CN114344484A - Metal organic framework nano particle for oral protein administration and preparation method thereof - Google Patents
Metal organic framework nano particle for oral protein administration and preparation method thereof Download PDFInfo
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- CN114344484A CN114344484A CN202210112750.2A CN202210112750A CN114344484A CN 114344484 A CN114344484 A CN 114344484A CN 202210112750 A CN202210112750 A CN 202210112750A CN 114344484 A CN114344484 A CN 114344484A
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Images
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Gastroenterology & Hepatology (AREA)
- Inorganic Chemistry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a metal organic framework nano particle for oral protein administration and a preparation method thereof, belonging to the technical field of pharmacy. The metal organic framework nano-particle provided by the invention can promote the oral absorption of protein/polypeptide with the molecular weight of 10000 daltons at most. The metal organic framework nano-particle is prepared by loading a nano-scale acid-resistant metal organic framework with a small-molecule protein/polypeptide drug through hydrophobic interaction and modifying a target molecule on the surface. The porous acid-resistant metal organic framework shows high drug-loading capacity for protein, strong protection, and good biocompatibility and slow and controlled release kinetics in vivo. The targeting molecule can target the receptor on the intestinal epithelial cell membrane, overcome the problem of extremely low permeation efficiency of the protein in the intestinal epithelial cell layer, and improve the oral bioavailability of the protein. The preparation method is simple and convenient, has low production cost, and is expected to realize painless, controlled release and convenient protein oral administration.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to a metal organic framework nano particle for oral protein administration and a preparation method thereof.
Background
The polypeptide and protein medicine is polypeptide and protein biological medicine for preventing, treating and diagnosing and has the advantages of high activity, high specificity, low toxicity, clear biological function, etc. The administration route is more critical due to the complex preparation process, low delivery efficiency, poor bioavailability and the like of polypeptide and protein medicines. However, the protein drug membrane has poor permeability and short half-life, and is easy to be damaged in strong acid, strong alkali and environment rich in protease. Thus, subcutaneous injection is the primary mode of administration of proteins. The long-term frequent protein injection can bring considerable pressure and pain to the mind and body of a patient, and the injection part can have serious side effects of skin red and swollen, itching, induration, infection, subcutaneous lipoatrophy, fibrosis hyperplasia and the like. Therefore, development of a non-invasive protein delivery method is urgently required. Among the many non-invasive modes of administration, oral administration is the most widely used mode because of its painlessness and convenience. However, due to the three major physiological barriers present in the gastrointestinal tract: the strong acids and proteases in the stomach, the mucus layer in the intestinal tract and the tightly associated intestinal epithelial cell layer, the oral bioavailability of proteins is extremely low and few pharmaceutical preparations of any protein are approved for oral administration in clinical practice.
In order to overcome the above-mentioned oral absorption barrier of macromolecules and improve the oral bioavailability of proteins, various platforms such as permeation enhancers, enzyme inhibitors, nano-formulations, etc. have been tried to be developed and applied. However, penetration enhancers risk disrupting the tight junctions of the intestinal epithelial cell layer, possibly leading to bacterial infection. Enzyme inhibitors may seriously affect the digestive absorption of proteins and may cause adverse symptoms such as nausea and vomiting. However, most of the nano-preparations (such as liposome, polymer nanoparticle and silica nanoparticle) still have limited capability in practical protein delivery applications, and have the problems of low drug loading, low protein protection efficiency, low intestinal permeability, uncontrollable drug release or complex formulation synthesis strategy, and the like. Therefore, it is important to develop a nano-platform that does not disrupt the intestinal epithelial cell layer tight junctions and enables efficient oral absorption of proteins.
