CN105749288A - Near-infrared light monitoring and controllable medicine released mesoporous silicon dioxide microsphere and synthesis method thereof - Google Patents
Near-infrared light monitoring and controllable medicine released mesoporous silicon dioxide microsphere and synthesis method thereof Download PDFInfo
- Publication number
- CN105749288A CN105749288A CN201610108385.2A CN201610108385A CN105749288A CN 105749288 A CN105749288 A CN 105749288A CN 201610108385 A CN201610108385 A CN 201610108385A CN 105749288 A CN105749288 A CN 105749288A
- Authority
- CN
- China
- Prior art keywords
- infrared
- silicon dioxide
- mesoporous silicon
- nanocrystalline
- particle
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
- A61K38/385—Serum albumin
-
- 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
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1664—Compounds of unknown constitution, e.g. material from plants or animals
Abstract
The invention belongs to the technical field of nano biological materials, and in particular relates to a near-infrared light monitoring and controllable medicine released mesoporous silicon dioxide microsphere and a synthesis method thereof. The mesoporous silicon dioxide microsphere is of a multi-layer structure, that is, the kernel is a smooth silicon dioxide nanoparticle for adjusting the particle size of the microsphere and carrying near-infrared nano crystal; under excitation of near-infrared light of certain wavelength, the near-infrared nano crystal can be transformed, that is, near-infrared light of specific wave length can be emitted; a secondary outer layer is a smooth silicon dioxide shell layer for fixing and protecting the near-infrared nano crystal of an inner layer; the outermost layer is a mesoporous silicon dioxide shell layer for carrying a target medicine and quenching molecules of the near-infrared nano crystal and connecting or wrapping a response polymer, and thus controllable medicine release can be achieved. By adopting the silicon dioxide microsphere provided by the invention, not only is controllable release of the medicine achieved, but also the release amount of the medicine and the metabolism situation of a carrier can be monitored by means of living biological imaging.
Description
Technical field
The invention belongs to nano meter biomaterial technical field, be specifically related to a kind of near infrared light monitoring, the mesoporous silicon dioxide micro-sphere of controlled drug release and synthetic method thereof.
Background technology
Drug molecule transports and there is a lot of problem freely, including relatively low stability, poor selectivity and relatively low dissolving dispersibility.The controlled drug of Nano/micron carrier transports, and can overcome these problems.Nano/micron carrier transports for controlled drug molecule and the principle that discharges is based on driving interiorly or exteriorly, makes the medicine of load leak.In internal drive system, the release of medicine compares to unique physiological property of its hetero-organization in response to destination organization, such as pH, oxidation-reduction quality, temperature etc..Therefore, utilizing the change of these microenvironments, the Nano/micron carrier transported to realize controlled drug becomes the emphasis of current drug carrier material research.And in these Nano/micron carriers, mesoporous silicon oxide has been a great concern.It is not only because the high stability of mesoporous silicon oxide, chemical inertness, controlled aperture, optical clear and building-up process high advantage simple, controlled, repeatable, and the exist for load of Subsequent pharmacological molecule, the grafting of biomacromolecule and the adhesion of nano-particle of mesoporous silicon oxide are provided convenience.
Since last decade, near-infrared bio-imaging receives the extensive concern of scientific researcher because of its outstanding behaviours in the early diagnosis and therapy of disease.Comparing to traditional tomography technology (such as CT, PET, MRI etc.), near-infrared bio-imaging can realize higher time and spatial resolution；And comparing to ultraviolet-visible light, near infrared light itself just has deeper of penetration depth (1-2cm).Based on this, scientific researcher can simply nearly infrared nanometer material (nir dye, near-infrared quantum dots, near-infrared rare earth nano crystal, noble-metal nanoclusters etc.) embed in the skeleton of mesopore silicon oxide or duct, to realize the purpose of real-time tracking pharmaceutical carrier.But, entering after biological tissue when pharmaceutical carrier carries medicine, conventional near-infrared bio-imaging often can only play the effect following the tracks of pharmaceutical carrier, and for the monitoring of the burst size of medicine and rate of release, just seems helpless.In a rational drug-supplying system, the burst size of medicine and rate of release, for doctor or scientific research personnel, will be important information feedback.Therefore, a kind of near-infrared monitoring of exploitation, the pharmaceutical carrier of controlled drug release has had become as the task of top priority that Nano/micron medicine carrying field is developed further.
Summary of the invention
It is an object of the invention to provide a kind of near infrared light monitoring, the mesoporous silicon dioxide micro-sphere of controlled drug release and synthetic method thereof.
Near infrared light of the present invention monitoring, controlled drug release mesoporous silicon dioxide micro-sphere, be a kind of multiple structure Nano/micron material, be specifically made up of numerous near-infrared nanocrystalline bodies of most kernel, secondary outer layer, outermost layer and most kernel and secondary outer interlayer.Wherein, described most kernel is a smooth nano SiO 2 particle, and it is used for regulating microspherulite diameter and load near-infrared nanocrystalline body；This nano SiO 2 particle can adhere to a large amount of near-infrared nanocrystalline body, and these near-infrared nanocrystalline bodies are under the near infrared light of certain wavelength excites, it is possible to lower transduction occurs, namely sends the near infrared light (wavelength ratio exciting light length) of specific wavelength；Described outer layer is one layer of smooth silica shell, for fixing and protect the near-infrared nanocrystalline body of internal layer；Described outermost layer is mesoporous silicon oxide shell, and the mesoporous silicon oxide of this layer may be used for the quencher molecule of load target medicine and near infrared light nanocrystal, and connects or cladding responsive polymer, to realize controlled drug release.
