CN113318237B - Transmembrane drug delivery method based on biological enzyme driven micropump - Google Patents
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Abstract
The invention belongs to the technical field of medicine research, and particularly relates to a transmembrane medicine delivery method based on a biological enzyme driven micropump. According to the invention, a one-dimensional nanotube is used as a physical channel for transferring a transmembrane substance, an artificial micro-nano machine-biological nano pump is embedded into the surface of a cell membrane, a biocompatible biological enzyme catalytic reaction is utilized to provide an energy source, the movement of a flow field in the nanotube is driven, and extracellular substances are transferred into cells, so that a novel pumping type transmembrane substance transferring mode is established at two sides of the cell membrane, and the limitation of a traditional nano drug carrier is expected to be broken through.
Description
Technical Field
The invention belongs to the technical field of medicine research, and particularly relates to a transmembrane medicine delivery method based on a biological enzyme driven micropump.
Background
The traditional chemotherapy has the defects of poor specificity, strong side effect and the like, so the nanometer medical treatment method capable of improving the specificity and reducing the side effect is widely studied. In nanotherapeutics, nanomedicines rely primarily on endocytosis of cells into cells. The drug is loaded on the nano-carrier, the cell membrane is depressed, the nano-carrier loaded with the drug is wrapped to form inclusion bodies to enter the cell, and then the nano-carrier escapes from the inclusion bodies to enter cytoplasm, and the drug is released in the cytoplasm for treatment.
The defects of the existing biomedical nano-carriers mainly exist in the following aspects: (1) Because of the loading mode of surface adsorption or chemical bonding, the loading rate of the loading substance (namely the ratio of the loading substance to the nano-carrier material) is relatively fixed, and the effective release rate in cells is also generally low; (2) The loading mode may negatively affect the biomedical functional properties of the loaded material, for example, after the chemical bond-connected drug is released, the residual binding group on the molecular structure of the loaded material may affect the original physicochemical properties and corresponding pharmacokinetic properties of the drug molecule, and the functional therapeutic protein and gene loaded by electrostatic adsorption also have the problems of protein denaturation and gene degradation during adsorption and desorption, thereby affecting the biomedical efficacy thereof; (3) After phagocytic entry into cells, the process by which the nanocarriers escape from the inclusion bodies into the cytoplasm is a new transmembrane transport barrier.
Therefore, how to realize active delivery of transmembrane drugs with good biocompatibility, accuracy, controllability and high efficiency is of great significance for efficient drug delivery and improvement of the effective treatment rate of diseases.
Disclosure of Invention
Under the condition of guaranteeing biomedical functions, the invention discloses a novel substance transmembrane transport method, which realizes high-efficiency transmembrane transfer of functional substances and provides a new idea for nano medical treatment. The one-dimensional microtube is used as a physical channel for transferring transmembrane substances, an artificial micro-nano machine-a biological micrometer pump is embedded into the surface of a cell membrane, a biocompatible biological enzyme is utilized for catalyzing reaction to provide energy sources, the movement of a fluid field in the microtube is driven, and extracellular substances are transferred into cells, so that a novel pumping type transmembrane substance transferring mode is established at two sides of the cell membrane, and the limitation of a traditional nano drug carrier is expected to be broken through.
The invention is oriented to life health of people, aims at providing subversion treatment means for future accurate medical treatment, aims at developing an artificial transmembrane drug delivery system based on a bionic micron pump, utilizes a tubular machine to establish a transmembrane bionic micron channel driven by biological enzyme reaction, breaks through the limitation of passive delivery of the existing nano drug carrier, realizes active delivery of transmembrane drugs with good biocompatibility, accuracy, controllability and high efficiency, and provides a new idea for treating serious diseases such as tumors.
Aiming at the problems of low efficiency of nano drug carrier entering cells, poor treatment effect and the like, a bionic nano pump artificial transmembrane channel is established, and the invention is realized by the following technical scheme:
a method of transmembrane drug delivery based on a bio-enzyme driven micropump, comprising:
(1) Preparation of a bionic self-driven micro pump: the silica microtubes are selected, glutaraldehyde is used for activating the microtubes and urease is modified on the surface of the microtubes to prepare the enzyme pumps.
The preferred structure, materials and preparation process are as follows: silica microtubes having a diameter of 1 μm and a length of 20 μm were prepared using a polycarbonate film as a template and ultrapure water, 3-aminopropyl triethoxysilane (APTES), triethanolamine (TEOA) and Tetraethylorthosilicate (TEOS).
