the small intestine, and the reabsorption rate of the BS can reach over 90%. In BS, primary Bile Acids (BAs) and amphiphilic conjugated bile acids (cBA) are synthesized by the liver and secreted to the duodenum through the bile duct and gallbladder to digest lipid-like substances. Through the circulation of the liver and intestine, 12-18 g of BA and cBA can be recovered from the gastrointestinal tract and the liver of a normal human body every day. Based on the above theory, some researches have carried out to modify BA as a target head on the surface of the nanoparticle to promote the oral absorption of the polypeptide, and good results have been obtained. Related research reports show that the nanoparticles with affinity to the ASBT can enter intestinal endothelial cells through the ASBT-mediated endocytosis, help loaded drugs to realize lysosome escape, form chylomicrons through endoplasmic reticulum and Golgi body intracellular transport pathways, and enter blood circulation through a lymphatic transport system after reaching a cell basal layer, so that the absorption mode can greatly avoid the liver first-pass effect of the drugs and remarkably improve the oral bioavailability of the drugs. An oral nano delivery system coated with biomacromolecule drugs modified by glycocholic acid is prepared in the early stage of a subject group and used for treating type II diabetes, and research results show that the oral bioavailability of the drugs is improved by 2 times after the glycocholic acid is modified, and related research achievements have already applied for a patent (Gao Zhonggao. An oral nano polymer targeted delivery system coated with biomacromolecules: china, 201910927139.3[ P ]. 2019-9-27.).
The chitosan is a cationic polymer polysaccharide with good biological safety, and researches show that the chitosan can be used as a biomembrane adhesion material so as to prolong the retention time of the medicine in intestinal tracts and improve the oral absorption of the medicine. In addition, there have been many studies to modify chitosan on the surface of liposomes, which can improve the oral stability of liposomes.
Quercetin (QT) is a natural flavonoid compound with high content in plants such as tea, onion and the like, and researches show that the QT can competitively antagonize MDR families including P-gp, MRP1 and BCRP, and the P-gp inhibitor as a natural source shows good P-gp efflux inhibition biological function in a plurality of drug-resistant cell lines. Paclitaxel (Paclitaxel, PTX) is used as a typical P-gp substrate, the absorption of the P-gp overexpressed in intestinal tract in epithelial cells of small intestine is greatly limited, QT is used as a P-gp inhibitor to be connected to polysaccharide surface to load PTX to prepare oral Paclitaxel nanoparticles, and pharmacokinetic data in vivo show that the nanoparticles modified by QT can improve the oral bioavailability of PTX by 6 times.
The invention constructs an oral paclitaxel nano delivery system based on cholic acid modification, and a chitosan material with a biomembrane adhesion effect is coated on the surface of liposome loaded with PTX and modified by QT, so that the stability of nanoparticles is improved, the intestinal transport capacity and lymph transport of PTX are improved through a bile salt passage, QT synergistically exerts the effect of inhibiting the excretion of P-gp in the intestinal tract, the oral bioavailability of PTX is further improved, and finally a better anti-tumor effect can be realized.
Disclosure of Invention
The technical problem to be solved by the invention is to provide cholic acid modified oral paclitaxel nanoparticles, which comprise a paclitaxel cholesterol complex, phospholipid, cholesterol, phospholipid-polyethylene glycol-quercetin polymer, glucose and cholic acid-chitosan polymer, wherein the weight ratio of paclitaxel to cholesterol in the paclitaxel cholesterol complex is 1.
In order to solve the technical problem, the invention provides the following technical scheme:
the technical scheme of the invention provides cholic acid modified oral paclitaxel nanoparticles, which are characterized by comprising total lipid, chitosan-glycocholic acid polymer and glucose, wherein the total lipid comprises: paclitaxel cholesterol complex, phospholipid, cholesterol, phospholipid-polyethylene glycol-quercetin polymer; the weight ratio of the paclitaxel to the cholesterol in the paclitaxel cholesterol complex is 1.1-1:1, preferably 1.
In the invention, an inner layer paclitaxel liposome structure is composed of paclitaxel cholesterol compound, phospholipid, cholesterol, phospholipid polyethylene glycol and phospholipid-polyethylene glycol-quercetin polymer, and chitosan-glycocholic acid polymer is wrapped on an outer layer to form final nanoparticles.