The mesoporous silicon dioxide micro-sphere that above-mentioned near infrared light provided by the invention monitoring, controlled drug discharge, it is possible not only to the alternative medicine release realizing under different physiological environments, and the position of near-infrared fluorescent in living imaging instrument and the change of intensity, reaction pharmaceutical carrier position and release amount of medicine can be passed through.
In the present invention, described smooth nano SiO 2 particle can be prepared by conventional sol-gel processes.Wherein, solvent can use alcohol-water system, and alcohol may is that methanol, ethanol, propanol or isopropanol；Catalyst usable acid or alkali, acid may is that hydrochloric acid, acetic acid, phosphoric acid or acidic amino acid, and alkali may is that ammonia, sodium hydroxide, potassium hydroxide or triethylamine；Silicon source may is that tetraethyl orthosilicate, methyl silicate or positive silicic acid propyl ester.The big I of described smooth nano SiO 2 particle is adjusted by the ratio or kind changing alcohol/water/catalyst/silicon source, and range of accommodation is 50-2000nm.The silica nanoparticle surface band great amount of hydroxy group that this method synthesizes, neutrallty condition lower surface is negative electricity, is the good site of hydrogen bond and electrostatic adsorption.
In the present invention, described near-infrared nanocrystalline body is a kind of rear-earth-doped nano crystal material, including substrate and centre of luminescence two parts；Wherein, host material is: fluoride, oxide, oxysulfide or halogenide；Fluoride is: CaF2、BaF2、LaF3、YF3、ZnF2、NaYF4、NaYbF4、LiYF4、KYF4、NaGdF4Or NaLuF4；Oxide is: La2O3、Y2O3、Yb2O3、Gd2O3Or Lu2O3；Oxysulfide is Y2O2S、CaS2Or La2S3；Halogenide is Cs3Lu2Br9；The centre of luminescence is Ce3+、Pr3+、Nd3+、Sm3+、Eu3+、Tb3+、Dy3+、Ho3+、Er3+、Tm3+、Yb3+In one or several；The molar content of the centre of luminescence is 0.01%-50%.This near-infrared nanocrystalline body can pass through Electrostatic Absorption or hydrogen bond action is adsorbed on above-mentioned smooth nano SiO 2 particle in a large number, forms silicon ball-near-infrared nanocrystalline nanocrystal composition.
In the present invention, described secondary outer layer is one layer of smooth silica shell, and this silica shell can be coated in the near-infrared nanocrystalline nanocrystal composition of above-mentioned smooth nano SiO 2 particle and load thereof by conventional sol-gel processes to obtain.Wherein, solvent can use alcohol-water system, and alcohol may is that methanol, ethanol, propanol or isopropanol；Catalyst usable acid or alkali, acid may is that hydrochloric acid, acetic acid, phosphoric acid or acidic amino acid, and alkali may is that ammonia, sodium hydroxide, potassium hydroxide or triethylamine；Silicon source may is that tetraethyl orthosilicate, methyl silicate or positive silicic acid propyl ester.After being coated with this layer, near-infrared nanocrystalline body will be embedded in the skeleton of silicate firmly, difficult drop-off, and therefore, the optical property of each granule also becomes to stabilize.
In the present invention, described outermost layer is mesoporous silicon oxide shell, it can by conventional sol-gel processes or two phase process be grown in time smooth silica shell of outer layer outside obtain.Wherein in conventional sol-gel processes, solvent can use alcohol-water system, and alcohol may is that methanol, ethanol, propanol or isopropanol；Catalyst usable acid or alkali, acid may is that hydrochloric acid, acetic acid, phosphoric acid or acidic amino acid, and alkali may is that ammonia, sodium hydroxide, potassium hydroxide or triethylamine；Silicon source may is that tetraethyl orthosilicate, methyl silicate or positive silicic acid propyl ester；Surfactant can be cetyl trimethylammonium bromide, hexadecyltrimethylammonium chloride or Dodecyl trimethyl ammonium chloride.And in two phase process, solvent includes water-oil phase, wherein, oil phase can be decahydronaphthalene, toluene, octadecylene or hexamethylene；Catalyst can be triethylamine, triethanolamine or trimethylamine；Silicon source can be tetraethyl orthosilicate, methyl silicate or positive silicic acid propyl ester；Surfactant can be cetyl trimethylammonium bromide, hexadecyltrimethylammonium chloride or Dodecyl trimethyl ammonium chloride.This is mesoporous in divergent shape, aperture can continuously adjust in the scope of 2 nanometers to 12 nanometers, the duct degree of depth can also continuously adjust in the scope of 20 nanometers to 500 nanometers, is conducive to the load (such as protein medicaments and genetic fragment etc.) of macromolecular drug and the lifting of load capacity.Before load, drug molecule can the dyestuff of cancellation near infrared light be combined with some, it is possible to make the near-infrared nanocrystalline body of embedding play the effect of sensor, thus monitoring burst size and the rate of release of drug molecule.It addition, the connection that this mesopore orbit surface is also responsive polymer (pH sensitivity, isotope of redox-sensitive, enzyme response etc.) provides site, mesoporous silicon dioxide micro-sphere of the present invention is made to realize the function of controllable release.
