KR101810761B1 - Multilayered nano-film for contolling drug relaease basaed on stimuli-responsive graphene - Google Patents

Multilayered nano-film for contolling drug relaease basaed on stimuli-responsive graphene Download PDF

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KR101810761B1
KR101810761B1 KR1020160003399A KR20160003399A KR101810761B1 KR 101810761 B1 KR101810761 B1 KR 101810761B1 KR 1020160003399 A KR1020160003399 A KR 1020160003399A KR 20160003399 A KR20160003399 A KR 20160003399A KR 101810761 B1 KR101810761 B1 KR 101810761B1
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drug
graphene
nanofilm
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film
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KR20170084421A (en
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홍진기
김성열
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중앙대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/52—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B32—LAYERED PRODUCTS
    • B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B18/00—Layered products essentially comprising ceramics, e.g. refractory products
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B32—LAYERED PRODUCTS
    • B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B9/00—Layered products comprising a layer of a particular substance not covered by groups B32B11/00 - B32B29/00
    • B32B9/005—Layered products comprising a layer of a particular substance not covered by groups B32B11/00 - B32B29/00 comprising one layer of ceramic material, e.g. porcelain, ceramic tile
    • B32B9/007—Layered products comprising a layer of a particular substance not covered by groups B32B11/00 - B32B29/00 comprising one layer of ceramic material, e.g. porcelain, ceramic tile comprising carbon, e.g. graphite, composite carbon
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B32/00—Carbon; Compounds thereof
    • C01B32/20—Graphite
    • C01B32/21—After-treatment
    • C01B32/23—Oxidation
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
    • C08L67/02—Polyesters derived from dicarboxylic acids and dihydroxy compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B32—LAYERED PRODUCTS
    • B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B2307/00—Properties of the layers or laminate
    • B32B2307/70—Other properties
    • B32B2307/748—Releasability

Abstract

The present invention relates to a multi-layered nanofilm comprising graphene capable of immediate drug release control by external electrical stimulation. The present invention also provides a drug delivery system comprising a plurality of said multi-layer nanofilms. The multilayer nanofilm according to the present invention has high mechanical strength, electric sensitivity, as well as barrier properties, and is capable of storing the drug in a very stable manner in a physiological environment, and is capable of releasing the loaded drug depending on the strength and time of the electric stimulus Implements an immediate response system.

Description

[0001] MULTILAYERED NANO-FILM FOR CONTROLLING DRUG RELAEASE BASED ON STIMULI-RESPONSIVE GRAPHENE [0002]

The present invention relates to a multi-layered nanofilm capable of immediate drug release control by external electrical stimulation and a drug delivery system containing the same.

Immediate response System-based drug release is essential in a variety of biomedical fields, including tissue engineering, biomedical devices, in vitro diagnostics, and drug delivery. In particular, much effort has been devoted to the development of techniques for keeping drugs or proteins that are difficult to maintain their activity in the physiological environment in a stable manner, and administering the drug at an appropriate time for the amount required for the patient's treatment.

Recently, many researches have been conducted in relation to drug delivery. Most drug-related studies are based on a system in which a drug is released by specific stimuli such as pH change, thermal change, ultrasound, and near-infrared. The system for controlling drug release by such external stimuli is a careful and appropriate material Structure is required. In addition, the physiological environment is a very poor environment for a single protein or an existing film to withstand, and in the conventional case, most of the proteins lose their activity. Therefore, it is very important to construct a system that stably stores proteins and drugs in a physiological environment and emits them when needed.

Conventionally, a drug delivery device capable of being inserted into the body has a form in which a liquid drug is carried and released. In this case, when a liquid drug is altered due to environmental changes or the drug pocket is broken, There was a fear of shock generation due to excessive supply to the body at one time.

Accordingly, the present inventors completed the present invention in order to solve the above problems.

Korean Patent Publication No. 10-2014-0112314 Korean Patent Publication No. 10-2013-0079011

One embodiment of the present invention is directed to a method of generating electrons by external electrical stimulation produced using graphene oxide, reduced graphene oxide and a drug using layer-by-layer assembly Layer nanofilms capable of immediate drug release control. In addition, an embodiment of the present invention provides a drug delivery system comprising a plurality of the multilayer nanofilms.

