CN113797226B - Ammonia borane/silicon sphere/mesoporous silica nano composite particle, preparation and application thereof - Google Patents
Ammonia borane/silicon sphere/mesoporous silica nano composite particle, preparation and application thereof Download PDFInfo
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- CN113797226B CN113797226B CN202111073604.5A CN202111073604A CN113797226B CN 113797226 B CN113797226 B CN 113797226B CN 202111073604 A CN202111073604 A CN 202111073604A CN 113797226 B CN113797226 B CN 113797226B
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- ammonia borane
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- JBANFLSTOJPTFW-UHFFFAOYSA-N azane;boron Chemical compound [B].N JBANFLSTOJPTFW-UHFFFAOYSA-N 0.000 title claims abstract description 98
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 239000002245 particle Substances 0.000 title claims abstract description 41
- 239000000377 silicon dioxide Substances 0.000 title claims abstract description 35
- 239000002114 nanocomposite Substances 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 229910052710 silicon Inorganic materials 0.000 title claims abstract description 19
- 239000010703 silicon Substances 0.000 title claims abstract description 19
- 229910004298 SiO 2 Inorganic materials 0.000 claims abstract description 83
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- 238000000034 method Methods 0.000 claims abstract description 20
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 9
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- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 17
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- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical group [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 10
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- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 8
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- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 4
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- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
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- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 1
- KISWVXRQTGLFGD-UHFFFAOYSA-N 2-[[2-[[6-amino-2-[[2-[[2-[[5-amino-2-[[2-[[1-[2-[[6-amino-2-[(2,5-diamino-5-oxopentanoyl)amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)p Chemical compound C1CCN(C(=O)C(CCCN=C(N)N)NC(=O)C(CCCCN)NC(=O)C(N)CCC(N)=O)C1C(=O)NC(CO)C(=O)NC(CCC(N)=O)C(=O)NC(CCCN=C(N)N)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 KISWVXRQTGLFGD-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/22—Boron compounds
-
- 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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B33/00—Silicon; Compounds thereof
- C01B33/113—Silicon oxides; Hydrates thereof
- C01B33/12—Silica; Hydrates thereof, e.g. lepidoic silicic acid
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B33/00—Silicon; Compounds thereof
- C01B33/113—Silicon oxides; Hydrates thereof
- C01B33/12—Silica; Hydrates thereof, e.g. lepidoic silicic acid
- C01B33/18—Preparation of finely divided silica neither in sol nor in gel form; After-treatment thereof
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B6/00—Hydrides of metals including fully or partially hydrided metals, alloys or intermetallic compounds ; Compounds containing at least one metal-hydrogen bond, e.g. (GeH3)2S, SiH GeH; Monoborane or diborane; Addition complexes thereof
- C01B6/06—Hydrides of aluminium, gallium, indium, thallium, germanium, tin, lead, arsenic, antimony, bismuth or polonium; Monoborane; Diborane; Addition complexes thereof
- C01B6/10—Monoborane; Diborane; Addition complexes thereof
- C01B6/13—Addition complexes of monoborane or diborane, e.g. with phosphine, arsine or hydrazine
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/01—Particle morphology depicted by an image
- C01P2004/04—Particle morphology depicted by an image obtained by TEM, STEM, STM or AFM
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nanotechnology (AREA)
- Pharmacology & Pharmacy (AREA)
- Inorganic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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Abstract
The invention relates to an ammonia borane/silicon sphere/mesoporous silica nano composite particle, a preparation method and application thereof, wherein the chemical formula of the nano composite particle is AB/SiO 2 @mSiO 2 The method is characterized in that silicon dioxide spheres are used as a substrate, mesoporous silicon dioxide is used as a shell, and a gas prodrug capable of generating hydrogen in an acidic microenvironment is loaded. The nano composite particles are used as drug carriers, imaging diagnosis, gas treatment, anti-inflammation, synergistic enhancement of nerve function recovery, reduction of fibrotic scar formation, and promotion of nerve regeneration by inhibition of oxidative stress. Compared with the prior art, the AB/SiO method of the invention 2 @mSiO 2 The nano composite particle has novel structure, and can be used for loading gas prodrug, controllably releasing gas and superelevationThe method has wide application prospect in the aspects of acoustic imaging and diagnosis and treatment of spinal cord injury, can transmit gas prodrug to injured lesion sites, and can perform diagnosis and real-time observation of treatment conditions through imaging, thereby comprehensively regulating oxidation and inflammation imbalance in microenvironment and effectively and visually treating spinal cord injury.
Description
Technical Field
The invention belongs to the technical field of carriers for diagnosing and treating diseases related to oxidative stress, and relates to ammonia borane/silicon spheres/mesoporous silica nano composite particles, and preparation and application thereof.
