CN111671736B - Metal organic framework-based drug carrier, preparation method thereof and application thereof in oral drug carrier - Google Patents
Metal organic framework-based drug carrier, preparation method thereof and application thereof in oral drug carrier Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to a metal organic framework-based drug carrier, a preparation method thereof and application thereof in oral drug carriers. According to the invention, MOFs with good stability is synthesized by a solvothermal method, then 5-FU is loaded into the MOFs by a solvent volatilization method, and CS & MOFs @5-FU is obtained after chitosan is coated on the surface of the MOFs. The prepared CS & MOFs @5-FU can increase the stability of MOFs in an acidic environment, and meanwhile, chitosan can enhance the adhesion behavior to mucus through the non-covalent bond interaction with a mucus chain, so that a certain slow release effect is achieved, the permeability of intestinal mucosa can be improved, and the oral bioavailability of the medicine can be improved. In addition, the chitosan also has the hole sealing effect, so that a large amount of medicines are prevented from being leaked in advance. The invention provides feasibility for taking MOFs as oral drug carriers.
Description
Technical Field
The invention relates to the field of preparation of metal organic framework drug carriers, in particular to a preparation method of a drug-loaded metal organic framework coated by chitosan and application of the drug-loaded metal organic framework as an oral drug carrier.
Background
Metal-organic frameworks (MOFs) are a new class of very promising crystalline microporous materials, and two-dimensional or three-dimensional solid materials with periodic network structures are constructed by coordination of metal ions or metal clusters and organic bridging ligands. Compared with traditional inorganic porous materials, MOFs have larger porosity and specific surface area, especially adjustable pore size and variable functional groups. Currently, MOFs have been applied to hydrogen storage, catalytic reactions, biosensors, gas adsorption and separation, and the like. The research on metal organic frame materials relates to the latest results of organic chemistry, inorganic chemistry, coordination chemistry, material chemistry, life science, computer science and other disciplines, so in recent years, the MOFs are receiving more and more attention from research teams. As a novel functional molecular material, MOFs exhibit many characteristics required as a drug carrier, including extremely high specific surface area and large pore size capable of supporting drug molecules, and biodegradability due to relatively unstable coordination bonds, so that MOFs have become important candidate materials for drug carriers in recent years.
Many chemotherapy drugs are mainly administered by injection, but many drugs are not suitable for administration by injection, such as macromolecular drugs and drugs with short half-life. And the patient is considered to have strong compliance to the oral preparation, convenient use and good safety. Therefore, the drug carrier which has high loading efficiency, good biocompatibility and easy structural modification and can realize the sustained and controlled release of oral administration is urgently needed to be searched at present.
The MOFs have the excellent characteristics of drug loading, however, most of the MOFs are weak in coordination bond and easy to be damaged by acid and alkali, the stability of the MOFs is poor under the condition of gastrointestinal tracts, and some drugs loaded in large pore sizes are easy to leak, so that the intestinal absorption is insufficient, and the application of the MOFs in oral administration is limited, so that most of the researches related to the MOFs as drug carriers are concentrated on intravenous administration at present.
The chitosan has the activities of antibiosis, antioxidation, combination, promotion of wound healing, hemostasis and the like, has the characteristics of non-antigenicity, biodegradability, nontoxicity and the like, and is a promising renewable polymer packaging material. Chitosan is widely applied to oral preparations at present, has transitivity and adhesion property in human gastrointestinal tracts, can prevent inactivation and degradation of drugs caused by low pH value of the gastrointestinal tracts and enzymes, and more importantly is used as a penetration enhancer to adjust intestinal barriers, and simultaneously enhances the adhesion behavior to mucus through the non-covalent interaction with mucus chains and remains on the surface of the mucosa for subsequent removal, so the chitosan is a typical biological material for improving the oral absorption of the drugs.
Disclosure of Invention
The invention aims to provide a drug carrier based on a metal organic framework. The chitosan is wrapped on the outer surface of the MOFs, so that the stability of the MOFs in the stomach is improved, the adhesion in the intestine is increased, the permeability of intestinal mucosa is improved, and the oral bioavailability of the medicine is improved.
In order to achieve the purpose, the invention adopts the following technical scheme: a drug carrier based on a metal organic framework is composed of a drug-carrying metal organic framework with chitosan coated on the surface.
