CN111481680A - Adhesive microcarrier imitating boston ivy and preparation method thereof - Google Patents
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
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- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
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Abstract
The invention relates to a parthenocissus tricuspidata adhesion-imitating microcarrier and a preparation method thereof. The microcarrier has bionic macroscopic morphology, increases the contact area and is beneficial to enhancing the adhesion effect, and the porous microscopic morphology provides a large area for fixing the drug and provides a good carrier for prolonging the drug release time by the long-time retention of the drug through the adhesion in a complex environment. The preparation method provided by the invention is simple and feasible, has low cost and is convenient for large-scale production, and the prepared microcarrier is non-toxic and has excellent biocompatibility, biological functionality and biodegradability. Provides a new carrier for safe and efficient drug delivery.
Description
Technical Field
The invention relates to the technical field of research on drug microcarriers, in particular to a parthenocissus tricuspidata adhesion-imitating microcarrier and a preparation method thereof.
Background
Drug therapy is an important means of treating a wide variety of diseases. The drug is delivered to its specific site of action in the body by different modes of administration to achieve a therapeutic effect. The drug carrier is a carrier for carrying drugs, and drug molecules are wrapped in a carrier matrix or attached to the surface of the carrier, so that the drug can be effectively transmitted and delivered, and the functions of slow release, controlled release and the like of the drug can be realized by degradation or responsiveness of functional materials. In recent years, there has been great progress in particulate drug carriers for safer and more efficient drug delivery. Among them, microparticles are considered to be one of the best drug controlled delivery routes because they have distinct advantages of easy production and characterization, high drug loading, low toxicity, etc. compared to nanosystems. However, the carriers used in the drug delivery systems are mostly spherical, and the spherical morphology makes the contact area of the carriers and the target object small, resulting in poor adhesion. Insufficient adhesion of the carrier to the target substance results in a rapid decrease in drug concentration, further reducing the drug delivery efficiency. Even with a spherical carrier surface that is carefully designed to achieve greater adhesion, carrier adhesion is not expected in complex fluid environments such as the esophagus, gastrointestinal tract. Therefore, a new demand for the development of microparticles with strong adhesion as drug carriers has been raised.
The parthenocissus tricuspidata is a widely existing climbing plant, and an antenna on a tendril can grow vertically on a wall. The antenna of the tiger creeper can be firmly attached to a contact object for a long time and shows good adhesion performance due to the fact that the antenna has the surface array nano structure and mucopolysaccharide is secreted when the antenna is in contact with a substance. However, due to its complex structure, few methods are currently available to effectively mimic this excellent bonding mechanism. In contrast, colloidal crystals as a single assembly unit provide another approach because they can be assembled into a variety of heterogeneous particles with complex structures. However, to our knowledge, assembly of colloidal crystals is rarely used for complex drug carrier designs.
Disclosure of Invention
The invention aims to provide a drug microcarrier imitating the adhesiveness of parthenocissus tricuspidata and a preparation method thereof, wherein the drug microcarrier is simple in preparation process, controllable in size, good in uniformity and repeatability, capable of increasing the contact area with a target and good in adhesiveness and biocompatibility.
In order to achieve the purpose, the technical scheme provided by the invention is as follows:
the preparation method of the bionic parthenocissus tricuspidata adhesion microcarrier comprises the following steps:
(1) preparation of a droplet template:
based on a capillary assembly microfluidic chip, preparing a single emulsion template with controllable particle size and uniform size by controlling the flow of a discrete phase and a continuous phase;
(2) deformation and solidification of the liquid drop template:
placing the single emulsion template in a vertical channel containing a rapid solvent extractant to enable the single emulsion template to freely fall, and obtaining microparticles with a simulated parthenocissus tentacle structure by extraction deformation of the rapid solvent extractant;
(3) obtaining hydrogel microcarrier:
firstly, drying the microparticles, then placing the microparticles in a gel liquid with higher viscosity and capable of temperature control solid-liquid conversion, filling the gel liquid into the pores in the microparticles, curing the gel liquid by temperature control, and then mechanically removing redundant gel solid;
then placing the microparticles in a functional hydrogel pre-coagulation liquid with good biocompatibility, filling nanometer gaps in the microparticles with the functional hydrogel pre-coagulation liquid, solidifying the functional hydrogel pre-coagulation liquid, and mechanically removing redundant functional hydrogel solids;
and finally, controlling the temperature to melt the gel solid in the holes of the microparticles, and removing the template to obtain the hydrogel microcarrier with the anti-creeping saxifrage structure.