The present invention provides above-mentioned near infrared light to monitor, the synthetic method of the mesoporous silicon dioxide micro-sphere of controlled drug release, specifically comprises the following steps that
(1) preparation of near-infrared nanocrystalline body:
A, employing oleic acid, oleyl amine, trioctylphosphine, octadecylene, liquid paraffin are high-temperature solvent, and rare earths material adopts rare earth chloride, rare earth trifluoroacetate, rare earth nitrate or lanthanon acetate；Reactant also should include one or several in ammonium fluoride, sodium fluoride, lithium fluoride, potassium fluoride, sodium hydroxide, potassium hydroxide, Lithium hydrate；200-320 degree Celsius, reaction under nitrogen atmosphere, obtain dispersibility and the good oil-soluble near-infrared nanocrystalline body of uniformity；
B, employing hydrochloric acid, acetic acid, phosphoric acid, citric acid are solvent, and oil-soluble near-infrared nanocrystalline body prepared by previous step washs, and is finally dispersed in water, obtains water solublity near-infrared nanocrystalline body；
(2) preparation of smooth nano SiO 2 particle and the adhesion to it of the near-infrared nanocrystalline body
A, smooth nano SiO 2 particle adopt conventional sol-gel processes to prepare.Wherein, solvent alcohol-water system, alcohol adopts methanol, ethanol, propanol or isopropanol；Catalyst acid or alkali, acid may is that hydrochloric acid, acetic acid, phosphoric acid or acidic amino acid, and alkali may is that ammonia, sodium hydroxide, potassium hydroxide or triethylamine；Silicon source adopts tetraethyl orthosilicate, methyl silicate or positive silicic acid propyl ester.Its big I is adjusted by the ratio or kind changing alcohol/water/catalyst/silicon source, and range of accommodation is 50-2000nm；
B, the adhesion to smooth silica nano-particle of the near-infrared nanocrystalline body.Smooth silica nano-particle synthesized by previous step is scattered in water with finite concentration, then water solublity near-infrared nanocrystalline body synthesized in step (1) is dropwise instilled；The near-infrared nanocrystalline body every time introduced and the mass ratio of smooth silica nano-particle are 1:1 to 50:1.Gained turbid solution is centrifugal or filtration after stirring 6-12 hour, can obtain silicon ball-near-infrared nanocrystalline nanocrystal composition；
(3) cladding of secondary outer layer (smooth silica shell)
Previous step gained silicon ball-near-infrared nanocrystalline nanocrystal composition is scattered in the mixed solvent of methanol, ethanol, propanol or isopropanol and water；Add one or more in appropriate strong aqua ammonia, sodium hydroxide, potassium hydroxide, triethylamine as catalyst；Finally it is added dropwise over one or more in appropriate tetraethyl orthosilicate, methyl silicate or positive silicic acid propyl ester as silicon source；Wherein, the amount in catalyst and silicon source all accounts for 0.1% to the 5% of gross mass.Room temperature reaction is centrifugal or filtration after 6-12 hour；
(4) cladding of outermost layer (mesoporous silicon oxide shell)
The available conventional sol-gel processes of the cladding of outermost layer (mesoporous silicon oxide shell) or two phase process.
At this, introduce the operating process of the coating mesoporous silica shell of two phase process:
A, previous step products obtained therefrom is scattered in water, and adds one or more in appropriate strong aqua ammonia, sodium hydroxide, potassium hydroxide, triethylamine as catalyst；It is subsequently adding one or more in appropriate cetyl trimethylammonium bromide, hexadecyltrimethylammonium chloride, Dodecyl trimethyl ammonium chloride as surfactant；Finally, drip one or more in decahydronaphthalene, toluene, octadecylene, hexamethylene on the surface of this aqueous solution as oil phase, and in oil phase, be mixed into one or more in appropriate tetraethyl orthosilicate, methyl silicate or positive silicic acid propyl ester as silicon source；Wherein, the amount in catalyst, surfactant and silicon source all accounts for 0.5% to the 10% of gross mass.This reaction carries out under 40-90 degree Celsius, centrifugal or filtration after 6-24 hour；
B, by previous step gained sample dispersion in hydrochloric acid-alcoholic solution that volume ratio is 1-5%, 50-60 degree Celsius reflux 10-12 hour, be then centrifuged for or filter, repeating 2-5 time.
Accompanying drawing explanation
Fig. 1 near infrared light is monitored, the structural representation of the mesoporous silicon dioxide micro-sphere of controlled drug release.
Fig. 2 near infrared light is monitored, the transmission electron microscope photo (low amplification) of the mesoporous silicon dioxide micro-sphere of controlled drug release.