A preparation method of a drug carrier based on a metal organic framework comprises the following steps:
1) dissolving a drug X in alcohol, then adding the alcohol solution of the drug X into an alcohol dispersion solution of a metal organic framework material MOFs, ultrasonically mixing, rotatably evaporating, dissolving in alcohol, washing, centrifuging and drying to obtain a drug-loaded metal organic framework MOFs @ X;
2) mixing the alcohol dispersion solution carrying the medicine metal organic framework MOFs @ X with the acetic acid water solution of chitosan CS, stirring, centrifuging, washing and drying to obtain the oral medicine carrier CS & MOFs @ X based on the metal organic framework.
Further, in the preparation method, the MOFs of the metal organic framework material is UiO-66 or UiO-66-NH2UiO-66-COOH, UiO-67 or Zr-NDC.
Further, the preparation method of the metal organic framework materials MOFs comprises the following steps: sequentially adding ZrCl into a container4The preparation method comprises the following steps of uniformly mixing an organic ligand, N-dimethylformamide, acetic acid or benzoic acid and deionized water, reacting at 100-130 ℃ for 12-36 hours, cooling, centrifuging, washing and drying to obtain a target product; the organic ligand is terephthalic acid, 2-amino-1, 4-phthalic acid, 1,2, 4-benzenetricarboxylic acid, 4' -biphenyldicarboxylic acid or 2, 6-naphthalenedicarboxylic acid.
Further, in the above preparation method, the alcohol is methanol, ethanol or propanol.
Further, the preparation method comprises the following steps of: MOFs is 1-3: 1, and the concentration of the medicine X is 1-3 mg/mL.
Further, according to the preparation method, according to the mass ratio, MOFs @ X: CS ═ 3: 1-4, and the concentration of the CS acetic acid aqueous solution is 1-4 mg/mL.
Further, in the preparation method, the medicament X is a chemotherapeutic medicament.
Further, in the above production method, the drug X is 5-fluorouracil (5-FU).
The invention relates to an application of a metal organic framework-based drug carrier as an oral drug carrier.
According to the invention, a metal organic framework material is used as a basic carrier, CS is wrapped on the outer surface of the structure after 5-FU is loaded to serve as an oral drug carrier, the stability of MOFs in an acidic environment can be increased, and chitosan is interacted with a mucus chain through a non-covalent bond to enhance the adhesion behavior to mucus, so that a certain slow release effect is achieved, the permeability of intestinal mucosa can be improved, and the oral bioavailability of the drug can be improved.
The invention has the following beneficial effects:
1. currently, metal organic framework materials have some desirable characteristics that can serve as drug carriers: the simple preparation method has the advantages of large specific surface area, high porosity, capability of wrapping more drug molecules, high thermal stability, low toxicity, good biocompatibility, weak coordination bond and easiness in being damaged by acid and alkali, thus showing inherent biodegradability.
2. The MOFs preparation method provided by the invention is simple, saves resources, and is suitable for industrial mass production.
3. According to the invention, the drug-loaded MOFs is coated by chitosan, so that the stability of the drug-loaded MOFs in an acidic environment can be increased, and the chitosan plays a certain slow release role, can improve the permeability of intestinal mucosa and can improve the oral bioavailability of the drug.
4. The CS-coated MOFs prepared by the invention can be loaded with 5-FU and other drugs, and provides an effective carrier for oral drugs.
Drawings
FIG. 1 is an XRD pattern of MOFs, five metal-organic framework materials prepared in example 1.
FIG. 2 is the scanning electron microscope images of Zr-NDC before (A), after (B) and after (C) chitosan coating.
FIG. 3 is an infrared spectrum of chitosan, Zr-NDC and chitosan coated Zr-NDC.
FIG. 4 is a TGA spectrum of chitosan, Zr-NDC and chitosan coated Zr-NDC.
FIG. 5 is an XRD spectrum of chitosan, Zr-NDC and chitosan coated Zr-NDC
FIG. 6A is a graph showing the drug release profile of chitosan coated CS & Zr-NDC @5-FU in artificial gastric juice.
