CN115040492B - Milk exosome nano preparation loaded with metformin, preparation method and application - Google Patents
Milk exosome nano preparation loaded with metformin, preparation method and application Download PDFInfo
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Abstract
The invention discloses a metformin-loaded milk exosome nano-preparation, wherein a milk exosome is used as a carrier to load metformin, and the preparation method of the metformin-loaded milk exosome nano-preparation comprises the following steps: (1) extracting fresh cow milk to obtain milk exosomes; (2) And ultrasonically mixing the milk exosomes with the metformin ice bath, and freezing and centrifuging to prepare the metformin-loaded milk exosomes nano preparation. The invention uses milk exosome as drug delivery carrier of metformin, can potentially enhance the distribution of metformin drug in liver and brain, and improve the efficacy of the drug, thereby improving the treatment effect of metformin in alcoholic liver and brain injury, and the developed milk exosome nano preparation loaded with metformin has low cost, easy acquisition, high biocompatibility and safety, can enhance the bioavailability through transnasal delivery, and has wide application prospect in treating liver oxidation injury and/or brain oxidation injury.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a metformin-loaded milk exosome nano preparation, a preparation method and application thereof.
Background
Excessive drinking and alcoholism can cause damage to multiple organs and systems of the human body, with liver and brain damage being the most serious. Alcoholic liver injury is a chronic liver disease caused by long-term high-volume drinking, usually manifests as fatty liver in the early stage, and further can develop into alcoholic hepatitis, alcoholic liver fibrosis and alcoholic liver cirrhosis, and can induce extensive hepatocyte necrosis and even liver failure when severe alcoholism occurs. Alcohol, which acts as a lipophilic central nervous system inhibitor, also has a strong affinity for the central nervous system and acute overintake can cause irreversible permanent damage to the central nervous system. Alcohol and its metabolite acetaldehyde can pass through blood brain barrier, combine with brain protein to cause nerve cell injury, and directly influence central nervous system and brain normal function. Alcohol exposure also activates the expression of inflammatory factors, affecting the activation of glial cells of the nervous system, leading to abnormal signaling associated with neuroinflammation and causing cellular damage. At present, no effective medicine for treating liver and brain injury caused by alcoholism exists, so that the search for effective treatment means is a current research hot spot.
Metformin is a biguanide compound extracted from goat beans (Galega officinalis l.) and, in addition to being a first-line therapeutic agent for type 2 diabetes, a number of studies have shown that metformin has anti-inflammatory, antitumor and anti-apoptotic effects. For example, metformin can protect the liver in a liver ischemia model through antioxidant and anti-inflammatory effects, alleviate lipopolysaccharide-induced hepatitis by inhibiting the level of inflammatory factors, and can also improve cognitive functions in patients with Alzheimer's disease and Parkinson's disease.
Exosomes are nano-sized extracellular vesicles (30-150 nm in diameter) secreted by cells due to environmental stimuli or self-activation. Exosomes are extremely important medium systems among cells, are rich in proteins, lipids, complex polysaccharides, nucleic acids, cell adhesion molecules and the like, and can realize substance exchange and information communication among cells. In recent years, research on drug carrier delivery systems for exosomes loaded with small molecule chemicals, proteins, peptides, nucleic acid drugs, and the like has been attracting attention. However, the exosomes derived from the cells are low in collection efficiency, high in cost and have a certain toxicity risk. Milk is used as a natural drink for supplementing nutrition in daily life, contains a large number of exosomes, and the double-layer membrane of the milk exosomes can be completely maintained in vitro for a long time, thus being a potential excellent drug carrier.
The Chinese patent document with publication number of CN112791092A discloses a milk exosome-loaded icariin nano-preparation, and the preparation method comprises the following steps: firstly, preparing milk exosome suspension by taking fresh cow milk as a raw material, and then, at room temperature, preparing the suspension by the volume ratio of 1:9 mixing icariin with exosome suspension; the exosome is loaded with icariin nanometer preparation prepared by freeze drying. The exosome-loaded icariin nano preparation has the capability of enhancing osteogenesis repair.
