CN114588127A - Modified zein nano drug delivery system wrapped by outer membrane vesicles of bacteria and preparation method and application thereof - Google Patents
Modified zein nano drug delivery system wrapped by outer membrane vesicles of bacteria and preparation method and application thereof Download PDFInfo
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- CN114588127A CN114588127A CN202210212624.4A CN202210212624A CN114588127A CN 114588127 A CN114588127 A CN 114588127A CN 202210212624 A CN202210212624 A CN 202210212624A CN 114588127 A CN114588127 A CN 114588127A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5063—Compounds of unknown constitution, e.g. material from plants or animals
- A61K9/5068—Cell membranes or bacterial membranes enclosing drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- 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 invention discloses a modified zein nano drug delivery system wrapped by outer membrane vesicles of bacteria, and a preparation method and application thereof. Dissolving the medicine in absolute ethyl alcohol, adding deionized water after ultrasonic dissolution, adding zein, and performing ultrasonic treatment; quickly adding a sodium caseinate solution into the obtained mixed solution under stirring, and stirring to obtain a modified zein drug-loaded nanoparticle solution; the bacterial outer membrane vesicle and the modified zein drug-loaded nanoparticle solution are uniformly mixed, high-pressure nitrogen is used as an extrusion pressure source, the mixed solution passes through a 200nm polycarbonate membrane and is extruded for 2-8 times, and the obtained product is centrifuged, collected and precipitated to form the modified zein drug-loaded nanoparticle system wrapped by the bacterial outer membrane vesicle. The nano drug delivery system provided by the invention has narrow particle size distribution range and good stability, and can be used for loading a hydrophobic drug capable of being dissolved in ethanol so as to enhance the solubility of the drug in water and improve the stability and bioavailability of the drug.
Description
Technical Field
The invention relates to a bionic natural biological polymer nano-carrier, in particular to a modified zein nano drug delivery system wrapped by outer membrane vesicles of bacteria, and a preparation method and application thereof.
Background
In recent years, there has been a great deal of interest in protein biopolymers for drug delivery systems. The protein has amphipathy, can well interact with the drugs and the solvent, is one of ideal materials for preparing a nano drug-carrying system, and has huge application prospect in the field of biomedicine. Key features that make natural proteins a potentially efficient nanocarrier are their availability of natural resources, inherent biocompatibility, biodegradability, nontoxicity and their biological function. Zein was listed as one of the safest biomaterials excipients by the FDA in 1985, and is widely applied to drug controlled release and biomedical drug delivery systems at present due to its good safety and biocompatibility. The zein drug-loaded nano particles can effectively improve the absorption of drugs after oral administration. The hydrophobic nature of zein makes it a good candidate for encapsulating hydrophobic drugs, which can be encapsulated in nanoparticles through hydrophobic, electrostatic and hydrogen bonding interactions. But the zein drug-loaded nano particles have poor stability and easy aggregation, and have the problem of poor re-dissolubility after drying.
The synthetic nanoparticles have larger difference with human endogenous substances, generally have poor interaction effect among cells, cannot exert the advantages of the synthetic nanoparticles, and even can be regarded as exogenous substances to cause immune response. When the free drug is directly bound to the cell membrane, the toxicity of the drug may affect the cell membrane, resulting in uncontrolled release of the drug. Therefore, cell membranes are often coated on the surface of synthetic nanoparticles. Therefore, the problem of drug toxicity is solved, the physical and chemical properties of the synthetic nanoparticles and the complex biological function of cell membranes are achieved, the immunogenicity of the nanoparticles can be effectively reduced, the targeting property of the drug is improved, and the in-vivo retention time of the drug is prolonged.
Disclosure of Invention
One of the purposes of the invention is to provide a modified zein nano drug delivery system wrapped by bacterial outer membrane vesicles, which has narrow particle size distribution range and good stability, and can be used for embedding hydrophobic drugs capable of being dissolved in ethanol so as to enhance the solubility of the drugs in water and improve the stability and bioavailability of embedded components.
The invention also aims to provide a preparation method of the modified zein nano drug delivery system wrapped by the bacterial outer membrane vesicles.