Among the existing numerous nanomaterials, the nanoscale metal-organic framework (nMOF) is a novel porous solid material formed by self-assembly of metal-containing nodes and organic ligands through coordination connection. Has great potential as a drug delivery carrier: (1) the specific surface area is high, the pore size is large, a large amount of drugs or biological molecules can be loaded, and the carrier is an ideal drug transport carrier; (2) ligands and metal sites in the MOFs can be used as reaction sites, modification is easy to carry out, and the MOFs can be connected with different molecules according to requirements to realize different functions, for example, active targeting can be realized by modifying targeting peptides or targeting molecules; (3) the adjustability of the composition and structure of the MOFs is beneficial to controllably synthesizing the MOFs with different compositions, functions and sizes; (4) under different physiological environments, the MOFs can generate reversible coordination between ligands and metal ions, so that the MOFs has controlled release, biodegradability, low toxicity and good biocompatibility. Farha et al (j.am. chem. soc.140,5678-5681(2018)) reported a method of using zirconium-based MOF as an oral carrier for insulin, and in vitro experimental results showed that the method can protect insulin from strong acid and enzymatic environments and control the release of insulin under physiological conditions (phosphate environment). However, this study does not solve the problem of the very low permeation efficiency of proteins in the intestinal epithelial cell layer.
In order to solve the problem that the protein has extremely low permeation efficiency in the intestinal epithelial cell layer, researches for improving the protein delivery efficiency by using permeation enhancers and the like have received great attention. However, penetration enhancers risk disrupting the tight junctions of the intestinal epithelial cell layer, resulting in bacterial infection. Therefore, it is important to achieve efficient protein absorption without disrupting the tight junctions of the intestinal epithelial cell layer. In recent years, some progress has been made in the research of designing macromolecular protein drug carriers using various specific receptors (e.g., transferrin receptor and FcRn receptor) highly expressed on the intestinal epithelial cell membrane. For example, transferrin is widely present in the human body and directs the absorption and transport of iron by binding to transferrin receptors on epithelial cells. Moreover, the study of transferrin/transferrin receptor mediated targeted protein delivery systems has produced exciting results in cancer, central nervous system diseases, and oral administration. It has been reported by Peppas et al that transferrin-insulin conjugates increase the penetration efficiency of insulin across epithelial barriers by receptor-mediated endocytosis (Bioconjugate chem.17,1376-1384 (2006)). Transferrin-conjugated insulin, however, is endocytosed before entering the lysosome, where abundant proteases may disrupt the protein structure, resulting in limited bioavailability. Therefore, the development of functional nanosystems to protect proteins from the harsh gastric environment, while increasing the efficiency of permeation through the intestinal tract and achieving controlled release, is of great importance for oral protein delivery.
Disclosure of Invention
The invention aims to overcome the defects of low oral bioavailability of protein, complex preparation process of a product and the like in the prior art, and provides a metal organic framework nano particle for oral protein administration and a preparation method thereof. The metal organic framework nano-particles for oral protein administration can protect protein from being damaged by gastric acid and digestive enzyme in gastrointestinal tracts, can accelerate the absorption of protein medicines by intestinal epithelial cells under the condition of not damaging the tight connection of intestinal tracts, and can achieve the aim of high-efficiency oral absorption of the protein.
The purpose of the invention is realized by the following technical scheme:
a metal organic framework nanoparticle for oral protein administration is a metal organic framework nanoparticle loaded with small molecule proteins/polypeptides, and can promote oral absorption of proteins with molecular weight of up to 10000 Dalton. The metal organic framework nano particle mainly comprises a nano acid-resistant metal organic framework, a therapeutic micromolecule protein/polypeptide drug and a targeting molecule, wherein the acid-resistant metal organic framework is a carrier of the micromolecule protein/polypeptide, is loaded with the therapeutic micromolecule protein/polypeptide and is coated with the targeting molecule on the surface. The targeting molecule can target a receptor on an intestinal epithelial cell membrane, so that effective uptake of nanoparticles is realized, and the problem of extremely low permeation efficiency of protein in the intestinal epithelial cell layer is solved. The acid-resistant metal organic framework, the small molecular protein/polypeptide and the targeting molecule are subjected to hydrophobic interaction, so that the acid-resistant metal organic framework encapsulates the small molecular protein/polypeptide, and the targeting molecule is modified on the surface of the acid-resistant metal organic framework to form stable nanoparticles.
The acid-resistant metal organic framework includes but is not limited to UiO-68-NH2、PCN-222、PCN-224。
The small molecular protein/polypeptide is protein/polypeptide with a molecular weight of less than 10000 daltons and a therapeutic effect, and comprises but is not limited to insulin, salmon calcitonin, glucagon, interferon, growth hormone and the like.