Background
Spinal cord injury (spinal cord injury, SCI) is a devastating type of central nervous system injury that often results in refractory neurological dysfunction, loss of sensory and autonomic nerve function to varying degrees and paralysis, severe and even death. The health care product has the characteristics of complex injury, long treatment and nursing period, high treatment cost, poor clinical prognosis and the like, not only causes health loss and life quality pressure to individuals and families, but also causes great burden to a sanitary system and social economy due to lost productivity and high nursing cost. However, with the aging population and the ever-increasing and widespread use of motor vehicles, the incidence of SCI continues to increase. And no effective prevention and treatment means exists at present, which is a major medical problem facing the world. At the same time, compared with highly cytotoxic pharmacotherapeutic agents, the biological gaseous molecules have attracted considerable attention due to their high selectivity and low systemic toxicity, such as Nitric Oxide (NO), hydrogen (H 2 ) Carbon monoxide (CO) and hydrogen sulphide (H) 2 S). The gas molecules existing in the nature or organism can influence metabolism and maintain the steady state of human physiological functions. Wherein,,H 2 because of its green and negligible side effects, hydrogen therapy is of great interest in the area of anti-inflammatory therapy as an emerging, promising strategy for anti-oxidative stress treatment. In addition to having biological permeability and biological safety, H 2 It has been demonstrated that intracellular ROS-induced cytotoxicity and inflammatory responses can be selectively reduced, with important physiological functions for regulation of homeostasis, including selective treatment of diseased cells and protection of normal cells. Thus H 2 Are proposed as a treatment for cancer and central nervous system injury. Inhalation H 2 Gas and administration enriched in H 2 Has been shown to protect neurons from SCI-induced apoptosis, and to protect mitochondrial structures, inhibiting reactive astrohyperplasia. However, how to construct nanoparticles incorporating gaseous molecules to achieve damaged areas H 2 Is a challenge to be solved.
At present, an integrated carrier capable of integrating image diagnosis, pH response and gas treatment into a whole and realizing efficient antioxidation stress diagnosis and treatment is urgently needed.
The Chinese patent application No. 201610315917.X discloses an amino modified Fe with mesoporous structure 3 O 4 @SiO 2 @mSiO 2 Preparation and application of composite particles and Fe with mesoporous structure 3 O 4 @SiO 2 @mSiO 2 The preparation method of the composite particles comprises the following steps: fe is added to 3 O 4 @SiO 2 Dispersing the powder in a mixed solution of ethanol, deionized water, ammonia water and a template agent to obtain a sol solution; then dripping tetraethyl orthosilicate to prepare Fe with mesoporous structure 3 O 4 @SiO 2 @mSiO 2 Composite particles. However, the technical solution of this patent has the following technical problems: 1) Fe (Fe) 3 O 4 @SiO 2 @mSiO 2 The synthesis process of the composite particles is long, which is not beneficial to the industrialized amplification operation. 2) Fe (Fe) 3 O 4 @SiO 2 @mSiO 2 The middle layer of the composite particles is made of Fe 3 O 4 Coating the core with a layer of SiO 2 On the basis of the layer, a layer of mesoporous SiO is coated 2 The layer of the material is formed from a layer,SiO in the middle 2 The layer has no substantial use and can be directly used in Fe 3 O 4 Direct growth of mesoporous SiO on the basis 2 The layers are synthesized in a simple manner. 3) Mesoporous SiO 2 Limited adsorption capacity of Fe 3 O 4 @SiO 2 @mSiO 2 The application of the composite particles in the aspect of heavy metal adsorption in the water treatment technology.
The Chinese patent application No. 201711453083.X discloses an acid response hydrogen release nano-drug and a preparation method thereof, which are used for tumor treatment. The antitumor drug is named as AB@MSN nano drug and comprises a mesoporous silica carrier and H with acid response characteristic supported in the mesoporous silica carrier 2 A prodrug. However, the technical solution of this patent has the following technical problems: 1) The particle size of the AB@MSN nano-drug is about 50nm, and the AB@MSN nano-drug is easy to be absorbed by the liver after being injected into the body, so that the drug effect of the AB@MSN nano-drug cannot be exerted, and the medical application is limited to a large extent; 2) The ethanol solution of hydrochloric acid is used for extracting the surfactant CTAC for three times, so that CTAC cannot be removed well, and the formation of a mesoporous structure is further influenced; 3) Whether hydrogen alone has a truly good anticancer effect has been questioned, and whether inhibition of cancer growth was observed is a secondary factor to be further explored.
Disclosure of Invention
The invention aims to overcome the technical problems in the prior art, and provides the ammonia borane/silicon spheres/mesoporous silica nano composite particles which are simple and mild in synthesis condition, convenient in raw material source, controllable in size and aperture, excellent in acid response effect, free of biotoxicity and excellent in stability.
The invention also aims to provide a preparation method of the ammonia borane/silicon spheres/mesoporous silica nano composite particles.
It is a further object of the present invention to provide the use of the ammonia borane/silica spheres/mesoporous silica nanocomposite particles.