Fig. 3 near infrared light is monitored, the transmission electron microscope photo (high-amplification-factor) of the mesoporous silicon dioxide micro-sphere of controlled drug release.
The absorption spectrum of Fig. 4 near-infrared nanocrystalline body and nickle tetrasulfo_phthalocyanine contrasts.
Fig. 5 near infrared light is monitored, the mesoporous silicon dioxide micro-sphere drug release situation under simulated body fluid (pH=1.2,6.0,7.4) of controlled drug release and the recovery situation of near-infrared fluorescent；Wherein drug release situation is monitored gained by ultraviolet-visible spectrometer, and near-infrared fluorescent recovery situation is monitored gained by fluorescence spectrophotometer.
Detailed description of the invention
Embodiment 1:
(1) preparation of near-infrared nanocrystalline body:
A, to take tri-mouthfuls of round-bottomed flasks of 50mL be reaction vessel, is firstly added 0.95mmolGdCl3, 0.5mmolNdCl3It is subsequently added 6mL oleic acid (OA), 15mL octadecylene (ODE).Said mixture is heated with stirring to 140 DEG C, vacuum dehydration deoxidation 60 minutes, finally give transparent mixed solution.After this clear solution is cooled to room temperature, by 2.5mmolNaOH and 4mmolNH4F is dissolved in 10mL methanol solution and mixes and inject in above-mentioned reaction solution reacts.After continuous stirring 20 minutes, reactant is warming up to 285 degrees Celsius of also insulation reaction 100 minutes with the speed of 10 DEG C/min under high-purity argon gas is protected.After question response terminates, add ethanol after reaction mother liquor is cooled to 50 DEG C and make product Precipitation from solution, be centrifuged subsequently, after using dehydrated alcohol cyclic washing 3-5 time, obtain product；
B, in above-mentioned product add 100mL dilute hydrochloric acid solution (pH=3) 12h is stirred at room temperature, filtration discards precipitation, filtrate is carried out ultracentrifugation (15000rpm) 10min, obtain solid product, and be scattered in 10mL deionized water with after dehydrated alcohol cyclic washing 3-5 time, it is water solublity near-infrared nanocrystalline body.
(2) smooth nano SiO 2 particle and the adhesion to it of the near-infrared nanocrystalline body
A, take two 100mL single port flasks, a flask adds 10mL deionized water, 10mL ethanol and 2mL strong aqua ammonia wherein；Another flask adds 20mL ethanol and 2mL tetraethyl orthosilicate, and two flasks mix rapidly after 0.5h is stirred at room temperature simultaneously.After room temperature reaction 2h centrifugal, obtain smooth nano SiO 2 particle after using dehydrated alcohol cyclic washing 3-5 time；
B, above-mentioned smooth nano SiO 2 particle is scattered in 10mL deionized water, take 1mL and add in 20mL beaker, slow magnetic agitation is while being added dropwise over 5mL water solublity near-infrared nanocrystalline body on one side, after the slow magnetic agitation 8h of room temperature centrifugal, obtain product after using deionized water cyclic washing 3-5 time.
(3) cladding of secondary outer layer (smooth silica shell)
Upper step gained silicon ball-near-infrared nanocrystalline nanocrystal composition is scattered in the mixed solvent of 4mL deionized water and 6mL ethanol, add 0.2mL strong aqua ammonia, it is stirred at room temperature after 0.5h and adds 0.2mL tetraethyl orthosilicate, centrifugal after room temperature reaction 6h, obtain product after using dehydrated alcohol cyclic washing 3-5 time.
(4) cladding of outermost layer (mesoporous silicon oxide shell)
A, upper step product is scattered in 20mL deionized water, join in 50mL single port flask, add 1g hexadecyltrimethylammonium chloride and 0.24mL triethylamine, it is slowly stirred dissolving at 60 DEG C, the 10mL hexamethylene dissolved with 0.3mL tetraethyl orthosilicate is slowly dropped in the surface of this aqueous solution again, 12h will be reacted after bottle sealing at 60 DEG C.Reaction is cooled to room temperature and is centrifuged after terminating, and obtains product after using dehydrated alcohol cyclic washing 3-5 time；
B, upper step product is scattered in hydrochloric acid-alcoholic solution that 20mL volume ratio is 2%, centrifugal or filter after 70 degrees Celsius of backflows 12 hours, in triplicate.
Mesoporous microsphere prepared in this embodiment has bigger aperture (8-9nm) and bigger specific surface area (200-300m2/ g), it is possible to meet load and the release of a lot of macromolecular drug.Under the near infrared light of 730nm or 808nm excites, this mesoporous microsphere can send the near-infrared fluorescent of 1060nm, and in the medicine of load compound some can absorb the dyestuff of near infrared light, just can this fluorescence of cancellation, thus giving the function of this carrier monitoring drug release, and outside duct, modifying the polymeric material of response, can be achieved with the controllable release function of medicine, reach near-infrared monitoring, the purpose of controlled drug release.
