KR101888763B1 - Nanofiber for storage and delivery of nitric oxide - Google Patents

Abstract

The present invention provides a nanofiber that allows NO release to take place slowly over a long period of time as a means of storing and transporting NO. For this purpose, the present invention relates to a method for producing a polymer electrolyte membrane, which comprises a mercaptoalkoxysilane in which NO is stored, a polymer having a functional group capable of a sol-gel reaction, and a network structure in which a backbone silane is bonded with a siloxane bridge (Si-O-Si) And NO provides nanofibers that are stably present in such a network structure. These nanofibers can control the NO storage and transferring performance depending on the concentration of mercaptoalkoxysilane stored in the manufacturing process, the concentration of mercaptoalkoxysilane, and the type of solvent. In addition, since NO is released under various conditions, it is possible to control the release rate and amount of NO by appropriately controlling them. In addition, there is an advantage that the NO storing process is easy.

Description

Nanofiber for storage and delivery of nitrogen monoxide (Nanofiber for storage and delivery of nitric oxide)

The present invention is directed to nanofibers capable of storing and transporting nitrogen monoxide. More specifically, the nanofibers of the present invention have a network structure in which a mercaptoalkoxysilane containing nitrogen monoxide is bonded by a siloxane bridge (Si-O-Si). This is a polymer having a functional group capable of sol- Gel reaction with silane. The nanofibers of the present invention are also obtained from electrospinning.

Nitric Oxide (Nitric Oxide) or NO (Nitric Oxide) is used in combination with the same Nitric Oxide (Nitric Oxide) , Immune response, and other physiological processes. Due to the discovery of the importance of the physiological role of nitrogen monoxide, studies have been actively made on methods for not only stably storing nitrogen monoxide in a substance but also accurately delivering it to a site to be delivered. There have been many reports of substances capable of storing and transporting nitrogen monoxide. Among the substances capable of storing and transporting nitrogen monoxide, there is a possibility that the nanofibers are excellent in biocompatibility and have a good effect in the medical field.

First, the N-substituted amine groups - Dia Jenny help diol rate (N -diazeniumdiolate) to form a sol for forming a polymer of an amino alkoxy silane and siloxane bridges (Si-O-Si) which stores nitrogen monoxide-electric gel after reaction There is a literature on nanofibers obtained by spinning (Korean Patent Laid-Open Publication No. 10-2014-0110360). However, according to this method, in the process of storing NO in the aminoalkoxysilane, it is dangerous to add poisonous NO gas to the high pressure of about 5 to 10 atm, and this condition is required to be maintained for 3 days, . In addition, N- diazeniumdiolate-based NO donor releases NO by heat or H ⁺ . At this time, since the amount of NO released at the early stage is large, it may cause cytotoxicity when applied to a living body. Since the primary amine groups contained in the aminoalkoxysilane are toxic, the remaining polymer itself may become toxic after the release of NO.

Next, there is a method of physically mixing a small molecule (a small molecule or a dendrimer) storing nitrogen monoxide with a polymer capable of electrospinning and then making nanofibers (Worley, BV; Soto, RJ; Kinsley, PC; Schoenfisch MH ACS Biomaterial 2016 , 2 , 426-437 and Koh, A .; Carpenter, AW; Slomberg, DL; Schoenfisch, MH ACS Appl. Mater. Interfaces 2013 , 5 , 7956-7964). However, there is a problem in that the substances storing physically the nitrogen monoxide stored in the nanofibers can easily escape out of the nanofibers, and the nitric oxide storage material thus exiting can not know what side effects are caused in the living body.

(Lowe, A .; Deng, W .; Smith, DW; Balkus, KJ ACS Macromolecules 2012 , 45 , 5894-5900), in which nanofibers are prepared first by melt- This method is disadvantageous in that it can not be radiated in the state where NO is stored and also it is necessary to expose the NO gas to high pressure NO gas for a long time after fabricating the nanofiber and since NO is not stored in the inside of the nanofiber, And the storage efficiency of NO is lower than that of the polymer storing NO before.

Finally, first making a polymer with SH groups way to create nanofibers to store NO (Damodaran, VB; Joslin, JM; Wold, KA; Lantvita, SM;.. Reynolds, MM J. Mater Chem 2012, 22 , 5990) is difficult to control the storage and release characteristics of NO because the amount of NO stored depends on the degree of polymerization and composition of the polymer itself.

The present invention seeks to provide a means for storing and delivering NO to allow NO release to take place slowly over a long period of time. In addition, it is possible to control the storage and transmission of NO in the manufacturing process of nanofibers, and it is then easy to control the release rate and amount in the process of releasing NO. Also, it is an object of the present invention to provide a nanofiber for NO storage and delivery which is easy to manufacture because no NO gas is required for a long time or a high pressure even in the process of storing NO.

The present invention relates to a method for producing a polymer electrolyte membrane comprising a mercaptoalkoxysilane in which nitrogen monoxide is stored, a polymer having a functional group capable of sol-gel reaction, and a NO (NO) structure in which a backbone silane is bonded with a siloxane bridge (Si-O- Providing nanofibers for storage and delivery.