The patent starts from the oxidation resistance angle of hydrogen, finds another brand new nano composite particle, inhibits oxidation stress reaction and promotes the treatment of nerve regeneration, and has good clinical transformation significance.
The aim of the invention can be achieved by the following technical scheme:
the chemical formula of the ammonia borane/silicon spheres/mesoporous silica nano composite particles is AB/SiO 2 The @ mSiO2 is prepared by taking solid silicon spheres as cores and mesoporous silicon dioxide as shells and loading ammonia borane which is a gas precursor capable of generating hydrogen in an acidic environment.
Preferably, the diameter of the nano composite particles is 180-230nm. More preferably 220nm.
The invention relates to a preparation method of ammonia borane/silicon spheres/mesoporous silica nano composite particles, which specifically comprises the following steps:
1) Tetraethyl orthosilicate is used as a silicon source, and monodisperse solid silicon Spheres (SiO) are prepared by hydrolysis reaction in an alkaline environment 2 )；
2) The SiO prepared in the step 1) is used in the presence of a template agent 2 Coating a layer of thick silicon oxide on the surface of the nano particles to prepare SiO 2 @SiO 2 A nanoparticle;
3) SiO obtained in the step 2) 2 @SiO 2 The nano particles remove template agent through methanol to construct SiO with mesoporous structure 2 @mSiO 2 A nanoparticle;
4) SiO obtained in the step 3) 2 @mSiO 2 The nanometer particle loaded gas prodrug Ammonia Borane (AB) is prepared into AB/SiO 2 @mSiO 2 Nano composite medicine.
Preferably, the method comprises the steps of,
the step 1) adopts a sol-gel method, and the sol-gel method comprises the following process steps: in a reaction vessel, according to the measurement of the reaction process of tetraethyl orthosilicate and water, ethanol is used as a solvent, water is used as a medium for mixing, ammonia water is used as a catalyst, stirring is carried out for 8-25min at 20-40 ℃, then a certain amount of tetraethyl orthosilicate is dripped into the reaction vessel for hydrolysis polymerization reaction, water bath stirring is carried out for 1-2.5h at 20-40 ℃, then alcohol washing and water washing are carried out, the final product is dispersed in a certain amount of water, and finally, the monodisperse solid SiO is obtained by vacuum drying 2 Particles; the ammonia water and the ethyleneThe mass ratio of the alcohol, the deionized water and the tetraethyl orthosilicate is 1-2.5:40:5-10:1-4. More preferably, the dosage ratio of the ammonia water, the ethanol, the deionized water and the tetraethyl orthosilicate is 3.2mL:74mL:15mL:2.5-4.5mL.
The specific process steps of the step 2) are as follows: adding a template agent and triethanolamine into a certain amount of ultrapure water, stirring for 0.5-1.5h, and heating to 78-90 ℃; then adding SiO dispersed in deionized water prepared in the step 1) 2 The nano particles and tetraethyl orthosilicate are stirred for 0.5 to 2 hours at the temperature of 78 to 90 ℃ to wrap a layer of thick silicon dioxide, and the SiO is prepared by washing and centrifuging 2 @SiO 2 A nanoparticle; the template agent can be Cetyl Trimethyl Ammonium Chloride (CTAC) or Cetyl Trimethyl Ammonium Bromide (CTAB); the template agent, triethanolamine and SiO dispersed in deionized water 2 The dosage ratio of the nano particles to the tetraethyl orthosilicate is 0.8-1.5g:0.1-0.8g:5-15mL:1.5-2.5mL. More preferably, the template, triethanolamine, siO dispersed in deionized water 2 The dosage ratio of the nano particles to the tetraethyl orthosilicate is 1-1.5g:0.2-0.3g:8-15mL:1.5-2mL.
The methanol removal template agent structure in the step 3) has a mesoporous structure and comprises the following process steps: taking the obtained SiO 2 @SiO 2 Stirring the nano particles with a certain amount of methanol containing 1% NaCl at 40-65deg.C for 4-12 hr, centrifuging, washing with water for three times, and dispersing in water to obtain mesoporous SiO 2 @mSiO 2 And (3) compounding nano particles. The dosage of the methanol with 1% NaCl can be based on SiO 2 The weight of the shell and the reaction time are adjusted.
The process steps of the step 4) are as follows: dissolving ammonia borane in SiO prepared in the step 3) 2 @mSiO 2 Stirring in composite nanoparticle buffer solution at room temperature for 30-40 hr, centrifuging, washing with water, and dispersing in water to obtain AB/SiO 2 @mSiO 2 Composite nanoparticles; the SiO is 2 @mSiO 2 The mass concentration of the composite nano particles in deionized water is 10-30mg/mL (preferably 20 mg/mL); the ammonia borane and SiO 2 @mSiO 2 The mass ratio of the composite nano particles is 4-15:1 (preferably in a mass ratio of 4.5-7:1).
