CN113318237A - 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 drug research, and particularly relates to a transmembrane drug delivery method based on a biological enzyme driven micropump. The invention takes a one-dimensional nanotube as a physical channel for transmembrane material transfer, an artificial micro-nano machine, namely a biological nano pump, is embedded in the surface of a cell membrane, and the energy source is provided by utilizing biocompatible biological enzyme catalytic reaction to drive a flow field in the nanotube to move and transfer extracellular substances into the cell, so that a novel pumping type transmembrane material transfer mode is established on two sides of the cell membrane, and the limitation of the traditional nano drug carrier is expected to be broken through.
Description
Technical Field
The invention belongs to the technical field of drug research, and particularly relates to a transmembrane drug delivery method based on a biological enzyme driven micropump.
Background
The conventional chemotherapy for cancer has disadvantages of poor specificity and strong side effects, and thus, a nano-medical method capable of improving specificity and reducing side effects has been widely studied. In nano-therapy, nano-drugs mainly rely on endocytosis of cells into cells. The drug is loaded on the nano-carrier, the cell membrane is sunken, the nano-carrier loaded with the drug is wrapped to form inclusion bodies to enter cells, and then the nano-carrier escapes the inclusion bodies to enter cytoplasm and releases the drug in the cytoplasm for treatment.
The defects of the current biological medicine nano-carrier mainly exist in the following aspects: (1) due to 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 generally low; (2) the loading mode may cause negative influence on the biomedical functional properties of the loaded substance, for example, after the drug connected by chemical bonds is released, the residual binding groups on the molecular structure can influence the original physicochemical properties and corresponding pharmacokinetic properties of the drug molecules, and the functional therapeutic protein and gene loaded by electrostatic adsorption also have the problems of protein denaturation and gene degradation in the adsorption and desorption processes so as to influence the biomedical efficacy of the functional therapeutic protein and gene; (3) after phagocytosis into the cell, the escape of nanocarriers from inclusion bodies into the cytoplasm is a new barrier to transmembrane transport.
Therefore, how to realize active transmembrane drug delivery with good biocompatibility, accuracy, controllability and high efficiency has important significance for high-efficiency drug delivery and improvement of the effective rate of disease treatment.
Disclosure of Invention
Under the condition of ensuring the biomedical function, the invention invents a novel substance transmembrane transport method, realizes the high-efficiency transmembrane transmission of functional substances and provides a new idea for nano medical treatment. The one-dimensional micron tube is used as a physical channel for transmembrane material transfer, an artificial micro-nano machine, namely a biological micron pump, is embedded in the surface of a cell membrane, and the biocompatible biological enzyme catalytic reaction is used for providing an energy source to drive a flow field in the micron tube to move, so that extracellular substances are transmitted into cells, and a novel pumping type transmembrane material transfer mode is established on two sides of the cell membrane, so that the limitation of the traditional nano drug carrier is expected to be broken through.
The invention aims at the life health of people, provides an overturned therapeutic means for future precise medical treatment, aims to develop an artificial transmembrane drug delivery system based on a bionic micron pump, establishes a transmembrane bionic micron channel driven by biological enzyme reaction by utilizing a tubular machine, breaks through the limitation of passive delivery of the existing nano drug carrier, realizes the active delivery of transmembrane drugs with good biocompatibility, precision, controllability and high efficiency, and provides a new idea for treating serious diseases such as tumors and the like.
Aiming at the problems of low efficiency of entering cells, poor treatment effect and the like of a nano-drug carrier, the invention establishes an artificial transmembrane channel of a bionic nano-pump, and is realized by the following technical scheme:
a method of transmembrane drug delivery based on a bio-enzyme driven micropump, comprising:
(1) preparing a bionic self-driven micron pump: selecting a silicon dioxide micron tube, activating the micron tube by using glutaraldehyde, and modifying urease on the surface of the micron tube to prepare a micron enzyme pump.
The preferable structure, material and preparation process are as follows: a silica microtube having a diameter of 1 μm and a length of 20 μm was prepared using ultrapure water, 3-Aminopropyltriethoxysilane (APTES), Triethanolamine (TEOA) and Tetraethoxysilane (TEOS) with a polycarbonate film as a template.