One embodiment of the present invention is a multi-layered nanofilm in which a plurality of graphene thin films are laminated, wherein at least one of the plurality of graphene thin films includes a drug, and the graphene thin film containing the drug has an upper, Layered nanofilm having different electric charge from the stacked graphene thin film.

According to one embodiment of the present invention, the graphene thin film may comprise graphene oxide or reduced graphene oxide having a charge, specifically having a positive charge or negative charge.

As used herein, the term "graphene thin film" may include graphene oxide (GO) or reduced graphene oxide (rGO). The two materials have a barrier property that is strong enough to prevent permeation of an atomic unit material, so that it is possible to stably maintain the morphology of a multi-layered nanofilm or a drug delivery system in a physiological environment, It can be kept.

In the present invention, the graphene oxide or the graphene thin film containing the reduced graphene oxide may have a charge, specifically, a positive charge or a negative charge. Specifically, "graphene thin film having positive electric charge" as used in the present invention GO-NH 3 + or rGO-NH 3 + may be, "graphene thin film having a negative charge" as used in the present invention GO-COO - Or rGO-COO < - >.

According to one embodiment of the present invention, the multi-layered nanofilm may further comprise a poly (beta -amino ester) (PAE) layer, and is preferably located at an outermost position of the multi-layered nanofilm. As used herein, "poly (beta -amino ester)" is a polyester-based polymer having an ester group (R-COO-R) and contains a tertiary amine group and has positive charge properties. Polyester materials are generally less toxic than positively charged polymers in physiological environments and are degraded into non-toxic metabolites. Non-toxic poly (β-amino ester) is deposited inside the film and hydrolyzed when exposed to the physiological environment, thereby disrupting the balance of the mutual attraction between the materials inside the film and helping to release the drug .

The number of graphene thin films including graphene oxide or reduced graphene oxide in the multi-layered nanofilm can be freely controlled according to the properties of the multilayer nanofilms required in each situation, Or the conductivity can be adjusted proportionally. Specifically, as the composition ratio of graphene oxide increases, the barrier property increases, and as the composition ratio of reduced graphene oxide increases, the conductivity of the multilayer nanofilm becomes better.

According to an embodiment of the present invention, at least one of the plurality of graphene films constituting the multi-layered nanofilm of the present invention may include a drug, and there is no limitation on the position of the graphene film containing the drug, May be a graphene thin film except for the outermost layer of the multilayer nanofilm. The drug contained in the graphene thin film includes not only the drug in the graphene thin film but also the graphene in the case where the drug is placed on one side or both sides of the plate-like graphene thin film .

The term "laminate " as used herein means that the mentioned components are stacked in order of production. Such a laminated structure can be produced by a non-limiting method known in the art and can be produced by alternately dipping into various kinds of solutions, for example, using a layer and layer lamination method.

According to the present invention, the graphene thin film containing the drug of the present invention has different charges from the graphene thin film stacked on the top, bottom or top and bottom. Furthermore, they have different charges even among graphene films that do not contain adjacently stacked drugs. That is, the multi-layered nanofilm of the present invention can be bonded and laminated based on the electrostatic attraction between the graphene films having opposing kinds of charges. According to an embodiment of the present invention, when a drug having a positive charge on a surface of a graphene thin film having a negative charge is included in a plate form, since the graphene film observed in the direction in which the drug is contained has a negative charge, The laminated graphene thin film has a positive charge. On the other hand, since the graphene film observed in the direction in which the drug is not contained is positively charged, the graphene film laminated in the direction has a negative charge. Furthermore, the multilayer nanofilm of the present invention has charge opposite to that of the outermost layer, and can bond with other multilayer nanofilament units to form a larger multilayer nanofilm aggregate.

According to an embodiment of the present invention, there is no limitation on the number of the graphene thin films constituting the multilayer nanofilament of the present invention, but among the plurality of graphene thin films, x is the number of the graphene thin film containing the drug, When the graphene thin film is a y thin film, x may be a natural number and y may be an integer equal to or greater than 0, and the total thickness of the graphene thin film is preferably two to eight. Specifically, the value of (2x + y) is preferably an even number, more preferably the value of (2x + y) is 2, 4, 6, 8 or 10, 8, and even more preferably 6. In the present invention, a six-layered layer in which x is 1 and y is 4 exhibits the most excellent effect in terms of conductivity and barrier properties.