In the present invention, the paclitaxel cholesterol complex, in weight percent, represents 0.1% to 50% of the total lipid, preferably 1% to 10%, and 0.1% to 50% of the total lipid, chitosan-glycocholic acid, preferably 1% to 15%. In the present invention, the phospholipids in the inner liposome include all types of phospholipids, including but not limited to soybean phospholipids, lecithin, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, diphosphatidylglycerol; lecithin is preferred, and soybean lecithin is more preferred. The outer layer of chitosan material comprises chitosan of all molecular weights, including but not limited to chitosan material of molecular weight 1000-100 ten thousand; preferably a chitosan material with a molecular weight of 1000-10 ten thousand, more preferably a chitosan material with a molecular weight of 3000-5 ten thousand.
In the present invention, the cholesterol in the inner paclitaxel liposome accounts for 0.1-50%, preferably 2.5-25% of the total lipid by weight.
In the present invention, the phospholipid-polyethylene glycol in the inner paclitaxel liposome accounts for 1-80% of the total lipid, preferably 10-30% by weight.
In the present invention, the phospholipid-polyethylene glycol-quercetin polymer in the inner liposome of the cholic acid modified oral paclitaxel nanoparticle accounts for 1-50%, preferably 1-10% of the total lipid by weight percentage.
In the invention, the glucose in the inner paclitaxel liposome is 5% glucose injection.
In the invention, the preparation method of the cholic acid modified oral paclitaxel nanoparticle is characterized by comprising the following steps: mixing paclitaxel and cholesterol according to the proportion, adding a proper amount of organic solvent for dissolving, stirring at a proper temperature, removing the organic solvent by rotary evaporation at a proper temperature, and drying in vacuum to obtain a paclitaxel cholesterol compound; weighing paclitaxel cholesterol complex, soybean lecithin, cholesterol, phospholipid-polyethylene glycol-quercetin polymer according to a prescription proportion, dissolving in chloroform until completely dissolving into clear solution, sterilizing and filtering with a 0.22 μm filter membrane, adding into a rotary bottle, placing in a constant temperature water bath (40 ℃ +/-5 ℃) and decompressing into a dry lipid membrane; putting the rotary bottle with the formed lipid membrane into a vacuum drying oven, and performing vacuum drying for 1-2 hours at the temperature of 40 +/-5 ℃; adding 5% glucose solution into the rotary bottle with lipid membrane, hydrating in 40 + -5 deg.C water bath until suspension has no visible insoluble substance, subjecting the hydrated liquid to ultrasonic treatment with ice water bath probe, and grading by extrusion or ultrasonic method to obtain inner layer paclitaxel liposome mixed solution with desired particle size. Adding the formed paclitaxel liposome mixed solution at the inner layer into a round-bottom flask, weighing chitosan-glycocholic acid according to the proportion of the prescription, dissolving in 5% glucose solution, stirring and mixing with the paclitaxel liposome mixed solution for 15min-30min, and standing at room temperature for 20-50min to obtain cholic acid modified oral paclitaxel nanoparticle mixed solution meeting the particle size requirement. The invention also provides application of the cholic acid modified oral paclitaxel nanoparticle pharmaceutical composition in preparing a medicament for treating tumors.
The beneficial technical effects are as follows:
1) The cholic acid modified oral paclitaxel nanoparticle prepared by the invention has the advantages of high encapsulation rate and good stability.
2) The cholic acid modified oral paclitaxel nanoparticles prepared by the invention have the advantages of good intestinal permeability, good biocompatibility and good biomembrane adhesion, so that the oral bioavailability of paclitaxel can be effectively improved, and further good antitumor effect is obtained.
3) The cholic acid modified oral paclitaxel nanoparticles prepared by the invention provide a safe and convenient oral administration mode, can improve the compliance of patients, reduce the toxic and side effects of infection, vascular stimulation and the like caused by intravenous injection, and have the advantage of good safety.