In the step (1), the discrete phase is a silica particle aqueous solution with the mass fraction of 20%, and the flow rate of the discrete phase is 0.15 ml/h; the continuous phase is one of triacetyl glycerine, ethyl acetate and propylene carbonate, and the flow rate of the continuous phase is 15 ml/h.
In the step (2), the fast solvent extractant is one of triacetic acid, ethyl acetate and propylene carbonate.
In the step (3), the gel liquid with higher viscosity and capable of temperature control solid-liquid conversion is gelatin; the functional hydrogel with good biocompatibility is a methacrylated hydrogel added with functional particles or molecules.
The functional particles or molecules can be one of magnetic nanoparticles, mucopolysaccharides and charged molecules.
In the step (3), the curing method is ultraviolet irradiation; one of hydrofluoric acid and sodium hydroxide is adopted in the step of removing the template.
The hydrogel microcarrier with the anti-creeping parthenocissus tricuspidata structure is loaded with drugs so as to realize safe and effective drug delivery.
The prepared hydrogel microcarrier is soaked in a target drug solution for a certain time, and then drug loading can be realized.
Compared with the prior art, the invention has the beneficial effects that:
the preparation method of the bionic parthenocissus tricuspidata adhesion microcarrier comprises the steps of preparation of a liquid drop template, deformation and solidification of the liquid drop template, acquisition of a hydrogel microcarrier and loading of a medicament. The microcarrier has bionic macroscopic morphology, increases the contact area and is beneficial to enhancing the adhesion effect, the porous microscopic morphology provides a large area for fixing the drug, provides a good carrier for prolonging the drug release time by the long-time retention of the drug through the adhesion in a complex environment, and can realize high-efficiency drug loading and safe and effective drug delivery. The invention has simple preparation, low cost and high universality, and greatly enhances the performance of a drug carrier.
Drawings
FIG. 1 is a process for preparing a droplet template.
Fig. 2 is a deformation process of a droplet template.
FIG. 3 is a process for preparing a hydrogel carrier.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The following examples are intended to illustrate the invention only and are not intended to limit the scope of the invention.
Example 1
A parthenocissus tricuspidata adhesion-imitating microcarrier and a preparation method thereof are specifically implemented by the following steps:
(1) preparation of a droplet template:
based on a capillary assembly micro-fluidic chip, a silicon dioxide aqueous solution with the mass fraction of twenty percent is used as a discrete phase, the flow rate is 0.15ml/h, propylene carbonate is used as a continuous phase, and the flow rate is 15ml/h, so that the single emulsion with controllable particle size and uniform size is prepared.
(2) Deformation and solidification of the liquid drop template:
and (2) placing the single emulsion template prepared in the step (1) into a vertical channel filled with propylene carbonate, enabling liquid drops to freely fall in the environment, and obtaining the micron particles with the imitated parthenocissus tentacle structure due to rapid solvent extraction deformation.