According to one embodiment of the present invention, the multi-layered nanofilm of the present invention is characterized in that the drug is released from the graphene thin film containing the drug by an external stimulus, preferably an electrical stimulus or a magnetic stimulus, more preferably an electrical stimulus . Specifically, the stimulus supplied from the outside to the multilayer nanofilm of the present invention causes electron transfer between the graphene thin films, thereby changing the electron density. As a result, a repulsive force acts between the thin films having the same charge, , The drug contained in the graphene thin film is released.

As used herein, the term "external electrical stimulation" may be an electrical stimulation that may occur in the human body, or an electrical stimulation provided finely outside the human body, but is not limited thereto. For example, three electrodes may be connected to an apparatus capable of applying and maintaining a constant potential to supply electrical stimulation to the multilayer nanofilm of the present invention. As the working electrode, the film was laminated on a gold-coated silicon wafer, a platinum mesh was used as a counter electrode, and silver-silver chloride was used as a conventional electrode. Figure 4 is a schematic diagram of a system installed to provide electrical stimulation.

As used herein, the term "drug" refers to a drug that is subject to controlled release, and may be a charged drug, specifically a solid drug that is positively charged or negatively charged. Even if it is a neutral substance, it may be included in the scope of the drug of the present invention if it is modified so as to be charged on the surface by a method known in the art. The drug of the present invention is not limited in its kind and molecular weight, and may be preferably selected from the group consisting of proteins, amino acids, hormones, vitamins, minerals, antibodies and modified small molecules.

The physiological environment includes a number of substances such as enzymes, cells, proteins, carbohydrates, etc. These drugs have various functional groups, and these functional groups easily combine with substances in the physiological environment to cause structural and chemical transformation, . However, in the absence of electrical stimulation, the drug in the multilayer nanofilm maintains a very stable state based on mutual attraction with the constituent materials of the film, and maintains the activity and structure of the drug if the drug is not released into the solution Without any deformation.

Another embodiment of the present invention provides a drug delivery system comprising the multilayer nanofilm. Biodegradable or biocompatible delivery systems for injection, immersion or insertion in or on the body to promote topical therapeutic effects. The term "biodegradable " as used herein refers to a substance that is actively or passively degraded over time by the action of a body enzyme, or other similar mechanism in the human body. As used herein, the term "biocompatibility" refers to, based on a clinical risk / benefit assessment, not causing clinically relevant tissue irritation or necrosis at the local site requiring removal of the device prior to termination of treatment do.

According to one embodiment of the present invention, the drug delivery system of the present invention can be used for the treatment of diseases or pathologies, such as injection, surgical incision, tumor or tissue removal, , Or any other similar cavity, space, or pocket, and immediately reacts to electrical stimulation through a power supply that is inserted into the drug delivery system or is wired or wirelessly connected to the drug delivery system So that it can release the correct amount exactly at the required time.

According to one embodiment of the present invention, the multi-layered nanofilm of the present invention can be applied to a three-dimensional device, but it can be manufactured in a patch-shaped drug delivery system because it can be manufactured in a smaller, thin and flexible state.

As used herein, the term " comprising " means the presence of stated elements, phases, numbers, etc., and does not preclude the presence or addition of other elements, steps,

According to the present invention, it is possible to freely adjust the thickness, structure, and capacity of a drug, etc., according to the need, and the protein is stably stored in the physiological environment through the multilayered film of the present invention, To release the correct amount exactly at the point of need. In addition, it provides a basis for many effects and continuous control with one operation.

