CN114404386B - Microelement-loaded yeast micro-nano robot sugar pill - Google Patents
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Abstract
The invention provides a microelement-loaded yeast micro-nano robot sugar pill which is characterized by comprising an external polysaccharide capsid and at least one yeast micro-nano robot, wherein the yeast micro-nano robot consists of a yeast cell, biological enzymes with half surfaces covered on the yeast cell and microelements loaded in the yeast cell. The polysaccharide capsids of the yeast micro-nano robot sugar pills can be degraded in intestinal tracts to release the yeast micro-nano robot loaded with trace elements, and the yeast micro-nano robot can autonomously move by taking glucose in the intestinal tracts as power, so that barriers such as mucous barriers and epithelial barriers can be penetrated to reach intestinal walls, and the absorption of trace elements by organisms is efficiently promoted.
Description
Technical Field
The invention belongs to the technical field of drug carriers, and particularly relates to a yeast micro-nano robot sugar pill loaded with trace elements.
Background
Trace elements have very small proportion in human body, but have very great effect in physiological activities of human body. If trace elements are absent for a long period of time, various diseases can result. Such as iron deficiency anemia, and low immunity caused by iodine deficiency, such as cretinism, local goiter, and selenium deficiency. Too much trace element intake can also cause diseases, so that efficient and accurate trace element intake is very important. Researches show that the inorganic trace elements are directly supplemented, so that the activity is low, the residence time in the body is short, the trace elements supplementing efficiency is low, and the dosage cannot be accurately controlled.
Yeast cells are recognized as safe and edible probiotics that have a highly efficient capacity to immobilize trace elements. However, after the yeast cells rich in microelements are orally taken, the yeast cells need to overcome the emptying movement of the intestinal cavity, the resistance of the intestinal mucus barrier, the intestinal epithelial barrier and the like, and then the yeast cells can enter the intestinal wall, so that the microelements are released and are utilized by a human body. The yeast cannot move, so that the barrier effect is difficult to break through, and the absorption efficiency is limited.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a yeast micro-nano robot sugar pill loaded with trace elements and a preparation method thereof. The polysaccharide capsids of the yeast micro-nano robot sugar pellets can be degraded in intestinal tracts to release a group of yeast micro-nano robots carrying microelements, and the yeast micro-nano robots can automatically perform cluster movement by taking glucose in the decomposed intestinal tracts as power, so that barriers such as mucus barriers and epithelial barriers penetrate through to reach intestinal walls, and the absorption of the microelements by organisms is effectively promoted.
The method is realized by the following technical scheme:
the yeast micro-nano robot sugar pill loaded with trace elements comprises an external polysaccharide capsid and an internal yeast micro-nano robot, wherein the yeast micro-nano robot consists of yeast cells, biological enzymes partially covered on the yeast cells and trace elements loaded in the yeast cells.
Further, the polysaccharide shell comprises one or more of lactose, maltose, sucrose, dextrin, starch, fructose, xylose or microcrystalline cellulose.
Further, the biological enzymes are glucose oxidase and catalase.
Further, the microelements are one or more of calcium, iron, zinc, selenium, copper, molybdenum, chromium, cobalt, iodine, fluorine and manganese.
The invention also provides a preparation method of the yeast micro-nano robot sugar pill loaded with the trace elements, which is characterized by comprising the following steps:
(1) Resuscitating the yeast cells to allow the yeast cells to breathe and produce carbon dioxide within the cells;
(2) Mixing the yeast cells recovered in the step (1) with a trace element salt solution, incubating, and performing biomineralization to obtain trace element-loaded yeast cells;
(3) Mixing the yeast cells carrying the microelements with a masking agent, and then drying, and removing the redundant masking agent after drying to obtain partially masked yeast cells;
(4) Adding an activating agent into the partially masked yeast cells in the step (3) for activation, and removing unreacted activating agent after activation to obtain partially activated yeast cells;
(5) Adding glucose oxidase and catalase into the partially activated yeast cells obtained in the step (4) for reaction, and removing unbound enzyme after the reaction to obtain the trace element-loaded yeast micro-nano robot;
(6) Mixing the polysaccharide with the microelement-loaded yeast micro-nano robot in the step (5), and then preparing sugar pills to obtain microelement-loaded yeast micro-nano robot sugar pills.
Preferably, in the step (3), the mass ratio of the yeast cells carrying trace elements to the masking agent is 1 (0.01-0.25), and in the step (4), the mass ratio of the partially masked yeast cells to the activating agent is 1 (40-80).