As a preferable technical scheme of the invention, the specific steps are as follows: 60mg of TEOA is added into 24mL of deionized water, and the mixture is stirred evenly under the condition of 500rpm by magnetic force; adding 30 mu L of APTES into the system, stirring at 500rpm for 30min, and heating the system to 80 ℃; finally 240. Mu.L of TEOS and polycarbonate film were added to the above system and stirred at 200rpm at 80℃for 4 hours. After the reaction is finished, polishing silicon dioxide on the surface of the film by using aluminum oxide particles, and after polishing is completed, flushing the aluminum oxide particles by using ultrapure water; the polycarbonate film was dissolved using DMF, centrifuged at 8000rpm twice, followed by washing with absolute ethanol twice, and finally washing with PBS twice to obtain silica microtubes dispersed in PBS. And the silicon dioxide material has better biocompatibility, and the prepared silicon dioxide micro-tube is proved to be nontoxic to cells by MTT experiments. And the preparation is convenient and the cost is lower.
As a preferred embodiment of the present invention, the step of modifying the urease comprises: using glutaraldehyde as a connecting agent, firstly adding 50 mu L of glutaraldehyde into a PBS solution of a silica micro-tube, carrying out shaking reaction for 3 hours, adding 10mg of urease after PBS is centrifugally washed three times, continuing the shaking reaction for 16 hours, and finally centrifugally washing 3 times by using the PBS solution.
The applicant's research found that, due to the small thickness of the cell wall thickness, when the diameter of the tube is greater than 2 microns, it is not possible to act as a transmembrane channel and the cells cannot fully engulf the entire cross section.
(2) Co-culturing human cervical cancer cells (Hela) and a micro-enzyme pump, and enabling one end of the micro-enzyme pump to enter the cells by utilizing endocytosis of the cells and the other end to be outside the cells, so that a bionic micro-pump artificial transmembrane channel is constructed.
As a preferred technical scheme of the invention, the culture step comprises the following steps: 1ml of a cell suspension having a cell concentration of 20 ten thousand cells/ml was added to the dish, and the cells were cultured in an incubator for 4 hours for adherent growth. 100. Mu.L of SMT@Urea (urease modified silica tube, i.e.enzyme pump) was added to the system at a concentration of 50. Mu.g/ml, and the cells were co-cultured for 4h to establish a micro-enzyme pump artificial transmembrane channel.
The culture method fully considers the interaction rule of the bionic self-driven micropump and the cell membrane and the mechanism for constructing the artificial transmembrane channel, and is beneficial to constructing the artificial transmembrane channel of the bionic micropump.
(3) Urea is added into a bionic micron pump system, and a catalytic reaction of urease on the urea is utilized to decompose a substrate so as to generate a micro-nano flow field in the enzyme pump, and extracellular substances are driven into cells under the action of micro-nano fluid, so that the effect of high-efficiency and active delivery of the medicine is achieved.
As a preferred embodiment of the present invention, urea is added to a biomimetic micron pump system, and 100. Mu.L of a 550mM urea solution is added to 1ml of a culture medium system to give a final concentration of 50mM urea in the system.
As a preferred technical scheme of the invention, the culture conditions are as follows: the enzyme-catalyzed reaction of the modified urease on silica microtubes occurs in the presence of urea substrate in a 37 degree incubator, medium conditions. The catalytic reaction drives surrounding fluid to generate a counter flow field, so that extracellular substances are enhanced to diffuse into cells, and the delivery efficiency of the medicine is improved.
The invention has the following beneficial effects on the prior art:
by the transmembrane drug delivery method based on the bioenzyme-driven micropump, the diagnosis and treatment performance of the transmembrane drug delivery of the self-driven micropump is simulated, so that the efficient transmembrane delivery of auxiliary drugs is realized.
After the artificial transmembrane channel of the bionic micro-pump is successfully established, the auxiliary effect of the micro-enzyme pump on drug delivery is verified by comparing the transmembrane delivery condition of the drug Propidium Iodide (PI) under the condition of urea presence/absence. The invention promotes extracellular substances to enter cells efficiently under the assistance of a micro-nano flow field generated by urea catalytic decomposition.
Drawings
FIG. 1 is a schematic diagram of a biomimetic micro-enzyme pump facilitating drug delivery across a membrane;
FIG. 2 is a schematic diagram of biomimetic micro-enzyme pump assisted delivery of PI transmembrane at different concentrations;
FIG. 3 is a schematic diagram of a comparison of a manual channel without adding silica nanotubes (SMT) and without adding silica nanotubes (SMT).
