WO2023104027A1 - Yeast immune micro-nano biorobot loaded with blood coagulation drugs, preparation thereof and application thereof - Google Patents
Yeast immune micro-nano biorobot loaded with blood coagulation drugs, preparation thereof and application thereof Download PDFInfo
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- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The present invention provides a yeast immune micro-nano biorobot loaded with blood coagulation drugs, a preparation method therefor and an application thereof. The yeast immune micro-nano biorobot loaded with blood coagulation drugs comprises yeast microcapsules, nanoparticles embedded in the yeast microcapsules and loaded with blood coagulation drugs, and carbonate crystals half grown on the yeast microcapsules. The yeast immune micro-nano biorobot loaded with blood coagulation drugs provided by the present invention can quickly stop bleeding in the deep layer of the wound, and at the same time, on the basis of the autoimmune effect of the yeast microcapsules, can quickly repair the tissue.
Description
本发明属于止血药物技术领域，具体涉及一种载凝血药酵母免疫微纳生物机器人及其制备方法和应用。The invention belongs to the technical field of hemostatic drugs, and in particular relates to a yeast immune micro-nano biological robot loaded with blood coagulation drugs and a preparation method and application thereof.
失血过多是造成50%以上战场死亡、20%医院患者死亡以及30%创伤性死亡的主要原因。目前临床上常用的纤维蛋白胶、明胶海绵、壳聚糖止血粉等止血产品对浅表伤口有较好的止血效果，但对于严重的内脏，如胃、主动脉/静脉破裂等不规则伤口或贯穿型伤口控制效果有限。因其不具有能够主动运动并定向深层组织出血灶的功能，很难快速高效止血。止血后如何防止伤口的感染并促进伤口的快速愈合也面临巨大挑战。Excessive blood loss is the leading cause of more than 50% of battlefield deaths, 20% of hospital patient deaths, and 30% of traumatic deaths. At present, hemostatic products such as fibrin glue, gelatin sponge, and chitosan hemostatic powder commonly used in clinical practice have good hemostatic effect on superficial wounds, but for serious internal organs, such as irregular wounds such as stomach, aortic/vein rupture or Penetrating wound control is limited. Because it does not have the function of actively moving and directing the deep tissue bleeding focus, it is difficult to quickly and efficiently stop bleeding. How to prevent wound infection and promote rapid wound healing after hemostasis is also a huge challenge.
为了克服上述现有技术的缺陷，本发明提出了一种快速伤口止血及修复的载凝血药酵母免疫微纳生物机器人及其制备方法和应用，本发明的载凝血药酵母免疫微纳生物机器人能够对伤口深层进行快速止血，同时，基于酵母微囊自身免疫学效应，能够对组织进行快速修复。In order to overcome the defects of the above-mentioned prior art, the present invention proposes a yeast immune micro-nano biological robot loaded with blood coagulation drug and its preparation method and application for fast wound hemostasis and repair. The yeast immune micro-nano biological robot loaded with blood coagulation drug of the present invention can Rapid hemostasis on the deep layer of the wound, and at the same time, based on the autoimmune effect of yeast microcapsules, it can quickly repair the tissue.
具体通过以下技术方案实现：Specifically, it is realized through the following technical solutions:
一种载凝血药酵母免疫微纳生物机器人，包括酵母微囊、包埋于所述酵母微囊内部的载凝血药物纳米粒以及半边生长于所述酵母微囊的碳酸盐结晶。A yeast immune micro-nano biological robot loaded with blood coagulation medicine, comprising yeast microcapsules, blood coagulation drug nanoparticles embedded in the yeast microcapsules and carbonate crystals grown on half of the yeast microcapsules.
进一步地，所述酵母微囊来源于可食用酵母细胞，所述酵母微囊的成分为β-(1,3)-D-葡聚糖，所述可食用酵母细胞为酿酒酵母、葡萄汁有孢汉逊酵母、季也蒙有孢汉逊酵母、东方伊萨酵母、毕赤克鲁维酵母、膜璞毕赤酵母、美极梅奇酵母、红冬孢酵母或假丝酵母。Further, the yeast microcapsules are derived from edible yeast cells, the components of the yeast microcapsules are β-(1,3)-D-glucan, and the edible yeast cells are Saccharomyces cerevisiae, grape juice Hansenula sporogenes, Hansenula mongolica, Issa orientalis, Kluyveromyces pichia, Pichia pichia, Maggimeki, Rhodosporidium, or Candida.
进一步地，所述载凝血药物纳米粒的纳米粒为带电脂质聚合物纳米粒、脂质体、聚合物纳米粒或白蛋白纳米粒。Further, the nanoparticles loaded with coagulation drug nanoparticles are charged lipopolymer nanoparticles, liposomes, polymer nanoparticles or albumin nanoparticles.
进一步地，所述载凝血药物的纳米粒中的凝血药物为卡巴克洛、曲克芦丁、垂体后叶素、维生素C、糖皮质激素、酚磺乙胺、维生素K、凝血酶、巴曲酶、抗血友病球蛋白、鱼精蛋白、凝胶海绵中的一种或多种。Further, the blood coagulation drugs in the nanoparticles loaded with blood coagulation drugs are carbaclogol, troxerutin, pituitrin, vitamin C, glucocorticoids, phensulfame, vitamin K, thrombin, batroxobin One or more of enzyme, antihemophilic globulin, protamine, gel sponge.