Preferably, in step (5), the mass ratio of catalase to glucose oxidase is 1 (2-5). Glucose oxidase takes in-vivo glucose as a substrate, glucose is oxidized into gluconic acid and hydrogen peroxide, hydrogen peroxide is decomposed into water and oxygen by catalase, and the two enzyme reactions are cascade reactions. At this mass ratio, the two enzymes are fully reacted and can provide sufficient power.
Preferably, in the step (6), the mass ratio of the yeast micro-nano robot to the polysaccharide is 1 (50-200).
Preferably, the temperature of the reaction is 4-25 ℃, and the duration of the reaction is 16-24 hours.
The yeast micro-nano robot provided by the invention can be used for preparing medicines for treating diseases caused by trace element deficiency.
The beneficial effects of the invention include the following aspects:
1. the edible fungus yeast cells are used as carriers, so that the edible fungus yeast cells are green and safe, and can be widely eaten and used for medicines;
2. the yeast micro-nano robot can actively move to break through the intestinal barrier, so that the drug administration is more efficient;
3. the yeast micro-nano robot sugar pill gathers a plurality of or single yeast micro-nano robots together, the sugar pill in the intestinal tract is degraded, and the yeast micro-nano robots perform cluster motion, so that the drug administration efficiency is further improved.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are needed in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present application, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic diagram of a yeast micro-nano robot sugar pill loaded with trace elements;
FIG. 2 is a schematic diagram and a physical diagram of a micro-nano yeast robot sugar pill preparation carrying trace elements;
FIG. 3 is a diagram showing the comparison of motion trajectories of unmodified yeast cells and trace element-loaded yeast micro-nano robot sugar pellets prepared by the embodiment of the invention, wherein FIG. 3 (1) is a diagram showing the motion trajectories of unmodified yeast cells, and FIG. 3 (2) is a diagram showing the motion trajectories of trace element-loaded yeast micro-nano robot sugar pellets;
FIG. 4 is a diagram of the trace element-loaded yeast micro-nano robot sugar pill reaching the intestinal tract to be imaged;
FIG. 5 is a graph showing statistics of data in intestinal tracts after oral administration of yeast cells, a single trace element-loaded yeast micro-nano robot and trace element-loaded yeast micro-nano robot sugar pellets, respectively;
fig. 6 is a graph of safety HE of trace element loaded yeast micro-nano robot sugar pellets to the intestinal tract after oral administration.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and fully with reference to the accompanying drawings, in which it is evident that the embodiments described are only some, but not all embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The research shows that the trace elements are adsorbed on the outer surface of the micro-nano robot, and gas is generated through the reaction of enzyme in gastric acid, so that the micro-nano robot is driven to actively move to the stomach, and the absorption efficiency of the trace elements is greatly improved. It was also found that the clustering effect of micro-nano robots is far greater than the individual micro-nano robot effects. If a single micro-nano robot cannot cross an obstacle, a group of micro-nano robots can easily bypass the obstacle, and more interestingly, a half of the robots which can move are mixed with the robots which cannot move, so that all particles can move. Therefore, the administration efficiency can be greatly improved by utilizing the cluster movement phenomenon.
The invention provides a microelement-loaded yeast micro-nano robot sugar pill, which comprises an external polysaccharide capsid and at least one yeast micro-nano robot in the interior, wherein the yeast micro-nano robot consists of a yeast cell, biological enzymes partially covered on the yeast cell and microelements loaded in the yeast cell. The polysaccharide capsids of the yeast micro-nano robot sugar pills can be degraded in intestinal tracts to release the yeast micro-nano robot carrying microelements, and the yeast micro-nano robot can autonomously move by taking glucose in the intestinal tracts as power, so that barriers such as mucus barriers and epithelial barriers can be penetrated to reach intestinal walls, and the absorption of microelements by organisms is efficiently promoted.
In some specific embodiments, the ingredients of the multiple sugar shells can be one or more of lactose, maltose, sucrose, dextrin, starch, fructose, xylose, microcrystalline cellulose. The polysaccharides can be degraded in vivo, so that the yeast micro-nano robot inside the capsid can be released.
Further, the biological enzymes are glucose oxidase and catalase. Glucose oxidase can decompose glucose in intestinal tracts into gluconic acid and hydrogen peroxide, and hydrogen peroxide is further decomposed into water and oxygen by catalase, so that the two enzymes are in cascade reaction, and power is provided for the yeast micro-nano robot, so that the yeast micro-nano robot can move autonomously.