FIG. 4 is a schematic of biomimetic microzyme pump assisted delivery with and without urea under the conditions of comparative example 2.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and examples, but embodiments of the present invention are not limited thereto.
Example 1
A method of transmembrane drug delivery based on a bio-enzyme driven micropump, comprising:
(1) Preparation of a bionic self-driven micro pump: the silica microtubes are selected, glutaraldehyde is used for activating the microtubes and urease is modified on the surface of the microtubes to prepare the enzyme pumps.
Specifically: silica microtubes having a diameter of 1 μm and a length of 20 μm were prepared using a polycarbonate film as a template and ultrapure water, APTES, TEOA and TEOS. 60mg of TEOA is added into 24mL of deionized water, and the mixture is stirred evenly under the condition of 500rpm by magnetic force; adding 30 mu L of APTES into the system, stirring at 500rpm for 30min, and heating the system to 80 ℃; finally 240. Mu. LTEOS and polycarbonate film were added to the above system and stirred at 200rpm at 80℃for 4 hours. After the reaction is finished, polishing silicon dioxide on the surface of the film by using aluminum oxide particles, and after polishing is completed, flushing the aluminum oxide particles by using ultrapure water; the polycarbonate film was dissolved using DMF, centrifuged at 8000rpm twice, followed by washing with absolute ethanol twice, and finally washing with PBS twice to obtain silica microtubes dispersed in PBS. The step of modifying urease comprises the following steps: using glutaraldehyde as a connecting agent, firstly adding 50 mu L of glutaraldehyde into a PBS solution of a silica micro-tube, carrying out shaking reaction for 3 hours, adding 10mg of urease after PBS is centrifugally washed three times, continuing the shaking reaction for 16 hours, and finally centrifugally washing 3 times by using the PBS solution.
(2) Co-culturing human cervical cancer cells (Hela) and a micro-enzyme pump, and enabling one end of the micro-enzyme pump to enter the cells by utilizing endocytosis of the cells and the other end to be outside the cells, so that a bionic micro-pump artificial transmembrane channel is constructed. The culturing steps are as follows: 1ml of a cell suspension having a cell concentration of 20 ten thousand cells/ml was added to the dish, and the cells were cultured in an incubator for 4 hours for adherent growth. 100. Mu.L of SMT@Urea (urease modified silica tube, i.e.enzyme pump) was added to the system at a concentration of 50. Mu.g/ml, and the cells were co-cultured for 4h to establish a micro-enzyme pump artificial transmembrane channel.
(3) Urea is added into a bionic micron pump system, and a catalytic reaction of urease on the urea is utilized to decompose a substrate so as to generate a micro-nano flow field in the enzyme pump, and extracellular substances are driven into cells under the action of micro-nano fluid, so that the effect of high-efficiency and active delivery of the medicine is achieved. As particularly shown in fig. 1.
Specifically, 100. Mu.L of a urea solution at a concentration of 550mM was added to 1ml of the culture system to give a final concentration of urea in the system of 50mM; in a 37℃incubator environment (carbon dioxide concentration 5%), urease enzyme-catalyzed reactions were performed in the presence of urea substrate under medium conditions.
Example 2
By adopting the transmembrane drug delivery method based on the biological enzyme-driven micropump of the embodiment 1, after the artificial transmembrane channel of the bionic micropump is successfully established, the auxiliary effect of the micropump on drug delivery is verified by comparing the transmembrane delivery condition of the drug Propidium Iodide (PI) with/without urea. As shown in figure 2, the invention promotes extracellular substances to enter cells efficiently with the assistance of a micro-nano flow field generated by urea catalytic decomposition.
Comparative example 1
Referring to example 1, the results of the cell flow experiments at different PI concentrations were as follows:
as shown in fig. 3, no Silica Microtubes (SMT) were added to the left and silica microtubes were added to the right. After SMT is added as an artificial transmembrane channel, the fluorescence intensity of the cells is correspondingly increased, which indicates that the addition of SMT enables the fluorescent substance Propidium Iodide (PI) which does not permeate the cell membrane of the living cells to enter the cells more. The SMT has the effect of assisting substances in entering cells.