进一步地，所述碳酸盐结晶呈花状，所述碳酸盐结晶成分为碳酸钙、碳酸镁、碳酸锌中的一种或多种。Further, the carbonate crystals are flower-shaped, and the carbonate crystal components are one or more of calcium carbonate, magnesium carbonate, and zinc carbonate.
本发明还提供上述酵母免疫微纳生物机器人的制备方法，包括以下步骤：The present invention also provides a method for preparing the yeast immune micro-nano biological robot, comprising the following steps:
（1）将载凝血药物的纳米粒与酵母微囊恒温共孵育，然后离心、沉淀，得到载凝血药物的酵母微囊；恒温共孵育的时长优选为0.5-24小时；(1) Incubate the nanoparticles loaded with coagulation drugs with yeast microcapsules at constant temperature, then centrifuge and precipitate to obtain yeast microcapsules loaded with coagulation drugs; the duration of co-incubation at constant temperature is preferably 0.5-24 hours;
（2）将载凝血药物的酵母微囊与表面活性剂、金属盐溶解到乙醇水溶液中，然后搅拌；其中，所述金属盐为钙盐、镁盐或锌盐中的一种或多种；优选搅拌0.5-1小时；(2) Dissolving yeast microcapsules loaded with coagulation drugs, surfactants, and metal salts into an aqueous ethanol solution, and then stirring; wherein, the metal salts are one or more of calcium salts, magnesium salts, or zinc salts; Preferably stirring for 0.5-1 hour;
（3）向步骤（2）中缓慢滴加可溶性碳酸盐乙醇水溶液，然后在室温下搅拌后静置，得到酵母免疫微纳生物机器人前驱体；优选在室温下剧烈搅拌1-3小时后静置24-48小时；(3) Slowly add soluble carbonate ethanol aqueous solution dropwise to step (2), then let it stand still after stirring at room temperature to obtain the precursor of yeast immune micro-nano biorobot; preferably vigorously stir at room temperature for 1-3 hours and then stand Set for 24-48 hours;
（4）将步骤（3）所制得的酵母免疫微纳生物机器人前驱体进行洗涤、离心纯化后干燥，所述干燥优选在50-60℃真空干燥48-72小时，得到载凝血药酵母免疫微纳生物机器人。(4) The yeast immune micro-nano biorobot precursor prepared in step (3) is washed, centrifuged and purified, and then dried. The drying is preferably vacuum-dried at 50-60°C for 48-72 hours to obtain the blood coagulation drug-loaded yeast immune Micro-nano bio-robots.
进一步地，所述步骤（2）中的表面活性剂为阳离子表面活性剂 ，阳离子表面活性剂吸附在带负电荷的载凝血药物的酵母微囊表面。载凝血药物的酵母微囊：阳离子表面活性剂：乙醇的质量比为1：（0.05-0.5）：（50-100）。Further, the surfactant in the step (2) is a cationic surfactant, and the cationic surfactant is adsorbed on the surface of the negatively charged yeast microcapsules loaded with coagulation drugs. The mass ratio of yeast microcapsules loaded with coagulation drugs: cationic surfactant: ethanol is 1: (0.05-0.5): (50-100).
所述阳离子表面活性剂优选为烷基三甲基溴化铵、烷基三甲基氯化铵、烷基苄基二甲基氯化铵、二烷基二甲基氯化铵和烷基吡啶氯化物中的一种或多种。The cationic surfactant is preferably alkyltrimethylammonium bromide, alkyltrimethylammonium chloride, alkylbenzyldimethylammonium chloride, dialkyldimethylammonium chloride and alkylpyridine One or more of chlorides.
优选地，步骤（3）中滴加可溶性碳酸盐乙醇水溶液：金属盐的摩尔比为1:1，可以使碳酸根离子与金属离子反应完全。Preferably, in step (3), the molar ratio of soluble carbonate ethanol solution: metal salt is 1:1, which can completely react the carbonate ions and metal ions.
本发明所提供的载凝血药酵母免疫微纳生物机器人，可应用于制备止血治疗药物。尤其是，所述载凝血药酵母免疫微纳生物机器人用于制备止血及免疫感染药物。The yeast immune micro-nano biological robot loaded with blood coagulation drug provided by the present invention can be applied to the preparation of hemostatic treatment drug. In particular, the yeast immune micro-nano biological robot loaded with blood coagulation drug is used to prepare hemostatic and immune infection drugs.
具体的，可将载凝血药酵母免疫微纳生物机器人与质子酸盐混合，用于深型、贯穿型及主动脉或静脉破裂的不规则伤口的快速止血与修复。Specifically, yeast immune micro-nano biorobots loaded with blood coagulation drugs can be mixed with protonic acid salts for rapid hemostasis and repair of deep, penetrating and irregular wounds with ruptured aorta or veins.