The targeting molecule can target receptors on intestinal epithelial cell membranes, so that effective uptake of nanoparticles is realized, and the problem of extremely low permeation efficiency of proteins in the intestinal epithelial cell layers is solved. Including but not limited to transferrin, neonatal Fc receptor protein, cell penetrating peptide, octaarginine, and the like.
The preparation method of the metal organic framework nano-particle for oral protein administration comprises the following steps: adding the micromolecule protein/polypeptide or the solution thereof into the acid-resistant metal organic framework water solution, and continuously stirring to ensure that the acid-resistant metal organic framework is coated with the micromolecule protein/polypeptide; and adding the targeting molecule or the solution thereof, continuously stirring to enable the targeting molecule to be adhered to the acid-resistant metal organic framework, and removing the small molecular protein/polypeptide or the targeting molecule which is not carried or adhered by centrifugation to obtain the metal organic framework nano particle for oral protein administration.
In some embodiments, the above-described method for preparing metal-organic framework nanoparticles for oral protein administration is performed at 4-35 ℃.
In some embodiments, the metal organic framework nanoparticle for oral protein administration comprises an acid-resistant metal organic framework of UiO-68-NH2The small molecular protein/polypeptide is insulin, and the targeting molecule is transferrin. Wherein, UiO-68-NH2The mass ratio of the insulin to the insulin is preferably 1: 1-1: 6, UiO-68-NH2The mass ratio of the transferrin to the transferrin is preferably 1: 0.1-1: 1. The preparation method comprises the following steps:
(a) dissolving insulin powder in dilute hydrochloric acid solution, slowly dropwise adding the insulin hydrochloric acid solution into UiO-68-NH newly synthesized by solvothermal method under the condition of stirring at room temperature2In an aqueous solution and stirring is continued for 0.1 to 12 hours to obtain insulin @ metal organic framework nanoparticles (I @ U).
(b) Subsequently, the transferrin powder is dissolved in the aqueous solution, and the transferrin solution is added to the solution obtained in (b) with stirring at room temperature and stirring is continued for 0.1 to 12 hours to obtain transferrin @ insulin @ metal organic framework nanoparticles (T @ I @ U). The unencapsulated or unattached proteins were removed by centrifugation.
The invention has the following effects and advantages:
(1) the porous acid-resistant metal organic framework shows high drug-loading capacity for protein, strong protection, and good biocompatibility and slow and controlled release kinetics in vivo.
(2) The metal organic framework nano particle for oral protein administration simultaneously overcomes the gastric juice barrier, the enzyme barrier and the intestinal epithelial cell barrier of oral protein, and can greatly improve the oral bioavailability of the protein.
(3) The invention does not need to load enteric-coated materials, has low price, simple synthesis process and easy industrialization, and is expected to realize painless, controlled-release and convenient oral administration of protein.
Drawings
Figure 1 is the protein loading of the metal-organic framework nanoparticles prepared in example 1.
Fig. 2 is a transmission electron microscope image (scale: 100nm) of the metal-organic framework nanoparticles prepared in example 1.
FIG. 3 is the effect of insulin released from equal amounts of free insulin and protein oral nanoparticles on blood glucose in normal rats in example 2.
FIG. 4 is the protein degradation curves of I @ U and T @ I @ U from example 3 after incubation with trypsin in HBSS buffer at 37 ℃ for various time points.
FIG. 5 is the in vitro release kinetics results for I @ U and T @ I @ U of example 4 under different pH, salt conditions.
FIG. 6 is the results of in vitro permeation of free insulin, I @ U and T @ I @ U in different intestinal segments (A. duodenum. B. jejunum. C. ileum) from example 5.
FIG. 7 is the blood glucose level change and serum insulin concentration (C) of diabetic BALB/C mice (A) and SD rats (B) following oral administration of free insulin, I @ U and T @ I @ U in example 6.
Detailed Description
While the preferred embodiments of the present invention are described below, it should be understood that various changes and modifications can be made by one skilled in the art without departing from the principles of the invention, and such changes and modifications are also considered to be within the scope of the invention.