The Chinese patent document with publication number of CN112656836A discloses application of a transdermal peptide modified radix Puerariae exosome nano preparation in preparing an anti-skin aging product.
Disclosure of Invention
The invention provides a metformin-loaded milk exosome nano preparation, wherein the milk exosome is used as a carrier to load the metformin, the brain targeting of the milk exosome can improve the curative effect of the metformin on treating alcoholic hepatic and cerebral injury, and the metformin-loaded milk exosome nano preparation has low cost, easy acquisition and high biocompatibility and safety.
The technical scheme adopted is as follows:
the metformin-loaded milk exosome nano preparation comprises milk exosomes and metformin, wherein the milk exosomes are used as carriers for loading the metformin, and the mass ratio of the milk exosomes to the metformin is 1:1-3.
The milk exosome is stable in property, good in biocompatibility, low in cost and low in toxicity, has brain targeting, and can be used as a drug delivery carrier of the metformin, so that the distribution of the metformin drug in the liver and brain can be potentially enhanced, the efficacy of the drug is improved, and the treatment effect of the metformin in liver and brain injury is improved.
The invention also provides a preparation method of the metformin-loaded milk exosome nano-preparation, which comprises the following steps:
(1) Extracting fresh cow milk to obtain milk exosomes;
(2) And ultrasonically mixing the milk exosomes with the metformin ice bath, and freezing and centrifuging to prepare the metformin-loaded milk exosomes nano preparation.
Preferably, the preparation method of the milk exosome comprises the following steps:
(1) Centrifuging fresh milk at 0-10deg.C to obtain middle layer whey at 2000-3000g for 15-20min;
(2) Uniformly mixing the middle layer whey with sodium citrate solution, centrifuging at 0-10deg.C, and collecting supernatant to obtain defatted whey; centrifuging under 10000-12000g for 60-90min;
(3) Centrifuging 35000-40000g of defatted whey at 0-10deg.C for 60-90min to obtain supernatant, centrifuging 70000-80000g for 60-90min to obtain supernatant, centrifuging 100000-135000g for 120-180min to obtain precipitate to obtain milk exosome.
Further preferably, the preparation method of the milk exosome comprises the following steps:
(1) Centrifuging fresh cow milk at 4deg.C to obtain middle layer whey under the condition of 3000g and 15min;
(2) Uniformly mixing the middle layer whey with an equal volume of 2wt% sodium citrate solution, and centrifuging at 4 ℃ to obtain supernatant to obtain defatted whey; centrifuging at 12000g for 60min;
(3) Centrifuging 35000g of defatted whey at 4deg.C for 60min to obtain supernatant, and centrifuging at 70000g for 60min to obtain supernatant; and centrifuging at 100000g for 60min and 135000g for 120min to obtain milk exosome precipitate.
Preferably, the average particle size of the milk exosomes is 100-200nm. The milk exosome prepared by the method has proper particle size range, and is suitable for loading metformin to prepare a nano preparation for nasal administration.
In the step (2), the milk exosomes and the metformin are mixed in PBS buffer solution according to the mass ratio of 1:1-3 ice bath ultrasonic mixing.
Preferably, in the step (2), the milk exosomes and the metformin are mixed in a PBS buffer solution according to a mass ratio of 1:1, mixing under ice bath at 90-110W power for 5-10 min.
Preferably, in step (2), the mixture is refrigerated and centrifuged at 100000-135000g at 0-10deg.C for 60-180min.
The invention also provides application of the metformin-loaded milk exosome nano-preparation in treating liver oxidative damage and/or brain oxidative damage, in particular application in treating alcoholic liver brain damage.
The administration mode of the milk exosome nano-preparation loaded with the metformin is nasal delivery. Nasal delivery may enhance the bioavailability of the metformin-loaded milk exosome nanoformulation.