进一步地，所述载凝血药酵母免疫微纳生物机器人与所述质子酸的质量比为1:（1-100）。Further, the mass ratio of the yeast immune micro-nano biorobot loaded with blood coagulation drug to the protonic acid is 1:(1-100).
本发明所提供载凝血药酵母免疫微纳生物机器人，可制备口服型止血药，将所述载凝血药酵母免疫微纳生物机器人制成胶囊、片剂、口服液等剂型，用于直接口服，在胃酸的环境下，所述载凝血药酵母免疫微纳生物机器人可自主运动到胃壁，用于胃出血的快速治疗与修复。The yeast immune micro-nano biological robot loaded with blood coagulation drug provided by the present invention can prepare oral hemostatic drug, and the yeast immune micro-nano biological robot loaded with blood coagulation drug is made into capsules, tablets, oral liquid and other dosage forms for direct oral administration. Under the environment of gastric acid, the yeast immune micro-nano biological robot loaded with blood coagulation drug can autonomously move to the stomach wall for rapid treatment and repair of gastric bleeding.
本发明与相比具有如下优点：The present invention has following advantage compared with:
1.以酵母细胞壁为载体制备载凝血药酵母免疫微纳生物机器人，材料来源经济广泛，以可食用酵母为原材料，安全无毒，生物相容性好。1. Yeast immune micro-nano biorobots loaded with coagulation drugs are prepared using yeast cell walls as a carrier. The material sources are economical and extensive. Edible yeast is used as raw materials, which are safe, non-toxic, and have good biocompatibility.
2. 酵母微囊自身具有激活巨噬细胞免疫功能，在快速止血的同时，又能防止伤口感染并促进创伤愈合，具有多功能性。2. Yeast microcapsules can activate the immune function of macrophages. While rapidly stopping bleeding, they can also prevent wound infection and promote wound healing, which is multifunctional.
3.通过凝胶-溶胶原理在酵母微囊表面单轴生长花状碳酸盐结晶，不需要特殊的设备，制备工艺简单，可大量生产，适合大规模制备。3. Uniaxial growth of flower-like carbonate crystals on the surface of yeast microcapsules through the gel-sol principle, no special equipment is required, the preparation process is simple, mass production is possible, and it is suitable for large-scale preparation.
为了更清楚地说明本申请实施例中的技术方案，下面将对实施例描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings that need to be used in the description of the embodiments will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present application. For those skilled in the art, other drawings can also be obtained based on these drawings without creative effort.
图1为载凝血药酵母免疫微纳生物机器人制备示意图；Figure 1 is a schematic diagram of the preparation of yeast immune micro-nano biorobot loaded with blood coagulation drug;
图2为载凝血药物的酵母微囊和载凝血药酵母免疫微纳生物机器人的荧光成像图；Figure 2 is a fluorescence imaging diagram of yeast microcapsules loaded with blood coagulation drugs and yeast immune micro-nano biorobots loaded with blood coagulation drugs;
图3为健康组的胃部组织图以及用本发明提供的载凝血药酵母免疫微纳生物机器人和用非机器人组治疗小鼠胃出血的效果对比图。Fig. 3 is a diagram of the stomach tissue of the healthy group and a comparison diagram of the effect of using the yeast-loaded coagulation drug provided by the present invention to immunize the micro-nano biological robot and using the non-robot group to treat gastric bleeding in mice.
以下所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也视为本发明的保护范围。The following description is a preferred embodiment of the present invention, it should be pointed out that for those skilled in the art, without departing from the principle of the present invention, some improvements and modifications can also be made, and these improvements and modifications are also considered Be the protection scope of the present invention.
本发明提供一种载凝血药酵母免疫微纳生物机器人，其结构包括酵母微囊、包埋于所述酵母微囊内部的载凝血药物的纳米粒以及半边生长于所述酵母微囊的碳酸盐结晶，碳酸盐结晶成分为碳酸钙、碳酸镁、碳酸锌中的一种或多种。The present invention provides a yeast immune micro-nano biological robot loaded with blood coagulation medicine, the structure of which includes yeast microcapsules, nano-particles of blood coagulation medicine embedded in the yeast microcapsules, and half of the carbonic acid that grows in the yeast microcapsules. Salt crystals, the carbonate crystals are composed of one or more of calcium carbonate, magnesium carbonate and zinc carbonate.