FIG. 6B is a graph showing the release profile of CS & Zr-NDC @5-FU coated with chitosan in artificial intestinal juice
Fig. 7 is a graph of plasma mass concentration versus time in rats.
Detailed Description
The present invention will be described in further detail with reference to specific examples, which are not intended to limit the present invention but are merely illustrative thereof.
Example 1
Preparation of metal organic framework materials MOFs
Preparation of (a) Metal organic framework Material (UiO-66)
0.897g of terephthalic acid is weighed in a 250mL round-bottom flask, 1.0036g of zirconium chloride, 67mL of DMF (N, N-dimethylformamide) and 29mL of glacial acetic acid are added, the mixture is shaken and dissolved, then 5mL of deionized water is added, the mixture is stirred uniformly and then reacts in an oil bath at 120 ℃ for 12 hours, and a milky mixture is obtained. Cooling to room temperature, centrifuging at 10000r/min for 5min, discarding supernatant, washing with anhydrous ethanol, ultrasonic treating (50Hz, 5min), centrifuging (10000r/min, 5min), and repeating for three times. And discarding the supernatant, and drying the obtained solid in a vacuum drying oven at 55 ℃ to obtain the metal organic framework material (UiO-66).
(II) Metal organic framework Material (UiO-66-NH)2) Preparation of
Weighing 0.752g of 2-amino-1, 4-phthalic acid into a 250mL round bottom flask, adding 0.996g of zirconium chloride, 67mL of DMF (N, N-dimethylformamide) and 29mL of glacial acetic acid, shaking, adding 5mL of deionized water after dissolving, stirring uniformly, and carrying out oil bath reaction at 120 ℃ for 12 hours to obtain a milky mixture. Cooling to room temperature, centrifuging at 10000r/min for 5min, discarding supernatant, washing with anhydrous ethanol, ultrasonic treating (50Hz, 5min), centrifuging (10000r/min, 5min), and repeating for three times. Discarding supernatant, and oven drying the obtained solid in a vacuum drying oven at 55 deg.C to obtain metal organic framework material (UiO-66-NH)2)。
(III) preparation of Metal-organic framework Material (UiO-66-COOH)
0.463g of zirconium chloride and 0.424g of 1,2, 4-benzenetricarboxylic acid were weighed into a 25mL reaction vessel, and 8.8mL of deionized water, 10mL of DMF, and 12.5mL of glacial acetic acid were added. And (3) placing the reaction kettle in a vacuum drying oven at 100 ℃ for 24 hours to obtain milky white suspension, cooling to room temperature, and transferring to a 50mL centrifuge tube for centrifugation (10000r/min, 5 min). Then washing with absolute ethyl alcohol (10mL), performing ultrasonic treatment (40Hz, 5min), repeating for three times, centrifuging, and drying the obtained solid in a vacuum drying oven at 55 ℃ for 24h to obtain the metal organic framework material (UiO-66-COOH).
Preparation of (tetra) Metal organic framework Material (UiO-67)
0.12g of zirconium chloride and 0.674g of benzoic acid are weighed into a 100mL reaction kettle, and 20mL of DMF is added to dissolve for standby. Weighing 0.13g of 4, 4' -biphenyldicarboxylic acid into a 50mL centrifuge tube, adding 20mL of DMF, ultrasonically dissolving, adding into the reaction kettle, adding 0.028mL of deionized water, ultrasonically treating for 10min, placing the reaction kettle into a 120 ℃ forced air drying oven, heating for 24h, taking out, cooling to room temperature, centrifuging the mixture at 10000r/min for 5min, discarding the supernatant, adding 10mL of DMF, uniformly mixing, standing for 2h at room temperature, centrifuging, discarding the supernatant, washing with absolute ethyl alcohol, ultrasonically treating for 5min at 50Hz, centrifuging, and repeating for three times. Discarding the supernatant, and drying the obtained solid in a vacuum drying oven at 55 ℃ to obtain the metal organic framework material (UiO-67).