The technical scheme adopted by the invention is as follows: a preparation method of a modified zein nano drug delivery system wrapped by bacterial outer membrane vesicles comprises the following steps:
1) dissolving the medicine in anhydrous alcohol, performing ultrasonic treatment to completely dissolve the medicine, adding deionized water, adding zein, and performing ultrasonic treatment for 5-15 min; quickly adding the sodium caseinate solution into the mixed solution under stirring, and stirring for 0.5-1.5h to obtain a modified zein drug-loaded nanoparticle solution;
2) uniformly mixing the bacterial outer membrane vesicle with the modified zein drug-loaded nanoparticle solution obtained in the step 1), extruding the obtained mixed solution for 2-8 times through a 200nm polycarbonate membrane by using high-pressure nitrogen as an extrusion pressure source, centrifuging the obtained product for 20min at 6000r/min at 4 ℃, collecting precipitates, and wrapping the precipitates with the bacterial outer membrane vesicle.
Further, in the above preparation method, step 1), the ratio of absolute ethanol to deionized water is 4:1 by volume.
Further, in the preparation method, step 1), the sodium caseinate solution is rapidly added under the stirring speed of 10-20 r/min.
Further, in the above preparation method, in step 1), the ultrasonic frequency is 80 Hz.
Further, in the above preparation method, step 2), the bacterial outer membrane vesicle is an escherichia coli DH5a outer membrane vesicle.
Further, in the preparation method, step 2), the ratio of the bacterial outer membrane capsule to the modified zein drug-loaded nanoparticle solution is 4:1 by volume.
The modified zein nano drug delivery system coated by the bacterial outer membrane vesicles provided by the invention is applied as a drug carrier.
Further, the drug is a hydrophobic drug.
Further, the hydrophobic drug is a hydrophobic drug soluble in ethanol.
Further, the hydrophobic drug is paclitaxel.
The invention has the following beneficial results:
1. the modified zein nano drug delivery system wrapped by the bacterial outer membrane vesicle has good stability and the particle size is about 175 nm.
2. The modified zein nano drug delivery system wrapped by the outer membrane vesicles of the bacteria prepared by the invention is of a smooth spherical structure, the particle size is highly concentrated, and the particle size distribution range is narrow.
3. The modified zein nano drug delivery system coated by the bacterial outer membrane vesicles prepared by the invention can resist the damage of partial gastric acid, so that the drug cannot be leaked early.
4. The modified zein nano drug delivery system wrapped by the bacterial outer membrane vesicles, prepared by the invention, has no burst release phenomenon in artificial intestinal juice and has good slow release characteristics.
5. According to the modified zein nano drug carrying system wrapped by the outer membrane vesicles of the bacteria, the sodium caseinate is sodium salt of casein, and is odorless and tasteless and high in safety. It is a soluble mixture of multiple proteins, contains various hydrophobic groups and hydrophilic groups, and is a natural stabilizer and emulsifier. The sodium caseinate improves the stability and the dispersibility of the zein drug-loaded nanoparticles in water through surface adsorption. In the process of preparing the zein drug-loaded nanoparticles, a proper amount of sodium caseinate is added as a stabilizer, so that the zein drug-loaded nanoparticles are wrapped by the sodium caseinate, the sodium caseinate provides steric hindrance and an electrostatic effect, and the stability and redissolution property of the zein drug-loaded nanoparticles are effectively improved.
Drawings
Fig. 1 is a scanning electron microscope image of a modified zein nano drug delivery system wrapped by bacterial outer membrane vesicles.
Fig. 2 is a graph showing the change of particle size and PDI of the bacterial outer membrane vesicle-encapsulated modified zein nano drug delivery system in PBS buffer for 48 h.
Fig. 3 is a graph of the release rate of the drug encapsulated by the modified zein nano drug loading system encapsulated by the bacterial outer membrane vesicle in artificial gastric juice.
Fig. 4 is a graph of the release rate of the drug encapsulated by the modified zein nano drug loading system encapsulated by the bacterial outer membrane vesicle in the artificial intestinal juice.
Detailed Description
Example 1 modified zein nano drug delivery system coated by bacterial outer membrane vesicles
The preparation method of the modified zein nano drug delivery system coated by the bacterial outer membrane vesicles comprises the following steps:
1. preparation of modified zein drug-loaded nanoparticle solution
Accurately weighing 12.5mg of sodium caseinate by using an analytical balance, dissolving the sodium caseinate in 7mL of deionized water, and completely dissolving the sodium caseinate by ultrasonic treatment to obtain a sodium caseinate solution.