所提供的载凝血药酵母免疫微纳生物机器人，通过凝胶-溶胶原理在酵母微囊表面单轴生长花状碳酸盐结晶：首先加入的阳离子表面活性剂吸附于阴离子的酵母微囊表面，构成类似于胶束的凝胶状态，当滴加可溶性碳酸盐的乙醇水溶液后，液滴中的乙醇分子将酵母微囊表面的阳离子表面活性剂溶解，于此同时，液滴中的碳酸根离子立即与该点的金属离子反应生成不溶的碳酸盐晶核，静置后，碳酸盐在晶核处逐渐生长成花状的碳酸盐结晶。盐解碳酸盐结晶在出血灶通过产生二氧化碳气体，自主推进进入出血伤口的深层组织，然后通过释放凝血药达到止血目的。并且基于酵母微囊自身具有激活巨噬细胞免疫功能，在快速止血的同时，又能防止伤口感染并促进创伤愈合。The provided yeast immune micro-nano biological robot loaded with blood coagulation medicine grows flower-like carbonate crystals uniaxially on the surface of yeast microcapsules through the gel-sol principle: firstly, the cationic surfactant added is adsorbed on the surface of anionic yeast microcapsules, It forms a gel state similar to micelles. When the ethanol aqueous solution of soluble carbonate is added dropwise, the ethanol molecules in the droplets dissolve the cationic surfactant on the surface of the yeast microcapsules. At the same time, the carbonate groups in the droplets The ions immediately react with the metal ions at this point to form an insoluble carbonate crystal nucleus. After standing still, the carbonate gradually grows into a flower-shaped carbonate crystal at the crystal nucleus. Salt-dissolved carbonate crystals generate carbon dioxide gas at the hemorrhage lesion, self-propelled into the deep tissue of the bleeding wound, and then achieve the purpose of hemostasis by releasing coagulation drugs. And based on the fact that the yeast microcapsule itself has the function of activating macrophage immunity, it can prevent wound infection and promote wound healing while rapidly hemostasis.
本发明还提供了一种载凝血药酵母免疫微纳生物机器人的制备方法，包括将载凝血药物的纳米粒与酵母微囊恒温共孵育，然后离心、沉淀，得到载凝血药物的酵母微囊；将载凝血药物的酵母微囊与表面活性剂、以及钙盐或镁盐或锌盐溶解到乙醇水溶液中，然后搅拌；接着缓慢加入碳酸钠溶液，然后在室温下搅拌后静置，得到酵母免疫微纳生物机器人前驱体；最后将所制得的酵母免疫微纳生物机器人前驱体进行洗涤、离心纯化后干燥，得到酵母免疫微纳生物机器人。The present invention also provides a method for preparing a yeast immune micro-nano biological robot loaded with blood coagulation drugs, including co-incubating the nanoparticles loaded with blood coagulation drugs and yeast microcapsules at constant temperature, and then centrifuging and precipitating to obtain the yeast microcapsules loaded with blood coagulation drugs; Dissolve the yeast microcapsules loaded with coagulation drugs, surfactants, and calcium salts, magnesium salts, or zinc salts into ethanol aqueous solution, and then stir; then slowly add sodium carbonate solution, and then stand still after stirring at room temperature to obtain yeast immunity Micro-nano bio-robot precursor; finally, the prepared yeast immune micro-nano bio-robot precursor is washed, centrifuged and purified, and then dried to obtain the yeast-immune micro-nano bio-robot.
阳离子表面活性剂包括但不限于烷基三甲基溴化铵、烷基三甲基氯化铵、烷基苄基二甲基氯化铵、二烷基二甲基氯化铵和烷基吡啶氯化物中的一种或多种。Cationic surfactants include, but are not limited to, alkyltrimethylammonium bromide, alkyltrimethylammonium chloride, alkylbenzyldimethylammonium chloride, dialkyldimethylammonium chloride, and alkylpyridine One or more of chlorides.
酵母微囊来源于可食用酵母细胞的细胞壁，酵母微囊的成分为β-(1,3)-D-葡聚糖，在一些具体的实施例中，酵母细胞可以选自酿酒酵母、葡萄汁有孢汉逊酵母、季也蒙有孢汉逊酵母、东方伊萨酵母、毕赤克鲁维酵母、膜璞毕赤酵母、美极梅奇酵母、红冬孢酵母和假丝酵母中的一种或多种。Yeast microcapsules are derived from the cell wall of edible yeast cells, and the composition of yeast microcapsules is β-(1,3)-D-glucan. In some specific embodiments, the yeast cells can be selected from Saccharomyces cerevisiae, grape juice One or more of Hansenula spp., Hansenula spp., Isakula orientalis, Kluyveromyces pichia, Pichia pichia, Maggimeki, Rhodosporidium and Candida Various.
在一些具体的实施例中，纳米粒为带电脂质聚合物纳米粒、脂质体、聚合物纳米粒和白蛋白纳米粒中的一种或多种，纳米粒用于负载上凝血药物。凝血药物可以选自卡巴克洛、曲克芦丁、垂体后叶素、维生素C、糖皮质激素、酚磺乙胺、维生素K、凝血酶、巴曲酶、抗血友病球蛋白、鱼精蛋白、凝胶海绵中的一种或多种。In some specific embodiments, the nanoparticles are one or more of charged lipopolymer nanoparticles, liposomes, polymer nanoparticles and albumin nanoparticles, and the nanoparticles are used to load blood coagulation drugs. Blood coagulation drugs can be selected from carbacl, troxerutin, pituitrin, vitamin C, glucocorticoids, phensulfame, vitamin K, thrombin, batroxobin, antihemophilic globulin, protamine One or more of protein and gel sponge.