In some specific embodiments, the microelements are one or more of calcium, iron, zinc, selenium, copper, molybdenum, chromium, cobalt, iodine, fluorine and manganese, so that the requirements of organisms on different microelement types can be met.
The invention also provides a preparation method of the yeast micro-nano robot sugar pill loaded with the trace elements, which comprises the following steps:
(1) Mixing the yeast cells with a culture medium, and incubating at 25-37 ℃ for 0.5-1 hour to revive the yeast cells, so that the yeast cells perform respiration and carbon dioxide is generated inside the cells;
(2) Mixing the yeast cells recovered in the step (1) with a trace element salt solution, and incubating for 1-24 hours at 25-37 ℃ to carry out biomineralization to obtain trace element-loaded yeast cells; the mass ratio of the yeast cells to the trace element salt solution is preferably 1 (10-100);
(3) Uniformly mixing the yeast cells carrying the microelements with a masking agent, pouring the mixture into a plate, drying the plate, and then cleaning the plate with ultrapure water for three times to remove the excessive masking agent, thereby obtaining partially masked yeast cells; the mass ratio of the yeast cells carrying microelements to the masking agent is 1: (0.01-0.25).
(4) Adding an activating agent into the partially masked yeast cells in the step (3) for activation, and removing unreacted activating agent after activation to obtain partially activated yeast cells; the activator is preferably a hydroxyl activator; the mass ratio of the yeast cells to the activating agent is 1 (40-80);
(5) Adding glucose oxidase and catalase into the partially activated yeast cells obtained in the step (4), reacting for 16-24 hours at the temperature of 4-25 ℃, and removing unbound enzyme after the reaction to obtain the trace element-carrying yeast micro-nano robot; wherein the mass ratio of the catalase to the glucose oxidase is 1 (2-5).
(6) Mixing polysaccharide with the micro-nano yeast robot carrying the microelements in the step (5), and then preparing sugar pills to obtain micro-nano yeast robot sugar pills carrying the microelements; the mass ratio of the yeast micro-nano robot to the polysaccharide is preferably 1 (50-200).
Examples
The yeast micro-nano robot sugar pill loaded with the trace elements is characterized by comprising an external polysaccharide capsid and at least one yeast micro-nano robot, wherein the yeast micro-nano robot consists of yeast cells, biological enzymes partially covered on the yeast cells and trace elements loaded in the yeast cells.
In some specific embodiments, the ingredients of the multiple sugar shells can be one or more of lactose, maltose, sucrose, dextrin, starch, fructose, xylose, microcrystalline cellulose. The polysaccharides can be degraded in vivo, so that the yeast micro-nano robot inside the capsid can be released.
In some specific embodiments, the microelements are one or more of calcium, iron, zinc, selenium, copper, molybdenum, chromium, cobalt, iodine, fluorine and manganese, so that the requirements of organisms on different microelement types can be met.
A preparation method of yeast micro-nano robot sugar pellets loaded with trace elements comprises the following steps:
(1) Mixing 10mg of yeast cells with 20mg of maltose culture medium, and incubating at 25-37 ℃ for 0.5-1 hour to revive the yeast cells, so that the yeast cells perform respiration and carbon dioxide is generated inside the cells;
(2) Mixing recovered 10mg yeast cells with 100mg zinc chloride solution, incubating for 1-24 hours at 25-37 ℃, and performing biomineralization reaction to obtain trace element-carrying yeast cells;
(3) Uniformly mixing 10mg of yeast cells carrying trace elements with 0.1mg of glycerol, pouring the mixture into a plate, drying, and then washing the plate with ultrapure water for three times to remove the superfluous glycerol, thereby obtaining half-masked yeast cells;
(4) Adding 40mg of carbonyldiimidazole into half-masked yeast cells, and activating at room temperature for 1-2 hours; washing with ultrapure water for three times to remove unreacted carbonyl diimidazole and obtain half-surface activated yeast cells;
(5) Adding 3mg of glucose oxidase and 1mg of catalase into the half-surface activated yeast cells, reacting for 16-24 hours at the temperature of 4-25 ℃, and then washing with ultrapure water for three times to remove unbound enzymes, so as to obtain the trace element-loaded yeast micro-nano robot;
(6) 100mg lactose/maltose (60%/40%) and 1mg yeast micro-nano robot are uniformly mixed, put into a grinding tool, and pressed into sugar pills, thus obtaining the yeast micro-nano robot sugar pills loaded with trace elements.