Accurately weighing 3mg paclitaxel by an analytical balance, dissolving in 1.6mL absolute ethanol, performing ultrasonic treatment to completely dissolve the paclitaxel, adding 0.4mL deionized water to make the ethanol concentration reach 80% (volume), adding 10mg zein, and performing ultrasonic treatment at 80Hz frequency for 7min to obtain a mixed solution. And quickly pouring 7mL of sodium caseinate solution into the mixed solution at the rotating speed of 15r/min, stirring for 1h, and volatilizing ethanol to obtain the paclitaxel-loaded modified zein nanoparticle solution modified by the sodium caseinate and marked as Zine-CAS-PTX.
2. Modified zein nano paclitaxel-loaded system for preparing bacterial outer membrane vesicle package
Uniformly mixing the escherichia coli DH5a outer membrane vesicle and the modified zein-loaded paclitaxel nanoparticle solution according to the volume ratio, wherein the bacterial outer membrane vesicle is the modified zein-loaded paclitaxel nanoparticle solution which is 4:1, then using high-pressure nitrogen as an extrusion pressure source, passing the mixed solution through a 200nm polycarbonate membrane, extruding for 6 times, centrifuging the obtained product at 4 ℃ for 20min at 6000r/min, collecting bottom sediment, and obtaining the modified zein-loaded paclitaxel nano system wrapped by the bacterial outer membrane vesicle, wherein the modified zein-loaded paclitaxel nano system is marked as OMVs-NPs.
(III) detection
1. Characterization of OMVs-NPs morphology
The morphology of OMVs-NPs nanoparticles was observed by transmission electron microscopy. And (3) sucking 10 mu L of OMVs-NPs nanoparticle solution by using a pipette gun, dripping the solution on a carbon support membrane, drying the membrane, dyeing the membrane by using a 1% uranyl acetate solution, putting the sample in the air, naturally airing the sample, and observing the sample by using a transmission electron microscope.
As shown in fig. 1, it can be seen that the nanoparticles encapsulated by OMVs have a spherical structure. OMV-NPs have an obvious shell-core structure, and prove that OMVs are successfully coated on the surface of Zein-CAS-PTX nanoparticles.
2. Consideration of OMVs-NPs stability
OMVs-NPs were allowed to stand in a refrigerator at 4 ℃ for 48 hours, and the change in particle size and PDI was measured.
As shown in FIG. 2, the changes in particle size and PDI of OMVs-NPs in PBS buffer were not significant, indicating that the OMVs-NPs had good stability.
3. Examination of in vitro release of OMVs-NPs
Preparing artificial gastric juice and artificial intestinal juice, respectively placing 30mL of the artificial gastric juice and the artificial intestinal juice into 50mL centrifuge tubes, and adding 1% sodium dodecyl sulfate to enable the artificial gastric juice and the artificial intestinal juice to reach a leakage groove condition. 2mL of Zein-CAS-PTX nanoparticle solution and OMV-NPs solution are respectively sucked by a pipette gun and placed in a dialysis bag (molecular weight is 3500Da) which is treated, and then the dialysis bag is placed in a centrifuge tube. Measuring drug release rate by shaking table method under the experimental conditions of 37 deg.C and 120rpm, and sucking release liquid by artificial gastric juice group at 0.5, 1, 1.5, and 2 hr; the artificial intestinal juice group sucks release liquid in 1, 2, 3, 6, 8, 10, 12, 24 and 48 hours. At the same time, the same volume of release medium is replenished after each removal of release solution. Measuring the ultraviolet absorption value of the release liquid, substituting the ultraviolet absorption value into a standard curve to calculate the PTX concentration at different sampling time points, calculating the cumulative drug release percentage according to a cumulative drug release formula, and drawing an in vitro release curve chart.
As shown in figure 3, the cumulative drug release amount of the Zein-CAS-PTX nanoparticles in artificial gastric juice for 2h is 12.58%, and the cumulative drug release amount is lower, which indicates that the Zein-CAS-PTX nanoparticles are less corroded by gastric acid environment. This is because Zein is a hydrophobin that protects the drug from the acidic environment and prevents release of the drug in the stomach. The accumulative release amount of OMVs-NPs in artificial gastric juice for 2h is 8.89%, which is lower than that of Zein-CAS-PTX nano-particles, and shows that OMVs play a role in protection, can resist the damage of partial gastric acid and prevent the medicine from premature leakage.