Drawings
FIG. 1: cholic acid-modified oral paclitaxel nanoparticle Dynamic Light Scattering (DLS) particle size distribution diagram
FIG. 2: cholic acid modified oral paclitaxel nanoparticle Dynamic Light Scattering (DLS) potential map
FIG. 3: cholic acid-modified oral paclitaxel nanoparticle transmission electron micrograph
FIG. 4: in vitro release curve of cholic acid modified oral paclitaxel nanoparticles
FIG. 5 is a schematic view of: stability result chart of cholic acid modified oral paclitaxel nanoparticles in artificial gastric juice
FIG. 6: stability result chart of cholic acid-modified oral paclitaxel nanoparticles in artificial intestinal juice
FIG. 7: graph of experimental results of safety of oral nanoparticles modified by blank cholic acid on human colorectal cells Caco-2 cells
FIG. 8: cholic acid-modified oral paclitaxel nanoparticles human colorectal cell Caco-2 cell safety experiment result chart
FIG. 9: cholic acid-modified oral paclitaxel nanoparticle in-vitro human small intestine epithelial cell transport efficiency result chart
FIG. 10: result graph of apparent permeability coefficient of cholic acid modified oral paclitaxel nanoparticles in vitro human small intestine epithelial cells
FIG. 11: results of blood concentration-time curve of cholic acid-modified oral paclitaxel nanoparticles in SD rats
FIG. 12: cholic acid modified oral paclitaxel nanoparticle in-vitro tumor inhibition effect result chart
FIG. 13: results of tumor weight of cholic acid-modified oral paclitaxel nanoparticles after 12 days of tumor-bearing mice treatment
FIG. 14: in vitro safety investigation result graph of cholic acid modified oral paclitaxel nanoparticles
Detailed Description
The following examples are intended to illustrate the invention without further limiting it. The present invention will be further illustrated in detail with reference to examples, but the present invention is not limited to these examples and the preparation method used. Also, equivalent substitutions, combinations, improvements or modifications of the invention may be made by those skilled in the art based on the description of the invention, but these are included in the scope of the invention.
Example 1: preparation of paclitaxel cholesterol complex
Table 1 is the composition of paclitaxel cholesterol complex:
Figure BDA0003109787170000051
weighing paclitaxel and cholesterol according to the prescription amount, placing the paclitaxel and cholesterol into a triangular flask with a stopper, adding 100ml of acetone to dissolve the paclitaxel and cholesterol, stirring the mixture for 2 hours at the temperature of 45 ℃, transferring the mixture into a rotary evaporator, removing the acetone by rotary evaporation, and drying the mixture for 15 hours in vacuum at the temperature of 45 ℃ to obtain the paclitaxel and cholesterol compound.
Example 2: preparation of cholic acid modified oral paclitaxel nanoparticles
Table 2 is the formulation composition of cholic acid-modified oral paclitaxel nanoparticles:
Figure BDA0003109787170000052
the preparation method comprises the following steps: dissolving 8mg of paclitaxel cholesterol complex, 280mg of soybean lecithin, 7mg of cholesterol, 50mg of phospholipid-polyethylene glycol and 30mg of phospholipid-polyethylene glycol-quercetin polymer in 6ml of chloroform in a 100ml eggplant-shaped bottle until the compounds are completely dissolved into clear solution, sterilizing and filtering the solution by a 0.22 mu m filter membrane, adding the solution into a rotary bottle, placing the rotary bottle in a constant temperature water bath (40 +/-2 ℃) and decompressing to obtain a dry lipid membrane; putting the rotary bottle with the formed lipid membrane into a vacuum drying oven, and drying for 1-2 hours at 40 ℃; and adding a 5% glucose solution into the rotary bottle with the lipid membrane formed, hydrating the mixture under the condition of 40 ℃ water bath until suspension does not have visible insoluble substances, and ultrasonically finishing the hydrated liquid by using an ice water bath probe to obtain the inner-layer paclitaxel liposome meeting the particle size requirement. Adding the formed paclitaxel liposome mixed solution into a round-bottom flask, weighing 60mg of chitosan-glycocholic acid, dissolving in 2.5ml of 5% glucose solution, stirring and mixing with the paclitaxel liposome mixed solution for 15min-30min, and standing at room temperature for 20-50min to obtain cholic acid modified oral paclitaxel nanoparticle mixed solution meeting the particle size requirement. The invention also provides application of the cholic acid modified paclitaxel nanoparticles in preparing an oral anti-tumor nano delivery system.
Physical properties of cholic acid-modified oral paclitaxel nanoparticles: particle size: measured by a dynamic light scattering method, the particle size is 87.5nm, and the PDI is 0.228; potential: measured by a dynamic light scattering method, the concentration is +14.1mV; encapsulation efficiency: 99.05% as determined by high performance liquid chromatography; drug loading rate: the content of the extract was 1.51% as determined by high performance liquid chromatography.