(V) preparation of Metal organic framework Material (Zr-NDC)
0.4g of zirconium chloride is weighed and placed in a 100mL reaction kettle, 20mL of DMF is added, ultrasonic dispersion is carried out at 50-60 ℃, and 2.85mL of glacial acetic acid is added for dissolution for standby. Weighing 0.45g of 2, 6-naphthalenedicarboxylic acid, adding into a 50mL centrifuge tube, adding 20mL of DMF, performing ultrasonic dissolution, adding into the reaction kettle, adding 0.2mL of deionized water, performing ultrasonic treatment at 50-60 ℃ for 30min, placing the reaction kettle in a 120 ℃ forced air drying oven, heating for 36h, taking out, cooling to room temperature, centrifuging the mixture at 10000r/min for 5min, discarding the supernatant, adding 10mL of DMF, uniformly mixing, standing at room temperature for 2h, centrifuging, discarding the supernatant, washing with absolute ethyl alcohol, performing ultrasonic treatment at 50Hz for 5min, centrifuging, and repeating for three times. And discarding the supernatant, and drying the obtained solid in a vacuum drying oven at 55 ℃ to obtain the metal organic framework material (Zr-NDC).
(VI) detection
FIG. 1 shows five prepared metal organic framework materials UiO-66 and UiO-66-NH2The X-ray diffraction spectrums of the five metal organic framework materials, UiO-66-COOH, UiO-67 and Zr-NDC show different high-intensity crystal sharp diffraction patterns from figure 1. The five MOFs are all crystal structures.
Example 2
An oral drug carrier based on a metal organic framework, namely CS & Zr-NDC @5-FU, consists of the metal organic framework which is coated with chitosan and carries the 5-FU.
The preparation method comprises the following steps:
1. preparation of metal organic framework material Zr-NDC: same as example 1 (five)
2. Preparation of Zr-NDC @5-FU
20.0mg of 5-fluorouracil (5-FU) was weighed out and placed in a 100mL round-bottomed flask, and 10mL of ethanol was added thereto to dissolve it for use. Weighing 10.0mg of Zr-NDC in 10mL of ethanol, ultrasonically dispersing, adding the Zr-NDC into a 5-FU ethanol solution to prepare a mixed solution (m drugs: mMOFs is 2:1), ultrasonically dispersing for 20min, placing a flask in a rotary evaporator for evaporation and concentration, adding 10mL of absolute ethanol after the solvent is evaporated to dryness, ultrasonically mixing for 3min, washing off 5-fluorouracil adsorbed on the surface, centrifuging at 12000r/min for 5min, repeating the steps for three times, and drying the obtained solid in a freeze dryer for 24h to obtain the drug-loaded metal organic framework (Zr-NDC @ 5-FU). The combined supernatants were collected and placed in a flask and rotary evaporated to dryness before adding 10mL of water to dissolve for subsequent assay.
3. Preparation of CS & Zr-NDC @5-FU
30mg of chitosan was weighed into a 100mL round-bottomed flask, 10mL of a 0.2% acetic acid aqueous solution was added, and the mixture was stirred overnight. 8.6mL of ethanol was added to 30mg of Zr-NDC @5-FU and dispersed by sonication. Adding the ethanol dispersed solution of Zr-NDC @5-FU into an acetic acid aqueous solution of chitosan, stirring for 30min, centrifuging the product for 5min at a speed of 10000r/min, washing the product with a 1% acetic acid aqueous solution, centrifuging to remove redundant chitosan, then washing the product with 10mL of distilled water, centrifuging, removing an upper solution layer, repeating the steps for three times, and drying the obtained solid in a freeze dryer for 24h to obtain CS & Zr-NDC @ 5-FU.
(II) the result of the detection
1. FIG. 2 is a scanning electron microscope image of Zr-NDC (A) before drug loading, Zr-NDC @5-FU (B) after drug loading, and CS & Zr-NDC @5-FU (C) coated by chitosan, wherein, as can be seen from FIG. 2, the Zr-NDC is in a regular octahedral structure, and the particle size is about 800 nm. The crystal structure of the Zr-NDC @5-FU still has a good regular octahedron structure after the medicine is loaded, and the particle size is not obviously changed, which shows that the medicine loading process has no influence on the crystal structure of the Zr-NDC. The CS & Zr-NDC @5-FU structure after CS wrapping is still kept complete, which shows that the wrapping test of chitosan has no influence on the structure of Zr-NDC.