AB/SiO of the invention 2 @mSiO 2 The nano composite medicine as medicine carrier can be used for high-effectively coating carrier gas prodrug, and has extensive application prospect in the aspect of gas treatment. Meanwhile, the preparation has strong acid responsiveness, can effectively and accurately treat spinal cord injury under pH sensitive release or ultrasonic controlled release at a lesion and injury part, synergistically enhance nerve function recovery, reduce fibrosis scar formation, and promote nerve regeneration by inhibiting oxidative stress reaction.
Compared with the existing numerous nano carriers, the AB/SiO of the invention 2 @mSiO 2 Nanocomposite particle research is leading since its construction is based on SiO 2 ，SiO 2 Has the advantages of controllable pore size, easy surface modification, no toxicity, no harm, good biocompatibility and the like, provides a brand new idea and concept for the design of inorganic materials on the medical nanometer scale, and simultaneously, provides a novel solution for the preparation of the inorganic materials on the basis of SiO 2 The surface is modified, and the gas prodrug with biological functions is entrapped, so that the visual treatment of spinal cord injury can be efficiently and controllably realized.
The present invention differs from the prior patent 201610315917.X in that: (1) Likewise mSiO 2 Is a shell, but the preparation method is quite different. The invention takes silicon dioxide nano particles as a matrix, a layer of silicon spheres is coated outside, and then methanol is used for removing a template agent to form mesoporous structure SiO 2 @mSiO 2 。(2)mSiO 2 Is different in use. The invention uses mesoporous SiO 2 On the one hand utilize SiO 2 Good biocompatibility is used as an excellent drug delivery system; on the other hand, the mesoporous structure is utilized to carry out good loading of the gas prodrug. (3) the application of the nanoparticle is different. The nanoparticles of the invention are useful for loading gas prodrugs, releasing hydrogen in an acidic environment for use as anti-inflammatory therapy.
Compared with the prior art, the invention has the following technical effects:
1) AB/SiO obtained by the method 2 @mSiO 2 The nano composite particle reaction device and the condition are simple and convenient, and the source of the needed raw materials is availableIs widely used, low cost and biocompatible, in particular the gas prodrug ammonia borane, which has a very high hydrogen content (196 gH 2 And/kg), has good water solubility and dispersibility, is non-biotoxic and is stable in storage under normal conditions. The preparation period of the nano-carrier is greatly shortened, and the final nano-particles have high stability and are convenient to store;
2) AB/SiO prepared by the method of the invention 2 @mSiO 2 The particle size of the nano composite particles is 180-230nm, and the high permeability of lesion and injury parts can be well realized after the nano medicine enters an animal body.
3) AB/SiO prepared by the method of the invention 2 @mSiO 2 The mesoporous structure of the nano composite particles can ensure the loading of the gas prodrug and can better realize anti-inflammatory treatment. AB/SiO obtained by the method 2 @mSiO 2 The nano composite particles have flexible and adjustable pore size distribution, can well load the gas prodrug Ammonia Borane (AB), have pH response release and ultrasonic controllable drug release performance, and can accurately release H at lesion sites 2 The effects of relieving spinal cord injury are achieved, and simultaneously, the nerve function recovery is synergistically enhanced, and the nerve regeneration is promoted.
From AB/SiO of example 1 2 @mSiO 2 The results of low-power and high-power TEM of the particle size of the composite nanoparticle are shown in FIG. 1, and it can be seen that AB/SiO 2 @mSiO 2 The composite nanoparticle has a particle size of about 220nm, which is very suitable for both cell experiments and in vivo therapies.
From AB/SiO of example 1 2 @mSiO 2 H of composite nanoparticle 2 Release results fig. 2, it can be seen that in ph=7.4, there is substantially no significant H 2 Releasing. Clearly, H in an acidic environment 2 The release rate of (2) is faster. Description AB/SiO under physiological conditions 2 @mSiO 2 The composite nanoparticle cannot be decomposed into H 2 Whereas acidic conditions may significantly promote H 2 Releasing.
From AB/SiO of example 1 2 @mSiO 2 Cytotoxicity evaluation result graph of composite nanoparticle3, it can be seen that AB/SiO 2 @mSiO 2 The composite nanoparticle still has no obvious cytotoxicity at the concentration of up to 400 mug/mL.
From AB/SiO of example 1 2 @mSiO 2 Results of the intracellular evaluation of composite nanoparticles FIG. 4, it can be seen that AB/SiO 2 @mSiO 2 The composite nanoparticle continues to accumulate in the nucleus after 4 hours after incubation with the cells.
From AB/SiO of example 1 2 @mSiO 2 Results of in vivo antioxidant level evaluation of composite nanoparticles FIG. 5, it can be seen that AB/SiO 2 @mSiO 2 The DHE dyeing intensity can be obviously reduced after the intervention of the composite nano particles, which shows that AB/SiO 2 @mSiO 2 The composite nanoparticle effectively eliminates excessive accumulation of ROS and relieves spinal cord injury.