As shown in figure 4, the Zein-CAS-PTX nano-particle has the cumulative drug release amount of 15.87 percent in the artificial intestinal fluid for 2 hours, and the cumulative drug release amount is higher than that in the artificial gastric fluid, which indicates that the stability of the Zein in the artificial gastric fluid is higher than that of the artificial intestinal fluid. The Zein-CAS-PTX nano-particle is released in the artificial intestinal juice for 48 hours, the cumulative release amount can reach 68.97%, and the sudden release phenomenon does not exist, which indicates that the Zein-CAS-PTX nano-particle has good slow release characteristics. The cumulative release amount of the OMVs-NPs in the artificial intestinal juice for the first 2h is 3.14%, compared with the artificial gastric juice, the OMVs-NPs have better stability, the cumulative release amount of the OMVs-NPs in the artificial intestinal juice for 48h is 35.84%, and the cumulative release amount of the OMVs-NPs is lower than that of the Zein-CAS-PTX nanoparticle group, so that the OMVs are wrapped to increase the slow release effect of the drugs.
Claims (10)
1. A preparation method of a modified zein nano drug carrying system wrapped by bacterial outer membrane vesicles is characterized by comprising the following steps:
1) dissolving the medicine in anhydrous alcohol, performing ultrasonic treatment to completely dissolve the medicine, adding deionized water, adding zein, and performing ultrasonic treatment for 5-15 min; quickly adding the sodium caseinate solution into the mixed solution under stirring, and stirring for 0.5-1.5h to obtain a modified zein drug-loaded nanoparticle solution;
2) uniformly mixing the bacterial outer membrane vesicle with the modified zein drug-loaded nanoparticle solution obtained in the step 1), extruding the obtained mixed solution for 2-8 times through a 200nm polycarbonate membrane by using high-pressure nitrogen as an extrusion pressure source, centrifuging the obtained product for 20min at 6000r/min at 4 ℃, collecting precipitates, and wrapping the precipitates with the bacterial outer membrane vesicle.
2. The preparation method of claim 1, wherein in the step 1), the volume ratio of absolute ethyl alcohol to deionized water is 4: 1.
3. The method according to claim 1, wherein the sodium caseinate solution is added rapidly at a stirring speed of 10-20r/min in step 1).
4. The method according to claim 1, wherein the ultrasonic wave in step 1) has a frequency of 80 Hz.
5. The method according to claim 1, wherein in step 2), the bacterial outer membrane vesicle is an Escherichia coli DH5a outer membrane vesicle.
6. The preparation method according to claim 1, wherein in the step 2), the ratio of the bacterial outer membrane capsule to the modified zein drug-loaded nanoparticle solution is 4:1 by volume.
7. Use of a modified zein nanoparticel system encapsulated by bacterial outer membrane vesicles prepared according to the method of any one of claims 1 to 6 as a drug carrier.
8. The use of claim 7, wherein the drug is a hydrophobic drug.
9. The use of claim 8, wherein the hydrophobic drug is an ethanol soluble hydrophobic drug.
10. The use of claim 9, wherein the hydrophobic drug is paclitaxel.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114983970A (en) * | 2022-07-08 | 2022-09-02 | 辽宁大学 | Biomembrane-coated drug-loaded protein nanoparticle and preparation method thereof |
| CN114983976A (en) * | 2022-06-23 | 2022-09-02 | 浙江工业大学 | Taxol nano preparation and preparation method and application thereof |
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2022
- 2022-03-04 CN CN202210212624.4A patent/CN114588127A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103813786A (en) * | 2011-02-25 | 2014-05-21 | 南达科他州立大学 | Protein nanocarriers for topical delivery |
| CN104225669A (en) * | 2014-08-25 | 2014-12-24 | 华南理工大学 | Bioactive bacterial cellulose-zein composite film and preparation method thereof |
| CN106692978A (en) * | 2016-12-08 | 2017-05-24 | 广东药科大学 | Zein/protein-polysaccharide electrostatic complex core/shell type nanocarrier as well as preparation method and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114983976A (en) * | 2022-06-23 | 2022-09-02 | 浙江工业大学 | Taxol nano preparation and preparation method and application thereof |
| CN114983976B (en) * | 2022-06-23 | 2023-07-25 | 浙江工业大学 | Taxol nano preparation and preparation method and application thereof |
| CN114983970A (en) * | 2022-07-08 | 2022-09-02 | 辽宁大学 | Biomembrane-coated drug-loaded protein nanoparticle and preparation method thereof |
| CN114983970B (en) * | 2022-07-08 | 2024-03-22 | 辽宁大学 | Biological film coated drug-loaded protein nanoparticle and preparation method thereof |
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