本发明提供的载凝血药酵母免疫微纳生物机器人，可应用于制备止血治疗药物。尤其是，所述载凝血药酵母免疫微纳生物机器人用于制备止血及免疫感染药物。具体可将载凝血药酵母免疫微纳生物机器人与质子酸盐混合，用于深型、贯穿型及主动脉/静脉破裂等不规则伤口的快速止血与修复，酵母免疫微纳生物机器人与所述质子酸的质量比例为1:（1-100）。本发明提供的载凝血药酵母免疫微纳生物机器人也可以直接口服，适用于胃出血的快速治疗与修复。The yeast immune micro-nano biological robot loaded with coagulation medicine provided by the present invention can be applied to the preparation of hemostatic treatment medicine. In particular, the yeast immune micro-nano biological robot loaded with blood coagulation drug is used to prepare hemostatic and immune infection drugs. Specifically, yeast immune micro-nano biorobots loaded with coagulation drugs can be mixed with protonic acid salts for rapid hemostasis and repair of irregular wounds such as deep, penetrating, and aortic/venous ruptures. The mass ratio of protonic acid is 1:(1-100). The yeast immune micro-nano biological robot loaded with coagulation medicine provided by the present invention can also be directly taken orally, and is suitable for rapid treatment and repair of gastric bleeding.
下面结合具体实施例进一步说明本发明的有益效果。The beneficial effects of the present invention will be further described below in conjunction with specific examples.
实施例1Example 1
（1）将1mg载凝血酶的纳米粒与10mg酵母微囊混匀，37℃恒温孵育1小时，之后5000rpm/min离心10分钟，超纯水洗涤三次，沉淀即得到载凝血药物的酵母微囊；(1) Mix 1 mg of thrombin-loaded nanoparticles with 10 mg of yeast microcapsules, incubate at 37°C for 1 hour, then centrifuge at 5000 rpm/min for 10 minutes, wash with ultrapure water three times, and precipitate to obtain yeast microcapsules loaded with coagulation drugs ;
（2）将步骤（1）制备的载凝血药物的酵母微囊、36.4mg 十六烷基三甲基溴化铵(CTAB)、111mg氯化钙（CaCl
2）加入到50mL 50%的乙醇水溶液中，剧烈搅拌0.5-1小时；
(2) Add the yeast microcapsules loaded with blood coagulation drugs prepared in step (1), 36.4mg of cetyltrimethylammonium bromide (CTAB), and 111mg of calcium chloride (CaCl 2 ) into 50mL of 50% ethanol aqueous solution , stir vigorously for 0.5-1 hour;
（3）之后在剧烈搅拌的情况下滴加50mL 2.12 mg/mL的碳酸钠/50%乙醇溶液（Na
2CO
3）。混合液室温静置24-48小时，得到酵母免疫微纳生物机器人前驱体；
(3) After that, 50 mL of 2.12 mg/mL sodium carbonate/50% ethanol solution (Na 2 CO 3 ) was added dropwise with vigorous stirring. The mixture was left at room temperature for 24-48 hours to obtain the yeast immune micro-nano biorobot precursor;
（4）将（3）中制得的酵母免疫微纳生物机器人前驱体用硝酸铵/乙醇洗涤三次，以除去CTAB，之后放入50-60℃烘箱中真空干燥24-48小时，得到载凝血药酵母免疫微纳生物机器人。(4) Wash the yeast immune micro-nano biorobot precursor prepared in (3) three times with ammonium nitrate/ethanol to remove CTAB, and then put it in an oven at 50-60°C for 24-48 hours to obtain coagulated blood Medicinal yeast immune micro-nano biological robot.
酵母免疫微纳生物机器人制备示意图可参见图1。图1中，A为酵母微囊，B为载凝血药物的纳米粒，C为内埋有载凝血药物的酵母微囊，D为本发明提供的酵母免疫微纳生物机器人。See Figure 1 for the schematic diagram of yeast immune micro-nano biorobot preparation. In Fig. 1, A is a yeast microcapsule, B is a nanoparticle loaded with a coagulation drug, C is a yeast microcapsule embedded with a coagulation drug, and D is a yeast immune micro-nano biological robot provided by the present invention.
实施例2Example 2
（1）将1mg载卡巴克洛的纳米粒与5mg酵母微囊混匀，37℃恒温孵育124小时，之后5000rpm/min离心10分钟，超纯水洗涤三次，沉淀即为载卡巴克洛的酵母微囊；(1) Mix 1mg of carbaclochlor-loaded nanoparticles with 5mg of yeast microcapsules, incubate at a constant temperature of 37°C for 124 hours, then centrifuge at 5000rpm/min for 10 minutes, wash with ultrapure water three times, and the precipitate is carbaclocol-loaded yeast Microcapsules;
（2）将（1）制备的载凝血药物的酵母微囊、36.4mg 十六烷基三甲基溴化铵(CTAB)、111mg氯化钙（CaCl
2）加入到50mL 70%的乙醇水溶液中，剧烈搅拌0.5-1小时；
(2) Add the yeast microcapsules loaded with coagulation drugs prepared in (1), 36.4mg of cetyltrimethylammonium bromide (CTAB), and 111mg of calcium chloride (CaCl 2 ) into 50mL of 70% ethanol aqueous solution , stirring vigorously for 0.5-1 hour;
（3）之后在剧烈搅拌的情况下滴加50mL 2.12 mg/mL的碳酸钠/70%乙醇溶液（Na
2CO
3），混合液室温静置24-48小时，得到酵母免疫微纳生物机器人前驱体；
(3) Afterwards, 50 mL of 2.12 mg/mL sodium carbonate/70% ethanol solution (Na 2 CO 3 ) was added dropwise under vigorous stirring, and the mixture was allowed to stand at room temperature for 24-48 hours to obtain the yeast immune micro-nano biorobot precursor body;
（4）将（3）中制得的酵母免疫微纳生物机器人前驱体用硝酸铵/乙醇洗涤三次，以除去CTAB，之后放入50-60℃烘箱中真空干燥24-48小时，制得酵母免疫微纳生物机器人。(4) Wash the yeast immune micro-nano biorobot precursor prepared in (3) three times with ammonium nitrate/ethanol to remove CTAB, and then put it in a 50-60°C oven for 24-48 hours to obtain yeast Immune micro-nano bio-robots.