From AB/SiO of example 1 2 @mSiO 2 In vivo nerve repair evaluation results of composite nanoparticles FIG. 6, it can be seen that AB/SiO 2 @mSiO 2 The composite nano particles can obviously increase the expression of MBP protein, NF200 protein and beta iii-tubulin, and prove that AB/SiO 2 @mSiO 2 The preparation has remarkable effects in preserving neurons and promoting axon regeneration, thereby promoting the recovery of nerve functions.
From AB/SiO of example 1 2 @mSiO 2 Results of toxicity test of composite nanoparticles in vivo FIG. 7, it can be seen that AB/SiO 2 @mSiO 2 The composite nano-drug has good biocompatibility and no obvious biotoxicity, and is very promising for repairing spinal cord injury.
Drawings
FIG. 1 is a diagram of SiO in example 1 of the present invention 2 、SiO 2 @mSiO 2 TEM spectrum of nano particle, wherein a and b are respectively dSiO 2 A low-power TEM spectrum and a high-power TEM spectrum of the nano particles, wherein c and d are SiO respectively 2 @mSiO 2 A low-power TEM profile and a high-power TEM profile of the nanoparticle;
FIG. 2 is a schematic diagram of AB/SiO in example 1 of the present invention 2 @mSiO 2 PH responsive hydrogen generation and recombination of nanoparticlesReleasing;
FIG. 3 is an AB/SiO layer in example 1 of the present invention 2 @mSiO 2 Survival rate of the composite nanoparticle at different concentrations of mouse microglial cells (Bv 2 cells);
FIG. 4 is a schematic diagram of AB/SiO in example 1 of the present invention 2 @mSiO 2 In vitro confocal fluorescence images of Bv2 cells incubated for 2h and 4h with the composite nanoparticles. The scale bar is 50 mu m;
FIG. 5 is a schematic diagram of AB/SiO in example 1 of the present invention 2 @mSiO 2 The composite nanoparticle reduced the oxidative stress level of injured spinal cord in SCI rats, DHE staining showed ROS production in each group of 2 dpi.
FIG. 6 is an AB/SiO layer in example 1 of the present invention 2 @mSiO 2 The composite nanoparticles affect western blot images and semi-quantitative levels of Myelin Basic Protein (MBP), βiii-tubulin, and neurofilament-200 (NF 200) expression in longitudinal spinal cord tissue.
FIG. 7 is a schematic diagram of AB/SiO in example 1 of the present invention 2 @mSiO 2 Pathology H of major organs (including heart, liver, spleen, lung and kidney) collected in vivo untreated and 3 days after injection of the composite nanoparticles&E staining the image.
Detailed Description
The invention will now be described in detail with reference to the drawings and specific examples.
The reagent purchase sources involved in the examples of the present invention are described below:
tetraethyl orthosilicate, ethanol, aqueous ammonia, cetyltrimethylammonium chloride, triethanolamine, sodium chloride, methanol, and ammonia borane were all purchased from Shanghai microphone Biochemical technologies Co. All antibodies were purchased from Ai Bokang (Shanghai) trade company, inc. BCA protein assay kit was purchased from sameimers technology, fluorescent staining reagents and peroxidase-conjugated secondary antibodies were purchased from the bi cloud biotechnology institute, and ECL kit was purchased from merck. All animal protocols were approved by the ethical committee of the university of eastern China and were conducted in accordance with guidelines of the animal care and ethical committee of the university of eastern China.
Example 1
In this example, ammonia borane/silica spheres/mesoporous silica nanocomposite particles (AB/SiO 2 @mSiO 2 ) The composite nano particle takes solid silicon spheres as cores and silicon oxide as shells, and mesoporous SiO is obtained by removing template agent with methanol 2 @mSiO 2 The ammonia borane small molecule prodrug is then loaded.