1 shows a schematic diagram of protein release by electric stimulation in the multilayer nanofilm of the present invention.
2 shows the thickness of the nanofilm coated on the surface of a silicon substrate by the layer and layer deposition method.
Fig. 3 shows an FE-SEM image of a cross section of the multilayer nanofilm of the present invention through an electron scanning microscope.
4 is a schematic view of an experiment for confirming drug release behavior of the nanofilm of the present invention by electric stimulation.
5 is a graph showing the electrical reactivity of the nanofilm of the present invention.
FIG. 6 is a graph showing the degree of the release of ovalbumin according to the intensity of an external electrical stimulus in the nanofilm of the present invention.
FIG. 7 is a graph showing the amount of erythropoietin released according to the presence or absence of external electrical stimulation in the nanofilm of the present invention. Here, the black bar represents the amount of the offspring to be released in the presence of the electrical stimulus, and the red bar represents the amount of the offspring to be released when the electrical stimulation is absent.

Hereinafter, the present invention will be described in more detail with reference to one or more embodiments. However, these embodiments are illustrative of one or more embodiments, and the scope of the present invention is not limited to these embodiments.

1. Materials and Methods

1.1. Chemicals and Reagents

Poly (? -Amino ester) (PAE, M n : 17,500) was synthesized by a method known in the art. Fluorescein-conjugated ovalbumin (OVA) was purchased from Invitrogen.

1.2. Grapina Of oxide (GO)  synthesis

Graphene oxide (GO) was synthesized from graphite powder (45 micron, Sigma-Aldrich) using the Hummers method and reduced. It was prepared - this by introducing a carboxyl group (-COOH) of GO (GO-COO) negatively charged. (GO) through a carboxylic acid (and / or epoxide) and an excess of ethylenediamine N-ethyl-N '- (3- dimethyl- aminopropyl) carbodiimide methiodide A positively charged GO sheet was prepared by introducing an amine group (-NH 2 ) to the surface of the sheet, thereby preparing a positively charged stable GO suspension (GO-NH 3 + ).

1.3. Film manufacturing

The films were assembled by all layer and layer lamination methods using a customized programmable in-house machine. The film was constructed on an FTO-coated glass substrate treated with O 2 plasma for 5 minutes before use. Subsequently, the substrate was immersed in PAE solution (2.0 mg / ml in NaOAc 100 mM buffer) for 10 minutes and subjected to a sequential rinsing step for 3 minutes in total for 1 minute each with pH-adjusted MililQ water, COO / (r) GO-NH 3 + . The substrate was immersed first in a negatively charged (r) GO-COO - (pH 6.0) for 10 minutes, then sequentially rinsed three times for 1 minute each in DI water, followed by a gentle stream of nitrogen, ≪ / RTI > A solution of cationic (r) GO-NH 3 + (pH 6.0) was then deposited on the (r) GO-COO - (pH 6.0) -coated film through the same adsorption and rinsing steps. The substrate was placed in an ovalbumin solution (1 mg / ml in 100 mM NaOAc buffer) for 10 minutes and exposed to the same washing step as described above. To the repeated, the first six-layer film ((PAE / rGO / GO / OVA / GO / rGO) n = 1) - Then, the graphene layer deposition step (GO-NH 3 + / ( r) GO-COO) . These deposition steps were repeated until a desired number of six layers (PAE / rGO / GO / OVA / GO / rGO) n were coated on the substrate. The concentration of the carbon-object solution used in all deposition experiments was fixed at 0.1 wt% without ionic salts. The film thickness was observed with profilometry (Tecan) at five different locations on the dried film surface.

1.4. Electrochemical stimulation

The three electrode system in a single compartment cell was used for electrochemical synthesis and characterization. The working electrode was gold-coated silicon (Au / Ti / Si), the counter electrode was a platinum mesh, and the reference electrode was Ag / AgCl. EG & G (Model 273A) A potentiostat / galvanostat was used for all electrochemical experiments.

1.5. Calculation of protein release

Release experiments were carried out by immersing the prepared multilayer film in a 20 ml vial containing 3.0 ml of phosphate-buffered saline (PBS, usually osmotic pressure and ion concentration in a human-like solution) to expose the physiological environment 5% CO 2 , 37 캜). At another set of times, the film was transferred to another vial and a fresh PBS solution of eastern blood was added. After release of the ovalbumin from the multilayer film, the fluorescence spectrum of the released fluorescein-labeled ovalbumin in the PBS solution (Quantumaster Fluorometer, PTI) was measured (absorbance 494 nm / maximum fluorescence emission 520 nm). If the fluorimeter lamp was on, a calibration curve of fluorescence at a given concentration was prepared for each and every emitted urine count. An aliquot at any point in time for all released ovalbumin solutions was applied to the calibration curve to calculate the exact amount of ovalbumin. All release and film degradation studies were performed three times.

Circular polarization dichroism (CD) spectroscopy was also performed on a partial sample of the medium that was released (at 0.5 V potential).

2. Experimental results

2.1. Layers and layers Laminated  Multilayer nanofilm

It was confirmed that the thickness of the film can be controlled according to the number of repetition of the deposition step in the manufactured multi-layered nanofilm (refer to FIG. 2), and the multi-layered nanofilm can be confirmed by FE-SEM (See FIG. 3, deposition step is repeated 40 times).

2.2. Multilayer nanofilms in response to electrical stimulation

In order to check the effect of electrical stimulation, the current intensity was observed over time. As a result, when a voltage of 0.4 V was applied, a current flow was initially observed, which was the same as observed in a general conductive film.

2.3. Control of protein release by electrical stimulation

As a result of observing the degree of the discharge of the ovalbumin according to the intensity of the external electric stimulus, it was confirmed that when a strong electric stimulus was applied, a larger amount of the ovalbumin was emitted during the same time and a small amount of the ovalbumin was released from the weak electric stimulus 6). This confirms that the intensity of the stimulus can be controlled to control the release of ovalbumin as needed.

On the other hand, in the presence of electrical stimulation, it was confirmed that the discharge amount of ovalbumin gradually increased with the lapse of time, whereas the discharge of ovalbumin did not occur when electrical stimulation was absent (see Fig. 7). Through this, it was confirmed that the electrical stimuli sensitive graphene-based multi-layer nanofilm can store the ovalbumin very stably without electrical stimulation even in the physiological environment, and can release the ovalbumin at any time by the electrical stimulation.

As a result of carrying out the circularly polarized dichroism spectroscopy on a partial sample of the medium, it was confirmed that the spectrum retained the secondary structure of the released ovalbumin without denaturation (33% alpha-helix, 5% beta-structure and 62% random coil).

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than the foregoing description, and all changes or modifications derived from the meaning and scope of the claims and equivalents thereof are included in the scope of the present invention. .

Claims (10)

A multilayer nanofilm in which a plurality of graphene thin films are laminated,
Wherein at least one of the plurality of graphene thin films comprises a drug,
The graphene thin film containing the drug has different charges from the graphene thin film stacked on the upper, lower or upper and lower portions,
The graphene thin film comprises graphene oxide (GO), reduced graphene oxide (rGO) and poly (? -Amino ester) (PAE) layers having charge,
The graphene oxide (GO), the reduced graphene oxide (rGO) and the poly (β- amino ester) (PAE) layer (PAE / rGO / GO / drug / GO / rGO) n that are repeated in units of ,
Wherein the drug is released from the graphene film comprising the drug by external electrical or magnetic stimulation. delete The method according to claim 1,
Wherein the multi-layered nanofilm is controlled in proportional to barrier properties or conductivity, respectively, according to the number of graphene thin films including graphene oxide or reduced graphene oxide. The method according to claim 1,
Among the plurality of graphene films, x is a graphene film containing a drug and y is a graphene film containing no drug, x is a natural number, and y is an integer of 0 or more. 5. The method of claim 4,
Wherein the graphene thin film has a total of 2 to 8 layers. delete The method according to claim 1,
Wherein the degree of drug release from the graphene thin film comprising the drug is controlled by controlling the intensity of external electrical stimulation or magnetic stimulation. delete The method according to claim 1,
Wherein the drug is selected from the group consisting of proteins, amino acids, hormones, vitamins, minerals, antibodies, and modified small molecules. A drug delivery system comprising the multilayer nanofilm according to any one of claims 1, 3, 4, 5, 7, and 9.
KR1020160003399A 2016-01-11 2016-01-11 Multilayered nano-film for contolling drug relaease basaed on stimuli-responsive graphene KR101810761B1 (en)

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ACS Nano, 6(1), 81-88, 2012.
ACS Nano, 8(2), 1834-1843, 2014

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