参见图2，对载凝血药物的酵母微囊与酵母免疫微纳生物机器人进行荧光成像。第一排的4张图分别为载药酵母微囊在明场下的荧光成像、载药酵母微囊在钙荧光白下的荧光成像、对载药酵母微囊中的纳米粒进行荧光成像以及第一排前三张图的组合图，第二排的4张图分别为载凝血药酵母免疫微纳机器人在明场下的荧光成像、载药酵母微囊在钙荧光白下的荧光成像、对载药酵母微囊中的纳米粒进行荧光成像以及第二排前三张图的组合图。可见酵母免疫微纳生物机器人成功负载上了纳米粒，且半边有呈花状的碳酸钙结晶。See Figure 2, the fluorescence imaging of yeast microcapsules loaded with coagulation drugs and yeast immune micro-nano biorobots. The four pictures in the first row are fluorescence imaging of drug-loaded yeast microcapsules under bright field, fluorescence imaging of drug-loaded yeast microcapsules under calcium fluorescent white, fluorescence imaging of nanoparticles in drug-loaded yeast microcapsules, and The combination of the first three pictures in the first row, and the four pictures in the second row are the fluorescence imaging of the yeast immune micro-nano robot loaded with blood coagulation drug under bright field, the fluorescence imaging of yeast microcapsules loaded with drug under calcium fluorescent white, Fluorescent imaging of nanoparticles in drug-loaded yeast microcapsules and a combination of the first three images in the second row. It can be seen that the yeast immune micro-nano biological robot is successfully loaded with nanoparticles, and there are flower-shaped calcium carbonate crystals on one side.
实验例Experimental example
将本发明的酵母免疫微纳生物机器人用于治疗小鼠身体内部不同部位的出血，并与不用本发明酵母免疫微纳生物机器人进行修复时间对比，结果见表1。The yeast-immunized micro-nano biorobot of the present invention was used to treat bleeding in different parts of the mouse body, and the repair time was compared with that without the yeast-immunized micro-nano biorobot of the present invention. The results are shown in Table 1.
表1Table 1
由表1可以看出，用本发明提供的酵母免疫微纳生物机器人治疗小鼠身体内部不同部位的出血症状，不论是从止血时间还是伤口修复时间上，表现情况均优于非机器人组。It can be seen from Table 1 that the use of the yeast immune micro-nano biological robot provided by the present invention to treat bleeding symptoms in different parts of the mouse body is better than that of the non-robot group in terms of hemostasis time and wound repair time.
图3为用本发明提供的酵母免疫微纳生物机器人以及用非机器人组（即不使用本发明提供的载凝血药酵母免疫微纳生物机器人，直接使用凝血药物）进行治疗胃出血以及跟健康组相对比的效果图，由图3可以看出，跟健康组对比，用本发明提供的载凝血药酵母免疫微纳生物机器人相比于非机器人组，治疗胃出血的效果更加优异。Figure 3 shows the treatment of gastric bleeding with the yeast immune micro-nano biological robot provided by the present invention and the non-robot group (that is, without using the yeast immune micro-nano biological robot loaded with blood coagulation drug provided by the present invention, directly using the blood coagulation drug) and the healthy group As can be seen from Figure 3, compared with the healthy group, compared with the healthy group, the effect of treating gastric bleeding with the yeast immune micro-nano biological robot loaded with coagulation medicine provided by the present invention is better than that of the non-robot group.
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection of the present invention. within range.
Claims (10)
- 一种载凝血药酵母免疫微纳生物机器人，其特征在于，包括酵母微囊、包埋于所述酵母微囊内部的载凝血药物的纳米粒以及半边生长于所述酵母微囊的碳酸盐结晶。A yeast immune micro-nano biological robot loaded with blood coagulation medicine, characterized in that it includes yeast microcapsules, nanoparticles containing blood coagulation medicine embedded in the yeast microcapsules, and half of the carbonate grown in the yeast microcapsules crystallization.