Comparative example 2
Using the biomimetic micro-enzyme pump obtained in example 1, the cell flow assay delivers the fluorescent substance coumarin 6 (see fig. 2) using an enzyme pump. When the concentration of coumarin 6 is 10 mug/mL, one end of the cell phagocytase pump constructs an artificial transmembrane channel (the phagocytosis time is 4 h). 10. Mu.g/mL coumarin 6 solution was co-cultured with cells for 20min (control group without urea, experimental group with urea as substrate for catalytic decomposition), washed three times with PBS, and then subjected to cell flow assay. The experimental result is shown in figure 4, and is similar to the result in figure 2, and after urea is added, SMT@Urea forms an enzyme pump, so that the technical scheme of the invention effectively promotes the hydrophobic medicine coumarin 6 to enter cells.
It will be readily appreciated by those skilled in the art that the foregoing description is merely a preferred embodiment of the invention and is not intended to limit the invention, but any modifications, equivalents, improvements or alternatives falling within the spirit and principles of the invention are intended to be included within the scope of the invention.
Claims (5)
1. A method of transmembrane drug delivery based on a bio-enzyme driven micropump, comprising:
(1) Preparation of a bionic self-driven micro pump: selecting a silicon dioxide micro-tube, using a polycarbonate film as a template, preparing the silicon dioxide micro-tube with the diameter of 1 mu m and the length of 20 mu m by using ultrapure water, APTES, TEOA and TEOS, activating the micro-tube by using glutaraldehyde and modifying urease on the surface of the micro-tube to prepare a micro-enzyme pump;
(2) Co-culturing human cervical cancer Hela cells and a micro-enzyme pump, and enabling one end of the micro-enzyme pump to enter the cells by utilizing endocytosis of the cells and the other end to be outside the cells, so as to construct a bionic micro-pump artificial transmembrane channel;
(3) Urea is added into a bionic micron pump system, and a catalytic reaction of urease on the urea is utilized to decompose a substrate so as to generate a micro-nano flow field in the enzyme pump, and extracellular substances are driven into cells under the action of micro-nano fluid, so that the effect of high-efficiency and active delivery of the medicine is achieved;
the preparation method of the silica microtube comprises the steps of adding 60mg of TEOA into 24mL of deionized water, and magnetically stirring uniformly under the condition of 500 rpm; adding 30 mu L of APTES into the system, stirring at 500rpm for 30min, and heating the system to 80 ℃; finally, 240 mu L of TEOS and a polycarbonate film are added into the system, stirred for 4 hours at 200rpm and 80 ℃, after the reaction is finished, the silica on the surface of the film is polished by using alumina particles, and after the polishing is completed, the alumina particles are washed clean by using ultrapure water; the polycarbonate film was dissolved using DMF, centrifuged at 8000rpm twice, followed by washing with absolute ethanol twice, and finally washing with PBS twice to obtain silica microtubes dispersed in PBS.
2. The method of transmembrane drug delivery based on a bioenzyme driven micropump of claim 1, wherein the step of modifying the urease enzyme comprises: using glutaraldehyde as a connecting agent, firstly adding 50 mu L of glutaraldehyde into a PBS solution of a silica micro-tube, carrying out shaking reaction for 3 hours, adding 10mg of urease after PBS is centrifugally washed three times, continuing the shaking reaction for 16 hours, and finally centrifugally washing 3 times by using the PBS solution.
3. A method of transmembrane drug delivery based on a bio-enzyme driven micropump according to claim 1, comprising: the human cervical carcinoma Hela cells are co-cultured with a micro enzyme pump, and the culturing steps are as follows: 1ml of cell suspension with the cell concentration of 20 ten thousand cells/ml is added into a culture dish, the cell is cultivated in an incubator for 4h for adherent growth, 100 mu L of SMT@Urea with the concentration of 50 mu g/ml is added into the system, and a micro-enzyme pump artificial transmembrane channel is established by co-cultivation with the cells for 4 h.
4. A method of transmembrane drug delivery based on a bio-enzyme driven micropump according to claim 1, comprising: urea was added to the biomimetic micrometer pump system, and 100. Mu.L of a urea solution having a concentration of 550mM was added to 1ml of the culture medium system to give a final concentration of urea in the system of 50mM.
5. A method of transmembrane drug delivery based on a bio-enzyme driven micropump according to claim 1, comprising: urea is added into a bionic micron pump system, and the catalytic reaction conditions are as follows: in a 37℃incubator environment, the concentration of carbon dioxide is 5%, and under this culture condition, the urease enzyme undergoes an enzyme-catalyzed reaction in the presence of a urea substrate.
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