2. FIG. 3 shows CS, Zr-NDC and chitosan-coated CS&IR spectrum of Zr-NDC (without drug loading). As can be seen in FIG. 3, CS is coated with chitosan&The IR spectrum of the Zr-NDC (without drug loading) shows a characteristic peak (1400 cm)-1、1200cm-1、800cm-1、700cm-1、500cm-1) Also appears the characteristic absorption peak (1600 cm) of chitosan amino denaturation-1) And the chitosan is proved to be successfully coated on the surface of the Zr-NDC.
3. FIG. 4 is a TGA plot of chitosan, Zr-NDC and chitosan coated CS & Zr-NDC (without drug loading). As can be seen from FIG. 4, CS is subjected to weight loss at 250-450 ℃, and the chitosan-coated CS & Zr-NDC (without drug loading) also loses 4.84% of weight in the CS weight loss interval, which indicates that the modification degree of CS is 4.84%.
4. FIG. 5 is an XRD pattern of chitosan, Zr-NDC and chitosan coated CS & Zr-NDC (without drug loading). As can be seen from FIG. 5, the CS diffraction pattern has no characteristic diffraction peak, while the main characteristic diffraction peak of Zr-NDC in the chitosan-coated CS & Zr-NDC (without drug loading) diffraction pattern still exists and the small diffraction peak is covered and disappeared, which indicates that the CS coating is successful and the structure of the Zr-NDC is not changed.
(III) in vitro release test of chitosan-coated drug-loaded metal organic framework CS & Zr-NDC @5-FU
An appropriate amount of Zr-NDC @5-FU and CS & Zr-NDC @5-FU are precisely weighed and respectively placed in a 50mL centrifuge tube filled with 20mL artificial gastric juice and 20mL artificial intestinal juice, and a constant temperature oscillator (120r/min) at 37 ℃. 0.5mL of release medium is taken at each time point of 10min, 20min, 30min, 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 60h and 72h respectively, and fresh release medium solution is supplemented in time.
FIG. 6A is the drug release profile of chitosan coated drug loaded metal organic frameworks CS & Zr-NDC @5-FU in simulated gastric fluid. As can be seen from FIG. 6A, the chitosan-uncoated Zr-NDC @5-FU drug-loaded solution releases nearly 95% of the drug in 2h, the chitosan-coated CS & Zr-NDC @5-FU drug is slowly released, and the cumulative release rate of the drug after 72h is 40%, which indicates that most of the drug is released from the interior due to the Zr-NDC skeleton collapse caused by the erosion action of the acidic environment on the chitosan-uncoated Zr-NDC. The chitosan-coated drug-loaded metal-organic framework CS & Zr-NDC @5-FU has the function of resisting acid erosion due to the influence of the external chitosan coating, so that the Zr-NDC is correspondingly protected, and most of the drug in the Zr-NDC can stay in the Zr-NDC due to the fact that the skeleton is kept complete. The chitosan has the effect of resisting gastric acid and also has the effect of sealing holes, so that the internal medicine cannot flow out.
FIG. 6B is a graph showing drug release of chitosan coated drug loaded metal organic frameworks CS & Zr-NDC @5-FU in artificial intestinal fluid. As can be seen from FIG. 6B, the chitosan-uncoated drug loaded Zr-NDC @5-FU released nearly 95% of the drug in 1h, the chitosan-coated CS & Zr-NDC @5-FU slowly released the drug, and the cumulative release rate of the drug after 72h was 70%. It is demonstrated that most of the drug is released from the inside because the Zr-NDC without coating chitosan is easily attacked by alkaline environment and corresponding pancreatic enzyme, which results in the collapse of the Zr-NDC skeleton. And the medicament in the Zr-NDC can be gradually released into an external medium due to the damage of the chitosan structure under the action of the erosion of external trypsin and pancreatic lipase on the medicament-carrying metal-organic framework CS & Zr-NDC @5-FU wrapping the chitosan.