Embodiment 2:
Being released to example with the pH responsive type of protein medicaments, selecting nickle tetrasulfo_phthalocyanine is by the nir dye of compound.The hydrophobic region of nickle tetrasulfo_phthalocyanine and albumen is by being combined more closely, and its absworption peak can cover the region of 700-750nm；Therefore, under the exciting light of 730nm, it is possible to use its absorptance is better than far away the character (about 1000 times) of near-infrared nanocrystalline body, reach the effect of cancellation near-infrared fluorescent, and under the exciting light of 808nm, nickle tetrasulfo_phthalocyanine absorbs only small, so there is no quenching effects.To sum up, we can select 808nm exciting light for the tracking of pharmaceutical carrier, and 730nm exciting light is for the monitoring of drug release situation.
(1) preparation of nickle tetrasulfo_phthalocyanine-bovine serum albumin complex
Select bovine serum albumin as simulated albumin class medicine.Take 200mg bovine serum albumin, be dissolved in 10mL water, be slowly stirred the aqueous solution (1mg/mL) dropwise instilling 0.2mL nickle tetrasulfo_phthalocyanine, 0.5h is stirred at room temperature；
(2) cladding of the load of nickle tetrasulfo_phthalocyanine-bovine serum albumin complex and pH responsive polymer
Selecting soybean extract is pH responsive polymer, and this extract<be hydrophobic shape when 7, it is intended to assemble, can be used for blocking mesoporous, and during pH>7 be hydrophilic shape, it is intended to expansion at pH, therefore can be used as the controlled release of pH response.Concrete operations are as follows: end-product 0.5g in treating excess syndrome example 1, it is scattered in 1mL water, dropwise drip the nickle tetrasulfo_phthalocyanine-bovine serum albumin complex of previous step, 12h is stirred at room temperature, after centrifugal, precipitation is dispersed in 1mL buffer (pH=5.5) again, it is sequentially added into 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and each 5mg of N-hydroxy-succinamide, 2mg soybean extract is added after stirring 1h, it is centrifuged after room temperature reaction 2h, wash 3-5 time with buffer (pH=5.5), end product is exactly near infrared light monitoring, the mesoporous silicon dioxide micro-sphere of controlled drug release.
Near infrared light monitoring in this example, the mesoporous silicon dioxide micro-sphere of controlled drug release can discharge protein medicaments under weak basic condition, outermost soybean extract, it is possible not only to control the pH selectivity release of medicine, and it can be avoided that the body fluid under relatively low pH is to the destruction of medicine in duct；Such as when oral administration, it is possible to achieve the selectivity administration of intestinal.And the release conditions of this administration process Chinese medicine can be monitored by the recovery ratio of near-infrared fluorescent, and the metabolic condition of pharmaceutical carrier also can obtain real-time tracing by the position of near-infrared fluorescent.
Claims (7)
1. the mesoporous silicon dioxide micro-sphere that a near infrared light monitoring, controlled drug discharge, it is characterized in that a kind of multiple structure Nano/micron material, be specifically made up of numerous near-infrared nanocrystalline bodies of most kernel, secondary outer layer, outermost layer and most kernel and secondary outer interlayer；Wherein, described most kernel is a smooth nano SiO 2 particle, and it is used for regulating microspherulite diameter and load near-infrared nanocrystalline body；This nano SiO 2 particle adheres to a large amount of near-infrared nanocrystalline bodies, and these near-infrared nanocrystalline bodies are under the near infrared light of certain wavelength excites, it is possible to lower transduction occurs, namely sends the near infrared light of specific wavelength；Described outer layer is one layer of smooth silica shell, for fixing and protect the near-infrared nanocrystalline body of internal layer；Described outermost layer is mesoporous silicon oxide shell, and the mesoporous silicon oxide of this layer may be used for the quencher molecule of load target medicine and near infrared light nanocrystal, and connects or cladding responsive polymer, to realize controlled drug release.
2. mesoporous silicon dioxide micro-sphere according to claim 1, it is characterized in that the described smooth nano SiO 2 particle for most kernel is prepared by conventional sol-gel processes, its size is adjusted by changing reaction condition, and range of accommodation is 50-2000nm.
3. mesoporous silicon dioxide micro-sphere according to claim 1, it is characterised in that described near-infrared nanocrystalline body is a kind of rear-earth-doped nano crystal material, including substrate and centre of luminescence two parts；Wherein, host material is: fluoride, oxide, oxysulfide or halogenide；Fluoride is: CaF2、BaF2、LaF3、YF3、ZnF2、NaYF4、NaYbF4、LiYF4、KYF4、NaGdF4Or NaLuF4；Oxide is: La2O3、Y2O3、Yb2O3、Gd2O3Or Lu2O3；Oxysulfide is Y2O2S、CaS2Or La2S3；Halogenide is Cs3Lu2Br9；The centre of luminescence is Ce3+、Pr3+、Nd3+、Sm3+、Eu3+、Tb3+、Dy3+、Ho3+、Er3+、Tm3+、Yb3+In one or several；The molar content of the centre of luminescence is 0.01%-50%.