Example 3: determination of in vitro release degree of cholic acid modified oral paclitaxel nanoparticles
0.5ml of cholic acid modified oral paclitaxel nanoparticle solution (containing 0.6mg of paclitaxel) is transferred into a dialysis bag, both ends of the solution are fastened and then placed into 30ml of hydrochloric acid aqueous solution with pH 1.2 and containing 0.5% Tween 80, and the solution is oscillated at constant temperature of 37 ℃ at the rotating speed of 100rpm by a device and a method of a third method (a small cup method) of a four-part dissolution determination method of Chinese pharmacopoeia 2015 edition. 0.5ml of release medium is taken out at 1, 1.5 and 2h in time, meanwhile, the same temperature and the same volume of fresh release medium is supplemented, then the dialysis bag is transferred into PBS solution with 0.5 percent of Tween 80 and with pH6.8 for continuous release, and 0.5ml of release medium is taken out at 3, 5, 7, 10, 12, 24, 36, 48 and 72h in time, meanwhile, the same temperature and the same volume of fresh release medium is supplemented. After the release medium is taken out and centrifuged (12000rpm, 10min), the accumulated content of the paclitaxel is determined by using a high performance liquid chromatography, and the in-vitro release degree of the commercial paclitaxel injection is determined by the same method.
Table 3 is the release data:
Figure BDA0003109787170000061
Figure BDA0003109787170000071
the results are shown in fig. 4, and show that in the environment of simulated artificial gastric juice at pH 1.2, the release rate of the oral paclitaxel nanoparticle group modified by cholic acid is less than 3% within 2h, after the release medium is transferred to pH6.8, the drug release of the paclitaxel injection group reaches 71.54% within 48h, and the drug release of the nanoparticles is 61.17% within 48 h. The prepared nanoparticles can be proved to have good stability in the gastrointestinal tract and can meet the oral administration condition.
Example 4: stability of cholic acid modified oral paclitaxel nanoparticles in artificial gastric and intestinal juice
Preparing artificial gastric juice: dissolving 100ml hydrochloric acid solution with pH of 1.2 in 320mg pepsin.
Preparing artificial intestinal juice: dissolving 100ml buffer solution with pH6.8 in 1000mg trypsin.
Respectively taking 1ml of cholic acid modified oral paclitaxel nanoparticles and 1ml of cholic acid-free modified oral paclitaxel nanoparticles, mixing and incubating with 2ml of artificial gastric juice and artificial intestinal juice, and placing at 37 ℃ and shaking at constant temperature of 100rpm. Wherein, 300ul of samples are respectively taken at 1h and 2h time points in the artificial gastric juice group samples, 300ul of samples are respectively taken at 1h,2h, 4h and 6h time points in the artificial intestinal juice group samples. And (3) measuring the particle size and the particle size distribution of the sampled sample, and inspecting the stability of the sample in simulated artificial gastric juice and intestinal fluid.
Table 4 shows the particle size of the nanoparticles at different time points in the artificial gastric juice
Figure BDA0003109787170000072
Table 5 shows the particle diameters of the nanoparticles at different time points in the intestinal juice
Figure BDA0003109787170000073
Fig. 5 and 6 and tables 4 and 5 show that the cholic acid-modified oral paclitaxel nanoparticles have good stability in artificial gastric juice of 2h and artificial intestinal juice of 6h, and the particle size and PDI are maintained at stable levels. It is demonstrated that the oral paclitaxel system provided by the present patent has certain advantages in terms of gastrointestinal stability, and can reach the absorption site of small intestine in a relatively intact state.
Example 5: cytotoxicity Studies of materials
Diluting the blank cholic acid modified oral nanoparticle preparation with a culture solution to obtain a solution with a predetermined concentration. Each concentration was set with 6 duplicate wells, and a control and zero-adjusted group were set. Human colon cancer cells Caco-2 cells and1×10 4 the density of each well was plated in 96-well plates and after further incubation for 24h, the medium was replaced with fresh medium containing blank micelle concentrations of 1, 10, 20, 50, 100, 200. Mu.g/ml and further incubation was continued for 24h, respectively. 20 μ l of CCK-8 reagent was added to each well. Incubation was continued for 1-4h, and absorbance was measured at 450nm, with 650nm as the reference wavelength. Cell viability was calculated by the formula:
cell viability (%) = [ (OD) Experiment of -OD Zero setting )/(OD Control of -OD Zero setting )]×100
Table 6 shows the proliferation inhibition of human colon cancer cells Caco-2 cells by oral paclitaxel nanoparticles modified by blank cholic acid
Concentration (μ g/ml) Cell survival rate (%)
1 96.10％±0.04
10 91.86％±0.05
20 94.06％±0.04
50 86.67％±0.12
100 90.03％±0.05
200 83.38％±0.02
Fig. 7 and table 6 show that the activity of Caco-2 cells of oral paclitaxel nanoparticles modified by blank cholic acid is over 80% in the measured concentration range, which indicates that the material itself has low cytotoxicity. The cholic acid modified oral nanoparticle system provided by the patent has advantages in safety.