(IV) rat in vivo pharmacokinetics test 1 of chitosan-coated drug-loaded metal-organic framework CS & Zr-NDC @5-FU, and drawing of blood drug mass concentration-time curve
SD male rats were randomly divided into 3 groups (body weight 200 + -20 g), 6 per group, fasted for 12 h. The first group was administered 5mg/mL 5-fluorouracil (5-FU) solution at a dose of 50mg/kg by gavage; a second group of gavages was given drug-loaded Zr-NDC (calculated as 5-fluorouracil at 50mg/kg) (Zr-NDC @ 5-FU); a third group was gavaged with chitosan-encapsulated drug-loaded Zr-NDC (50 mg/kg calculated as 5-fluorouracil) (CS & Zr-NDC @ 5-FU). After administration, 0.5mL of orbital blood was collected at 0.25, 0.5, 1,2,4, 6, 8, 10, 12, 24, and 48h, placed in a centrifuge tube wetted with sodium citrate aqueous solution, centrifuged at 10000r/min for 5min, and plasma was aspirated to measure the plasma mass concentration and to plot the plasma concentration-time curve, and the results are shown in FIG. 7.
As can be seen from FIG. 7, T of 5-Fluorouracil solution groupmaxAbout 0.5h, CmaxAbout 20. mu.g/mL, T after loading of drug into MOFsmaxAbout 1h, CmaxAbout 12.5 mu g/mL, and T of drug-loaded MOFs after being wrapped by chitosanmaxAbout 4h, CmaxAbout 9. mu.g/mL. The results show that CS&The peak reaching time of the MOF @5-FU group is longer than that of the 5-degree uracil group and the MOF @5-FU group, the peak reaching concentration is low, the blood concentration curve is relatively gentle, and the release of the medicine is delayed, so that the release time of the medicine can be prolonged after the chitosan is coated on the surface of the medicine-carrying MOFs, and the slow release effect is achieved.
(V) calculation of pharmacokinetic parameters of chitosan-coated drug-loaded metal-organic framework CS & Zr-NDC @5-FU
The obtained blood mass concentration result is subjected to fitting analysis by a DAS calculation program, and the result shows that the half-life period of chitosan-coated drug-loaded CS & Zr-NDC @5-FU is 8.643 +/-5.408 h, which is obviously prolonged compared with a drug-loaded Zr-NDC @5-FU group (2.204 +/-0.629 h) and a 5-fluorouracil solution group (1.473 +/-0.449 h); the AUC of the chitosan-coated drug-loaded CS & Zr-NDC @5-FU group is 145.420 +/-26.989 mu g/mL, which is approximately 3 times of that of the 5-fluorouracil solution group (54.564 +/-15.013 mu g/mL) and the drug-loaded Zr-NDC group (55.178 +/-1.297 mu g/mL). The half-life of the drugs in the animal body can be prolonged after the drugs are loaded into the MOFs, the half-life of the drugs is obviously prolonged after the drugs are coated outside the MOFs, and the release of the drugs is further delayed. The three groups of AUC results show that the AUC of the drug-loaded MOFs wrapping the chitosan is approximately 3 times that of the 5-fluorouracil solution group and the drug-loaded MOFs group, and the drug-loaded MOFs can improve the oral bioavailability of the drug after being coated with the chitosan.
Example 3
An oral drug carrier based on a metal organic framework, namely CS & UiO-66@5-FU, consists of a metal organic framework which is coated with chitosan and carries the 5-FU. The preparation method comprises the following steps:
1. preparation of metal organic framework material UiO-66: same as example 1 (a)
2. Preparation of UiO-66@5-FU
20.0mg of 5-fluorouracil (5-FU) was weighed out and placed in a 100mL round-bottomed flask, and 10mL of ethanol was added thereto to dissolve it for use. Weighing 10.0mg of UiO-66 in 10mL of ethanol, ultrasonically dispersing, adding into 5-FU ethanol solution to prepare mixed solution (m drugs: mMOFs is 2:1), ultrasonically dispersing for 20min, placing a flask in a rotary evaporator for evaporation and concentration, adding 10mL of absolute ethanol after the solvent is evaporated to dryness, ultrasonically mixing for 3min, washing off 5-fluorouracil adsorbed on the surface, centrifuging at 12000r/min for 5min, repeating for three times, and drying the obtained precipitate in a freeze dryer for 24h to obtain drug-loaded metal organic framework UiO-66@ 5-FU.