FIG. 1 is a schematic diagram of a micro-nano yeast robot sugar pill loaded with trace elements, wherein 1 is an external polysaccharide shell, and 2 is an internal micro-nano yeast robot; fig. 2 is a schematic diagram and a physical diagram of preparation of yeast micro-nano robot sugar pellets loaded with trace elements. Wherein A is a yeast cell, B is a mineralized yeast cell, a masking agent C is added to carry out half-face masking, an activating agent R is added to carry out half-face activation, then a biological enzyme D is added to carry out half-face modification on the yeast cell, then the masking agent is dissolved out in the step E, and finally the mixture is mixed with polysaccharide F to prepare the yeast micro-nano robot sugar pill G. And H is a physical diagram of the yeast micro-nano robot sugar pill G.
FIG. 3 shows the trace of movement of unmodified yeast cells and trace element-loaded yeast micro-nano robot sugar pellets prepared in the example of the invention under 10mM glucose concentration, recorded in a microscope for 10 s. FIG. 3 (1) shows unmodified yeast cells, and FIG. 3 (2) shows a yeast micro-nano robot. After 10s, the recorded unmodified yeast cells of FIG. 3 (1) were Brownian in place, and the trace element-loaded yeast robot of FIG. 3 (2) was moved a distance of 30 μm and a movement speed of 3 μm/s. From the results, it can be seen that the yeast micro-nano robot can autonomously move in glucose.
Incubating 10mg of microelement-carrying yeast microcapsule or 10mg of single microelement-carrying yeast micro-nano robot or 10mg of microelement-carrying yeast micro-nano robot sugar pill with 1mg of FITC in DMSO for 2 hours to obtain FITC fluorescence labeled medicine, euthanizing the mice after oral administration of the same dose of 10mg for 2 hours, taking out the frozen sections of the intestinal tracts, and observing the interception quantity of the yeast micro-nano robot in the intestinal tracts. FIG. 4 is a graph of (1) unmodified trace element-carrying yeast microcapsules, with little fluorescence observed, illustrating that very small amounts of trace element-carrying yeast microcapsules are trapped in the intestinal tract; FIG. 2 is a single trace element-carrying yeast micro-nano robot, which has obvious fluorescence, and shows that the yeast micro-nano robot utilizes glucose in intestinal tracts to autonomously move to intestinal epithelium, so that the absorption of trace elements is increased; FIG. 3 shows that the yeast micro-nano robot sugar pill has very strong fluorescence.
Fig. 5 is a data statistics graph of the yeast cells, the single micro-nano robot loaded with trace elements, and the micro-nano robot pellets loaded with trace elements after administration, and as a result, compared with the unmodified yeast cells and the single micro-nano robot, the micro-nano robot pellets loaded with trace elements provided in this embodiment have a very significant increase in the number of the micro-nano robot pellets reaching the intestinal tract. The sugar pill utilizes the cluster effect of the robot, so that the administration efficiency is greatly increased.
Fig. 6 is a graph of the safety HE of the yeast micro-nano robotic sugar pill to the intestinal tract after oral administration. Wherein, fig. 6 (1) is a yeast cell, fig. 6 (2) is a single yeast micro-nano robot, and fig. 6 (3) is a yeast micro-nano robot sugar pill. The intestinal health state in fig. 6 (3) is equivalent to that in fig. 6 (1) and fig. 6 (2), which shows that the microelement-loaded yeast micro-nano robot sugar pill provided by the embodiment is safe and nontoxic, and does not cause damage to the organism.
The yeast micro-nano robot sugar pill loaded with trace elements provided by the invention takes edible fungus yeast cells as a carrier, is green and safe, and can be widely eaten and used for medicines; the yeast micro-nano robot can actively move to break through the intestinal barrier, so that the drug delivery is more efficient; in addition, the yeast micro-nano robot sugar pellets gather single or multiple yeast micro-nano robots together, so that sugar pellets in the intestinal tract are degraded, and the yeast micro-nano robots perform cluster motion, so that the administration efficiency is further improved.
Therefore, the yeast micro-nano robot sugar pill loaded with the trace elements can be used for preparing medicines for treating diseases caused by trace element deficiency, but is not limited to being prepared into sugar pills, and can also be prepared into other forms of medicine preparations such as granules, tablets and the like, so that the yeast micro-nano robot sugar pill is convenient for oral administration.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.