Example 1 preparation and characterization of oral insulin Metal organic framework nanoparticles (T @ I @ U)
Preparation of UiO-68-NH by solvothermal method2: amino-TPDC (10.5mg, 0.031mmol) and ZrOCl2·8H2O (8.3mg, 0.026mmol) was dissolved in 2mL DMF. The mixture was sonicated for 5 minutes until it was clear and transparent. To the mixture was added 40. mu.L of acetic acid, followed by heating at 90 ℃ for 6 hours. The mixture was centrifuged at 11000rpm and washed 3 times with DMF to obtain purified UiO-68-NH2. Centrifugation was continued at 11000rpm for 3 exchanges of DMF to ddH2O。
50-300. mu.L of insulin solution (20mg/mL, pH 2.0, dilute hydrochloric acid as solvent) was added dropwise to 4mL of freshly synthesized UiO-68-NH with stirring at room temperature2(0.25mg/mL) in water, stirring was continued for 12 hours to obtain insulin @ metal organic framework nanoparticles (I @ U). Subsequently, 40 μ L of an aqueous transferrin solution (5mg/mL) was added to the above solution and stirring was continued for 12 hours to obtain transferrin @ insulin @ metal organic framework nanoparticles (T @ I @ U), and the unencapsulated protein was removed by low temperature centrifugation at 11000rpm at 4 ℃. The drug loading of the protein was determined using the BCA method. As shown in figure 1, the metal organic framework greatly improves the drug loading of insulin when the islets of LangerhansWhen the feeding mass ratio of the insulin to the metal organic framework reaches (4: 1), the drug loading of the insulin reaches 33 percent. Thus, I @ U, T @ I @ U, insulin and metal organic frameworks used in the examples which follow, were all 4: 1 in mass ratio.
Subsequently, the particle size and morphology of I @ U and T @ I @ U were examined by transmission electron microscopy, as shown in FIG. 2, with little change in the morphology and particle size of the NPs after loading with insulin. After the transferrin is physically adhered to the surface of I @ U, the shape of the nanoparticle is gradually changed from a regular octahedron to a sphere, and the particle size is increased. The above results indicate that oral insulin metal organic framework nanoparticles were successfully synthesized.
Example 2 insulin Activity assay
To verify that insulin still has comparable biological activity during the preparation and release of the nanoformulations, in this example, I @ U and T @ I @ U, freshly prepared as in example 1, were immersed in 1mL of PBS buffer at 37 ℃ for 24 hours and centrifuged at low temperature and ultra-speed (11000rpm) to obtain a supernatant. The content of released insulin in the supernatant was determined using the BCA kit, and then the released insulin (5IU/kg) and the insulin without drug loading (5IU/kg) were administered to the overnight fasted SD rats, respectively, by subcutaneous injection. The blood glucose concentration of rats was measured at different time points. The results are shown in fig. 3, which shows that the prepared insulin metal-organic framework nano-particles do not damage the biological activity of insulin in the preparation process.
Example 3 study of the protective Properties of T @ I @ U on insulin
In order to determine UiO-68-NH2Whether insulin can be protected from digestive enzymes I @ U and T @ I @ U freshly prepared as in example 1 were incubated in HBSS buffer with trypsin (1mg/mL) at 37 ℃. Aliquots (100. mu.L) were removed at specified time intervals, 200. mu.L of DMSO containing 0.1% trifluoroacetic acid was added to stop the enzymatic reaction, and the concentration of insulin in the solution was determined using an Elisa kit. As shown in FIG. 4, I @ U and T @ I @ U protect insulin well within 2 hours.
EXAMPLE 4 Release kinetics of T @ I @ U in different Release media
I @ U and T @ I @ U were placed in dialysis bags (MWCO ═ 10KDa) and dispersed in ddH at 37 ℃ respectively2O, FaSSGF, FaSSIF (without phosphate) and PBS for 24 hours, 100 μ L of buffer was taken at different time points, and an equal volume of fresh buffer was added to ensure constant volume. The content of insulin in the taken buffer was measured using the BCA kit, and as a result, as shown in FIG. 5, T @ I @ U was hardly released from the simulated gastrointestinal tract solution, whereas insulin was released from UiO-68-NH under PBS conditions2Is released slowly and almost completely within 12 hours. Experimental results show that the prepared T @ I @ U has the characteristic of controlled release.