3. Preparation of CS & UiO-66@5-FU
30mg of chitosan was weighed into a 100mL round-bottomed flask, 10mL of a 0.2% acetic acid aqueous solution was added, and the mixture was stirred overnight. 8.6mL of ethanol was added to 30mg of UiO-66@5-FU and dispersed by sonication. Adding the ethanol dispersed solution of UO-66 @5-FU into acetic acid aqueous solution of chitosan, stirring for 30min, centrifuging the product at 10000r/min for 5min, washing with 1% acetic acid aqueous solution, centrifuging to remove excessive chitosan, washing the product with 10mL of distilled water, centrifuging to remove the upper solution layer, repeating for three times, and drying the obtained solid in a freeze dryer for 24h to obtain CS & UO-66 @ 5-FU.
Example 4
Oral drug carrier-CS based on metal organic framework&UiO-66-NH2@5-FU, which is composed of a 5-FU-loaded metal organic framework coated with chitosan. The preparation method comprises the following steps:
1. metal organic framework material UiO-66-NH2The preparation of (1): (ii) same as in example 1
2、UiO-66-NH2Preparation of @5-FU
20.0mg of 5-fluorouracil (5-FU) was weighed out and placed in a 100mL round-bottomed flask, and 10mL of ethanol was added thereto to dissolve it for use. Then 10.0mg of UiO-66-NH is weighed2Adding the mixture into 5-FU B after ultrasonic dispersion in 10mL of ethanolPreparing a mixed solution (m drugs: mMOFs is 2:1) in an alcohol solution, ultrasonically dispersing for 20min, placing a flask in a rotary evaporator for evaporation concentration, adding 10mL of absolute ethyl alcohol after the solvent is evaporated to dryness, ultrasonically mixing for 3min, washing off 5-fluorouracil adsorbed on the surface, centrifuging at 12000r/min for 5min, repeating the steps for three times, drying the obtained precipitate in a freeze dryer for 24h to obtain a drug-loaded metal organic framework UiO-66-NH2@5-FU。
3、CS&UiO-66-NH2Preparation of @5-FU
30mg of chitosan was weighed into a 100mL round-bottomed flask, 10mL of 0.2% acetic acid aqueous solution was added, and the mixture was stirred overnight for use. 8.6mL of ethanol was added to 30mg of UiO-66-NH2In @5-FU, the ultrasonic dispersion is uniform. Mixing UiO-66-NH2Adding ethanol dispersed solution of @5-FU into acetic acid aqueous solution of chitosan, stirring for 30min, centrifuging the product at 10000r/min for 5min, washing with 1% acetic acid aqueous solution, centrifuging to remove excessive chitosan, washing the product with 10mL distilled water, centrifuging to remove the upper solution layer, repeating for three times, drying the obtained solid in a freeze dryer for 24h to obtain CS&UiO-66-NH2@5-FU。
Example 5
An oral drug carrier based on a metal organic framework, namely CS & UiO-66-COOH @5-FU, consists of a metal organic framework which is coated with chitosan and is loaded with 5-FU. The preparation method comprises the following steps:
1. preparation of metal organic framework material UiO-66-COOH: (ii) same as in example 1
2. Preparation of UiO-66-COOH @5-FU
20.0mg of 5-fluorouracil (5-FU) was weighed out and placed in a 100mL round-bottomed flask, and 10mL of ethanol was added thereto to dissolve it for use. Weighing 10.0mg of UiO-66-COOH in 10mL of ethanol, performing ultrasonic dispersion, adding the mixture into a 5-FU ethanol solution to prepare a mixed solution (m drugs: mMOFs is 2:1), performing ultrasonic dispersion for 20min, placing a flask in a rotary evaporator for evaporation and concentration, after the solvent is evaporated to dryness, adding 10mL of absolute ethanol, performing ultrasonic mixing for 3min, washing off 5-fluorouracil adsorbed on the surface, centrifuging at 12000r/min for 5min, repeating the steps for three times, and drying the obtained precipitate in a freeze dryer for 24h to obtain drug-loaded metal organic framework UiO-66-COOH @ 5-FU.