In an alcoholic liver and brain injury animal model, the metformin-loaded milk exosome nano preparation is delivered through nose to act on the animal model, and is verified by liver index, glutamic-pyruvic transaminase (ALT), glutamic-oxalacetic transaminase (AST) and Triglyceride (TG) levels in serum to obtain the metformin-loaded milk exosome nano preparation, so that the damage degree of liver cells can be reduced, and meanwhile, the total superoxide dismutase (SOD) and Malondialdehyde (MDA) levels in liver and brain tissues are verified to obtain the metformin-loaded milk exosome nano preparation which has a protective effect on oxidative injury.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention uses milk exosomes as the drug delivery carrier of the metformin, can potentially enhance the distribution of the metformin drug in the liver and brain and improve the efficacy of the drug, thereby improving the treatment effect of the metformin in alcoholic liver and brain injury.
(2) The milk exosome nano preparation loaded with the metformin, which is prepared by the method, has good biocompatibility, low cost, low toxicity and high yield, can be produced in a large scale, can be used for treating liver oxidation injury and/or brain oxidation injury, and has wide application prospect in the aspect of treating alcoholic liver and brain injury.
Drawings
FIG. 1 is a transmission electron microscope image of the metformin-loaded milk exosome nano-preparation prepared in example 2.
Fig. 2 shows the therapeutic results of the metformin-loaded milk exosome nano-preparation prepared in example 2 on a liver and brain injury model after nasal administration, wherein a is a healthy rat control group, B is an alcoholic liver and brain injury rat model group, and C is a metformin milk exosome therapeutic group.
Detailed Description
The invention is further elucidated below in connection with the drawings and the examples. It is to be understood that these examples are for illustration of the invention only and are not intended to limit the scope of the invention.
In the embodiment of the invention, fresh cow milk is sourced from Zhejiang university milk institute in-line test pasture, and metformin is sourced from Shanghai microphone Biochemical technology Co.
Example 1
Extraction of milk exosomes
(1) Taking fresh cow milk, centrifuging at 3000g for 15min at 4 ℃, and taking middle-layer whey;
(2) Uniformly mixing the middle layer whey with an equal volume of 2wt% sodium citrate solution, centrifuging for 60min at 4 ℃ and 12000g, carefully taking the supernatant, and discarding the precipitate to obtain defatted whey;
(3) Centrifuging 35000g of defatted whey at 4deg.C for 60min to obtain supernatant;
(4) Centrifuging 70000g of the supernatant obtained in the step (3) for 60min at 4 ℃, and taking the supernatant again;
(5) Centrifuging the supernatant in the step (4) at 4 ℃ for 60min with 100000g, centrifuging for 120min with 135000g after increasing the speed, discarding the supernatant, and collecting the precipitate to obtain milk exosomes.
The size, structure and morphology of the milk exosomes prepared in this example were observed by transmission electron microscopy, and the results show that the average particle size of the milk exosomes prepared in this example is 100-200nm, and the milk exosomes have a typical cup-shaped structure of exosomes.
Example 2
Synthesis of milk exosome nano-preparation loaded with metformin
In PBS buffer solution, the mass ratio is 1:1 mixing the milk exosomes prepared in example 1 with metformin, using a cytobreaker probe to carry out ultrasonic treatment for 5min under ice bath at 105W power, centrifuging 100000g under ice bath at 4 ℃ for 60min, discarding supernatant, and re-dissolving and precipitating with 1mL PBS buffer solution to obtain the metformin-loaded milk exosomes nano-preparation.
The morphology, size and structure of the metformin-loaded milk exosome nano preparation prepared in the embodiment are observed and analyzed by a transmission electron microscope, and as a result, as shown in fig. 1, cup-shaped vesicles with more particle sizes of about 100nm are visible in the visual field, the boundary is clear, the three-dimensional effect is achieved, and the structure is complete.
Example 3
In PBS buffer solution, the mass ratio is 1:3 mixing the milk exosomes prepared in example 1 with metformin, using a cytobreaker probe to carry out ultrasonic treatment for 5min under ice bath at 110W power, centrifuging 120000g under ice bath at 4 ℃ for 100min, discarding supernatant, and re-dissolving and precipitating with 1mL PBS buffer solution to obtain the metformin-loaded milk exosomes nano-preparation.