4. mesoporous silicon dioxide micro-sphere according to claim 1, it is characterised in that described is the smooth silica shell of time outer layer, is coated in the near-infrared nanocrystalline nanocrystal composition of nano SiO 2 particle and load thereof by conventional sol-gel processes and obtains.
5. mesoporous silicon dioxide micro-sphere according to claim 1, it is characterised in that described for outermost mesoporous silicon oxide shell, is obtained be grown in the smooth silica shell of described secondary outer layer by conventional sol-gel processes or two phase process outside.
6. the synthetic method of the mesoporous silicon dioxide micro-sphere as described in one of claim 1-5, it is characterised in that specifically comprise the following steps that
(1) preparation of near-infrared nanocrystalline body:
A, employing oleic acid, oleyl amine, trioctylphosphine, octadecylene or liquid paraffin are high-temperature solvent, and rare earths material adopts rare earth chloride, rare earth trifluoroacetate, rare earth nitrate or lanthanon acetate；Reactant also should include one or several in ammonium fluoride, sodium fluoride, lithium fluoride, potassium fluoride, sodium hydroxide, potassium hydroxide, Lithium hydrate；200-320 degree Celsius, reaction under nitrogen atmosphere, obtain dispersibility and the good oil-soluble near-infrared nanocrystalline body of uniformity；
B, employing hydrochloric acid, acetic acid, phosphoric acid or citric acid are solvent, and oil-soluble near-infrared nanocrystalline body prepared by previous step washs, and is finally dispersed in water, obtains water solublity near-infrared nanocrystalline body；
(2) preparation of smooth nano SiO 2 particle and the adhesion to it of the near-infrared nanocrystalline body
A, smooth nano SiO 2 particle adopt conventional sol-gel processes to prepare；Wherein, solvent alcohol-water system, alcohol adopts methanol, ethanol, propanol or isopropanol；Catalyst acid or alkali, acid is: hydrochloric acid, acetic acid, phosphoric acid or acidic amino acid, and alkali is: ammonia, sodium hydroxide, potassium hydroxide or triethylamine；Silicon source adopts tetraethyl orthosilicate, methyl silicate or positive silicic acid propyl ester；Its size is adjusted by the ratio or kind changing alcohol/water/catalyst/silicon source, and range of accommodation is 50-2000nm；
B, the adhesion to smooth silica nano-particle of the near-infrared nanocrystalline body, be scattered in the smooth silica nano-particle synthesized by previous step in water with finite concentration, is more dropwise instilled by water solublity near-infrared nanocrystalline body synthesized in step (1)；The near-infrared nanocrystalline body every time introduced and the mass ratio of smooth silica nano-particle are 1:1 to 50:1；Gained turbid solution is centrifugal or filtration after stirring 6-12 hour, namely obtains nano SiO 2 particle-near-infrared nanocrystalline nanocrystal composition；
(3) cladding of the smooth silica shell of secondary outer layer
Previous step gained nano SiO 2 particle-near-infrared nanocrystalline nanocrystal composition is scattered in the mixed solvent of methanol, ethanol, propanol or isopropanol and water；Add one or more in appropriate strong aqua ammonia, sodium hydroxide, potassium hydroxide, triethylamine as catalyst；Finally it is added dropwise over one or more in tetraethyl orthosilicate, methyl silicate or positive silicic acid propyl ester as silicon source；Wherein, the amount in catalyst and silicon source all accounts for 0.1% to the 5% of gross mass；Room temperature reaction is centrifugal or filtration after 6-12 hour；
(4) cladding of outermost layer mesoporous silicon oxide shell
The cladding of outermost layer mesoporous silicon oxide shell adopts conventional sol-gel processes or two phase process.
7. the synthetic method of a mesoporous silicon dioxide micro-sphere as claimed in claim 6, it is characterised in that the concrete operations of the coating mesoporous silica shell of two phase process are as follows:
A, previous step products obtained therefrom is scattered in water, and adds one or more in appropriate strong aqua ammonia, sodium hydroxide, potassium hydroxide, triethylamine as catalyst；It is subsequently adding one or more in appropriate cetyl trimethylammonium bromide, hexadecyltrimethylammonium chloride, Dodecyl trimethyl ammonium chloride as surfactant；Finally, drip one or more in decahydronaphthalene, toluene, octadecylene, hexamethylene on the surface of this aqueous solution as oil phase, and in oil phase, be mixed into one or more in appropriate tetraethyl orthosilicate, methyl silicate or positive silicic acid propyl ester as silicon source；Wherein, the amount in catalyst, surfactant and silicon source all accounts for 0.5% to the 10% of gross mass；Reaction carries out under 40-90 degree Celsius, centrifugal or filtration after 6-24 hour；
