CN114129734A - Gallbladder tissue targeted drug-loaded exosome and preparation method and application thereof - Google Patents
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Abstract
The invention belongs to the technical field of biological medicine, and discloses a biliary tissue targeted drug-loading exosome and a preparation method and application thereof, wherein the biliary tissue targeted drug-loading exosome comprises a biliary tissue targeted exosome and a drug loaded in the biliary tissue targeted exosome and used for treating biliary tissue diseases, and the biliary tissue targeted exosome is derived from liver cells; the biliary tissue targeted drug-loaded exosome can be used for preparing a drug for treating biliary tissue. Compared with the prior art, the invention realizes the targeted treatment of the biliary tissue diseases by loading the medicaments for treating the biliary tissue diseases into the biliary tissue targeted exosomes, improves the treatment effect of the biliary tissue diseases and reduces the toxic and side effects of the medicaments.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a targeted drug-loading exosome for biliary tissues, and a preparation method and application thereof.
Background
Biliary tissue disease is a common disease. Such as cholecystitis, cholecystolithiasis, gallbladder polyp, gallbladder cancer, and bile duct cancer. Gallbladder cancer is the most common tumor of biliary system in clinic. Early-stage gallbladder cancer has hidden symptoms, is usually classified in middle and late stages when clinically confirmed, is easy to cause local invasion and distant metastasis, and is the most invasive biliary system tumor. The overall prognosis of gallbladder cancer is poor, and the 5-year survival rate of patients is less than 5%. In recent years, the diagnosis and treatment of the gallbladder cancer is changed from single surgical treatment to a comprehensive diagnosis and treatment mode which is dominated by multidisciplinary cooperation group evaluation and operation combined auxiliary treatment, and the prognosis of a gallbladder cancer patient is effectively improved.
Chemotherapy is widely used in the treatment of a variety of neoplastic diseases as an adjunctive treatment to surgery. The current common chemotherapeutic drugs for gallbladder cancer include cisplatin, gemcitabine, fluorouracil, adriamycin and the like. Most of the traditional chemotherapy schemes are combined chemotherapy mainly by 5-fluorouracil, and the traditional chemotherapy schemes are limited in clinical application because the traditional chemotherapy schemes often cause severe toxic and side effects. Gemcitabine is a chemotherapeutic drug widely used in neoplastic diseases, and the clinical efficacy of gemcitabine in treating advanced gallbladder cancer is gradually recognized, and gemcitabine becomes a first-line drug for patients with advanced gallbladder cancer who lose the chance of surgery. Researches show that gemcitabine of a patient with advanced gallbladder cancer is combined with platinum chemotherapeutic drugs, and the treatment effective rate can reach 17%. However, some patients with gallbladder cancer are not sensitive to chemotherapeutic drugs, and the common side effects include anorexia, nausea, vomiting, diarrhea, impaired liver function, alopecia, bone marrow suppression, and the like.
Therefore, how to specifically deliver the medicine to the biliary tissue, increase the curative effect of the medicine, improve the sensitivity of the patient to the medicine, and reduce the toxic and side effects of the medicine on non-specific tissues is the key to the success of the treatment of the gallbladder cancer and the bile duct cancer.
Therefore, in the process of treating gallbladder and bile duct diseases, the problems that the curative effect of the medicine is reduced and the medicine has toxic and side effects in nonspecific tissues in the treatment process need to be solved urgently.
Therefore, the preparation of a biliary tissue targeted drug-loaded exosome for treating biliary tissue-related diseases is urgently needed.
Disclosure of Invention
The invention aims to solve the defects in the prior art, and provides a biliary tissue targeted drug-loading exosome, and a preparation method and application thereof, so as to solve the problems that the curative effect of a drug is reduced and the drug has toxic and side effects in non-specific tissues in the process of treating biliary tissue diseases by using the drug.
In order to achieve the purpose, the invention is implemented according to the following technical scheme:
the first purpose of the invention is to provide a biliary tissue targeted drug-loading exosome, which comprises a biliary tissue targeted exosome and a drug loaded in the biliary tissue targeted exosome and used for treating biliary tissue diseases, wherein the biliary tissue targeted exosome is derived from hepatocytes.
Further, as a preferred embodiment of the present invention, the liver cells include, but are not limited to, human liver cells, animal liver cells, human liver cancer cells, animal liver cancer cells, and induced pluripotent stem cell-induced liver cells.