Application example 1
The metformin-loaded milk exosome nano-preparation prepared in example 2 was nasally delivered to a rat model for alcoholic hepatic and cerebral injury, after the last administration, blood was taken, left to stand for 30min, centrifuged at 4 ℃ for 10min at 3000rpm, and the upper serum was sucked into a centrifuge tube, and the glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST) and Triglyceride (TG) contents in the serum were measured. Taking isolated liver and brain tissue, weighing, centrifuging at 12000rpm for 30min at 4deg.C after tissue homogenate, collecting supernatant, and determining total superoxide dismutase (SOD) and Malondialdehyde (MDA) content in the tissue homogenate according to the instruction of the kit. The extent of hepatic cell damage was examined by the liver index and ALT, AST and TG levels in serum, and the protective effect against oxidative damage was examined by the levels of SOD and MDA in hepatic brain homogenates. The result proves that the milk exosome nano preparation loaded with the metformin can reduce the damage degree of liver cells and has a protective effect on oxidative damage of liver and brain tissues.
Meanwhile, the treatment result of the metformin-loaded milk exosome nano preparation on the liver and brain injury model is examined through HE staining, the result is shown in figure 2, and the result in the figure shows that the liver tissue arrangement of the healthy rat control group is regular, the rope structure is full and clear, and the structure of liver cells is clear. The liver sinus is not significantly dilated (a in fig. 2, right side is an enlarged view of left side); in contrast, the liver tissue arrangement of the alcoholic hepatic and cerebral injury rat model group is disordered, the strip rope structure is shrunken, fat drop cavities with different sizes are visible in liver cells, and most of the liver cells are in edema (B in fig. 2, the right side is an enlarged view on the left side); the liver tissue of the rat in the metformin milk exosome treatment group is orderly arranged, and the phenomena of the edema of liver cells and the cavitation of fat drop are reduced compared with those of the rat in the model group (C in figure 2, the right side is an enlarged view on the left side), which proves that the dimethyldiguanide-loaded milk exosome nano preparation prepared by the invention has obvious treatment effect on alcoholic hepatic brain injury.
While the foregoing embodiments have been described in detail in connection with the embodiments of the invention, it should be understood that the foregoing embodiments are merely illustrative of the invention and are not intended to limit the invention, and any modifications, additions, substitutions and the like made within the principles of the invention are intended to be included within the scope of the invention.
Claims (3)
1. The metformin-loaded milk exosome nano preparation is characterized by comprising a milk exosome and metformin, wherein the milk exosome is used as a carrier to load the metformin, and the mass ratio of the milk exosome to the metformin is 1:1, a step of; the average grain size of the milk exosomes is 100-200 nm;
the preparation method of the metformin-loaded milk exosome nano-preparation comprises the following steps:
(1) Extracting fresh cow milk to obtain milk exosomes;
(2) Ultrasonically mixing the milk exosomes with metformin ice bath, and freeze-centrifuging to prepare the metformin-loaded milk exosomes nano preparation;
the preparation method of the milk exosome comprises the following steps:
(i) Centrifuging fresh milk at 0-10deg.C to obtain middle layer whey, wherein the centrifugation condition is 2000-3000g, and 15-20min;
(ii) Uniformly mixing the middle layer whey with sodium citrate solution, centrifuging at 0-10deg.C, and collecting supernatant to obtain defatted whey; centrifuging for 60-90min under 10000-12000 g;
(iii) Centrifuging skim whey 35000-40000g at 0-10deg.C for 60-90min to obtain supernatant, centrifuging 70000-80000g for 60-90min to obtain supernatant, centrifuging 100000-135000g for 120-180min to obtain precipitate to obtain milk exosome;
in the step (2), the milk exosomes and the metformin are mixed in PBS buffer solution according to the mass ratio of 1:1, mixing under ice bath under power of 90-110W for 5-10 min;
in the step (2), the mixture is refrigerated and centrifuged at 0-10 ℃ for 100000-135000g and 60-180 min;
the administration mode of the milk exosome nano-preparation loaded with the metformin is nasal delivery.
2. Use of a metformin-loaded milk exosome nano-formulation according to claim 1 in the preparation of a medicament for treating liver oxidative damage and/or brain oxidative damage.
3. Use of the metformin-loaded milk exosome nano-preparation according to claim 1 in the preparation of a medicament for treating alcoholic hepatic brain injury.
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