Example 6: cytotoxicity research of drug-loaded nanoparticles
Diluting the oral paclitaxel nanoparticles modified by cholic acid into a solution with a predetermined concentration by using a culture solution. Each concentration was set with 6 duplicate wells, and a control and zero-adjusted group were set. Human colon cancer cells Caco-2 cells at 1X 10 4 Inoculating the cells/well into a 96-well plate, continuously culturing for 24h, replacing the medium with fresh culture solution containing 1, 10, 20, 50, 100 and 200 mu g/ml cholic acid modified oral paclitaxel nanoparticles, and respectively continuously culturing for 24h. 20. Mu.l of CCK-8 reagent was added to each well. Incubation was continued for 1-4h, and absorbance was measured at 450nm, with 650nm as the reference wavelength. Calculating the cell activity and the cell proliferation inhibition rate, and the formula is as follows:
cell growth inhibition ratio (%) = [1- (OD) Experiment of -OD Zero setting )/(OD Control -OD Zero setting )]×100
Table 7 shows the proliferation inhibition of cholic acid-modified oral paclitaxel nanoparticles on human colon cancer Caco-2 cells
Concentration (μ g/ml) Cell proliferation inhibition (%)
1 98.26％±0.04
10 85.21％±0.04
20 90.12％±0.02
50 81.60％±0.05
100 85.27％±0.02
200 80.92％±0.04
Fig. 8 and table 7 show that, in the drug concentration range of 1-200 μ g/mL, after cholic acid-modified oral paclitaxel nanoparticles are incubated with Caco-2 for 4 hours, the cell survival rate is all above 80%, and it is proved that, in the concentration range, the oral paclitaxel nanoparticles provided by the present invention can meet the safety requirements of the tranwell monolayer model transport test.
Example 6: preparation of coumarin 6-labeled cholic acid modified oral nanoparticles
The coumarin 6-labeled nanoparticles were prepared according to the nanoparticle preparation method described in example 1 above. Weighing soybean lecithin, cholesterol, phospholipid-polyethylene glycol and phospholipid-polyethylene glycol-quercetin polymer according to the prescription amount, dissolving the soybean lecithin, cholesterol, phospholipid-polyethylene glycol and phospholipid-polyethylene glycol-quercetin polymer in chloroform until the soybean lecithin, cholesterol, phospholipid-polyethylene glycol and phospholipid-polyethylene glycol-quercetin polymer are completely dissolved to form a clear solution, adding a certain amount of coumarin 6 chloroform solution into the solution to ensure that the concentration of the coumarin 6 is about 15 mu g/ml or 120 mu g/ml, sterilizing and filtering the solution by a 0.22 mu m filter membrane, and adding the solution into a rotary bottle to be placed in a constant temperature water bath (40 +/-2 ℃) for decompression to form a dry lipid membrane; putting the rotary bottle with the lipid membrane into a vacuum drying oven, and vacuum-drying at 40 deg.C for 1-2 hr; adding 5% glucose solution into the rotary bottle with lipid membrane, hydrating in 40 deg.C water bath until suspension has no insoluble substances, and ultrasonically granulating the hydration liquid with ice water bath probe to obtain Cou-6-Lip labeled with coumarin 6. Adding the formed Cou-6-Lip mixed solution into a round bottom flask, weighing chitosan-glycocholic acid or chitosan according to a formula proportion, dissolving the chitosan-glycocholic acid or chitosan in a 5% glucose solution, stirring and mixing the chitosan-glycocholic acid or chitosan with the inner layer paclitaxel liposome mixed solution for 15min to 30min, and standing the mixture at room temperature for 20 to 50min to obtain cholic acid modified oral nanoparticle mixed solution Cou-6-GQL meeting the particle size requirement and cholic acid-free modified oral nanoparticle mixed solution Cou-6-CQL.