Further, as a preferred embodiment of the present invention, the animal liver cell and the animal liver cancer cell include but are not limited to monkey, mouse, rat and hamster; the human liver cells include but are not limited to human liver cells L-02, QSG-7701, HL-7702, WRL-68, human hepatic stellate cells LX-2, human liver immortalized cells THLE-3, human fetal liver cells HL-2 and LC-1; human hepatoma cell lines: HepG2, SMMC-7721, HHCC, PLC/PRF/5, HB611, BEL-7402, BEL-7404, BEL-7405.
Further, as a preferred embodiment of the present invention, the drug for treating biliary tissue diseases includes, but is not limited to, nucleic acid drugs, proteins, antibodies, and small molecule drugs.
Further, as a preferred embodiment of the present invention, the nucleic acid drug includes, but is not limited to, microRNA, siRNA, shRNA, and mRNA.
The second purpose of the invention is to provide a preparation method of the biliary tissue targeted drug-loaded exosome, which comprises the following steps:
1) taking a gallbladder tissue targeting exosome and a medicine for treating the gallbladder tissue diseases in a mass ratio of 1:1, and transferring the gallbladder tissue targeting exosome and the medicine for treating the gallbladder tissue diseases into an electric transfer cup;
2) performing electric conversion on the biliary tissue target exosome and the medicine for treating biliary tissue diseases by using an exponential or square wave through an electric rotating cup by using 50-300V voltage to form an electric conversion product;
3) heating the electrotransformation product in 37 ℃ water bath for 30min, ultracentrifuging at 100000g for 120min, collecting supernatant, and removing free drug to obtain purified biliary tissue targeted drug-loaded exosome.
Further, as a preferred embodiment of the present invention, the specific preparation steps of the biliary tissue targeting exosome are as follows:
1) collecting the hepatic cells, and culturing the hepatic cells by using exosome-free serum and a culture medium to obtain a hepatic cell culture solution;
2) centrifuging the hepatocyte culture solution under 2000g centrifugal force for 10min to obtain supernatant A;
3) centrifuging the supernatant A for 30min under 10000g of centrifugal force to obtain supernatant B, and removing cell debris and precipitates;
4) centrifuging the supernatant B for 2h under the centrifugal force of 100000g, re-suspending and collecting the precipitate by using sterile PBS, and storing at 4 ℃ for a short time to obtain the bile tissue targeted exosome.
The third purpose of the invention is to provide an application of the biliary tissue targeted drug-loaded exosome in preparation of a drug for treating biliary tissue.
Compared with the prior art, the invention has the following beneficial effects:
1. the medicine for treating the diseases of the biliary tissue is loaded into the biliary tissue targeting exosome, the biliary tissue targeting exosome is derived from liver cells, and the problem of the yield of the biliary tissue targeting exosome is solved by using the biliary tissue targeting exosome secreted by the liver cells.
2. The medicine is transported to the gallbladder tissue through the gallbladder tissue targeted medicine-carrying exosome, the gallbladder tissue targeted medicine-carrying exosome can be enriched in the gallbladder tissue without any modification, and targeted medicine-feeding treatment is carried out on the gallbladder tissue, so that the treatment on the gallbladder tissue diseases is more effective, safe and controllable, the treatment effect on the gallbladder tissue diseases is improved, and the toxic and side reaction of the medicine is reduced.
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FIG. 1 is a diagram of the detection of a biliary tissue targeted exosome marker protein secreted by human liver immortalized cell THLE-3 in the preparation method of the biliary tissue targeted drug-loaded exosome of the present invention.
FIG. 2 is a diagram showing the particle size distribution detection of the biliary tissue target exosome secreted by human liver immortalized cell THLE-3 in the preparation method of the biliary tissue target drug-loading exosome of the present invention.
FIG. 3 is a distribution diagram of the bile tissue target exosome secreted by the PKH 67-labeled human liver immortalized cell THLE-3 in different tissues in the bile tissue target drug-loaded exosome of the present invention.
FIG. 4 is an in vitro detection diagram of the antitumor activity of the biliary tissue targeted drug-loaded exosome loaded with cisplatin for treating gallbladder cancer in the biliary tissue targeted drug-loaded exosome of the present invention.