Claims (8)
1. The yeast micro-nano robot sugar pill loaded with the trace elements is characterized by comprising an external polysaccharide capsid and at least one yeast micro-nano robot, wherein the yeast micro-nano robot consists of yeast cells, biological enzymes partially covered on the yeast cells and trace elements loaded in the yeast cells; the biological enzyme is glucose oxidase and catalase;
the preparation method of the yeast micro-nano robot sugar pill loaded with the trace elements comprises the following steps:
(1) Resuscitating the yeast cells to allow the yeast cells to breathe and produce carbon dioxide within the cells;
(2) Mixing the yeast cells recovered in the step (1) with a trace element salt solution, incubating, and performing biomineralization to obtain trace element-loaded yeast cells;
(3) Mixing the yeast cells carrying the microelements with a masking agent, and then drying, and removing the redundant masking agent after drying to obtain partially masked yeast cells;
(4) Adding an activating agent into the partially masked yeast cells in the step (3) for activation, and removing unreacted activating agent after activation to obtain partially activated yeast cells;
(5) Adding glucose oxidase and catalase into the partially activated yeast cells obtained in the step (4) for reaction, and removing unbound enzyme after the reaction to obtain the trace element-loaded yeast micro-nano robot;
(6) Mixing the polysaccharide with the microelement-loaded yeast micro-nano robot in the step (5), and then preparing sugar pills to obtain microelement-loaded yeast micro-nano robot sugar pills.
2. The trace element loaded yeast micro-nano robot sugar pill of claim 1, wherein the polysaccharide shell comprises one or more of lactose, maltose, sucrose, dextrin, starch, fructose, xylose or microcrystalline cellulose.
3. The microelement-loaded yeast micro-nano robot sugar pill of claim 1, wherein the microelement is one or more of calcium, iron, zinc, selenium, copper, molybdenum, chromium, cobalt, iodine, fluorine and manganese.
4. The microelement-loaded yeast micro-nano robot sugar pill according to claim 1, wherein in the step (3), the mass ratio of the microelement-loaded yeast cells to the masking agent is 1 (0.01-0.25).
5. The microelement-loaded yeast micro-nano robot sugar pill of claim 1, wherein in the step (4), the mass ratio of the partially masked yeast cells to the activator is 1 (40-80).
6. The microelement-loaded yeast micro-nano robot sugar pill according to claim 1, wherein in the step (5), the mass ratio of catalase to glucose oxidase is 1 (2-5).
7. The microelement-loaded yeast micro-nano robot sugar pill of claim 1, wherein in the step (6), the mass ratio of the yeast micro-nano robot to the polysaccharide is 1 (50-200).
8. The microelement-loaded yeast micro-nano robot sugar pill according to claim 1, wherein in the step (5), the reaction temperature is 4-25 ℃, and the reaction time is 16-24 hours.
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| CN202111493812.0A CN114404386B (en) | 2021-12-08 | 2021-12-08 | Microelement-loaded yeast micro-nano robot sugar pill |
| PCT/CN2022/137373 WO2023104126A1 (en) | 2021-12-08 | 2022-12-07 | Yeast micro/nanorobot polysaccharide pill loaded with trace elements and preparation method therefor |
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| CN1081075A (en) * | 1993-01-01 | 1994-01-26 | 杭州民生药厂 | Se-yeast sweet pill as one health nutrient food |
| US10190100B1 (en) * | 2015-12-28 | 2019-01-29 | Verily Life Sciences Llc | Chemical modification of glucose oxidase and its application to biosensors |
| EP3663257A1 (en) * | 2018-12-05 | 2020-06-10 | Fundació Institut de Bioenginyeria de Catalunya (IBEC) | Functionalized enzyme-powered nanomotors |
| CN110182750B (en) * | 2019-05-14 | 2022-07-08 | 武汉理工大学 | Urease-driven pot-shaped micro-nano motor and preparation method thereof |
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2021
- 2021-12-08 CN CN202111493812.0A patent/CN114404386B/en active Active
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2022
- 2022-12-07 WO PCT/CN2022/137373 patent/WO2023104126A1/en unknown
Non-Patent Citations (2)
| Title |
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| 新型纳米酶马达的制备及其抗菌性能研究;王唯 等，;《分析化学》;第49卷(第12期);第1995-2004页 * |
| 酶驱动瓶状纳米马达的趋化行为研究;周昶 等，;《中国化学会第十七届全国胶体与界面化学学术会议论文（摘要）集（第二卷）》;第1028-1029页 * |
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| Publication number | Publication date |
|---|---|
| CN114404386A (en) | 2022-04-29 |
| WO2023104126A1 (en) | 2023-06-15 |
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