Example 5 Ex vivo intestinal permeation test
SD rats were fasted overnight and then sacrificed. The duodenum, jejunum and ileum were removed 5cm each and the ends were ligated. Then 200. mu.L of insulin, I @ U and T @ I @ U (10IU/mL) were injected into the intestinal lumen. The intestine was then incubated in 5mL PBS buffer at 37 ℃ with gentle stirring. At different time points, 100. mu.L of buffer was taken and an equal volume of fresh buffer was added to ensure constant volume. The amount of insulin released was quantified using an ELISA kit. The results are shown in FIG. 6, where T @ I @ U significantly increases the permeability of insulin in the intestinal tract via transferrin-mediated transport pathway, enabling oral delivery of insulin.
Example 6 in vivo pharmacodynamic and pharmacokinetic studies of T @ I @ U
Hypoglycemic effects (FIG. 7A, B) and insulin levels in the serum of SD rats (FIG. 7C) were tested after administration of equal amounts of insulin I @ U and T @ I @ U (20IU/kg) to diabetic mice (BALB/C mice) and rats (SD rats) by gavage. As a control group, one group of rats was administered insulin (20IU/kg) by gavage, and the other group was administered insulin (5IU/kg) by subcutaneous injection. Blood samples were collected from the orbital venous plexus and the hypoglycemic effects of the different samples were determined using a glucometer, the results of which are shown in fig. 7. It was shown that T @ I @ U rapidly reduced blood glucose levels to around 30% of the initial level and extended insulin potency to 10 hours, resulting in high oral bioavailability.
Claims (9)
1. A metal-organic framework nanoparticle for oral protein administration, characterized by: mainly comprises a nano-scale acid-resistant metal organic framework, a small molecular protein/polypeptide drug and a targeting molecule; the acid-resistant metal organic framework is loaded with small molecular protein/polypeptide, and the surface of the acid-resistant metal organic framework is coated with targeting molecules.
2. The metal-organic framework nanoparticle for oral protein administration of claim 1, wherein: the acid-resistant metal organic framework includes but is not limited to UiO-68-NH2、PCN-222、PCN-224。
3. The metal-organic framework nanoparticle for oral protein administration of claim 1, wherein: the small molecular protein/polypeptide is protein/polypeptide with molecular weight less than 10000 Dalton and has therapeutic effect, including but not limited to insulin, salmon calcitonin, glucagon, interferon and growth hormone.
4. The metal-organic framework nanoparticle for oral protein administration of claim 1, wherein: the targeting molecule can target receptors on intestinal epithelial cell membranes, including but not limited to transferrin, neonatal Fc receptor protein, cell penetrating peptide, and octaarginine.
5. The metal-organic framework nanoparticle for oral protein administration of claim 1, wherein: the acid-resistant metal organic framework is UiO-68-NH2The small molecular protein/polypeptide is insulin, and the targeting molecule is transferrin.
6. The metal-organic framework nanoparticle for oral protein administration of claim 5, wherein: UiO-68-NH2And the pancreatic isletsThe mass ratio of the element is 1: 1-1: 6, UiO-68-NH2The mass ratio of the transferrin to the transferrin is 1: 0.1-1: 1.
7. A method of preparing metal organic framework nanoparticles for oral protein administration according to any one of claims 1 to 6, characterized in that: the method comprises the following steps: adding the micromolecule protein/polypeptide or the solution thereof into the acid-resistant metal organic framework water solution, and continuously stirring to ensure that the acid-resistant metal organic framework is coated with the micromolecule protein/polypeptide; and adding the targeting molecule or the solution thereof, and continuously stirring to ensure that the targeting molecule is adhered to the acid-resistant metal organic framework to obtain the metal organic framework nano particle for oral protein administration.
8. The method of preparing metal organic framework nanoparticles for oral protein administration of claim 7, wherein: the preparation method is carried out at 4-35 ℃.
9. The method of preparing metal organic framework nanoparticles for oral protein administration of claim 7, wherein: the acid-resistant metal organic framework is UiO-68-NH2When the small molecular protein/polypeptide is insulin and the targeting molecule is transferrin, the preparation method comprises the following steps: dissolving insulin powder in dilute hydrochloric acid solution with pH 2.0, and dropwise adding the insulin hydrochloric acid solution to UiO-68-NH under stirring at room temperature2Adding the mixture into the aqueous solution and continuously stirring for 0.1 to 12 hours; under the condition of stirring at room temperature, adding the transferrin solution and continuously stirring for 0.1-12 hours; the unencapsulated or unattached proteins were removed by centrifugation.
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