FIG. 5 is an in vivo detection diagram of the antitumor activity of the biliary tissue targeted drug-loaded exosome loaded with cisplatin for treating gallbladder cancer in the biliary tissue targeted drug-loaded exosome of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. The specific embodiments described herein are merely illustrative of the invention and do not limit the invention.
Example 1
Collecting normal human liver immortalized cell THLE-3 (in the embodiment, the normal human liver immortalized cell THLE-3 is taken as an example), culturing the human liver immortalized cell THLE-3 by using exosome-free serum and a DMEM culture medium to obtain a culture solution of the human liver immortalized cell THLE-3, centrifuging the culture solution of the human liver cell THLE-3 for 10min under the centrifugal force of 2000g (g is the gravity acceleration), and taking supernatant A; centrifuging the supernatant A for 30min under 10000g centrifugal force, taking the supernatant B, and removing cell debris and precipitates; centrifuging the supernatant B for 2h under the centrifugal force of 100000g (g is gravity acceleration), re-suspending and collecting the precipitate with sterile PBS, and storing at 4 ℃ for a short period to obtain the bile tissue targeted exosome. The obtained gallbladder tissue targeting exosome surface marker protein and particle size distribution are shown in figure 1 and figure 2. The expression quantity of the exosome secreted by the human hepatocyte THLE-3 is measured, and the concentration of the exosome protein secreted by the human hepatocyte THLE-3 is detected to be 3.63 mug/muL by a BCA method.
Example 2
150 mu g of the exosome secreted by the human hepatocyte THLE-3 prepared in the example 1 and 150 mu g of cisplatin are mixed and transferred into an electric rotor for preparing the target drug-loading exosome of the biliary tissue, and the specification of the electric rotor can be 0.2cm or 0.4 cm. Wherein the selected electrotransfer buffer solution can be PBS, DMEM, Cytomix and Tris-HCl, and is complemented to 150 mu L; adopting exponential wave or square wave, and performing electric conversion on the medicine and the target exosome of the biliary tissue by using a voltage of 50-300V through an electric rotating cup to form an electric conversion product.
In this example, the biliary tissue targeting exosomes and cisplatin in the electroporation cuvette were electroporated with an exponential wave using a voltage of 250V. Meanwhile, the electric rotor can be electrically rotated using voltages of 50V, 100V, 200V and 300V.
And then centrifuging the electrotransformation product for 120min under 100000g of centrifugal force, collecting supernatant, and removing free drugs to obtain the target drug-loaded exosome of the biliary tissue.
Through the above steps, cisplatin was successfully loaded into biliary tissue targeting exosomes. Wherein 150 mug of biliary tissue target exosome and 150 mug of cisplatin are subjected to electrotransformation under the voltage of 250V, and the drug loading can reach 26.5%.
Example 3
Taking an exosome secreted by human hepatocyte THLE-3, staining the exosome with PKH67, and tracing the distribution of the exosome secreted by the human hepatocyte THLE-3 in vivo, wherein the method comprises the following specific steps:
100 mu g of bile tissue targeting exosome secreted by human hepatocyte THLE-3 is taken, incubated with 1 mu L of PKH 674 ℃ overnight in the dark, centrifuged for 2h under 100000g (g is gravity acceleration) of centrifugal force, supernatant is discarded, sterile PBS is used for resuspending THLE-3 cells after being washed twice, the bile tissue targeting exosome is obtained, and the bile tissue targeting exosome is injected into a C57bl/6 mouse through tail vein.
It should be noted that: in this example, male C57bl/6 was a 4-6 week mouse purchased from beijing waukang biotechnology limited, all of which were bred in SPF-level facilities; after 24h, anesthetizing the mouse, taking the heart, liver, spleen, lung, kidney, gallbladder, stomach and intestine of the mouse to make frozen sections, staining the cell nucleus by Hoechst33342, and observing the biological distribution of the target exosomes of the gallbladder tissue secreted by the human hepatocyte THLE-3 in each organ of the mouse.
The results show that: referring to fig. 3, the biliary tissue targeting exosome secreted by human hepatocyte THLE-3 is obviously enriched in biliary tissue, and the targeting efficiency of biliary tissue can reach 65% -90%; and enrichment does not occur in other tissues, which indicates that the prepared biliary tissue targeting exosome has the special characteristic of biliary tissue targeting.
Meanwhile, in the embodiment, in vivo and in vitro experiments further verify that the biliary tissue targeting exosome loaded with cisplatin serving as a medicament for treating gallbladder or bile duct cancer can effectively kill gallbladder cancer cells.