As a preferred technical scheme of the invention, the method comprises the following specific steps: adding 60mg of TEOA into 24mL of deionized water, and magnetically stirring the mixture evenly at 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 TEOS and polycarbonate film were added to the system and stirred at 200rpm, 80 ℃ for 4 hours. After the reaction is finished, polishing the silicon dioxide on the surface of the membrane by using aluminum oxide particles, and washing the aluminum oxide particles clean by using ultrapure water after the surface of the membrane is completely polished; the polycarbonate membrane was dissolved with DMF, centrifuged at 8000rpm twice, then centrifuged with absolute ethanol twice, and finally centrifuged with PBS twice to obtain silica microtubes dispersed in PBS. And the silicon dioxide material has better biocompatibility, and the prepared silicon dioxide micron tube is proved to be nontoxic to cells through MTT (methyl thiazolyl tetrazolium) experiment. And the preparation is convenient and the cost is lower.
As a preferred embodiment of the present invention, the step of modifying urease comprises: glutaraldehyde is used as a connecting agent, 50 mu L of glutaraldehyde is added into PBS solution of a silica micro-tube, oscillation reaction is carried out for 3 hours, 10mg of urease is added after PBS centrifugal washing is carried out for three times, oscillation reaction is carried out for 16 hours, and finally PBS solution is used for centrifugal washing for 3 times.
Applicants have found that due to the small thickness of the cell patch wall, when the diameter of the tube is greater than 2 microns, it cannot act as a transmembrane channel and the cell cannot completely phagocytose the entire cross-section.
(2) Co-culturing human cervical carcinoma cells (Hela) and the micron enzyme pump, and enabling one end of the micron enzyme pump to enter the cells and the other end of the micron enzyme pump to be outside the cells by utilizing the endocytosis of the cells, thereby constructing the bionic micron pump artificial transmembrane channel.
As a preferred technical scheme of the invention, the culture step comprises the following steps: 1ml of cell suspension with the cell concentration of 20 ten thousand/ml is added into a culture dish, and the cells are cultured for 4 hours in an incubator to grow adherently. To this system, 100. mu.L of SMT @ Urease (Urease-modified silica tube, i.e., enzyme pump) was added at a concentration of 50. mu.g/ml, and co-cultured with the cells 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 favorable for constructing the artificial transmembrane channel of the bionic micropump.
(3) Urea is added into the bionic micron pump system, a substrate is decomposed by utilizing the catalytic reaction of urease on the urea, a micro-nano flow field is generated inside the enzyme pump, and extracellular substances are driven to enter cells under the action of the micro-nano fluid, so that the effect of efficient and active delivery of the medicine is achieved.
As a preferred technical scheme of the invention, urea is added into a bionic micron pump system, 100 mu L of urea solution with the concentration of 550mM is added into 1ml of culture medium system, and the final concentration of the urea in the system is 50 mM.
As a preferred technical scheme of the invention, the culture conditions are as follows: and (3) a 37-degree incubator, the culture medium condition and the enzyme catalysis reaction of the modified urease on the silica micro-tube in the presence of the urea substrate. The catalytic reaction further drives surrounding fluid to generate a convection field, enhances the diffusion of substances outside the cells into the cells, and improves the delivery efficiency of the drug.
The beneficial effects of the invention on the prior art comprise:
through the transmembrane drug delivery method based on the biological enzyme driven micropump, diagnosis and treatment performance of transmembrane drug delivery of the bionic self-driven micropump is realized, so that efficient transmembrane delivery of auxiliary drugs is realized.
After the bionic micro-pump artificial transmembrane channel 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 existence/absence of urea. The invention promotes the extracellular substances to efficiently enter cells under the assistance of a micro-nano flow field generated by urea catalytic decomposition by urease.
Drawings
FIG. 1 is a schematic representation of a biomimetic micro-enzyme pump facilitating drug delivery across a membrane;
FIG. 2 is a schematic diagram of biomimetic micro-enzyme pump-assisted transmembrane delivery of PI at different concentrations;
FIG. 3 is a schematic diagram showing a comparison of artificial channels without silica micro-tubes (SMT) and without silica micro-tubes (SMT).