Example 7: establishment of Caco-2 cell transwell model of human colon cancer
Human colon cancer Caco-2 cells were cultured at 1X 10 5 The individual cells were seeded in 12-well tranwell chambers, 1.5ml of medium was added to the lower chamber, and the content of CO was 5% at 37 ℃% 2 Culturing in an incubator for 48h, discarding the medium to replace the fresh culture medium, at 37 deg.C, 5% 2 And continuing culturing in the incubator. And changing the liquid every two days in the previous week, changing the liquid every day after one week, and culturing for 21 days to obtain the in vitro human-like small intestine epithelial cell model.
Example 8: transport of drug-loaded nanoparticles on in vitro small intestine epithelial cell model
The liquid chromatography is utilized to quantitatively investigate the transport capacity of the cholic acid modified paclitaxel oral nanoparticle on in-vitro small intestine epithelial cells. The laboratory was primed with Hank's solution incubated at 37 ℃ and the chamber and outer chamber were rinsed 3 times. Adding 500uL of paclitaxel injection diluted with Hank's solution, cholic acid-modified paclitaxel oral nanoparticles and cholic acid-free modified paclitaxel oral nanoparticles into the small chamber, and continuously placing at 37 deg.C and 5% CO 2 Transport tests were performed in the incubator. Taking 300uL lower layer receiving solution from the outer chamber for paclitaxel content determination at 30min, 60min, 90min and 120min respectively, and supplementing Hank's solution preheated at 37 deg.C into the outer chamber in time. Each set was set with 3 multiple wells. Adding the obtained sample into acetonitrile with the same volume, uniformly mixing by vortex, carrying out ultrasonic treatment for 10min, centrifuging at 12000rpm for 10min, collecting supernatant, and carrying out content determination by high performance liquid chromatography.
Calculating three groups of oral paclitaxel nanoparticles without cholic acid modification, oral paclitaxel nanoparticles with cholic acid modification and paclitaxel injection at different timesTransport efficiency and apparent permeability coefficient. The apparent permeability coefficient is calculated by the formula: p app ＝dQ/dt×1/(A×C 0 )。
Table 8 shows the transport efficiency of cholic acid-modified oral paclitaxel nanoparticles in a model simulating human intestinal epithelial cells in vitro.
Figure BDA0003109787170000101
Table 9 shows the apparent permeability coefficient of cholic acid-modified oral paclitaxel nanoparticles in vitro in a model simulating human intestinal epithelial cells.
Figure BDA0003109787170000102
From tables 8-9 and fig. 9-10, it can be seen that the transport efficiency of the cholic acid-modified oral paclitaxel nanoparticle can reach 15.79% and the transport efficiency of the paclitaxel injection group is 2.95% when the cholic acid-modified oral paclitaxel nanoparticle is transported for 120min on an in vitro intestinal epithelial cell simulation model. The cholic acid modified oral paclitaxel nanoparticle transport permeability coefficient is 6.25 multiplied by 10^ a -6 cm/s, the transport permeability coefficient of the paclitaxel injection is 6 multiplied by 10^ s -7 cm/s. Therefore, the oral nanoparticles constructed by the invention can obviously improve the intestinal transport capacity of the paclitaxel.
Example 9: in vivo pharmacokinetics study of cholic acid-modified oral paclitaxel nanoparticles
The change of blood concentration of the cholic acid modified oral paclitaxel nanoparticles in SD rats is detected by using liquid. 150-160 g SD rats were taken, fasted for 12h, and then randomly divided into 6 groups of 3 rats. Wherein, the cholic acid modified oral paclitaxel nanoparticle + taurocholate group is perfused with taurocholate 1h ahead of time, the dosage is 25mg/kg, and the cholic acid modified oral paclitaxel nanoparticle + cycloheximide group is intraperitoneally injected with cycloheximide 1h ahead of time, the dosage is 6mg/kg. The dose of each group is 10mg/kg, 0.5ml of blood is taken from the outer canthus of rats at 0h, 0.05h, 0.25h, 0.5h, 1h, 1.5h, 2h,4h,6h, 8h, 12h and 24h respectively, and serum is collected by centrifugation at 4000rpm for 10 min. And mixing 100 mu L of serum with 300 mu L of acetonitrile solution containing an internal standard substance docetaxel, centrifuging at 12000rpm for 10min, collecting supernatant, and determining the blood concentration of paclitaxel in the plasma by using a prepared sample through liquid chromatography mass spectrometry.