In vitro experiments:
referring to FIG. 4, the gallbladder cancer cells GBC-SD were plated in 96-well plates at 5X 10 per well3And respectively adding a biliary tissue targeting exosome (contrast) and a biliary tissue targeting exosome loaded with a biliary tissue tumor treatment medicament cisplatin into each cell, and detecting the killing effect of the biliary tissue targeting exosome loaded with the biliary tissue tumor treatment medicament cisplatin on the gallbladder cancer cells by MTT (methyl thiazolyl tetrazolium).
In vitro experiments, the biliary tissue targeting exosome loaded with the biliary tissue tumor treatment drug can effectively kill tumor cells compared with a pure biliary tissue targeting exosome.
In vivo experiments:
in vivo experiments, a gallbladder cancer model is established, and 4 × 10 is used7A GBC-SD cell was injected subcutaneously into Balb/c nude mice (4-6 weeks) purchased from Beijing Huafukang Biotech, Inc., all grown in SPF-grade facility) and grown to about 100mm3In the course of treatment, the tail vein is injected with biliary tissue target exosome loaded with therapeutic medicine cisplatin for gallbladder cancer, every 3 days, and 4 times of injections are made, then every other day the tumor volume is measured, and its tumor volume is 1/2 × a × b2(ii) a a represents a long diameter, and b represents a short diameter.
In vivo experiments, please refer to fig. 5, the gallbladder tissue targeting exosome (cisplatin-exosome) carrying the gallbladder cancer therapeutic agent cisplatin can significantly reduce the tumor size of the mice compared with the free antitumor drug group (cisplatin) with equal dose.
Meanwhile, the liver cells can also be genetically modified and engineered to target biliary tissue, including but not limited to genetic modification, gene overexpression and deletion, and molecular modification. The biliary tissue targeting exosomes secreted by hepatocytes may also be surface modified and engineered to target biliary tissue, including but not limited to surface protein modifications and surface alterations, and the like.
The invention realizes that the target exosome of the biliary tissue secreted by the hepatocyte can be enriched in the biliary tissue without any modification, and the exosome derived from the hepatocyte solves the problem of the output of the target exosome of the biliary tissue, and has good application prospect of the target of the biliary tissue. Moreover, the target exosome of the biliary tissue from the hepatocyte can be loaded with different drugs and active molecules, and the targeted biliary tissue administration improves the treatment effect of biliary tissue diseases and reduces drug toxic and side effects.
It will be evident to those skilled in the art that the embodiments of the present invention are not limited to the details of the foregoing illustrative embodiments, and that the embodiments of the present invention are capable of being embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the embodiments being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (8)
1. A targeted drug-loaded exosome for biliary tissues is characterized in that: the biliary tissue targeted drug-loading exosome comprises a biliary tissue targeted exosome and a drug loaded in the biliary tissue targeted exosome and used for treating biliary tissue diseases, wherein the biliary tissue targeted exosome is derived from liver cells.
2. The biliary tissue-targeted drug-loaded exosome of claim 1, wherein: the liver cells include, but are not limited to, human liver cells, animal liver cells, human liver cancer cells, animal liver cancer cells, and induced pluripotent stem cell-induced liver cells.
3. The biliary tissue-targeted drug-loaded exosome of claim 2, wherein: animals in the animal liver cells and animal liver cancer cells include but are not limited to monkeys, mice, rats, and hamsters; the human liver cells include but are not limited to human liver cells L-02, QSG-7701, HL-7702, WRL-68, human hepatic stellate cells LX-2, human liver immortalized cells THLE-3, human fetal liver cells HL-2 and LC-1; human hepatoma cell lines: HepG2, SMMC-7721, HHCC, PLC/PRF/5, HB611, BEL-7402, BEL-7404, BEL-7405.
4. The biliary tissue-targeted drug-loaded exosome according to claim 1, wherein: the drugs for treating biliary tissue diseases include, but are not limited to, nucleic acid drugs, proteins, antibodies, and small molecule chemical drugs.
5. The biliary tissue-targeted drug-loaded exosome according to claim 1, wherein: the nucleic acid drugs include, but are not limited to, microRNA, siRNA, shRNA and mRNA.