Figure 4, schematic representation of biomimetic micro-enzyme pump assisted delivery with and without urea under comparative example 2 conditions.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, but the 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) preparing a bionic self-driven micron pump: selecting a silicon dioxide micron tube, activating the micron tube by using glutaraldehyde, and modifying urease on the surface of the micron tube to prepare a micron enzyme pump.
Specifically, the method comprises the following steps: a silica microtube having a diameter of 1 μm and a length of 20 μm was prepared using a polycarbonate film as a template and ultrapure water, APTES, TEOA and TEOS. Adding 60mg of TEOA into 24mL of deionized water, and magnetically stirring the mixture evenly at 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 EOS and polycarbonate film were added to the system and stirred at 200rpm, 80 ℃ for 4 hours. After the reaction is finished, polishing the silicon dioxide on the surface of the membrane by using aluminum oxide particles, and washing the aluminum oxide particles clean by using ultrapure water after the surface of the membrane is completely polished; the polycarbonate membrane was dissolved with DMF, centrifuged at 8000rpm twice, then centrifuged with absolute ethanol twice, and finally centrifuged with PBS twice to obtain silica microtubes dispersed in PBS. The step of modifying the urease comprises: glutaraldehyde is used as a connecting agent, 50 mu L of glutaraldehyde is added into PBS solution of a silica micro-tube, oscillation reaction is carried out for 3 hours, 10mg of urease is added after PBS centrifugal washing is carried out for three times, oscillation reaction is carried out for 16 hours, and finally PBS solution is used for centrifugal washing for 3 times.
(2) Co-culturing human cervical carcinoma cells (Hela) and the micron enzyme pump, and enabling one end of the micron enzyme pump to enter the cells and the other end of the micron enzyme pump to be outside the cells by utilizing the endocytosis of the cells, thereby constructing the bionic micron pump artificial transmembrane channel. The culture steps are as follows: 1ml of cell suspension with the cell concentration of 20 ten thousand/ml is added into a culture dish, and the cells are cultured for 4 hours in an incubator to grow adherently. To this system, 100. mu.L of SMT @ Urease (Urease-modified silica tube, i.e., enzyme pump) was added at a concentration of 50. mu.g/ml, and co-cultured with the cells for 4h to establish a micro-enzyme pump artificial transmembrane channel.
(3) Urea is added into the bionic micron pump system, a substrate is decomposed by utilizing the catalytic reaction of urease on the urea, a micro-nano flow field is generated inside the enzyme pump, and extracellular substances are driven to enter cells under the action of the micro-nano fluid, so that the effect of efficient and active delivery of the medicine is achieved. As shown in particular in figure 1.
Specifically, 100. mu.L of a 550mM urea solution was added to 1ml of the culture medium system so that the final concentration of urea in the system was 50 mM; in a 37-degree incubator environment (the concentration of carbon dioxide is 5%), under the condition of a culture medium, urease carries out an enzyme catalytic reaction in the presence of a urea substrate.
Example 2
After the artificial transmembrane channel of the bionic micropump is successfully established, the transmembrane delivery condition of the Propidium Iodide (PI) drug under the condition of existence/absence of urea is compared, and the auxiliary effect of the micrometer enzyme pump on drug delivery is verified. Specifically, as shown in fig. 2, the invention promotes extracellular substances to efficiently enter cells under the assistance of a micro-nano flow field generated by urea catalytic decomposition by urease.
Comparative example 1
Referring to example 1, the results of the flow cytometry experiments at different PI concentrations were as follows, using an artificial channel comparison without silica micro-tube (SMT) and without silica micro-tube (SMT):
as shown in fig. 3, Silica Micro Tubes (SMT) were not added to the left and silica micro tubes were added to the right. After the SMT is added as an artificial transmembrane channel, the fluorescence intensity of the cell is correspondingly increased, which indicates that the addition of the SMT enables the Propidium Iodide (PI) which is a fluorescent substance and does not permeate the cell membrane of the living cell to enter the cell more. Indicating that SMT has the efficacy of assisting substances in entering cells.