(1) The preparation method of the ammonia borane/silicon spheres/mesoporous silica nano composite particles comprises the following steps:
(1-1) silica dSiO 2 Preparation of nanoparticles: in a 100mL single-port bottle, 74mL of ethanol, 15mL of water and 3.2mL of ammonia water are added according to the measurement of the reaction process of tetraethyl orthosilicate and water, the mixture is stirred for 20min at 30 ℃, 2.8mL of tetraethyl orthosilicate is dripped into the mixture for hydrolysis polymerization reaction, the mixture is stirred for 2h in a water bath at 30 ℃, and the mixture is subjected to centrifugal alcohol washing for 2 times and water washing for 1 time, the final product is dispersed in water, and finally, the mixture is dried in vacuum to obtain monodisperse SiO 2 Particles;
(1-2) nanoparticle SiO 2 @SiO 2 Is prepared from the following steps: the process steps of the step (2) are as follows: to 50mL of ultrapure water were added 1g of cetyltrimethylammonium chloride (CTAC) and 0.3g of Triethanolamine (TEA), and the mixture was stirred for 1 hour and heated to 80 ℃. Then adding 10mL of SiO dispersed in deionized water 2 The nano particles and 1.8mL tetraethyl orthosilicate are stirred for 1h at 80 ℃ to wrap a layer of thick silicon dioxide, and the SiO is prepared by washing and centrifuging and dispersing in deionized water 2 @SiO 2 A nanoparticle;
(1-3) nanoparticle SiO 2 @mSiO 2 Is prepared from the following steps: taking the monodisperse SiO dispersed in deionized water 2 @SiO 2 Adding 50mL of methanol solution containing 1% NaCl into the nano particles to remove template agent CTAC, stirring for 6h, centrifuging, washing with water for three times, and dispersing in water to obtain mesoporous SiO 2 @mSiO 2 Composite nanoparticles;
(1-4) nanocomposite particles AB/SiO 2 @mSiO 2 Is prepared from the following steps: 180mg of ammonia borane is weighed and dissolved in 2mL (20 mg/mL) of SiO 2 @mSiO 2 Composite nanoparticle bufferingStirring the solution at room temperature for 36h, and then performing centrifugal water washing for three times to obtain AB/SiO 2 @mSiO 2 And (3) the composite nano particles are stored at the temperature of 4 ℃ for standby.
(2)AB/SiO 2 @mSiO 2 Particle size of composite nanoparticle: the low-power and high-power TEM are respectively shown in FIG. 1, and can be seen as AB/SiO 2 @mSiO 2 The composite nanoparticle has a particle size of about 220nm, which is very suitable for both cell experiments and in vivo therapies.
(3)AB/SiO 2 @mSiO 2 H of composite nanoparticle 2 Releasing: different volumes H are obtained by gas chromatography 2 Is a standard curve of (2). Buffers of ph=7.4 (normal tissue environment) and ph=6.6 (spinal cord injury microenvironment) were prepared separately and placed in a 100mL reactor equipped with a stirring device. Deoxidizing with argon at room temperature for 40min, removing excessive gas, and adding 5mg AB/SiO into the reactor 2 @mSiO 2 And (3) nano composite particles. Subsequently, 1mL of gas was drawn from the vessel at various time points and H was measured using a GC2060 system 2 Is released.
As can be seen from fig. 2, there is substantially no significant H at ph=7.4 2 Releasing. Clearly, H in an acidic environment 2 The release rate of (2) is faster. Description AB/SiO under physiological conditions 2 @mSiO 2 The composite nanoparticle cannot be decomposed into H 2 Whereas acidic conditions may significantly promote H 2 Releasing.
(4)AB/SiO 2 @mSiO 2 Cytotoxicity evaluation of composite nanoparticles: bv2 cells were seeded in 96-well plates with different concentrations of AB/SiO 2 @mSiO 2 Incubation was carried out for 24h, and then cell viability was determined using the standard Methylthiazoletetrazole (MTT) method (see FIG. 3 for results).
As can be seen from FIG. 3, AB/SiO 2 @mSiO 2 The composite nanoparticle still has no obvious cytotoxicity at the concentration of up to 400 mug/mL.
(5)AB/SiO 2 @mSiO 2 Cellular internalization evaluation of composite nanoparticles: in terms of in vitro cellular uptake, bv2 cells were cultured in 12-well plates for 24 hours. Then, usingContaining Cy5-AB/SiO 2 @mSiO 2 Fresh medium (500. Mu.g/ml) was further incubated for 2h and 4h. Followed by fixation with 4% paraformaldehyde solution for 15 minutes. The nuclei were then stained with Hoechst 33342 for 20min and washed 3 times with PBS. Finally, fluorescence images of the cells were observed using a Confocal Laser Scanning Microscope (CLSM).
As can be seen from FIG. 4, cy5-AB/SiO 2 @mSiO 2 The group showed red fluorescence due to Cy5, while the nuclei showed blue fluorescence due to Hoechst. After incubation for 2h, a relatively weak red fluorescence appears in the cytoplasm, indicating that the composite nanoparticle is phagocytized by Bv2 cells. Over time, hatching, AB/SiO 2 @mSiO 2 The composite nanoparticle continues to accumulate in the nucleus after 4 hours after incubation with the cells. Indicating that there are more complex nanoparticles entering Bv2 cells. That is, AB/SiO 2 @mSiO 2 The composite nanoparticle is capable of being delivered into a cell.
(6)AB/SiO 2 @mSiO 2 In vivo antioxidant level evaluation of composite nanoparticles: 220g female rats were selected to establish a spinal cord injury model, and then the rats were randomly divided into the following groups: spinal cord injury group (SCI group) to which 10. Mu.l PBS was intrathecally administered 1 day (1 dpi), 3dpi, and 7dpi after injury, respectively, and 10. Mu.l SiO was administered 2 @mSiO 2 (500. Mu.g/ml) group (SiO) 2 @mSiO 2 Group) and 10. Mu.l AB/SiO 2 @mSiO 2 Group (AB/SiO) of (500. Mu.g/ml) 2 @mSiO 2 A group). Spinal cord tissue from a 0.5 cm long area of the lesion center was harvested after 7 dpi. Frozen sections were prepared and stained with ROS fluorescent probe, diethyl ether (DHE).