Table 10 shows the results of blood paclitaxel concentrations in SD rats for each of the formulations.
Figure BDA0003109787170000111
As can be seen from table 10 and fig. 11, the absolute bioavailability of the cholic acid-modified oral paclitaxel nanoparticles is increased by 15 times compared to the oral paclitaxel injection, and Cmax is increased by 11 times compared to the oral paclitaxel injection. After an ASBT transporter inhibitor taurocholate is given in advance, the absolute bioavailability of the oral cholic acid modified paclitaxel nanoparticles is reduced by 1.3 times, and the ASBT transporter mediates the improvement of the oral bioavailability of the oral cholic acid modified paclitaxel nanoparticles in vivo provided by the patent. In conclusion, the cholic acid modified oral nanoparticle provided by the patent can obviously improve the oral bioavailability of paclitaxel, and has potential development value.
Example 10: establishment of Holl 2 lung cancer animal model
Collecting LL2 lung cancer cells in logarithmic growth phase, digesting with pancreatin, centrifuging, discarding supernatant, adding PBS, resuspending, and adding 1 × 10^ 6 The number of the mice is inoculated on the right foreleg side (under the armpit) of male C57BL/6 mice with the age of 4-6 weeks and the weight of 18-22 g, and a subcutaneous lung cancer animal model is formed. Tumor volume was measured dynamically with a vernier caliper.
Tumor volume calculation formula: v =0.5 × L × D 2 (V is tumor volume, L is tumor major diameter, and D is tumor minor diameter).
Example 10: inhibition effect of cholic acid modified oral paclitaxel nanoparticles on lung cancer
A subcutaneous lung cancer model was established according to the method of example 9 using 4-6 week-old male C57BL/6 mice. After the tumor volume reaches 100mm < 3 >, the C57BL/6 mice are randomly grouped into 6 mice each group. The yew injection is administrated once every 4 days in the intravenous injection group, the other oral preparation groups are administrated once every 2 days, the administration dose is 10mg/kg, the intravenous injection is administrated 3 times, and the oral administration is administrated 6 times. Tumor volumes of mice were recorded during the experiment. After 12 days, the administration was stopped. The pharmacodynamic group is subjected to dissection operation, and tumor tissues are taken out and weighed.
Table 11 shows the tumor weight statistics of tumor-bearing mice after 12 days of treatment with each formulation.
Figure BDA0003109787170000121
Table 12 is the statistical results of the intrabody weight of tumor-bearing mice treated with each formulation for 12 days.
Figure BDA0003109787170000122
From tables 11-12, FIGS. 12-14, the tumor size of the glucose injection oral group showed a continuous ascending trend, the cholic acid-modified oral paclitaxel nanoparticle group showed similar effect to that of paclitaxel injection intravenous injection at the same dose, and the tumor volume of the cholic acid-modified oral paclitaxel nanoparticle group was 1477.01 ± 671.17mm on day 12 3 The tumor volume of the paclitaxel injection intravenous injection group is 1593.22 +/-186.11 mm 3 The tumor volume of the paclitaxel injection oral group is 2411.65 +/-420.37 mm 3 The tumor volume of the oral paclitaxel nanoparticle group without the modification of the cholic acid is 1915.67 +/-411.90 mm 3 The tumor volume of the oral paclitaxel nanoparticle without quercetin is 1643.90 +/-498.75 mm 3 It can be seen that the oral paclitaxel nanoparticles provided by the patent have good anti-tumor effect, and the quercetin has a certain effect on enhancing the drug effect. In the aspect of safety, the weight of the paclitaxel injection intravenous injection group is in a descending trend at the later stage, and the weight of the oral paclitaxel nanoparticle group is in an ascending trend, so that the oral paclitaxel nanoparticle provided by the patent is proved to have good safety.

Claims (11)

1. A cholic acid-modified oral paclitaxel nanoparticle, which comprises total lipid, chitosan-glycocholic acid polymer and glucose, wherein the total lipid comprises: paclitaxel cholesterol complex, phospholipid, cholesterol, phospholipid-polyethylene glycol-quercetin polymer; the weight ratio of the paclitaxel to the cholesterol in the paclitaxel cholesterol complex is 1.1-1:1, preferably 1.