6. A method for preparing a biliary tissue targeted drug-loaded exosome according to any one of claims 1 to 5, comprising the steps of:
1) taking a gallbladder tissue targeting exosome and a medicine for treating the gallbladder tissue diseases in a mass ratio of 1:1, and transferring the gallbladder tissue targeting exosome and the medicine for treating the gallbladder tissue diseases into an electric transfer cup;
2) performing electric conversion on the biliary tissue target exosome and the medicine for treating biliary tissue diseases by using an exponential or square wave through an electric rotating cup by using 50-300V voltage to form an electric conversion product;
3) heating the electrotransformation product in 37 ℃ water bath for 30min, ultracentrifuging at 100000g for 120min, collecting supernatant, and removing free drug to obtain purified biliary tissue targeted drug-loaded exosome.
7. The preparation method of the biliary tissue targeted drug-loaded exosome according to claim 6, wherein the specific preparation steps of the biliary tissue targeted exosome are as follows:
1) collecting the hepatic cells, and culturing the hepatic cells by using exosome-free serum and a culture medium to obtain a hepatic cell culture solution;
2) centrifuging the hepatocyte culture solution under 2000g centrifugal force for 10min to obtain supernatant A;
3) centrifuging the supernatant A for 30min under 10000g of centrifugal force to obtain supernatant B, and removing cell debris and precipitates;
4) centrifuging the supernatant B for 2h under the centrifugal force of 100000g, re-suspending and collecting the precipitate by using sterile PBS, and storing at 4 ℃ for a short time to obtain the bile tissue targeted exosome.
8. Use of a biliary tissue targeted drug-loaded exosome according to any one of claims 1-5 in the preparation of a medicament for treating biliary tissue.
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| CN202210707554.XA CN114949234A (en) | 2021-12-01 | 2022-06-21 | Gallbladder-targeted drug-loaded exosome, application thereof and drug for treating gallbladder diseases |
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| CN115088678A (en) * | 2022-07-21 | 2022-09-23 | 吉林大学 | Method for establishing and analyzing subcutaneous tumor formation animal model of gallbladder cancer |
| WO2022268056A1 (en) * | 2021-06-22 | 2022-12-29 | 姜海涛 | Tissue-targeting exosomes and application thereof |
| CN116445404A (en) * | 2022-12-29 | 2023-07-18 | 贵州医科大学 | Preparation method and drug loading method and application of NK cell-derived exosomes |
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| US10493165B2 (en) * | 2015-01-30 | 2019-12-03 | The Johns Hopkins University | Extracellular vesicles for agent delivery |
| CN110152015A (en) * | 2018-02-11 | 2019-08-23 | 上海市第六人民医院东院 | Load human pluripotent stem cells excretion body of anti-tumor drug and preparation method thereof and purposes |
| CN110652492A (en) * | 2019-09-18 | 2020-01-07 | 浙江大学 | Drug-loaded exosome, application thereof and liver disease drug |
| CN113198020A (en) * | 2021-04-29 | 2021-08-03 | 深圳市第二人民医院(深圳市转化医学研究院) | Preparation method and application of exosome drug delivery system targeting osteosarcoma cells |
| CN113398092A (en) * | 2021-06-22 | 2021-09-17 | 姜海涛 | Bladder targeted drug-loaded exosome and application and drug for treating bladder diseases |
| CN113528427A (en) * | 2021-06-22 | 2021-10-22 | 姜海涛 | Colorectal targeted drug-loaded exosome, application thereof and drug for treating colorectal diseases |
| CN113476615A (en) * | 2021-06-22 | 2021-10-08 | 姜海涛 | Lung targeting drug-loaded exosome and application and lung disease treatment drug |
| CN113388571A (en) * | 2021-06-22 | 2021-09-14 | 姜海涛 | Liver targeted drug-loaded exosome and application and drug for treating liver diseases |
| CN113521294A (en) * | 2021-06-22 | 2021-10-22 | 姜海涛 | Stomach targeting drug-loaded exosome and application and drug for treating stomach diseases |
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| WO2022268056A1 (en) * | 2021-06-22 | 2022-12-29 | 姜海涛 | Tissue-targeting exosomes and application thereof |
| CN115088678A (en) * | 2022-07-21 | 2022-09-23 | 吉林大学 | Method for establishing and analyzing subcutaneous tumor formation animal model of gallbladder cancer |
| CN116445404A (en) * | 2022-12-29 | 2023-07-18 | 贵州医科大学 | Preparation method and drug loading method and application of NK cell-derived exosomes |
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