3. Preparation of CS & UiO-66-COOH @5-FU
30mg of chitosan was weighed into a 100mL round-bottomed flask, 10mL of a 0.2% acetic acid aqueous solution was added, and the mixture was stirred overnight. 8.6mL of ethanol is added into 30mg of UiO-66-COOH @5-FU, and the mixture is uniformly dispersed by ultrasonic. Adding the ethanol dispersion solution of UO-66-COOH @5-FU into acetic acid aqueous solution of chitosan, stirring for 30min, centrifuging the product at 10000r/min for 5min, washing with 1% acetic acid aqueous solution, centrifuging to remove excessive chitosan, washing the product with 10mL of distilled water, centrifuging to remove the upper solution layer, repeating for three times, and drying the obtained solid in a freeze dryer for 24h to obtain CS & UO-66-COOH @ 5-FU.
Example 6
An oral drug carrier based on a metal organic framework, namely CS & UiO-67@5-FU, consists of a metal organic framework which is coated with chitosan and carries 5-FU. The preparation method comprises the following steps:
1. preparation of metal organic framework material UiO-67: (ii) same as in example 1
2. Preparation of UiO-67@5-FU
20.0mg of 5-fluorouracil (5-FU) was weighed out and placed in a 100mL round-bottomed flask, and 10mL of ethanol was added thereto to dissolve it for use. Weighing 10.0mg of UiO-67 in 10mL of ethanol, ultrasonically dispersing, adding into 5-FU ethanol solution to prepare mixed solution (m drugs: mMOFs is 2:1), ultrasonically dispersing for 20min, placing a flask in a rotary evaporator for evaporation and concentration, adding 10mL of absolute ethanol after the solvent is evaporated to dryness, ultrasonically mixing for 3min, washing off 5-fluorouracil adsorbed on the surface, centrifuging at 12000r/min for 5min, repeating for three times, and drying the obtained precipitate in a freeze dryer for 24h to obtain drug-loaded metal organic framework UiO-67@ 5-FU.
3. Preparation of CS & UiO-67@5-FU
30mg of chitosan was weighed into a 100mL round-bottomed flask, 10mL of a 0.2% acetic acid aqueous solution was added, and the mixture was stirred overnight. 8.6mL of ethanol was added to 30mg of UiO-67@5-FU and dispersed by sonication. Adding the ethanol dispersed solution of UO-67 @5-FU into acetic acid aqueous solution of chitosan, stirring for 30min, centrifuging the product at 10000r/min for 5min, washing with 1% acetic acid aqueous solution, centrifuging to remove excessive chitosan, washing the product with 10mL of distilled water, centrifuging to remove the upper solution layer, repeating for three times, and drying the obtained solid in a freeze dryer for 24h to obtain CS & UO-67 @ 5-FU.
Claims (5)
1. The oral drug carrier based on the metal organic framework is characterized by consisting of a drug-loaded metal organic framework with chitosan coated on the surface, wherein the metal organic framework is made of Zr-NDC.
2. A preparation method of an oral drug carrier based on a metal organic framework is characterized by comprising the following steps:
1) dissolving 5-fluorouracil 5-FU in ethanol, adding the ethanol solution of 5-FU into ethanol dispersion solution of MOFs (metal organic framework), ultrasonically mixing, rotary evaporating, dissolving in alcohol, centrifuging, washing and drying to obtain medicine-carrying metal organic framework MOFs @ 5-FU; the MOFs of the metal organic framework material is Zr-NDC;
2) mixing the ethanol dispersed solution carrying the medicine metal organic framework MOFs @5-FU with the acetic acid aqueous solution of chitosan CS, stirring, centrifuging, washing and drying to obtain the oral medicine carrier CS & MOFs @5-FU based on the metal organic framework.
3. The method according to claim 2, wherein the method for preparing the MOFs comprises the following steps: sequentially adding ZrCl into a container4The preparation method comprises the following steps of uniformly mixing organic ligand 2, 6-naphthalene diacid, N-dimethylformamide, acetic acid and deionized water, reacting at 100-130 ℃ for 12-36 hours, cooling, centrifuging, washing and drying to obtain a target product.
4. The method according to claim 2, wherein the ratio by mass of 5-FU: the concentration of MOFs = 1-3: 1, 5-FU is 1-3 mg/mL.
5. The method according to claim 2, wherein the ratio by mass of the MOFs @ 5-FU: CS = 3: 1-4, and the concentration of the CS acetic acid aqueous solution is 1-4 mg/mL.
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