(3) Obtaining hydrogel microcarrier:
firstly, placing the dried template particles in high-temperature gelatin liquid, stirring the gelatin liquid to enable the gelatin liquid to enter large holes of the template particles, and solidifying the gelatin by reducing the temperature of the gelatin liquid. Excess gelatin solids outside the holes were then mechanically removed by gentle hand rubbing of the template microparticles. Then placing the template particles with the gelatin filled in the big holes into methacrylic acid hydrogel pre-coagulation liquid containing magnetic nano particles and a photoinitiator, curing the functional hydrogel through purple radiation, removing excessive gel solids by a thumb gentle kneading machine, and placing the particles into hot water to melt the gelatin in the big holes. And (3) placing the particles in hydrofluoric acid to corrode the silicon dioxide template to obtain the magnetic hydrogel microcarrier with the imitated parthenocissus tricuspidata structure.
(4) Loading of drugs
And soaking the prepared hydrogel microcarrier in a dexamethasone solution for 12 hours to obtain the dexamethasone drug carrier.
Example 2
A parthenocissus tricuspidata adhesion-imitating microcarrier and a preparation method thereof are specifically implemented by the following steps:
(1) preparation of a droplet template:
based on a capillary assembly micro-fluidic chip, a silicon dioxide aqueous solution with the mass fraction of 20% is used as a discrete phase, the flow rate is 0.15ml/h, ethyl acetate is used as a continuous phase, and the flow rate is 15ml/h, so that the single emulsion with controllable particle size and uniform size is prepared.
(2) Deformation and solidification of the liquid drop template:
and (2) placing the single emulsion template prepared in the step (1) into a vertical channel filled with ethyl acetate, enabling liquid drops to freely fall in the environment, and obtaining the micron particles with the imitated parthenocissus tentacle structure due to rapid solvent extraction deformation.
(3) Obtaining hydrogel microcarrier:
firstly, placing the dried template particles in high-temperature gelatin liquid, stirring the gelatin liquid to enable the gelatin liquid to enter large holes of the template particles, and solidifying the gelatin by reducing the temperature of the gelatin liquid. Excess gelatin solids outside the holes were then mechanically removed by gentle hand rubbing of the template microparticles. Then placing the template particles with the gelatin filled in the big holes into methacrylic acid-free hydrogel pre-coagulation liquid containing carboxymethyl cellulose and a photoinitiator, curing the functional hydrogel through purple radiation, removing excessive gel solids by a thumb gentle kneading machine, and placing the particles into hot water to melt the gelatin in the big holes. And putting the particles into sodium hydroxide to corrode the silicon dioxide template to obtain the negatively charged hydrogel microcarrier with the imitated parthenocissus tricuspidata structure.
(4) Loading of drugs
And soaking the prepared hydrogel microcarrier in a budesonide solution for 12 hours to obtain the budesonide drug carrier.
FIG. 1 shows a schematic diagram of the droplet template preparation process. In a capillary microfluidic device, the outer phase oil phase cuts the inner phase water phase into droplets of uniform size.
Fig. 2 shows a schematic diagram of the entrance of a droplet template into a vertical channel and its deformation. In a vertical device, the surrounding fast solvent extractant continuously extracts the aqueous solution in the liquid drop, so that the interface of the liquid drop is unstable, gradually deforms and is solidified into micron particles with the appearance of the imitative parthenocissus tricuspidata.
FIG. 3 shows the preparation of the hydrogel carrier. Firstly, the gel liquid with higher viscosity and capable of controlling temperature and solid-liquid conversion is used for filling large holes of particles, and the liquid is solidified through temperature control. Excess gel solids are then mechanically removed. The particles are then placed in a functional hydrogel pre-gel with good biocompatibility to fill the nanoslits in the microparticles. And after the functional hydrogel is solidified, mechanically removing redundant gel solids, melting the gel in the large holes by temperature control, and removing the template to obtain the hydrogel microcarrier with the anti-creeping saxifrage structure.
The microcarrier has bionic macroscopic morphology, increases the contact area and is beneficial to enhancing the adhesion effect, and the porous microscopic morphology provides a large area for fixing the drug and provides a good carrier for prolonging the drug release time by the long-time retention of the drug through the adhesion in a complex environment. The preparation method provided by the invention is simple and feasible, has low cost and is convenient for large-scale production, and the prepared microcarrier is non-toxic and has excellent biocompatibility, biological functionality and biodegradability. Provides a new carrier for safe and efficient drug delivery.