Preferably, the nanofibers are formed by electrospinning a gel formed from a sol-gel reaction.

Preferably, the mercaptoalkoxysilane is represented by the formula:

Si (OR ¹ ) _m R ² _n R ³ SH

R ¹ and R < ² > are each independently a C1-C14 alkyl group;

R ³ is a C1-C14 alkylene group which may contain 1 to 5 heteroatoms N or 0 respectively;

n + m = 3, 1? m? 3, and 1? n? 3.

Preferably, the functional group capable of sol-gel reaction is an alkoxysilane group.

Preferably, the polymer is selected from the group consisting of Nylon-6,6 (PA-6,6), Polyurethanes (PU), Polybenzimidazole (PBI), Polycarbonate (PC)), polyacrylonitrile (PAN), polyvinyl alcohol (PVA), polylactic acid (PLA), polyethylene-co- vinyl acetate (PEVA), polymethacrylate (PMA), polyethylene oxide (PEO), polyaniline (PANI), polyvinylcarbazole, polyethylene terephthalate (PET), polyacrylic acid-polypyreneemethanol (PAA-PM), polystyrene (PS), polymethylmethacrylate (PMMA), polyamide (PA) ), Polyvinylphenol (PVP), poly Polyvinylchloride (PVC), cellulose acetate (CA), polyvinyl alcohol (PVA), polyacrylamide (PAAm), poly (lactic-co-glycolic acid) ), Collagen, polycaprolactone (PCL), poly (2-hydroxyethyl methacrylate) (HEMA), poly (vinylidene fluoride) Polyetherimide (PEI), polyethylene glycol (PEG), nylon-4,6 (PA-4,6)), polyvinylidene fluoride (PVDF) , Poly (ferrocenyldimethylsilane) (PFDMS), poly (ethylene-co-vinyl alcohol), polyvinyl pyrrolidone (PVP )), Polymethaphenyleneisophthalamide, and combinations thereof.

Preferably, the polymer is poly (methyl methacrylate-co-hexyl methacrylate-co- (trimethoxysilylpropyl) methacrylate) (poly (MMA- co- HMA- co- SiMA).

 Preferably, the backbone silane is selected from the group consisting of methyltrimethoxysilane (MTMOS), ethyltrimethoxysilane (ETMOS), propyltrimethoxysilane (PTMOS), isobutyltrimethoxysilane isobutyltrimethoxysilane (BTMOS)), and combinations thereof.

Preferably, the mercaptoalkoxysilane containing NO is prepared by reacting NaNO ₂ and mercaptoalkoxysilane under acid catalysis in the absence of light, and then neutralizing the alkoxide.

Preferably, a Lewis base is used in the neutralization.

Preferably, the mercaptoalkoxysilane containing NO is contained in an amount of 1 to 15 mol%.

Preferably, at least one solvent selected from the group consisting of methanol, ethanol, propanol, butanol and pentanol is used as a solvent in the sol-gel reaction.

The mercaptoalkoxysilane used in the production of the nanofibers of the present invention is advantageous because it stores nitrogen monoxide in a short time (less than 1 hour) and does not use high-pressure NO gas. In addition, the storage and transport properties of NO can be controlled by the concentration of mercaptoalkoxysilane containing nitrogen monoxide and the selection of mercaptoalkoxysilane and solvent during the production of nanofibers. Furthermore, since various means such as light and heat exist in the means for emitting NO from the nanofibers, the release rate and the release amount of NO can be easily controlled by controlling them. In particular, when the nanofibers of the present invention are applied in vivo, since NO is continuously released for a long time in a small amount, the problem caused by the release of a large amount of NO at the same time can be solved.

FIG. 1 shows a process in which NO is stored and released under various conditions in the nanofiber of the present invention.
2 shows a network structure formed from the sol-gel reaction in the nanofiber manufacturing process of the present invention.
Figure 3 shows the process of storing nitrogen monoxide in a mercaptoalkoxysilane.
FIG. 4 shows a process in which a siloxane bridge (Si-O-Si) is formed from a hydrolysis and condensation reaction occurring in a sol-gel reaction.
Fig. 5 shows an electrospinning apparatus used for manufacturing nanofibers of the present invention.
FIG. 6 shows a process for producing an embodiment of a polymer (poly (MMA- co- HMA- co- SiMA)) included in the nanofibers of the present invention.
7 is a SEM photograph of the nanofibers prepared in Examples 1-1 and 1-2.
8 is a SEM photograph of the nanofibers prepared in Examples 2-1 to 2-4.
9 is a SEM photograph of the nanofibers prepared in Examples 3-1 to 3-4.
10 is an SEM photograph of nanofibers prepared in Examples 4-1 to 4-4.
11 is a SEM photograph of the nanofibers prepared in Examples 5-1 to 5-4.
12 is a SEM photograph of the nanofiber prepared in Example 6. Fig.
13 shows curves and instantaneous maximum emission ([NO] _m ) and total emission amount (t [NO]) of NO emission characteristics of the nanofibers produced in Examples 1-1 and 1-2.
14 is a graph showing curves and instantaneous maximum emission ([NO] _m ) and total emission amount (t [NO]) of NO emission characteristics of the nanofibers prepared in Examples 2-1 to 2-4.
FIG. 15 shows curves and instantaneous maximum emission ([NO] _m ) and total emission amount (t [NO]) of NO emission characteristics of the nanofibers prepared in Examples 3-1 to 3-4.
FIG. 16 shows curves and instantaneous maximum emission ([NO] _m ) and total emission amount (t [NO]) of NO emission characteristics of the nanofibers prepared in Examples 4-1 to 4-4.
17 shows curves and instantaneous maximum emission ([NO] _m ) and total emission amount (t [NO]) of NO emission characteristics of the nanofibers prepared in Examples 5-1 to 5-4.
FIG. 18 shows curves and instantaneous maximum emission ([NO] _m ) and total emission amount (t [NO]) of the NO emission characteristics of the nanofibers prepared in Example 6. FIG.
Fig. 19 shows elemental analysis results of the nanofibers prepared in Examples 3-4, 4-4, 5-4 and 6, and the sulfur content thereof together with the total emission amount (t [NO]) of NO.
20 shows the results of NO emission by the photocatalyst of the nanofibers prepared in Example 5-4.
Fig. 21 shows the results of thermal NO emission of the nanofibers prepared in Example 5-4. Fig.
22 shows the results of NO release by the copper catalyst of the nanofiber prepared in Example 5-4.

The present invention relates to biocompatible nanofibers for storing and delivering nirric oxide (NO), in particular mercaptoalkoxysilanes as means for storing nitrogen monoxide.

FIG. 1 shows a process in which nitrogen monoxide is stored in a mercaptoalkoxysilane and nitrogen monoxide is released therefrom by a catalyst such as light, heat or copper. In particular, as shown in the case of nitrogen monoxide emission, there are various conditions such as light, heat or metal catalyst (Cu ²⁺ , Ag ⁺ , Hg ⁺ ). Therefore, the release rate and the release amount can be easily adjusted by appropriately combining and adjusting them.

In the nanofiber of the present invention, the mercaptoalkoxysilane containing the nitrogen monoxide is stably bound to the network structure by the siloxane bridge (Si-O-Si). To this end, a siloxane bridge (Si-O-Si) is formed by sol-gel reaction of the alkoxysilane moiety of the mercaptoalkoxysilane containing nitrogen monoxide with a polymer having a functional group capable of sol-gel reaction in the molecule and a backbone silane, Structure. FIG. 2 shows a process for producing nanofibers according to the present invention. It can be seen that nitrogen monoxide stably exists in a network structure formed from a sol-gel reaction. In order to achieve such a network structure, the above-described siloxane bridges must be formed. Therefore, the polymer and the backbone silane used for preparing the nanofibers of the present invention must contain an alkoxysilane group.

The mercaptoalkoxysilane is represented by the formula:

Si (OR ¹ ) _m R ² _n R ³ SH

R ¹ and R < ² > are each independently a C1-C14 alkyl group;

R ³ is a C1-C14 alkylene group which may contain 1 to 5 heteroatoms N or 0 respectively;

n + m = 3, 1? m? 3, and 1? n? 3.

That is, Si may contain 1 to 3 alkoxy groups, and the thiol group (-SH) may be connected to Si through an alkylene group having 1 to 14 carbon atoms, wherein the carbon atom of the alkylene group to which the thiol group is connected is a heteroatom N or O may be included in each of 1 to 5 groups.

The present invention preferably provides 3-mercaptopropyltrimethoxysilane (MPTMS) or 3-mercaptopropyltriethoxysilane (MPTES) as the mercaptoalkoxysilane. However, the present invention is not limited thereto, and any mercaptoalkoxysilane containing a thiol group (-SH) at the terminal thereof and capable of forming a network structure by bonding with a polymer and a backbone silane and a siloxane bridge (Si-O-Si) And it is to be understood that such compounds also have the scope of the present invention.

In order to store nitrogen monoxide in the mercaptoalkoxysilane, Nitrite and mercaptoalkoxysilane are reacted with an acid catalyst for preferably about one hour in the state of blocking light to prepare an S -nitrosothiol solution. Since the acid is used as a catalyst in the process of storing nitrogen monoxide in mercaptosilane, the S -nitrosothiol solution is strongly acidic at a pH of 1 or less. However, since the sol-gel reaction proceeds by an acid or base catalyst, a strongly acidic S -nitrosothiol solution quickly undergoes a sol-gel reaction, making it impossible to conduct electrospinning. Therefore, it is necessary to neutralize the pH of the solution to about 5 ~ 6. At this time, if the Arlenius base such as NaOH is used for neutralization, water is generated as the neutralization reaction occurs, and a sol-gel reaction is also generated by the generated water, and a precipitate is formed in the S -nitrosothiol solution. Therefore, in the present invention, a S -nitrosothiol solution is neutralized using a Lewis base such as NaOMe to finally produce a mercaptoalkoxysilane ( S -nitrosothiol solution) containing nitrogen monoxide.

Next, a polymer having a functional group capable of sol-gel reaction in the molecule may have a functional group capable of sol-gel reaction in the molecule, or may have a sol-gel reaction And a polymer having a functional group capable of reacting with the polymer. The functional group capable of sol-gel reaction is preferably an alkoxysilane group as described above. The polymer may be specifically a polyamide such as Nylon-6,6 (PA-6,6), Nylon-4,6 (PA-4,6) (PA)), polyurethanes (PU), polybenzimidazole (PBI), polycarbonate (PC), polyacrylonitrile (PAN), polylactic acid Polylactic acid (PLA), polyethylene-co-vinyl acetate (PEVA), polymethacrylate (PMA), polyethylene oxide (PEO), and polyaniline PANI), polyvinylcarbazole, polyethylene terephthalate (PET), polyacrylic acid-polypyrenemethanole (PAA-PM), polystyrene (PS), poly Methyl methacrylate (PMMA), polyvinylphenol (PVP), poly Polyvinylchloride (PVC), cellulose acetate (CA), polyvinyl alcohol (PVA), polyacrylamide (PAAm), poly (lactic-co-glycolic acid) ), Collagen, polycaprolactone (PCL), poly (2-hydroxyethyl methacrylate) (HEMA), poly (vinylidene fluoride) Poly (vinylidene fluoride) (PVDF), polyether imide (PEI), polyethyleneglycol (PEG), poly (ferrocenyldimethylsilane) (PFDMS) (Ethylene-co-vinyl alcohol), polyvinyl pyrrolidone (PVP), polymethaphenyleneisophthalamide, and combinations thereof. And the like.

In the present invention, poly (methyl methacrylate-co-hexyl methacrylate-co- (trimethoxysilylpropyl) methacrylate) (poly (MMA- co- HMA- co- SiMA) However, the present invention is not limited thereto, and any of the various polymers may be used without restriction as long as it contains an alkoxysilane group for the sol-gel reaction.

Finally, as the backbone silane, trimethoxysilane may be used as the silane coupling agent such as methyltrimethoxysilane (MTMOS), ethyltrimethoxysilane (ETMOS), propyltrimethoxysilane (PTMOS) or isobutyl (Isobutyltrimethoxysilane (BTMOS)) and the like can be used without limitation as long as they contain trialkoxy silane.

As described above, alkoxysilane groups are included in all of the three components used for manufacturing the nanofibers of the present invention, i.e., the mercaptoalkoxysilane storing the nitrogen monoxide, the polymer and the backbone silane, and when the sol-gel reaction is performed, siloxane bridges (Si -O-Si).

The sol-gel reaction is a process of forming a siloxane bridge (Si-O-Si) by hydrolysis and condensation reaction of an alkoxysilane group as shown in FIG. As a result, the nitrogen monoxide stored in the mercaptoalkoxysilane can stably exist in the network structure.

Sol-gel reactions include acid catalysts such as hydrochloric acid or acetic acid; A base catalyst such as ammonia water or KOH; Gold, copper or aluminum, and the rate of the reaction can be controlled by changing the type and amount of the solvent, the kind and amount of the catalyst, the amount of water, and the pH. The degree of reaction can be controlled by controlling the reaction time from several minutes to several tens of hours.

In the sol-gel reaction, alcohols such as methanol, ethanol, propanol, butanol or pentanol may be used as the solvent, but the present invention is not limited thereto. The type of solvent is related to the rate of sol-gel reaction with the type of mercaptoalkoxysilane in which the nitrogen monoxide is stored. That is, the reaction rate becomes slower as the solvent goes to methanol, ethanol, propanol and butanol. In the case of mercaptoalkoxysilane, the longer the length of the alkoxy group substituted with the silane group becomes, the more the 3-mercaptopropyltrimethoxysilane -mercaptopropyltrimethoxysilane (MPTMS), and 3-mercaptopropyltriethoxysilane (MPTES). The slower rate of the sol-gel reaction means that much more siloxane bridge (Si-O-Si) formation can occur among the molecules, thus allowing more stable storage of nitrogen monoxide within the network structure. As a result, the storage and transmission of nitrogen monoxide in the nanofibers are improved. Therefore, the nanofiber of the present invention can control the storage and transmission of nitrogen monoxide by controlling the substituent of the mercaptoalkoxysilane used in the production and the alkyl group of the solvent used.

However, in the case of the solvent, it is not only good that the length of the alkyl group is indefinitely long, and as shown in the following examples, the best preservation and storage of NO is achieved in the case of butanol.

Also, in the present invention, the storage stability and the achievement of NO can be controlled by controlling the amount of mercaptoalkoxysilane stored in the nitrogen monoxide included in the sol-gel reaction. That is, the amount of NO released from nanofibers produced in proportion to the concentration of mercaptoalkoxysilane in which nitrogen monoxide is stored increases. In the present invention, it is preferable that 1 to 15 mol% of mercaptoalkoxysilane containing nitrogen monoxide is contained in the production of nanofibers. If it is contained in an amount exceeding 15 mol%, the result is that the NO emission is reduced rather than the network structure. In addition, depending on the type of mercaptoalkoxysilane, there is a concentration showing a maximum amount of NO emission. For example, in the case of 3-mercaptopropyltrimethoxysilane, the network structure is formed even when the concentration is 9 mol% .

When the gel formed by the sol-gel reaction is electrospun, the nanofiber of the present invention is produced. As the electrospinning method, a conventional method used for producing nanofibers can be used. A schematic view of the apparatus is shown in Fig. In the vertically positioned spinning projections, an equilibrium between gravity and surface tension forms hemispherical droplets, and when an electric field is applied to the suspended polymer solution, a force opposite to the surface tension is generated. The hemispherical droplets are elongated conically, and when the electric field exceeds a certain level, the charged polymer solution forms a taylor corn while continuously overcoming the surface tension and is continuously discharged from the jet. When the viscosity is high, the jet does not collapse but the air is blown toward the grounded collecting plate, the solvent evaporates, and the charged polymer fibers in the continuous continuous phase are accumulated on the collecting plate. The jet of the polymer solution appears as a force that increases the surface area due to the repulsive force of the electrostatic field during movement, and as a result, the diameter of the fiber can be reduced to nano size.

Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are provided to facilitate understanding of the invention and should not be construed as limiting the invention thereto.

Example 1-1

1. Storage of nitrogen monoxide in a mercaptoalkoxysilane (Preparation of S -nitrosothiol solution)

Mercaptoacetyltrimethoxysilane (MPTMS) (194.34 g / mol, density: 1.051 , GELEST , SIM6476.0) as mercaptoalkoxysilane was added to 3.0265 mL of methanol as a solvent, and 0.1875 mL (1 mmol) 0.15 mL (1.5 mmol) of 10 M NaNO _{2 in} diethylene tetramine penta-acetic acid (DTPA) and 0.136 mmol (1.5 mmol) of 11 M HCl were added in turn as a nitrogen monoxide source, It was thoroughly mixed for 1 hour. At this time, proceeding with blocking of light (preparation of NO-MPTMS solution).

After 1 hour reaction, 5.4 M NaOMe in methanol (30 wt%) was added to 0.076 mL to neutralize the solution.

The prepared solution ( S - nitrosothiol solution) was kept in the refrigerator with the light blocked until use.

2. Synthesis of polymers with functional groups capable of sol-gel reaction

A polymer as shown in FIG. 6 was synthesized and used as a polymer having a functional group capable of sol-gel reaction. 30 mL of toluene was added as a solvent to a 100 mL two neck flask equipped with a distillation column, and the temperature was raised to 80 ° C. Next, 3.9 mL (30 mmol) of 60 mol% MMA (methylmethacrylate), 1.98 mL (10 mmol) of 20 mol% of HMA (hexylmethacrylate) and 2.35 mL (10 mmol) of 20 mol% of SiMA (trimethoxysilylpropyl) methacrylate And the mixture was thoroughly mixed. 16.4 mg of azobisisobutyronitile (AIBN) was dissolved in 2.5 mL of methanol, added at a rate of 5 mL / hr for 30 minutes, and then reacted at 80 ° C. for 12 hours to obtain a polymer Were synthesized. After the synthesis, toluene was removed by distillation under reduced pressure and vacuum drying. The remaining monomers and catalyst were removed by hexane three times, and vacuum dried again for 2 hours. The dried polymer was packed in vacuum until use.

3. Sol-gel reaction

The polymer prepared in 2 above was prepared as a 30 wt% polymer solution in a mixed solution of acetone and dimethylformamide (DMF) (acetone 75%, DMF 25%). Then, 1 g of the prepared S- (0.29 mmol) of methyltrimethoxysilane (MTMOS) as a backbone silane, and 746 μL of methanol as a solvent were mixed, and the mixture was stirred at 4 ° C in a state of blocking light The reaction was continued for 1 hour with stirring.

4. Electrospinning

The gel-like reaction product obtained by the sol-gel reaction was placed in a 5 mL syringe and fibers having a nano-level diameter were prepared using the electrospinning apparatus as shown in FIG. At this time, 25 G was used for the nozzle, and the distance between the nozzle and the electrode was fixed to 15 cm. The injection speed of the syringe pump was 0.6 mL / hr and the applied voltage was maintained at 17.5 kV.

Examples 1-2

Except using 518 μL (0.146 mmol) of S -nitrosothiol solution, 31.5 μL (0.22 mmol) of methyltrimethoxysilane (MTMOS) and 497 μL of methanol in the sol-gel reaction of Example 1-1 And the nanofibers were prepared in the same manner.

Example 2-1

The nanofibers were prepared in the same manner as in the preparation of the S -nitrosoethiol solution of Example 1-1 except that ethanol was used as a solvent instead of methanol and ethanol was used as a solvent in the sol-gel reaction.

Example 2-2

Except using 518 μL (0.146 mmol) of S -nitrosothiol solution, 31.5 μL (0.22 mmol) of methyltrimethoxysilane (MTMOS) and 497 μL of ethanol in the sol-gel reaction of Example 2-1 And the nanofibers were prepared in the same manner.

Example 2-3

Except for using 775 μL (0.22 mmol) of S -nitrosothiol solution, 21 μL (0.14 mmol) of methyltrimethoxysilane (MTMOS) and 248 μL of ethanol in the sol-gel reaction of Example 2-1 And the nanofibers were prepared in the same manner.

Examples 2-4

In the sol-gel reaction of Example 2-1, 1036 μL (0.29 mmol) of S -nitrosothiol solution and 10.5 μL (0.07 mmol) of methyltrimethoxysilane (MTMOS) were used and no ethanol was added The nanofibers were prepared in the same manner.

Example 3-1

In the preparation of the S -nitrosothiol solution of Example 2-1, 2.954 mL of ethanol as a solvent and 3-mercaptopropyltriethoxysilane (MPTES) (238.42 g / mol, density : 0.9325, GELEST , SIM 6475.0) 0.26 mL (1 mmol) was used.

Example 3-2

Except using 518 μL (0.146 mmol) of S -nitrosothiol solution, 31.5 μL (0.22 mmol) of methyltrimethoxysilane (MTMOS) and 497 μL of ethanol in the sol-gel reaction of Example 3-1 And the nanofibers were prepared in the same manner.

Example 3-3

Except that 21 μL (0.14 mmol) of S -nitrosothiol solution, 775 μL (0.22 mmol) of methyl-trimethoxysilane (MTMOS) and 250 μL of ethanol were used in the sol-gel reaction of Example 3-1 And the nanofibers were prepared in the same manner.

Example 3-4

In the sol-gel reaction of Example 3-1, 1036 μL (0.29 mmol) of S -nitrosothiol solution and 10.5 μL (0.07 mmol) of methyltrimethoxysilane (MTMOS) were used and no ethanol was added The nanofibers were prepared in the same manner.

Example 4-1

Production of nanofibers was carried out in the same manner except that 1-propanol was used as the solvent in the preparation of the S -nitrosoethiol solution of Example 3-1 and 1-propanol was used as the solvent in the sol-gel reaction Respectively.

Example 4-2

Using 518 μL (0.146 mmol) of S -nitrosothiol solution, 31.5 μL (0.22 mmol) of methyltrimethoxysilane (MTMOS) and 497 μL of 1-propanol in the sol-gel reaction of Example 4-1 The nanofibers were prepared in the same manner except that

Example 4-3

In the sol-gel reaction of Example 4-1, 21 μL (0.14 mmol) of S -nitrosothiol solution, 775 μL (0.22 mmol) of methyltrimethoxysilane (MTMOS) and 250 μL of 1-propanol The nanofibers were prepared in the same manner except that

Example 4-4

In the sol-gel reaction of Example 4-1, 1036 μL (0.29 mmol) of S -nitrosothiol solution and 10.5 μL (0.07 mmol) of methyltrimethoxysilane (MTMOS) were used and 1-propanol was not added The nanofibers were prepared in the same manner except that the catalyst was not added.

Example 5-1

In the same manner as in Example 3-1 except that n-butanol was used in place of ethanol as a solvent and n-butanol was used as a solvent in the sol-gel reaction in the preparation of the S -nitrosothiol solution of Example 3-1, Respectively.

Example 5-2

Using 518 μL (0.146 mmol) of S -nitrosothiol solution, 31.5 μL (0.22 mmol) of methyltrimethoxysilane (MTMOS) and 497 μL of n-butanol in the sol-gel reaction of Example 5-1 The nanofibers were prepared in the same manner except that

Example 5-3

In the sol-gel reaction of Example 5-1, 21 μL (0.14 mmol) of S -nitrosothiol solution, 775 μL (0.22 mmol) of methyltrimethoxysilane (MTMOS) and 250 μL of n- The nanofibers were prepared in the same manner except that

Examples 5-4

In the sol-gel reaction of Example 5-1, 1036 μL (0.29 mmol) of S -nitrosothiol solution and 10.5 μL (0.07 mmol) of methyltrimethoxysilane (MTMOS) were used and n-butanol was not added The nanofibers were prepared in the same manner except that the catalyst was not added.

Example 6

The nanofibers were prepared in the same manner except that n-pentanol was used in place of ethanol as a solvent in the preparation of the S -nitrosothiol solution of Example 3-4.

Table 1 below shows the components and contents used in the production of the nanofibers of Examples 1-1 and 1-2.

S -Nitrosothiol solution: NO-MPTMS solution 3.5 mL + 5.4 M NaOMe 0.076 mL (pH 5-6)

The following Table 2 shows the components and contents used in the preparation of the nanofibers of Examples 2-1 to 2-4.

S -Nitrosothiol solution: NO-MPTMS solution 3.5 mL + 5.4 M NaOMe 0.076 mL (pH 5-6)

The following Table 3 shows the components and contents used in the preparation of the nanofibers of Examples 3-1 to 3-4.

S -Nitrosothiol solution: 3.5 mL of NO-MPTES solution + 0.076 mL of 5.4 M NaOMe (pH 5 to 6)

Table 4 below shows the components and contents used in the production of nanofibers of Examples 4-1 to 4-4.

S -Nitrosothiol solution: 3.5 mL of NO-MPTES solution + 0.076 mL of 5.4 M NaOMe (pH 5 to 6)

The following Table 5 shows the components and contents used in the production of the nanofibers of Examples 5-1 to 5-4.

S -Nitrosothiol solution: 3.5 mL of NO-MPTES solution + 0.076 mL of 5.4 M NaOMe (pH 5 to 6)

Table 6 below shows the components and the contents used in the preparation of the nanofibers of Example 6.

S -Nitrosothiol solution: 3.5 mL of NO-MPTES solution + 0.076 mL of 5.4 M NaOMe (pH 5 to 6)

<Structure of Nanofiber>

SEM photographs of the structures of the nanofibers prepared in the above examples are shown in FIGS. 7 to 12. It was confirmed that the mesh structure was well formed in all the nanofibers.

<Evaluation of NO emission characteristics>

1. Setting of emission conditions

(1) NO emission by photocatalyst

The nanofibers prepared in Example 5-4 were repeatedly irradiated and blocked with light of 445,000 lux at 37 ° C to measure NO release (measurement equipment: Sievers chemiluminescence nitric oxide analyzer (NOA 280i), 0.1 M phosphate buffered saline , 0.05 M NaCl, pH 7.4 (hereinafter referred to as PBS, pH 7.4). The results are shown in Fig.

The results showed that when light was irradiated, NO emission was abruptly initiated and emission ceased when the light was blocked. In addition, it was confirmed that a considerable amount (100 ppb / mg or more) of NO emission was emitted over a considerable time (2.0 hr).

From this, it is expected that the nanofibers according to the present invention emit NO by light and control the intensity and irradiation time of the irradiated light, so that the release of NO can be performed over a long period of time.

(2) NO emission by heat

The nanofibers of Example 5-4 were placed in an environment at 10 ° C and the NO release was measured when the temperature was raised to 37 ° C. (Measurement equipment: Sievers chemiluminescence nitric oxide analyzer (NOA 280i, PBS, pH 7.4). The results are shown in Fig.

NO release was initiated when the temperature was raised from 10 占 폚 to 37 占 폚. From this, it can be confirmed that the nanofiber of the present invention releases NO at a predetermined temperature or higher, and can be a storage and delivery means of NO, which is particularly useful for application in the body.

(3) Release of NO by copper catalyst

NO emission of the nanofibers of Examples 5-4 to the copper catalyst (CuCl ₂ ) was measured (Sievers chemiluminescence nitric oxide analyzer (NOA 280i, PBS, pH 7.4). The results are shown in Fig.

As the concentration of CuCl ₂ increases, the amount of NO emission increases, and it is confirmed that the amount of released NO is released after a certain period of time after the catalytic contact.

2. Evaluation of emission characteristics

Next, to evaluate the NO emission characteristics of the nanofibers prepared in the examples of the present invention, the maximum instantaneous NO emission ([NO]) by light irradiation at 445,000 lux was measured using a Sievers chemiluminescence nitric oxide analyzer (NOA280i) _m ) and total emission (t [NO]) were measured. The sample was placed in the buffer while the light was blocked, and after 30 minutes, the distance between the light source and the sample was fixed at 10 cm. Light irradiation was continued until the NO emission was completed.

13 to 18 show the NO release results of the nanofibers prepared in Examples 1-1 to 6, together with the mercaptoalkoxysilane and the concentration of S -nitrosothiol alkoxysilane. In each figure, (a) is a real-time NO release curve, and (b) is a curve showing total NO emission amount.

The results show that the maximum instantaneous nitrogen monoxide release ([NO] _m ) and total release (t [NO]) depend on the concentration of S -nitrosothiol alkoxysilane, the type of mercaptoalkoxysilane and the type of solvent .

First, as the concentration of S - nitrosothiol alkoxysilane increases, the amount of NO stored increases, so that the maximum release amount as well as the total release amount is increased.

Next, when 3-mercaptopropyltrimethoxysilane (MPTMS) was used as the mercaptoalkoxysilane (Examples 2-1 to 2-4), 3-mercaptopropyltriethoxysilane (3-mercaptopropyltriethoxysilane, MPTES) (Examples 3-1 to 3-4) showed excellent NO release results.

Finally, in the case of using methanol as the solvent (Examples 1-1 and 1-2), the use of ethanol (Example 2-1 and Example 2-2) showed excellent NO emission results, The tendency is the same as that in Examples 3-1 to 3-4 to Examples 5-1 to 5-4, in which the solvent shows better release results toward ethanol, propanol, and n-butanol. However, it tended to decrease slightly in n-pentanol. That is, when using butanol as the solvent type, the best result was obtained.

From the above results, it can be seen that as the concentration of S -nitrosothiol alkoxysilane is increased in the production of nanofibers, more NO can be stored and transferred, and furthermore, the kind of the mercaptoalkoxysilane used for storing NO, It was found that the storage and transport characteristics of NO can be changed depending on what solvent is used.

Specifically, when the alkoxy of the mercaptoalkoxysilane is more ethoxy than methoxy, i.e., the substituent of the mercaptoalkoxysilane becomes longer; Further, when the solvent is methanol, ethanol, 1-propanol, or butanol, that is, as the alkyl group of the solvent used is longer, the sol-gel reaction proceeds slowly and the siloxane bridge (Si-O-Si) It was confirmed that nanofibers excellent in electric conductivity can be produced. However, in the case of the solvent, it is not only good that the alkyl group is extended indefinitely, but it is confirmed that it increases to butanol but tends to decrease in pentanol.

Therefore, the nanofibers in Examples 5-1 to 5-4 using 3-mercaptopropyltriethoxysilane as the mercaptoalkoxysilane and n-butanol as the solvent show the best NO release characteristics.

3. Elemental analysis of nanofibers

In the nanofibers of the present invention, since NO is stored in association with sulfur (S), in order to compare the correlation between the NO storage amount and the sulfur content, the nano fibers prepared in Examples 3-4, 4-4, 5-4, Elemental analysis was performed on the fibers. The results are shown in Fig. It can be seen that the sulfur content increases as the number of nanofibers stored with a large amount of NO increases, that is, the sulfur content increases as the amount of NO is increased from 5-4 as in Example 3-4, and as the NO storage amount decreases in Example 6, the sulfur content decreases.

Claims (11)

A mercaptoalkoxysilane in which nitrogen monoxide (NO) is stored, a polymer having a functional group capable of a sol-gel reaction, and a polymer in which a backbone silane is bonded with a siloxane bridge (Si-O-Si) formed by a sol-gel reaction Wherein the mercaptoalkoxysilane in which the NO is stored is reacted with the nitrite and the mercaptoalkoxysilane under acid catalysis in the state of blocking the light and neutralized, The nanofibers become. The method of claim 1,
Wherein the nanofibers are formed by electrospinning a gel formed from the sol-gel reaction. The method of claim 1,
Wherein the mercaptoalkoxysilane is represented by the following formula.
Si (OR ¹ ) _m R ² _n R ³ SH
R ¹ and R &lt; ² &gt; are each independently a C1-C14 alkyl group;
R ³ is a C1-C14 alkylene group which may contain 1 to 5 heteroatoms N or 0 respectively;
n + m = 3, 1? m? 3, and 1? n? 3. The method of claim 1,
Wherein the functional group capable of sol-gel reaction is an alkoxysilane group. The method of claim 1,
The polymer may be selected from the group consisting of polyurethanes (PU), polybenzimidazole (PBI), polycarbonate (PC), polyacrylonitrile (PAN), polylactic acid (PLA)), polyethylene-co-vinyl acetate (PEVA), polymethacrylate (PMA), polyethylene oxide (PEO), polyaniline (PANI) ), Polyvinylcarbazole, polyethylene terephthalate (PET), polyacrylic acid-polypyreneemethanol (PAA-PM), polystyrene (PS), polymethylmethacrylate (PMMA), polyamide (PA), polyvinylphenol (PVP), polyvinylchloride (PVC), cellulose acetate (CA), and the like. Polyvinyl alcohol (PVA), polyacrylamide (PAAm), PLGA (lactic-co-glycolic acid), collagen, polycaprolactone (PCL) (2-hydroxyethyl methacrylate) (HEMA), poly (vinylidene fluoride) (PVDF), polyether imide (PEI) ), Polyethylene glycol (PEG), poly (ferrocenyldimethylsilane) (PFDMS), poly (ethylene-co-vinyl alcohol) , Polyvinyl pyrrolidone (PVP), polymethaphenyleneisophthalamide, and combinations thereof. The nanofiber of claim 1, wherein the nanofibers are selected from the group consisting of polyvinyl pyrrolidone (PVP), polymethaphenyleneisophthalamide, and combinations thereof. The method of claim 1,
Wherein the polymer is poly (methyl methacrylate-co-hexyl methacrylate-co- (trimethoxysilylpropyl) methacrylate) (poly (MMA- co- HMA- co- SiMA) fiber. The method of claim 1,
The backbone silane may be selected from the group consisting of methyltrimethoxysilane (MTMOS), ethyltrimethoxysilane (ETMOS), propyltrimethoxysilane (PTMOS), isobutyltrimethoxysilane (BTMOS) )), And combinations thereof. &Lt; Desc / Clms Page number 13 &gt; delete The method of claim 1,
Wherein the neutralization uses a Lewis base. The method of claim 1,
Wherein the mercaptoalkoxysilane containing NO is contained in an amount of 1 to 15 mol%. The method of claim 1,
In the sol-gel reaction, at least one selected from the group consisting of methanol, ethanol, propanol, butanol and pentanol is used as the solvent.

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