KR101577951B1 - Emission control method of Nitrogen oxide using mesoporous core-shell nanoparticle and calcium phosphate - Google Patents
Emission control method of Nitrogen oxide using mesoporous core-shell nanoparticle and calcium phosphate Download PDFInfo
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Abstract
Description
The present invention relates to a method for controlling the release of nitrogen monoxide, and more particularly to a method for selectively releasing nitrogen monoxide using porous core-shell nanoparticles containing a substance capable of emitting protons by light irradiation and calcium phosphate ≪ / RTI >
Nitric oxide is a gas synthesized by a nitric oxide synthase in cells and has important functions as a physiologically active substance in vivo. In particular, it is known to be related to various physiological phenomena and diseases such as neurotransmission system, cardiovascular system and immune system.
For example, nitrogen monoxide shows opposing therapeutic effects in proportion to concentration and release time. For example, when a high concentration of nitrogen monoxide is released for a short period of time, an anticancer effect and an antibacterial effect are exhibited, and when a small amount of nitrogen monoxide is released for a long time, it is known to be associated with wound healing, cell growth and angiogenesis. However, since nitrogen monoxide exists in the form of gas, there are many restrictions on effective delivery.
The diazenium diolate, which is typically a functional group releasing nitrogen monoxide, is also referred to as a nonoate, the general formula of which can be represented by RR'NN (O) = NOR. Diazenium diolate is a solid form The diazenium diolate readily produces nitrogen monoxide and is relatively large in amount of nitrogen monoxide, such as nitrogen monoxide, carbon monoxide, But it has the problem of being released simultaneously with contact with water.
In order to overcome this, external nitric oxide release technology has been developed, but the application of external stimuli and biocompatible materials is very rare. Since drug delivery systems by external stimuli (light, pH, enzyme, temperature, magnetic field, etc.) have limited drug selectivity, it is necessary to develop a method for stable release of nitrogen monoxide in the body.
The present invention provides a porous core-shell nanoparticle capable of stably transferring an excess amount of nitrogen monoxide to a desired portion in order to solve the above problems.
In order to solve the problem of the diazenium diolate functional group which is exposed to water while simultaneously releasing nitrogen monoxide, the porous core-shell nanoparticles of the present invention induce the release of nitrogen monoxide only when irradiated from the outside, To provide an alternative method of releasing nitrogen monoxide.
The present invention relates to a porous membrane, comprising: a porous core part chemically modified with a silane coupling agent comprising a secondary amine group; And a shell part containing calcium phosphate, wherein the porous core part comprises a photoreactive pH adjusting agent, and a method for producing the same.
The present invention relates to a
The selective release method of nitrogen monoxide incorporating the porous core-shell nanoparticles of the present invention can stably transport nitrogen monoxide to a desired portion and can induce release of nitrogen monoxide only when exposed to light to maximize therapeutic effect It has the advantage of being able to.
In addition, the porous core-shell nanoparticles according to the present invention can additionally add other drugs, and it is expected that the therapeutic effect of drugs and the therapeutic effect of nitrogen monoxide can be seen through dual delivery.
Figure 1 illustrates a porous core-shell nanoparticle according to one embodiment of the present invention.
FIG. 2 illustrates a process for preparing porous core-shell nanoparticles according to an embodiment of the present invention. Referring to FIG.
FIG. 3 is a result of measurement of porous core-shell nanoparticles according to an embodiment of the present invention by transmission electron microscopy.
FIG. 4 is a graph showing the crystal structure of porous core-shell nanoparticles according to an embodiment of the present invention measured by Powder XRD. FIG.
5 is a graph illustrating the results of measurement of pH before and after light irradiation of porous core-shell nanoparticles according to an embodiment of the present invention.
FIG. 6 is a result of measurement of porous core-shell nanoparticles according to an embodiment of the present invention with an infrared spectroscope (FT-IR).
7 is a result of measurement of porous core-shell nanoparticles according to an embodiment of the present invention by ultraviolet-visible spectroscopy (UV-vis spectroscopy).
8 is a graph illustrating the results of measurement of porous core-shell nanoparticles according to an embodiment of the present invention by calcium ion detection method.
FIG. 9 is a result of measurement of porous core-shell nanoparticles according to an embodiment of the present invention through a nitrogen monoxide detector.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Reference will now be made in detail to the preferred embodiments of the present invention. Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the following description, The description of the known function and configuration will be omitted.