Comparative example 2
Using the biomimetic minim enzyme pump obtained in example 1, a cell flow assay was performed using an enzyme pump to deliver the fluorescent substance coumarin 6 (as shown in FIG. 2). When the concentration of coumarin 6 is 10 mug/mL, an artificial transmembrane channel is constructed at one end of a cell phagocytase pump (the phagocytosis time is 4 h). 10 ug/mL coumarin 6 solution was co-cultured with the cells for 20min (no urea was added to the control group and urea was added to the experimental group as a substrate for catalytic decomposition), washed three times with PBS, and then subjected to the cell flow assay. The experimental result is shown in fig. 4, and is similar to the result in fig. 2, after urea is added, the SMT @ urea forms an enzyme pump, and the technical scheme of the invention effectively promotes the hydrophobic drug coumarin 6 to enter cells.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (7)
1. A method of transmembrane drug delivery based on a bio-enzyme driven micropump, comprising:
(1) preparing a bionic self-driven micron pump: selecting a silicon dioxide micron tube, activating the micron tube by using glutaraldehyde, and modifying urease on the surface of the micron tube to prepare a micron enzyme pump;
(2) co-culturing a human cervical cancer cell (Hela) and a micron enzyme pump, and enabling one end of the micron enzyme pump to enter the cell and the other end of the micron enzyme pump to be outside the cell by utilizing the endocytosis of the cell, thereby constructing a bionic micron pump artificial transmembrane channel;
(3) urea is added into the bionic micron pump system, a substrate is decomposed by utilizing the catalytic reaction of urease on the urea, a micro-nano flow field is generated inside the enzyme pump, and extracellular substances are driven to enter cells under the action of the micro-nano fluid, so that the effect of efficient and active delivery of the medicine is achieved.
2. A method according to claim 1, wherein the method comprises: a silica microtube having a diameter of 1 μm and a length of 20 μm was prepared using ultrapure water, APTES, TEOA and TEOS, using a polycarbonate film as a template.
3. A method of bio-enzyme driven micropump-based transmembrane drug delivery according to claim 2, comprising: the preparation steps of the silicon dioxide micron tube are that 60mg TEOA is added into 24mL deionized water, and the mixture is stirred evenly by magnetic force 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 polycarbonate film were added to the system and stirred at 200rpm, 80 ℃ for 4 hours. After the reaction is finished, polishing the silicon dioxide on the surface of the membrane by using aluminum oxide particles, and washing the aluminum oxide particles clean by using ultrapure water after the surface of the membrane is completely polished; the polycarbonate membrane was dissolved with DMF, centrifuged at 8000rpm twice, then centrifuged with absolute ethanol twice, and finally centrifuged with PBS twice to obtain silica microtubes dispersed in PBS.
4. The method for transmembrane drug delivery based on the biological enzyme driven micropump according to claim 1 or 2, wherein the step of modifying the urease comprises: glutaraldehyde is used as a connecting agent, 50 mu L of glutaraldehyde is added into PBS solution of a silica micro-tube, oscillation reaction is carried out for 3 hours, 10mg of urease is added after PBS centrifugal washing is carried out for three times, oscillation reaction is carried out for 16 hours, and finally PBS solution is used for centrifugal washing for 3 times.
5. A method according to claim 1, wherein the method comprises: co-culturing human cervical cancer cells (Hela) and a micron enzyme pump, wherein the culture steps are as follows: 1ml of cell suspension with the cell concentration of 20 ten thousand/ml is added into a culture dish, and the cells are cultured for 4 hours in an incubator to grow adherently. To this system, 100. mu.L of SMT @ Urease (Urease-modified silica tube, i.e., enzyme pump) was added at a concentration of 50. mu.g/ml, and co-cultured with the cells for 4h to establish a micro-enzyme pump artificial transmembrane channel.
6. A method according to claim 1, wherein the method comprises: urea was added to the biomimetic micro pump system and 100. mu.L of 550mM urea solution was added to 1ml of the culture medium system to give a final concentration of 50mM urea in the system.
7. A method according to claim 1, wherein the method comprises: adding urea into the bionic micron pump system, wherein the catalytic reaction conditions are as follows: in a 37-degree incubator environment (the concentration of carbon dioxide is 5%), under the condition of a culture medium, urease carries out an enzyme catalytic reaction in the presence of a urea substrate.
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