B, by previous step gained sample dispersion in hydrochloric acid-alcoholic solution that volume ratio is 1-5%, 50-60 degree Celsius reflux 10-12 hour, be then centrifuged for or filter, repeating 2-5 time.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610108385.2A CN105749288B (en) | 2016-02-29 | 2016-02-29 | The mesoporous silicon dioxide micro-sphere and its synthetic method of a kind of monitoring of near infrared light, controlled drug release |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610108385.2A CN105749288B (en) | 2016-02-29 | 2016-02-29 | The mesoporous silicon dioxide micro-sphere and its synthetic method of a kind of monitoring of near infrared light, controlled drug release |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105749288A true CN105749288A (en) | 2016-07-13 |
| CN105749288B CN105749288B (en) | 2019-05-03 |
Family
ID=56331301
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610108385.2A Active CN105749288B (en) | 2016-02-29 | 2016-02-29 | The mesoporous silicon dioxide micro-sphere and its synthetic method of a kind of monitoring of near infrared light, controlled drug release |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105749288B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107383916A (en) * | 2017-08-21 | 2017-11-24 | 安徽旺旺禽业科技有限公司 | A kind of resistance to compression, degradable lunch box and preparation method thereof |
| CN107416849A (en) * | 2017-09-06 | 2017-12-01 | 青岛科技大学 | A kind of method for preparing monodisperse nano silicon dioxide particle |
| CN108057031A (en) * | 2017-08-22 | 2018-05-22 | 牛云飞 | Prevent the sustained release Indomethacin nano particle and its injection of hand heterotopic ossification following surgical |
| CN108079297A (en) * | 2018-01-16 | 2018-05-29 | 复旦大学 | A kind of application of up-conversion luminescence-thermochemotherapy composite Nano probe and preparation method thereof and therapeutic alliance Programmed control |
| CN112237567A (en) * | 2019-07-16 | 2021-01-19 | 厦门大学 | Mesoporous sponge spicule and preparation method and application thereof |
| CN113149023A (en) * | 2021-03-11 | 2021-07-23 | 昆明理工大学 | Preparation method of mesoporous silica nanoparticle percutaneous delivery eutectic system |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102199428A (en) * | 2011-04-11 | 2011-09-28 | 复旦大学 | Rare earth-doped upconversion nanometer crystal-based fluorescent coding microspheres and preparation method thereof |
| CN103865538A (en) * | 2014-02-23 | 2014-06-18 | 复旦大学 | Up/down conversion dual-mode fluorescent nanomaterial for Nd<3+> sensitization and synthesis method thereof |
| CN103923277A (en) * | 2014-04-28 | 2014-07-16 | 苏州大学 | Amphipathic polymer, preparation method thereof, composite nano medicine carrier and preparation method thereof |
| CN104277822A (en) * | 2014-10-07 | 2015-01-14 | 复旦大学 | 800nm-near-infrared-excited 1525nm-shortwave-infrared-emission fluorescence nano material and synthesis method thereof |
| CN104707138A (en) * | 2015-04-01 | 2015-06-17 | 哈尔滨工业大学 | Preparation method of three-layer core-shell structure drug carrier with near-infrared light remote response |
| CN104804741A (en) * | 2015-03-31 | 2015-07-29 | 复旦大学 | Single-emission up-conversion nano fluorescent probe and synthetic method thereof |
| CN105056233A (en) * | 2015-08-12 | 2015-11-18 | 苏州大学 | Multifunctional mesoporous silica nanoparticles having near-infrared photothermal and in-vivo fluorescence imaging characteristics as well as preparation method and application of mesoporous silica nanoparticles |
-
2016
- 2016-02-29 CN CN201610108385.2A patent/CN105749288B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102199428A (en) * | 2011-04-11 | 2011-09-28 | 复旦大学 | Rare earth-doped upconversion nanometer crystal-based fluorescent coding microspheres and preparation method thereof |
| CN103865538A (en) * | 2014-02-23 | 2014-06-18 | 复旦大学 | Up/down conversion dual-mode fluorescent nanomaterial for Nd<3+> sensitization and synthesis method thereof |
| CN103923277A (en) * | 2014-04-28 | 2014-07-16 | 苏州大学 | Amphipathic polymer, preparation method thereof, composite nano medicine carrier and preparation method thereof |
| CN104277822A (en) * | 2014-10-07 | 2015-01-14 | 复旦大学 | 800nm-near-infrared-excited 1525nm-shortwave-infrared-emission fluorescence nano material and synthesis method thereof |
| CN104804741A (en) * | 2015-03-31 | 2015-07-29 | 复旦大学 | Single-emission up-conversion nano fluorescent probe and synthetic method thereof |
| CN104707138A (en) * | 2015-04-01 | 2015-06-17 | 哈尔滨工业大学 | Preparation method of three-layer core-shell structure drug carrier with near-infrared light remote response |
| CN105056233A (en) * | 2015-08-12 | 2015-11-18 | 苏州大学 | Multifunctional mesoporous silica nanoparticles having near-infrared photothermal and in-vivo fluorescence imaging characteristics as well as preparation method and application of mesoporous silica nanoparticles |
Non-Patent Citations (3)
| Title |
|---|
| AMIRALI POPAT等: "Programmable drug release using bioresponsive mesoporous silica nanoparticles for site-specific oral drug delivery", 《CHEM. COMMUN.》 * |
| D.J. NACZYNSKI等: "Rare-earth-doped biological composites as in vivo shortwave infrared reporters", 《NATURE COMMUNICATIONS》 * |
