WO2017051989A1 - Method of selectively releasing nitrogen monoxide using mesoporous core-shell nanoparticle and calcium phosphate - Google Patents

Method of selectively releasing nitrogen monoxide using mesoporous core-shell nanoparticle and calcium phosphate Download PDF

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Publication number
WO2017051989A1
WO2017051989A1 PCT/KR2015/013351 KR2015013351W WO2017051989A1 WO 2017051989 A1 WO2017051989 A1 WO 2017051989A1 KR 2015013351 W KR2015013351 W KR 2015013351W WO 2017051989 A1 WO2017051989 A1 WO 2017051989A1
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mesoporous
nitrogen monoxide
nanoparticles
core
mesoporous core
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PCT/KR2015/013351
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English (en)
French (fr)
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Won Jong Kim
Jihoon Kim
Hyung Woo Choi
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Institute For Basic Science
Postech Academy-Industry Foundation
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Publication of WO2017051989A1 publication Critical patent/WO2017051989A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds

Definitions

  • the present invention relates to a method of controlling release of nitrogen monoxide, and more particularly, to a method of selectively releasing nitrogen monoxide using mesoporous core-shell nanoparticles including a material capable of emitting protons by light irradiation and calcium phosphate.
  • Nitrogen monoxide which is a gas synthesized by an intracellular nitrogen monoxide forming enzyme, has an important function as an in vivo physiologically active material.
  • it is known to be related to various physiological phenomena and diseases such as those in a neurotransmission system, a cardiovascular system and an immune system.
  • nitrogen monoxide shows conflicting therapeutic effects in proportion to a concentration and release time.
  • nitrogen monoxide with a high concentration is released for a short period of time, an anti-cancer effect and an anti-bacterial effect are generated, and when a small amount of nitrogen monoxide is released for a long period of time, it is related to wound healing, cell growth, angiogenesis and the like.
  • nitrogen monoxide is present in a gas form, there are a lot of constraints on an effective delivery thereof.
  • Diazeniumdiolate may be stably stored in a solid form, has a high solubility in water, decomposes under the condition of in vivo temperature and pH, and also has various release forms depending on the pH. Diazeniumdiolate may easily produce nitrogen monoxide, and release relatively a large amount of nitrogen monoxide, but has a problem of releasing nitrogen monoxide at the same time as contacting water.
  • an object of the present invention is to provide mesoporous core-shell nanoparticles capable of stably delivering excess nitrogen monoxide to a desired part.
  • an object of the present invention is to provide a method of selectively releasing nitrogen monoxide by inducing release of nitrogen monoxide only when irradiated with light from the outside, thereby capable of increasing a therapeutic effect, with the mesoporous core-shell nanoparticles of the present invention.
  • a mesoporous core-shell nanoparticle includes a mesoporous core portion chemically modified with a silane coupling agent including a secondary amine group; and a shell portion including calcium phosphate, wherein the mesoporous core portion includes a photoreactive pH adjusting agent. Also, a method of preparing the same is disclosed.
  • a method of selectively releasing nitrogen monoxide includes irradiating the mesoporous core-shell nanoparticles with light to release nitrogen monoxide.
  • the method of selectively releasing nitrogen monoxide to which the mesoporous core-shell nanoparticles of the present invention are introduced may stably deliver nitrogen monoxide to a desired part, and induce release of nitrogen monoxide only when irradiated with light, thereby maximizing a therapeutic effect.
  • mesoporous corer-shell nanoparticles according to the present invention, another drug may be further added, and it is expected that a therapeutic effect of nitrogen monoxide may be generated together with a therapeutic effect of a drug, via dual delivery.
  • FIG. 1 illustrates a mesoporous core-shell nanoparticle according to an exemplary embodiment of the present invention.
  • FIG. 2 illustrates a preparation process of the mesoporous core-shell nanoparticle according to an exemplary embodiment of the present invention.
  • FIG. 3 is a result of measuring the mesoporous core-shell nanoparticle according to an exemplary embodiment of the present invention with a transmission electron microscopy.
  • FIG. 4 is a crystal structure analysis graph of the mesoporous core-shell nanoparticle according to an exemplary embodiment of the present invention measured via powder XRD.
  • FIG. 5 is a result of measuring pH of the mesoporous core-shell nanoparticle according to an exemplary embodiment of the present invention before and after being irradiated with light.
  • FIG. 6 is a result of measuring the mesoporous core-shell nanoparticle according to an exemplary embodiment of the present invention with an infrared spectroscope (FT-IR).
  • FT-IR infrared spectroscope
  • FIG. 7 is a result of measuring the mesoporous core-shell nanoparticle according to an exemplary embodiment of the present invention with a UV-vis spectroscope.
  • FIG. 8 is a result of measuring the mesoporous core-shell nanoparticle according to an exemplary embodiment of the present invention via a calcium ion detection method.
  • FIG. 9, 10 are the results of measuring the mesoporous core-shell nanoparticle according to an exemplary embodiment of the present invention via a nitrogen monoxide detector.
  • the present invention relates to a mesoporous core-shell nanoparticle including:
  • a mesoporous core portion chemically modified with a silane coupling agent including a secondary amine group
  • mesoporous core portion includes a photoreactive pH adjusting agent.
  • a mesoporous core-shell nanoparticle refers to a mesoporous core-shell nanoparticle having uniform sized pores and arrangement of the pores in the structure.
  • photoreactive refers to a chemical bonding state being changed with light irradiation
  • a light source of the present invention may be an ultraviolet ray, preferably an ultraviolet ray having a wavelength of 200 to 400 nm.
  • a photoreactive pH adjusting agent refers to a substance capable of adjusting pH by producing protons by light irradiation.
  • the mesoporous core portion may include any one selected from 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 preferably include silica (SiO 2 ), but is not limited thereto.
  • the mesoporous core-shell nanoparticles of the present invention may have a average diameter of 30 - 200 nm, but are not limited thereto.
  • the mesoporous core-shell nanoparticles of the present invention may capture substances having various sizes, shapes and functions, and the biocompatible pores within the structure may capture foreign substances with excellent stability. Therefore, the mesoporous core-shell nanoparticles may be applied to drug and gene deliveries, cell imaging and cancer treatment.
  • mesoporous core-shell nanoparticles of the present invention are easily surface-functionalized, mesoporous core-shell nanoparticles which are surface-functionalized so as to be applied to stimulus-controlled release are introduced.
  • a functional group capable of releasing nitrogen monoxide was introduced to the mesoporous core-shell nanoparticles, and the functional group may be "diazeniumdiolate".
  • the diazeniumdiolate functional group since the diazeniumdiolate functional group releases two molecules of nitrogen monoxide per the functional group, it may generate nitrogen monoxide with a relatively high concentration, when it is included in a carrier. However, since it releases nitrogen monoxide at the same time as contacting water, there is needed a gatekeeper system controlling release of nitrogen monoxide via an external stimulus for efficient nitrogen monoxide delivery. Therefore, in the present invention, the diazeniumdiolate functional group may be reacted to release nitrogen monoxide, when exposed to a certain condition in vivo.
  • the present invention may use a silane coupling agent including a secondary amine group capable of forming a diazeniumdiolate functional group.
  • An alkoxysilyl (Si-OR) functional group of the silane coupling agent may become a silanol group when hydrolyzed to be bound to an inorganic material, thereby serving to connect an organic material and an inorganic material to each other.
  • the silane coupling agent may be represented by the following Chemical Formula 1:
  • R 1 and R 2 are independently of each other a (C1-C12) alkylene group; R 3 and R 4 are independently of each other a (C1-C4) alkyl group; and n is 1-3.
  • N-(2-aminoethyl)-3-aminopropyltrimethoxysilane may be used to obtain a desired effect of the present invention, but not limited thereto.
  • the present invention may control release of nitrogen monoxide by changing the pH, by using a photoreactive pH adjusting agent and calcium phosphate as a gatekeeper system controlling release of nitrogen monoxide.
  • the calcium phosphate used in the present invention is coated on a shell of the mesoporous core-shell nanoparticle, and when the pH is lowered, calcium phosphate coated layer decomposes, thereby selectively releasing nitrogen monoxide.
  • the photoreactive pH adjusting agent used in the present invention which is a material producing protons by light irradiation, may be any one selected from the group consisting of o-nitrobenzaldehyde (o-NBA), m-nitrobenzaldehyde (m-NBA), p-nitrobenzaldehyde (p-NBA), and mixtures thereof.
  • o-NBA o-nitrobenzaldehyde
  • m-NBA m-nitrobenzaldehyde
  • p-NBA p-nitrobenzaldehyde
  • mixtures thereof o-NBA
  • o-NBA which is a compound releasing protons upon exposure to UV having a certain wavelength, is changed to a nitrosobenzoic anion via an intramolecular proton transfer reaction in an excited state, and finally releases protons. Therefore, the pH changes rapidly by a photoreaction, and such pH change may decompose the calcium phosphate coated layer.
  • the calcium phosphate used in the present invention may refer to phosphates of calcium, and preferably hydroxyapatite may be used.
  • the Hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ) is a biological inorganic compound, and has the most similar structure to human bones, and thus, when it is bound to polymer, it has excellent bone regeneration ability, bioactivity, biocompatibility and biodegradability as a soft tissue substitute, thereby being mainly utilized in tissue engineering.
  • the hydroxyapatite may be used as a gatekeeper system controlling effective release of nitrogen monoxide, using its property of being decomposed with lowered pH.
  • the present invention may provide a method of preparing mesoporous core-shell nanoparticles including:
  • Treating the mesoporous nanoparticles with a silane coupling agent is as follows:
  • the method of preparing mesoporous nanoparticles of the present invention may be carried out by a person skilled in the art with a common method, and in the present invention, by adding a surfactant to a metal precursor.
  • the metal precursor may be preferably a silica precursor represented by Si-(OR) 4 (R is independently of each other hydrogen or a (C1-C4) alkyl group), for example, tetraethyl orthosilicate (TEOS), tetramethyl orthosilicate (TMOS), tetrapropyl orthosilicate (TPOS), and the like, but not limited thereto.
  • TEOS tetraethyl orthosilicate
  • TMOS tetramethyl orthosilicate
  • TPOS tetrapropyl orthosilicate
  • the surfactant may include one or more selected from the group consisting of a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a non-ionic surfactant.
  • an alkyltrimethylammonium salt, an alkylpyridinium salt, an alkyl quaternary ammonium salt, an alkyldimethylbenzylammonium salt, and the like may be used, and as the anionic surfactant, an alkylsulfate salt, an alkylsulfonate salt, an alkylphosphate salt, an alkylcarboxylate salt, and the like may be used.
  • amphoteric surfactant cocoamido propyl betaine, cocoamphoacetate, cocoamphocarboxyglycinate, alkyl amphoacetate, sodium lauroamphoacetate, and the like may be used.
  • the non-ionic surfactant may be a sorbitan-based surfactant, a sugar-based surfactant, or a poly(alkylene oxide)-based surfactant.
  • the sugar-based surfactant may be alkyl polyglucoside, and as the sugar, a monosaccharide or a disaccharide may be used, and sucrose distearate, sucrose monostearate and the like may be used.
  • the poly(alkylene oxide)-based surfactant may be alkyl or aryl-substituted poly(alkylene oxide), or a hydrophilic poly(alkylene oxide)-hydrophobic poly(alkylene oxide)-type block copolymer, and specifically, poly(ethylene oxide)-stearate, nonylphenol poly(ethylene oxide), ethylene oxide-added sorbitan fatty acid ester, a poly(ethylene oxide)-poly(propylene oxide) block copolymer, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer, and the like may be used.
  • a cationic surfactant consisting of a hydrophobic alkyl chain and hydrophilic amine
  • CTAB hexadecyltrimethylammonium bromide
  • CACl hexadecyltrimethylammonium chloride
  • the mesoporous nanoparticles may be prepared by centrifuging a mixture of the surfactant, the silica precursor and a solvent.
  • the solvent of the present invention may be alcohols, water, an ether-based solvent alone or in combination, and the alcohol solvent may be methanol, ethanol, isopropanol, propanol, butanol, pentanol, and the like, and the ether-based solvent may be tetrahydrofuran, methyltetrahydrofuran, dimethylether, dibutylether, and the like, but not limited thereto.
  • a silane coupling agent of the following Chemical Formula 1 may be mixed:
  • R 1 and R 2 are independently of each other a (C1-C12) alkylene group; R 3 and R 4 are independently of each other a (C1-C4) alkyl group; and n is 1-3.
  • the surfactant may be removed from the prepared mesoporous nanoparticles.
  • the mesoporous nanoparticles may be immersed in a mixed solution of hydrochloric acid and methanol.
  • step b) Adding the photoreactive pH adjusting agent to the mesoporous nanoparticles prepared in step a) is as follows:
  • the photoreactive pH adjusting agent used in the present invention may be any one selected from the group consisting of o-nitrobenzaldehyde, m-nitrobenzaldehyde, p-nitrobenzaldehyde, and mixtures thereof.
  • the calcium phosphate used in the present invention may be hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ), and as a preparation method of the hydroxyapatite, a wet process of preparing a water-soluble calcium salt and a phosphate using a liquid medium, but not limited thereto.
  • the hydroxyapatite of the present invention is sensitive to pH when reacted, and forms precipitates at about pH 12, but as the reaction proceeds, pH is lowered, and thus, at the end of the reaction, may form precipitates in a range of pH 7 to 11.
  • hydroxyapatite precipitates may not secure sufficient calcium within their crystal structure in a low pH range less than pH 7, thereby producing hydroxyapatite lacking calcium, that is, structurally collapsed hydroxyapatite.
  • pH may be adjusted to 7 to 11.
  • step d) Adding nitrogen monoxide gas to the mesoporous nanoparticles prepared in step c), thereby forming a diazeniumdiolate functional group, is as follows:
  • the diazeniumdiolate functional group may be obtained by reacting a secondary amine with nitrogen monoxide gas, as represented by the following Reaction Formula 1.
  • the nitrogen monoxide gas may be added under a pressure of 40 psi to 200 psi, preferably under a pressure of 80 psi to 150 psi, but is not limited thereto.
  • the mesoporous core-shell nanoparticles of the present invention as prepared above may be irradiated with light to selectively release nitrogen monoxide, and the light irradiation uses an ultraviolet ray at a wavelength of 200 to 400 nm.
  • the mesoporous core-shell nanoparticles of the present invention may further include a pharmacologically effective material within or on the surface of the particles. They may be used for the purpose of an additional pharmacological effect, together with the nitrogen monoxide effect of the present invention.
  • the pharmacologically effective material is not limited, but may include preferably a material preventing thrombopoiesis or blood cloths, an antioxidant, an anti-inflammatory agent, a wound healing promoting material, antibacterial agent, and the like, and the therapeutic effect of nitrogen monoxide may be generated together with the therapeutic effect of the drug.
  • a 2M NaOH solution was added to a solution of 1 g of cetyltrimethylammonium bromide (CTAB) dissolved in 500 ml of distilled water. After stirring for 15 minutes, 5 ml of tetraethyl orthosilicate (TEOS) was added. After stirring at 80 °C for 3 hours, the solution was filtered, washed three times with MeOH, and dried. 0.5 g of the dried powder, 100 ml of EtOH, and 0.5 ml of N-(2-aminoethyl)-3-aminopropyl trimethoxysilane (AEATS) were added to be refluxed with a suspension reaction for 3 hours.
  • CAB cetyltrimethylammonium bromide
  • TEOS tetraethyl orthosilicate
  • MSN-AEATS 100 mg was mixed with 10 ml of 2-nitrobenzaldehyde (o-NBA), and left at a room temperature for 24 hours. The mixture was freeze-dried for 48 hours to obtain pH@MSN-AEATS.
  • o-NBA 2-nitrobenzaldehyde
  • pH@MSN-AEATS 100 mg was dissolved in 10 ml of a 0.1M (NH 4 ) 2 HPO 4 solution, and then ammonia water was added thereto, thereby adjusting pH to 10.
  • 20 ml of 0.1M Ca(NO 3 ) 2 4H 2 O was added by dropwise, and reacted at 60 °C for 1 hour. After being separated by a centrifuge (7000 rpm, 10 min), washing was carried out three times with deionized water. The reactants were freeze-dried for 48 hours to obtain pH@MSN-AEATS.
  • pH@MSN-CaP 10 mg was dissolved in 3 ml of 0.5 M NaOMe/MeOH, and then added to a high pressure reactor. The reactor was purged twice with 20 psi of Ar gas and then reaction was carried out with 80 psi of NO gas for three days.
  • the pH@MSN-CaP-NO having a diazeniumdiolate group capable of releasing nitrogen monoxide was separated in a centrifuge (7000 rpm, 10 min), and then the remaining solvent was removed by vacuum drying.

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PCT/KR2015/013351 2015-09-23 2015-12-08 Method of selectively releasing nitrogen monoxide using mesoporous core-shell nanoparticle and calcium phosphate WO2017051989A1 (en)

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KR1020150134269A KR101577951B1 (ko) 2015-09-23 2015-09-23 다공성 코어-쉘 나노입자와 인산칼슘을 이용한 선택적 일산화질소 방출 방법
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Cited By (1)

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EP3371198A4 (en) * 2015-11-02 2019-06-12 The University of North Carolina at Chapel Hill FUNCTIONALIZED MESOPOROUS SILICA CONTACT

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3371198A4 (en) * 2015-11-02 2019-06-12 The University of North Carolina at Chapel Hill FUNCTIONALIZED MESOPOROUS SILICA CONTACT
EP3750624A1 (en) * 2015-11-02 2020-12-16 The University of North Carolina at Chapel Hill Functionalized mesoporous silica via an aminosilane surfactant ion exchange reaction: controlled scaffold design and nitric oxide release
US11420986B2 (en) 2015-11-02 2022-08-23 The University Of North Carolina At Chapel Hill Functionalized mesoporous silica via an aminosilane surfactant ion exchange reaction: controlled scaffold design and nitric oxide release

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