As can be seen from FIG. 5, the tissue DHE fluorescence expression of SCI group is evident, indicating high ROS level expression in spinal cord injury, siO alone 2 @mSiO 2 Group intervention did not affect DHE fluorescence expression. And AB/SiO 2 @mSiO 2 The DHE dyeing intensity can be obviously reduced after the intervention of the composite nano particles, which shows that AB/SiO 2 @mSiO 2 The composite nanoparticle effectively eliminates excessive accumulation of ROS and relieves spinal cord injury.
(7)AB/SiO 2 @mSiO 2 In vivo nerve repair assessment of composite nanoparticles: 120 female rats (-220 g) were selected to establish a spinal cord injury model, and then the rats were randomly divided into four groups: a group subjected to laminectomy only (sham group, n=30); spinal cord injury group (SCI group, n=30) injected with PBS alone, siO administration 2 @mSiO 2 Group of composite nanoparticles (SiO 2 @mSiO 2 Group, n=30) and AB/SiO administration 2 @mSiO 2 Group of composite nanoparticles (AB/SiO) 2 @mSiO 2 Group, n=30). SCI group, siO 2 @mSiO 2 Group and AB/SiO 2 @mSiO 2 Groups were given 10. Mu.l of PBS, siO intrathecally 1 day (1 dpi), 3dpi, 7dpi after injury, respectively 2 @mSiO 2 (500. Mu.g/ml) and AB/SiO 2 @mSiO 2 (500. Mu.g/ml) composite nanoparticles. Spinal cord tissue from a 0.5 cm long area of the lesion center was harvested after 7 dpi. Total protein was isolated by homogenization of the tissue in cold lysis buffer. After quantifying the protein concentration with the BCA protein assay kit, the proteins were separated by SDS-PAGE and transferred onto PVDF membranes. PVDF membranes were blocked with 5% Bovine Serum Albumin (BSA) and incubated with primary antibodies. After washing the membrane, the ECL kit was used to visualize the immunoreactive bands by incubating with a species-matched peroxidase-conjugated secondary antibody for 2 hours at room temperature. Finally, band densities were calculated using ImageJ software.
MBP protein, neurofilament-200 (NF 200) and βiii-tubulin are indicators of neurons and regenerative axons in the damaged area after SCI. As can be seen from FIG. 6, the expression of MBP protein, NF200 protein and βiii-tubulin of SCI group was significantly low, siO alone 2 @mSiO 2 Group intervention did not affect the expression of these proteins. However, with PBS and SiO 2 @mSiO 2 Group comparison, AB/SiO 2 @mSiO 2 The composite nano particles can obviously increase the expression of MBP protein, NF200 protein and beta iii-tubulin, and prove that AB/SiO 2 @mSiO 2 The preparation has remarkable effects in preserving neurons and promoting axon regeneration, thereby promoting the recovery of nerve functions.
(8)AB/SiO 2 @mSiO 2 In vivo toxicity assay for composite nanoparticlesAnd (3) testing: SD rats weighing about 220g were obtained from Shanghai laboratory animal center, national academy of sciences. AB/SiO by tail vein injection 2 @mSiO 2 (dispersed in 100. Mu.L of physiological saline) while injecting the same volume of physiological saline as the control group. Mice were sacrificed 3 days later, their major internal organs (heart, liver, spleen, lung and kidney) were collected and observed under an optical microscope for H&E staining tissue sections.
As can be seen from FIG. 7, tissue sections H of the experimental group and the control group&E staining was free of obvious organ damage or inflammatory lesions, further indicating AB/SiO 2 @mSiO 2 The composite nano-drug has good biocompatibility and no obvious biotoxicity, and is very promising for repairing spinal cord injury.
Example 2
The preparation method of the ammonia borane/silicon spheres/mesoporous silica nano composite particles of the present embodiment is basically the same as that of the embodiment 1, except that:
in the step (1-1), the addition amount of tetraethyl orthosilicate is 2.5mL.
In step (1-2), triethanolamine (TEA) was added in an amount of 0.2g, and monodisperse SiO was dispersed in deionized water 2 The amount of nanoparticles added was 8mL.
In the step (1-3), the addition amount of the 1% NaCl methanol solution was 40mL.
In the step (1-4), the addition amount of ammonia borane is 200mg, siO 2 @mSiO 2 The composite nanoparticle was 1.5mL.
The detection results and performances of the ammonia borane/silica spheres/mesoporous silica nanocomposite particles obtained in this example 2 were substantially the same as those of example 1.