The present invention relates to a porous membrane, comprising: a porous core part chemically modified with a silane coupling agent comprising a secondary amine group;
And a shell portion containing calcium phosphate,
Shell nanoparticles characterized in that the porous core portion comprises a photoreactive pH adjusting agent.
In the context of the present invention, porous core-shell nanoparticles refer to porous core-shell nanoparticles having pores and arrangements of uniform size within the structure. The photoreactivity means that the chemical bonding state is changed by light irradiation, and the light source of the present invention may be ultraviolet ray (ultraviolet ray), preferably 200 to 400 nm wavelength. Also, the photoreactive pH adjusting agent means a substance capable of generating a proton by light irradiation to adjust the pH.
Hereinafter, the porous core-shell nanoparticles of the present invention will be described in more detail.
The porous core portion of silica (SiO 2), alumina (Al 2 O 3), titania (TiO 2), zirconia (ZrO 2), antimony trioxide (Sb 2 O 3), molybdenum oxide (MoO 3), tin oxide (SnO 2 ), zinc oxide (ZnO), and mixtures thereof, and may include, but is not limited to, silica (SiO 2 ).
The average diameter of the porous core-shell nanoparticles of the present invention may be 30 to 200 nm, but is not limited thereto.
The porous core-shell nanoparticles of the present invention are capable of capturing materials having various sizes, shapes, and functions, and biocompatible pores in the structure can capture foreign materials with excellent stability. Thus, the porous core-shell nanoparticles can be applied to drug and gene delivery, cell imaging, and cancer treatment.
Particularly, since the porous core-shell nanoparticles of the present invention are easily surface-functionalized, porous core-shell nanoparticles functionalized on the surface can be applied to stimulation-controlled release.
In the present invention, a functional group capable of releasing nitrogen monoxide is introduced into the porous core-shell nanoparticle, and the functional group may be " diazenium diolate ".
The diazenium diolate functionality can be obtained by reacting a secondary amine with nitrogen monoxide as shown in
[Reaction Scheme 1]
The diazenium diolate functional group releases two molecules of nitrogen monoxide per functional group, so that it can generate relatively high concentrations of nitrogen monoxide when incorporated into the carrier. However, a gatekeeper system is needed to control the release of nitrogen monoxide through external stimuli for efficient NO transfer because of the release of NO in contact with water. Thus, the present invention is capable of releasing nitrogen monoxide by reacting diazenium diolate functional groups when exposed to certain conditions in vivo.
In the present invention, a silane coupling agent containing a secondary amine group capable of forming a diazenium diol functional group can be used. The alkoxysilyl (Si-OR) functional group of the silane coupling agent, when hydrolyzed, becomes a silanol group and bonds with the inorganic material, and can connect the organic material and the inorganic material to each other.
The silane coupling agent may be represented by the following general formula (1).
[Chemical Formula 1]
(In the
In the present invention, the desired effects of the present invention can be obtained by using N- (2-aminoethyl) -3-aminopropyltrimethoxysilane (AEATS), but the present invention is not limited thereto.
In the present invention, it is possible to control the release of nitrogen monoxide by changing the pH by using a photoreactive pH adjusting agent and calcium phosphate as a gatekeeper system for controlling the release of nitrogen monoxide. The calcium phosphate used in the present invention is coated on the shell of the porous core-shell nanoparticles. When the pH is lowered, the calcium phosphate coating layer is decomposed, so that nitrogen monoxide can be selectively released.
The photoreactive pH adjusting agent used in the present invention is a substance that generates a proton by light irradiation. The o-nitrobenzaldehyde (o-NBA), m-nitrobenzaldehyde (m-NBA), p Nitrobenzaldehyde (p-NBA), and mixtures thereof. The o-NBA is a compound that releases a proton when exposed to UV at a specific wavelength. The o-NBA is a compound that is activated by nitrosobenzoic anion And eventually release the proton. Therefore, the pH is rapidly changed by the photoreaction, and such a change in pH can decompose the calcium phosphate coating layer.
The calcium phosphate used in the present invention refers to a phosphate of calcium, and preferably apatite hydroxide can be used.
The above-mentioned apatite hydroxide (Ca 10 (PO 4 ) 6 (OH) 2 ) is a bio-inorganic compound most similar to the human bone, and binds with the polymer to provide excellent bone regeneration ability, bioactivity, biocompatibility and biodegradability It can be used mainly in tissue engineering because it has characteristics of sex. The present invention can be used as a gatekeeper system that controls the release of effective nitrogen monoxide by utilizing the decomposition property when the pH is lowered.
The present invention provides a process for preparing porous nanoparticles comprising: a) treating porous nanoparticles with a silane coupling agent;
b) adding a photoreactive pH adjusting agent to the porous nanoparticles prepared in step a);
c) coating the surface of the porous nanoparticles prepared in step b) with calcium phosphate; And
d) adding nitrogen monoxide gas to the porous nanoparticles prepared in step c) to form a diazenium diol functional group;
Shell nanoparticles comprising the porous core-shell nanoparticles.
a) treating the porous nanoparticles with a silane coupling agent;
The porous nanoparticles of the present invention can be prepared by a conventional method that can be prepared by those skilled in the art. In the present invention, the porous nanoparticles may be formed by adding a surfactant to the metal precursor. The metal precursor is preferably a silica precursor
The surfactant may include at least one selected from the group consisting of a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant.
Examples of the cationic surfactant include alkyltrimethylammonium salts, alkylpyridinium salts, alkyl quaternary ammonium salts and alkyldimethylbenzylammonium salts. Examples of anionic surfactants include alkylsulfate salts, alkylsulfonate salts, alkylphosphate salts, alkyl A carboxylate, and the like can be used.
Examples of amphoteric surfactants include cocoamidopropyl betaine, cocoamphoacetate, cocoamphocarboxy glycinate, alkyl amphoacetate, sodium lauroamphoacetate and the like.
The nonionic surfactant may be a sorbitan surfactant, a sugar surfactant, or a poly (alkylene oxide) surfactant. As the sugar surfactant, alkyl polyglucoside may be used. As the sugar, 1 sugar or 2 saccharides can be used, and sucrose distearate, sucrose monostearate and the like can be used. The poly (alkylene oxide) surfactant may be a block copolymer in the form of an alkyl or aryl substituted poly (alkylene oxide), hydrophilic poly (alkylene oxide) - hydrophobic poly (alkylene oxide) (Ethylene oxide) -stearate, nonylphenol poly (ethylene oxide), sorbitan fatty acid ester with ethylene oxide, poly (ethylene oxide) -poly (propylene oxide) block copolymer, poly (ethylene oxide) -poly ) -Poly (ethylene oxide) block copolymer and the like can be used.
In the present invention, a cationic surfactant composed of a hydrophobic alkyl chain and a hydrophilic amine may be preferably used, and hexadecyltrimethylammonium bromide (CTAB), hexadecyltrimethylammonium chloride (CTACl) or the like may be used. no.
The mixture of the surfactant, the silica precursor, and the solvent may be centrifuged to prepare the porous nanoparticles.
The solvent of the present invention may be selected from the group consisting of alcohols, water, ethers, and mixtures thereof. As the alcohol solvent, methanol, ethanol, isopropanol, propanol, butanol, pentanol, But are not limited to, tetrahydrofuran, methyltetrahydrofuran, dimethyl ether, dibutyl ether, and the like.
The porous nanoparticles may be mixed with a silane coupling agent represented by the following formula (1).
[Chemical Formula 1]
(In the
Also, in the step a), the prepared porous nanoparticles can remove the surfactant. It can be immersed in a mixture of hydrochloric acid and methanol to remove the surfactant.
b) adding a photoreactive pH adjusting agent to the porous nanoparticles prepared in the step a) is as follows.
The porous nanoparticle powder prepared in the step a) may be mixed with a liquid photoreactive pH adjusting agent and dried. The photoreactive pH adjusting agent used in the present invention may be any one selected from o-nitrobenzaldehyde, m-nitrobenzaldehyde, m-nitrobenzaldehyde and mixtures thereof. .
c) coating the surface of the porous nanoparticles prepared in step b) with calcium phosphate, as follows.
The calcium phosphate used in the present invention may be apatite hydroxide (Ca 10 (PO 4 ) 6 (OH) 2 ). The apatite hydroxide may be produced by a wet process in which water-soluble calcium salt and phosphate are prepared using a liquid medium , But is not limited thereto.
The apatite hydroxide of the present invention is sensitive to pH during the reaction, so that a precipitate is formed at a pH of about 12, but the pH is decreased as the reaction progresses, and precipitates may be formed in the range of 7 to 11 at the end of the reaction.
The hydroxide apatite precipitate does not secure sufficient calcium in the crystal structure thereof in a low region having a pH of 7 or less, so that calcium apatite hydroxide apatite, i.e., disrupted apatite hydroxide can be produced.
In the present invention, the step of adjusting the pH to 7 to 11 may be performed.
d) adding a nitrogen monoxide gas to the porous nanoparticles prepared in the step c) to form a diazenium diol functional group;
The diazenium diolate functionality can be obtained by reacting a secondary amine with a nitrogen monoxide gas as shown in
[Reaction Scheme 1]
In the present invention, the introduction of the nitrogen monoxide gas can be carried out at a pressure of 40 psi to 200 psi, preferably at a pressure of 80 psi to 150 psi, but is not limited thereto.
The porous core-shell nanoparticles of the present invention can selectively emit nitrogen monoxide by light irradiation, and the light irradiation preferably irradiates ultraviolet rays of 200 to 400 nm.
The porous core-shell nanoparticles of the present invention may additionally contain a pharmacological effect substance on the inside or on the surface thereof. In addition to the nitrogen monoxide effect of the present invention, additional pharmacological effects may be used for the purpose. Such pharmacological effect substances may include, but are not limited to, substances that prevent thrombus formation or blood coagulation, antioxidants, antiinflammatory agents, wound healing promoting substances, antibacterial agents, etc., The therapeutic effect of nitrogen can be seen.
Hereinafter, the present invention will be described in more detail by way of examples. It should be understood, however, that the following examples are only illustrative and not intended to limit the scope of the present invention.
[Example 1]
1. Reaction of porous silica nanoparticles with silane coupling agent (MSN-AEATS)
To a solution of 1 g of CTAB (Cetyltrimethylammonium bromide) in 500 ml of distilled water was added 3.5 ml of 2 M NaOH solution. After stirring for 15 minutes, 5 ml of TEOS (tetraethyl orthosilicate) was added. After stirring at 80 DEG C for 3 hours, the solution was filtered, washed with MeOH three times, and dried. 0.5 g of the dried powder, 100 ml of EtOH and 0.5 ml of AEATS (N- (2-aminoethyl) -3-aminopropyl trimethoxysilane) were added and refluxed for 3 hours in a suspension reaction. After centrifugation (7000 rpm, 10 min), the cells were washed three times with MeOH. The solution was dissolved in a mixture of 16 ml of MeOH and 1 ml of concentrated hydrochloric acid by dissolving at 60 ° C for 24 hours. Through this process, CTAB was dissolved to obtain porous silica nanoparticles (MSN-AEATS) mixed with AEATS.
2. Reaction of photoreactive pH adjusting agent (pH @ MSN-AEATS)
To 100 mg of MSN-AEATS obtained above, 10 ml of o-NBA (2-nitrobenzaldehyde) was mixed and allowed to stand at room temperature for 24 hours. And freeze-dried for 48 hours to obtain pH @ MSN-AEATS.
3. Reaction with calcium phosphate (pH @ MSN-CaP)
To 100 mg of the obtained pH @ MSN-AEATS was dissolved in 10 ml of 0.1 M (NH 4 ) 2 HPO 4 , and the pH was adjusted to 10 by addition of aqueous ammonia. 20 ml of 0.1 M Ca (NO 3 ) 2 .4H 2 O was added dropwise and reacted at 60 ° C for 1 hour. After centrifugation (7000 rpm, 10 min), the cells were washed three times with deionized water. And freeze-dried for 48 hours to obtain pH @ MSN-CaP.
4. Reaction of diazenium diolate functional groups (pH @ MSN-CaP-NO)
10 mg of the obtained pH @ MSN-CaP is dissolved in 3 ml of 0.5 M NaOMe / MeOH and placed in a high-pressure reactor. The reactor was purged twice with 20 psi of Ar gas and then reacted with 80 psi of NO gas for 3 days. The pH @ MSN-CaP-NO with a diazenium diolate group capable of releasing the nitrogen monoxide was separated by centrifugation (7000 rpm, 10 min) and the remaining solvent was removed by vacuum drying.
[Characteristic evaluation]
Light irradiation was observed for the porous silica nanoparticles and nitrogen monoxide release behavior after irradiation prior to 365nm (300μW / cm 2) UV .
(1) Confirmation of porous silica nanoparticles
Transmission Electron Microscopy (JEOL JEM-1011 Japan) was used to identify the porous silica nanoparticles. As a result of checking the size and distribution through FIG. 3, it was confirmed that the layer was uniformly formed with a size of about 4 to 50 nm, and the surface calcium phosphate layer was collapsed when exposed to ultraviolet rays.