The above description is only a preferred embodiment of the present invention, and should not be taken as limiting the invention in any way, and any person skilled in the art can make any simple modification, equivalent replacement, and improvement on the above embodiment without departing from the technical spirit of the present invention, and still fall within the protection scope of the technical solution of the present invention.
Claims (8)
1. The parthenocissus tricuspidata-imitating adhesive microcarrier is characterized in that: the preparation method comprises the following steps:
(1) preparation of a droplet template:
based on a capillary assembly microfluidic chip, preparing a single emulsion template with controllable particle size and uniform size by controlling the flow of a discrete phase and a continuous phase;
(2) deformation and solidification of the liquid drop template:
placing the single emulsion template in a vertical channel containing a rapid solvent extractant to enable the single emulsion template to freely fall, and obtaining microparticles with a simulated parthenocissus tentacle structure by extraction deformation of the rapid solvent extractant;
(3) obtaining hydrogel microcarrier:
firstly, drying the microparticles, then placing the microparticles in a gel liquid with higher viscosity and capable of temperature control solid-liquid conversion, filling the gel liquid into the pores in the microparticles, curing the gel liquid by temperature control, and then mechanically removing redundant gel solid;
then placing the microparticles in a functional hydrogel pre-coagulation liquid with good biocompatibility, filling nanometer gaps in the microparticles with the functional hydrogel pre-coagulation liquid, solidifying the functional hydrogel pre-coagulation liquid, and then mechanically removing redundant functional hydrogel solids;
and finally, controlling the temperature to melt the gel solid in the holes of the microparticles, and removing the template to obtain the hydrogel microcarrier with the anti-creeping saxifrage structure.
2. The imitated parthenocissus altimeter adhesive microcarrier of claim 1, wherein: in the step (1), the discrete phase is a silica particle aqueous solution with the mass fraction of 20%, and the flow rate of the discrete phase is 0.15 ml/h; the continuous phase is one of triacetyl glycerine, ethyl acetate and propylene carbonate, and the flow rate of the continuous phase is 15 ml/h.
3. The imitated parthenocissus altimeter adhesive microcarrier of claim 1, wherein: in the step (2), the fast solvent extractant is one of triacetic acid, ethyl acetate and propylene carbonate.
4. The imitated parthenocissus altimeter adhesive microcarrier of claim 1, wherein: in the step (3), the gel liquid with higher viscosity and capable of temperature control solid-liquid conversion is gelatin; the functional hydrogel with good biocompatibility is a methacrylated hydrogel added with functional particles or molecules.
5. The imitated parthenocissus altimeter adhesive microcarrier of claim 4, wherein: the functional particles or molecules can be one of magnetic nanoparticles, mucopolysaccharides and charged molecules.
6. The imitated parthenocissus altimeter adhesive microcarrier of claim 1, wherein: in the step (3), the curing method is ultraviolet irradiation; one of hydrofluoric acid and sodium hydroxide is adopted in the step of removing the template.
7. The imitated parthenocissus altimeter adhesive microcarrier of claim 1, wherein: the hydrogel microcarrier with the anti-creeping parthenocissus tricuspidata structure is loaded with drugs so as to realize safe and effective drug delivery.
8. The imitated parthenocissus altimeter adhesive microcarrier of claim 7, wherein: the prepared hydrogel microcarrier is soaked in a target drug solution for a certain time, and then drug loading can be realized.
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| CN113577296A (en) * | 2021-07-30 | 2021-11-02 | 复旦大学 | Preparation method of adhesive drug microcarrier |
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| CN113577296A (en) * | 2021-07-30 | 2021-11-02 | 复旦大学 | Preparation method of adhesive drug microcarrier |
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Application publication date: 20200804 |