Example 3
The preparation method of the ammonia borane/silicon spheres/mesoporous silica nano composite particles of the present embodiment is basically the same as that of the embodiment 1, except that:
in the step (1-1), the addition amount of tetraethyl orthosilicate is 4.5mL.
In the step (1-2), cetyltrimethylammonium chloride was added in an amount of 1.5g, and was monodisperse in deionized waterSiO of (2) 2 The amount of nanoparticles added was 15mL.
In the step (1-3), the addition amount of the 1% NaCl methanol solution was 65mL.
In the step (1-4), the ammonia borane was added in an amount of 300mg, siO 2 @mSiO 2 The composite nanoparticle was 2.5mL.
The detection result and performance of the ammonia borane/silica sphere/mesoporous silica nanocomposite obtained in this example 3 are substantially the same as those of example 1.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.
Claims (2)
1. A preparation method of ammonia borane/silicon spheres/mesoporous silica nano composite particles for treating spinal cord injury is characterized by comprising the steps of,
the ammonia borane/silicon sphere/mesoporous silica nano composite particle has a chemical formula of AB/SiO 2 @mSiO 2 Solid silicon spheres are taken as cores, mesoporous silicon dioxide is taken as a shell, and ammonia borane which is a gas prodrug and can generate hydrogen in an acidic environment is loaded;
the diameter of the nano composite particles is 180-230 nm;
the preparation method specifically comprises the following steps:
1) Tetraethyl orthosilicate is used as a raw material, and monodisperse solid silicon dioxide SiO is prepared by hydrolysis reaction in an alkaline environment 2 A nanoparticle;
2) In the template solution, siO produced in step 1) 2 Coating a layer of thick silicon oxide on the surface of the nano particles to prepare SiO 2 @SiO 2 A nanoparticle;
3) Will step by stepSiO produced in step 2) 2 @SiO 2 The nano particles remove the template agent through methanol to construct SiO with mesoporous structure 2 @mSiO 2 A nanoparticle;
4) SiO obtained in the step 3) 2 @mSiO 2 The nanometer particle is coated with the gas prodrug ammonia borane AB to prepare AB/SiO 2 @mSiO 2 Composite nanoparticles;
wherein,,
the step 1) adopts a sol-gel method, and the sol-gel method comprises the following process steps: in a reaction vessel, according to the measurement of the reaction process of tetraethyl orthosilicate and water, ethanol is used as a solvent, water is used as a medium for mixing, ammonia water is used as a catalyst, stirring is carried out for 8-25min at 20-40 ℃, then a certain amount of tetraethyl orthosilicate is dripped into the reaction vessel for hydrolysis polymerization reaction, water bath stirring is carried out for 1-2.5 and h at 20-40 ℃, then alcohol washing and water washing are carried out, the final product is dispersed in a certain amount of water, and finally, the monodisperse solid SiO is obtained by vacuum drying 2 Particles; the mass ratio of the ammonia water, the ethanol, the deionized water and the tetraethyl orthosilicate is 1-2.5:40:5-10:1-4;
the specific process steps of the step 2) are as follows: adding template agent and triethanolamine into a certain amount of ultrapure water, stirring for 0.5-1.5-h, and heating to 78-90 ℃; then adding SiO dispersed in deionized water prepared in the step 1) 2 The nano particles and tetraethyl orthosilicate are stirred at 78-90 ℃ for 0.5-2h, a layer of thick silicon dioxide can be coated, and the SiO is prepared by washing and centrifuging 2 @SiO 2 A nanoparticle;
the template agent is Cetyl Trimethyl Ammonium Chloride (CTAC) or Cetyl Trimethyl Ammonium Bromide (CTAB); the template agent, triethanolamine and SiO dispersed in deionized water 2 The dosage ratio of the nano particles to the tetraethyl orthosilicate is 0.8-1.5g:0.1-0.8g:5-15mL:1.5-2.5 mL;
the methanol removal template agent structure in the step 3) has a mesoporous structure and comprises the following process steps: taking the obtained SiO 2 @SiO 2 Stirring the nanoparticle with methanol containing 1% NaCl at 40-65deg.C for 4-12h, centrifuging, and washingDispersing in water for three times to obtain mesoporous SiO 2 @mSiO 2 Composite nanoparticles;
the process steps of the step 4) are as follows: dissolving ammonia borane in SiO prepared in the step 3) 2 @mSiO 2 Stirring 30-40h at room temperature in composite nanoparticle buffer solution, centrifuging, washing with water, and dispersing in water to obtain AB/SiO 2 @mSiO 2 Composite nanoparticles;
the SiO is 2 @mSiO 2 The mass concentration of the composite nano particles in deionized water is 10-30 mg/mL; the ammonia borane and SiO 2 @mSiO 2 The mass ratio of the composite nano particles is 4-15:1.
2. the use of the ammonia borane/silica spheres/mesoporous silica nano-composite particles prepared by the method of claim 1 in the preparation of a medicament for treating spinal cord injury.
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