(2) Analysis of crystal structure
The surface of the porous silica nanoparticles was observed through Powder XRD (using Cu Kα 1 radiation (λ = 1.54 A) from Rigaku SmartLab at 40 kV and 30 mA. powder XRD showed a specific peak only in porous silica nanoparticles and a decrease in surface area due to calcium phosphate and no change in crystal structure due to surface modification. The results are shown in Fig.
(3) Confirmation of operation of pH adjusting agent by UV
In order to confirm that the pH was changed by UV, o-NBA was irradiated with UV, and it was confirmed that the pH changed from 8 to 5. In the same way, the pH adjustment agent was added to the porous silica particles. And the pH was decreased. When pH was lowered by coating with calcium phosphate, it was confirmed that pH was increased due to phosphate ion (pKb = ~ 10 - 2 ) resulting from the collapse of calcium phosphate layer. The results are shown in Fig.
(4) Determination of nitrogen monoxide by infrared spectroscopy (FT-IR), UV-vis spectroscopy
As a result of observing the porous silica nanoparticles through the infrared spectroscope and the ultraviolet - visible spectroscope by the surface modification step, it was confirmed that the nitrogen was released due to nitrogen monoxide. UV-vis spectroscopy The absorption band of the diazenium diolate was recorded at 250-260 nm. The results are shown in Fig. 6 and Fig.
(5) Calcium ion detection by UV (Arsenazo assay)
(Arsenazo Ⅲ complexion method) [Micaylova Ⅴ. Et al., Anal. Chim. Acta, 53 (194), 1971]
The amount of calcium ions detected was determined by standing for 1 hour in UV to confirm that the pH adjuster was activated by UV to cause collapse of the surface calcium phosphate layer. 6.4% of calcium ions were detected in the case of no UV exposure, but 56% of calcium ions were detected in the case of irradiation, confirming the operation of the pH adjusting agent. The results are shown in Fig.
(6) Nitric oxide detector (SieversNOA)
The emission of nitrogen monoxide by light irradiation was checked using a nitrogen monoxide detector (SieversNOA, GE analytical instruments, USA). As a result, when nitrogen was not irradiated, the emission of nitrogen monoxide rarely occurred. 25 times and the total emission amount was increased more than 10 times. In addition, experiments on on / off of UV showed that the release of nitrogen monoxide occurs only when UV is on. The results are shown in Fig.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, Those skilled in the art will recognize that many modifications and variations are possible in light of the above teachings.
Accordingly, the spirit of the present invention should not be construed as being limited to the embodiments described, and all of the equivalents or equivalents of the claims, as well as the following claims, belong to the scope of the present invention .
Claims (12)
And a shell portion containing calcium phosphate,
Wherein the porous core portion comprises a photoreactive pH adjusting agent.
The porous core portion of silica (SiO 2), alumina (Al 2 O 3), titania (TiO 2), zirconia (ZrO 2), antimony trioxide (Sb 2 O 3), molybdenum oxide (MoO 3), tin oxide (SnO 2 ), zinc oxide (ZnO), and mixtures thereof.
Wherein the silane coupling agent is represented by the following formula (1).
[Chemical Formula 1]
(In the formula 1,
R 1 and R 2 are each independently a (C 1 to C 12) alkylene group, R 3 and R 4 are each independently a (C 1 to C 4) alkyl group, and n is 1 to 3.)
Wherein the silane coupling agent comprises a diazenium diolate functional group formed by the reaction of a secondary amine group with nitrogen monoxide.
Wherein the photoreactive pH adjusting agent is a porous core comprising at least one selected from o-nitrobenzaldehyde, m-nitrobenzaldehyde, m-nitrobenzaldehyde, Shell nanoparticles.
Wherein the calcium phosphate is apatite hydroxide (Ca 10 (PO 4 ) 6 (OH) 2 ).
b) adding a photoreactive pH adjusting agent to the porous nanoparticles prepared in step a);
c) coating the surface of the porous nanoparticles prepared in step b) with calcium phosphate; And
d) adding nitrogen monoxide gas to the porous nanoparticles prepared in step c) to form a diazenium diol functional group;
Shell nanoparticles. ≪ Desc / Clms Page number 20 >
Wherein the porous nanoparticles are formed by adding a surfactant to the metal precursor in the step a).
The metal precursor
Wherein the surfactant comprises at least one selected from the group consisting of a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant.
Wherein the pH is adjusted to 7 to 11 in the step c).
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