2. The cholic acid-modified oral paclitaxel nanoparticles according to claim 1, which are characterized in that: the inner layer paclitaxel liposome structure is composed of paclitaxel cholesterol compound, phospholipid, cholesterol, phospholipid polyethylene glycol, and phospholipid-polyethylene glycol-quercetin polymer, and the final nanoparticle is formed by coating chitosan-glycocholic acid polymer on the outer layer.
3. A cholic acid-modified oral paclitaxel nanoparticle according to any of claims 1 and 2, which is characterized in that: the paclitaxel cholesterol complex comprises 0.1% -50%, preferably 1% -10%, by weight of the total lipid, 0.1% -50%, preferably 1% -15% of the total lipid.
4. A cholic acid-modified oral paclitaxel nanoparticle according to any of claims 1 and 2, which is characterized in that: phospholipids constituting the inner liposomes include all types of phospholipids, including soybean phospholipids, lecithin, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, diphosphatidylglycerol; the chitosan material on the outer layer comprises chitosan with all molecular weights, including chitosan material with the molecular weight of 1000-100 ten thousand; preferably a chitosan material having a molecular weight of 1000 to 10 ten thousand, more preferably a chitosan material having a molecular weight of 3000 to 5 ten thousand.
5. A cholic acid-modified oral paclitaxel nanoparticle according to any of claims 1 and 2, which is characterized in that: the cholesterol in the cholic acid modified oral paclitaxel nanoparticles accounts for 0.1-50%, preferably 2.5-25% of the total lipid by weight percentage.
6. A cholic acid-modified oral paclitaxel nanoparticle according to any of claims 1 and 2, which is characterized in that: the phospholipid-polyethylene glycol in the cholic acid modified oral paclitaxel nanoparticles accounts for 1-80% of the total lipid, preferably 10-30% of the total lipid.
7. The cholic acid-modified oral paclitaxel nanoparticles according to claims 1 and 2, which are characterized in that: the phospholipid-polyethylene glycol-quercetin polymer in the cholic acid modified oral paclitaxel nanoparticles accounts for 1-50% of the total lipid by weight percentage, and preferably accounts for 1-10%.
8. The cholic acid-modified oral paclitaxel nanoparticles according to claims 1 and 2, which are characterized in that: according to the weight percentage, the chitosan-glycocholic acid polymer in the cholic acid modified oral paclitaxel nanoparticles accounts for 1-80%, preferably 10-30% of the total material.
9. The cholic acid-modified oral paclitaxel nanoparticles according to claims 1 and 2, which are characterized in that: the glucose in the cholic acid modified oral paclitaxel nanoparticles is 5% glucose injection.
10. The method for preparing cholic acid-modified oral paclitaxel nanoparticles according to any of claims 1 to 9, comprising the following steps: mixing paclitaxel and cholesterol according to a mass ratio of 1.1-1, adding an appropriate amount of acetone solution for dissolving, stirring at 30-50 ℃, removing the organic solvent by rotary evaporation at 30-50 ℃, and performing vacuum drying to obtain a paclitaxel cholesterol compound; weighing the paclitaxel cholesterol complex, the soybean lecithin, the cholesterol, the phospholipid-polyethylene glycol and the phospholipid-polyethylene glycol-quercetin polymer according to a mass ratio of 1.14; putting the rotary bottle with the lipid membrane into a vacuum drying oven, and carrying out vacuum drying for 1-2 hours at the temperature of 40 +/-5 ℃; adding 5% glucose solution into the rotary bottle with lipid membrane, hydrating in 40 + -5 deg.C water bath until suspension has no insoluble substances visible to naked eye, ultrasonically treating the hydrated liquid with ice water bath probe, and grading by extrusion, membrane or ultrasonic method to obtain inner layer paclitaxel liposome mixed solution with particle size requirement; adding the formed paclitaxel liposome mixed liquor at the inner layer into a round-bottom flask, weighing 40mg of chitosan-glycocholic acid according to the proportion of the prescription, dissolving the chitosan-glycocholic acid in 5% glucose solution, stirring and mixing the chitosan-glycocholic acid with the paclitaxel liposome mixed liquor for 15min to 30min, and standing at room temperature for 20min to 50min to obtain cholic acid modified oral paclitaxel nanoparticle mixed liquor meeting the particle size requirement.
11. Use of cholic acid-modified oral paclitaxel nanoparticles according to any of claims 1 to 10 for preparing an oral antitumor drug.
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