- 根据权利要求1所述的载凝血药酵母免疫微纳生物机器人，其特征在于，所述酵母微囊来源于可食用酵母细胞，所述酵母微囊的成分为β-(1,3)-D-葡聚糖，所述可食用酵母细胞为酿酒酵母、葡萄汁有孢汉逊酵母、季也蒙有孢汉逊酵母、东方伊萨酵母、毕赤克鲁维酵母、膜璞毕赤酵母、美极梅奇酵母、红冬孢酵母或假丝酵母。The yeast immune micro-nano biological robot loaded with blood coagulation medicine according to claim 1, wherein the yeast microcapsule is derived from edible yeast cells, and the composition of the yeast microcapsule is β-(1,3)-D -Glucan, the edible yeast cells are Saccharomyces cerevisiae, Hansenula vinifera, Hansenula quaterneria, Issaccharomyces orientalis, Kluyveromyces pichia, Pichia pichia, Maggi Metschnifts, Rhodosporidium, or Candida.
- 根据权利要求1所述的载凝血药酵母免疫微纳生物机器人，其特征在于，所述纳米粒为带电脂质聚合物纳米粒、脂质体、聚合物纳米粒或白蛋白纳米粒。The yeast immune micro-nano biological robot loaded with coagulation medicine according to claim 1, characterized in that the nanoparticles are charged lipopolymer nanoparticles, liposomes, polymer nanoparticles or albumin nanoparticles.
- 根据权利要求1所述的载凝血药酵母免疫微纳生物机器人，其特征在于，所述载凝血药物的纳米粒中的凝血药物为卡巴克洛、曲克芦丁、垂体后叶素、维生素C、糖皮质激素、酚磺乙胺、维生素K、凝血酶、巴曲酶、抗血友病球蛋白、鱼精蛋白或凝胶海绵中的一种或多种。The yeast immune micro-nano biological robot loaded with blood coagulation drug according to claim 1, characterized in that, the blood coagulation drug in the nanoparticle loaded with blood coagulation drug is carbaclol, troxerutin, pituitrin, vitamin C One or more of , glucocorticoid, ethylamine, vitamin K, thrombin, batroxobin, antihemophilic globulin, protamine or gel sponge.
- 根据权利要求1所述的载凝血药酵母免疫微纳生物机器人，其特征在于，所述碳酸盐结晶成分为碳酸钙、碳酸镁、碳酸锌中的一种或多种。The yeast immune micro-nano biological robot loaded with blood coagulation medicine according to claim 1, characterized in that, the carbonate crystalline component is one or more of calcium carbonate, magnesium carbonate, and zinc carbonate.
- 根据权利要求1-5任一项所述的载凝血药酵母免疫微纳生物机器人的制备方法，其特征在于，包括以下步骤：According to any one of claims 1-5, the preparation method of the yeast immune micro-nano biological robot loaded with blood coagulation drug is characterized in that it comprises the following steps:（1）将载凝血药物的纳米粒与酵母微囊恒温共孵育，然后离心、沉淀，得到载凝血药物的酵母微囊；(1) Incubate the nanoparticles loaded with blood coagulation drugs with yeast microcapsules at constant temperature, then centrifuge and precipitate to obtain yeast microcapsules loaded with blood coagulation drugs;（2）将载凝血药物的酵母微囊与表面活性剂、金属盐溶解到乙醇水溶液中，然后搅拌；其中，所述金属盐为钙盐、镁盐或锌盐中的一种或多种；(2) Dissolving yeast microcapsules loaded with coagulation drugs, surfactants, and metal salts into an aqueous ethanol solution, and then stirring; wherein, the metal salts are one or more of calcium salts, magnesium salts, or zinc salts;（3）向步骤（2）中缓慢滴加可溶性碳酸盐乙醇水溶液，然后在室温下搅拌后静置，得到酵母免疫微纳生物机器人前驱体；(3) Slowly add soluble carbonate ethanol aqueous solution dropwise to step (2), then leave it to stand after stirring at room temperature, to obtain the yeast immune micro-nano biorobot precursor;（4）将步骤（3）所制得的酵母免疫微纳生物机器人前驱体进行洗涤、离心纯化后干燥，得到载凝血药酵母免疫微纳生物机器人。(4) The yeast immune micro-nano biorobot precursor prepared in step (3) is washed, centrifuged and purified, and then dried to obtain the yeast immune micro-nano biorobot loaded with blood coagulation drug.
- 根据权利要求6所述的载凝血药酵母免疫微纳生物机器人的制备方法，其特征在于，步骤（2）中所述表面活性剂为阳离子表面活性剂，阳离子表面活性剂吸附在带负电荷的载凝血药物的酵母微囊表面，载凝血药物的酵母微囊：阳离子表面活性剂：乙醇的质量比为1：（0.05-0.5）：（50-100）。The method for preparing blood coagulation drug-loaded yeast immune micro-nano biological robot according to claim 6, characterized in that the surfactant in step (2) is a cationic surfactant, and the cationic surfactant is adsorbed on the negatively charged On the surface of the yeast microcapsule loaded with blood coagulation drug, the mass ratio of yeast microcapsule loaded with blood coagulation drug: cationic surfactant: ethanol is 1: (0.05-0.5): (50-100).
- 根据权利要求6所述的载凝血药酵母免疫微纳生物机器人的制备方法，其特征在于，步骤（3）中滴加可溶性碳酸盐乙醇水溶液：金属盐的摩尔比为1:1。The preparation method of yeast immune micro-nano biological robot loaded with blood coagulation drug according to claim 6, characterized in that, in step (3), the molar ratio of soluble carbonate ethanol solution: metal salt is 1:1.
- 根据权利要求1-5任一项所述载凝血药酵母免疫微纳生物机器人或根据权利要求6-8任一项所述的制备方法制得的载凝血药酵母免疫微纳生物机器人在制备止血治疗药物中的应用。According to any one of claims 1-5, the yeast immune micro-nano biological robot loaded with blood coagulation drug or the yeast immune micro-nano biological robot loaded with blood coagulation drug prepared according to the preparation method described in any one of claims 6-8 is prepared to stop bleeding application in therapeutic drugs.
- 根据权利要求9所述的应用，其特征在于，所述载凝血药酵母免疫微纳生物机器人用于制备止血及免疫感染药物。The application according to claim 9, characterized in that the yeast immune micro-nano biological robot loaded with blood coagulation drug is used to prepare hemostatic and immune infection drugs.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101001615A (en) * | 2004-06-16 | 2007-07-18 | 加里·R·奥斯特罗夫 | Drug delivery product and methods |
| WO2007109564A2 (en) * | 2006-03-17 | 2007-09-27 | University Of Massachusetts | Yeast cell particles as oral delivery vehicles for antigens |
| CN103120795A (en) * | 2011-10-27 | 2013-05-29 | 四川大学 | Preparation targeting macrophages |
| CN105168180A (en) * | 2015-09-30 | 2015-12-23 | 中国人民解放军第三军医大学 | Oral targeted carrier system based on yeast capsules and preparation method of oral targeted carrier system |
| CN107233298A (en) * | 2016-03-28 | 2017-10-10 | 复旦大学 | A kind of yeast cell wall microparticle formulation of promotion polypeptide drugs oral absorption |
| CN111135339A (en) * | 2020-01-16 | 2020-05-12 | 西南大学 | Preparation method of rapid hemostatic with directional propulsion function based on janus structure |
| US20210059945A1 (en) * | 2019-08-29 | 2021-03-04 | National Tsing Hua University | Oral Drug Delivery System and Method for Fabricating Thereof |
| CN114470228A (en) * | 2021-12-08 | 2022-05-13 | 深圳先进技术研究院 | Coagulation-carrying yeast immune micro-nano biological robot and preparation and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10864168B2 (en) * | 2014-10-29 | 2020-12-15 | The Regents Of The University Of California | Bioactive delivery vehicles |
| CN104910292B (en) * | 2015-05-14 | 2017-06-30 | 中国农业科学院农产品加工研究所 | The method for preparing yeast β D glucans using molecule assembling solubilization technique |
| CN110819614B (en) * | 2019-11-13 | 2023-04-11 | 武汉理工大学 | Method for improving driving force of enzyme-driven micro-nano motor |
| CN113616623A (en) * | 2021-09-10 | 2021-11-09 | 大连理工大学 | Microcapsule oral medicine based on yeast delivery carrier and preparation method and application thereof |
-
2021
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- 2022-12-06 WO PCT/CN2022/136899 patent/WO2023104027A1/en unknown
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101001615A (en) * | 2004-06-16 | 2007-07-18 | 加里·R·奥斯特罗夫 | Drug delivery product and methods |
| WO2007109564A2 (en) * | 2006-03-17 | 2007-09-27 | University Of Massachusetts | Yeast cell particles as oral delivery vehicles for antigens |
| CN103120795A (en) * | 2011-10-27 | 2013-05-29 | 四川大学 | Preparation targeting macrophages |
| CN105168180A (en) * | 2015-09-30 | 2015-12-23 | 中国人民解放军第三军医大学 | Oral targeted carrier system based on yeast capsules and preparation method of oral targeted carrier system |
| CN107233298A (en) * | 2016-03-28 | 2017-10-10 | 复旦大学 | A kind of yeast cell wall microparticle formulation of promotion polypeptide drugs oral absorption |
| US20210059945A1 (en) * | 2019-08-29 | 2021-03-04 | National Tsing Hua University | Oral Drug Delivery System and Method for Fabricating Thereof |
| CN111135339A (en) * | 2020-01-16 | 2020-05-12 | 西南大学 | Preparation method of rapid hemostatic with directional propulsion function based on janus structure |
| CN114470228A (en) * | 2021-12-08 | 2022-05-13 | 深圳先进技术研究院 | Coagulation-carrying yeast immune micro-nano biological robot and preparation and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| YAO ESTABLISHED, JIN TAO, TIAN NINGNING: "Preparation of Inorganic Shell on Yeast Cell Surface", JIANGSU AGRICULTURAL SCIENCES., vol. 43, no. 4, 25 April 2015 (2015-04-25), pages 44 - 46, XP093072256, DOI: 10.15889/j.issn.1002-1302.2015.04.014 * |
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