| MANJIE ZHANG等: "Near-Infrared Light and pH-Responsive Polypyrrole@Polyacrylic acid/Fluorescent Mesoporous Silica Nanoparticles for Imaging and Chemo-Photothermal Cancer Therapy", 《CHEM. EUR. J.》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107383916A (en) * | 2017-08-21 | 2017-11-24 | 安徽旺旺禽业科技有限公司 | A kind of resistance to compression, degradable lunch box and preparation method thereof |
| CN108057031A (en) * | 2017-08-22 | 2018-05-22 | 牛云飞 | Prevent the sustained release Indomethacin nano particle and its injection of hand heterotopic ossification following surgical |
| CN108057031B (en) * | 2017-08-22 | 2022-10-28 | 中国人民解放军海军军医大学第一附属医院 | Sustained-release indometacin nano-particles for preventing postoperative ectopic ossification and injection thereof |
| CN107416849A (en) * | 2017-09-06 | 2017-12-01 | 青岛科技大学 | A kind of method for preparing monodisperse nano silicon dioxide particle |
| CN108079297A (en) * | 2018-01-16 | 2018-05-29 | 复旦大学 | A kind of application of up-conversion luminescence-thermochemotherapy composite Nano probe and preparation method thereof and therapeutic alliance Programmed control |
| CN112237567A (en) * | 2019-07-16 | 2021-01-19 | 厦门大学 | Mesoporous sponge spicule and preparation method and application thereof |
| CN112237567B (en) * | 2019-07-16 | 2022-08-09 | 厦门大学 | Mesoporous sponge spicule and preparation method and application thereof |
| CN113149023A (en) * | 2021-03-11 | 2021-07-23 | 昆明理工大学 | Preparation method of mesoporous silica nanoparticle percutaneous delivery eutectic system |
| CN113149023B (en) * | 2021-03-11 | 2023-05-02 | 昆明理工大学 | Preparation method of mesoporous silica nanoparticle transdermal delivery eutectic system |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105749288B (en) | 2019-05-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105749288A (en) | Near-infrared light monitoring and controllable medicine released mesoporous silicon dioxide microsphere and synthesis method thereof | |
| Chen et al. | Current advances in lanthanide‐doped upconversion nanostructures for detection and bioapplication | |
| Zhang et al. | Exploring heterostructured upconversion nanoparticles: from rational engineering to diverse applications | |
| Wang et al. | Recent progress in biomedical applications of persistent luminescence nanoparticles | |
| Li et al. | Lab on upconversion nanoparticles: optical properties and applications engineering via designed nanostructure | |
| Qiu et al. | Recent advances in lanthanide-doped upconversion nanomaterials: synthesis, nanostructures and surface modification | |
| Li et al. | Rare earth fluoride nano-/microcrystals: synthesis, surface modification and application | |
| CN105903016B (en) | A kind of preparation method of the nuclear shell structure drug carrier of the near infrared light excitation light-operated drug release of supermolecule valve | |
| CN103865538A (en) | Up/down conversion dual-mode fluorescent nanomaterial for Nd<3+> sensitization and synthesis method thereof | |
| Wang et al. | ‘Green’-synthesized near-infrared PbS quantum dots with silica–PEG dual-layer coating: ultrastable and biocompatible optical probes for in vivo animal imaging | |
| Matsuyama et al. | Bioimaging application of highly luminescent silica-coated ZnO-nanoparticle quantum dots with biotin | |
| Choi et al. | Surface-modified silica colloid for diagnostic imaging | |
| CN101785862B (en) | Infrared light triggering controllable drug carrier and preparation method thereof based on up-conversion material | |
| CN103041409B (en) | Preparation method of pH and thermal dual-sensitive lipidosome loaded with magnetic carbon quantum dots on internal water phase | |
| CN112080278B (en) | Up/down conversion dual-mode luminescent nanocrystal and preparation method and application thereof | |
| WO2023041005A1 (en) | Virus-like hollow oxide loaded near-infrared two-b region excited rare earth nanocrystal, preparation method therefor and application thereof | |
| CN103387829A (en) | Phosphorescence silica nanometer probe with core shell composition and preparation method thereof | |
| CN110776916A (en) | Quantum dot dual-emission-ratio fluorescent probe and preparation method and application thereof | |
| Wang et al. | Dye-loaded zeolite L@ silica core-shell composite functionalized with europium (III) complexes for dipicolinic acid detection | |
| CN109172587A (en) | A kind of metal organic frame-that pH responds double drug releases goes up the preparation method and application of conversion nano system | |
| CN107929242B (en) | Drug carrier based on nano-diamond, drug complex, preparation method and application thereof | |
| CN107976538A (en) | A kind of immune labeled probe of silica fluorescent based on fluorescence resonance energy transfer, preparation method and application | |
| Chen et al. | Magnetic-fluorescent nanohybrids of carbon nanotubes coated with Eu, Gd Co-doped LaF3 as a multimodal imaging probe | |
| Dembski et al. | Core-shell nanoparticles and their use for in vitro and in vivo diagnostics | |
| Hong et al. | Controlled synthesis of gadolinium fluoride upconversion nanoparticles capped with oleic acid or polyethylene glycol molecules via one-step hydrothermal method and their toxicity to cancer cells |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |