CN101785862B - Infrared light triggering controllable drug carrier and preparation method thereof based on up-conversion material - Google Patents
Infrared light triggering controllable drug carrier and preparation method thereof based on up-conversion material Download PDFInfo
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- CN101785862B CN101785862B CN2010101077727A CN201010107772A CN101785862B CN 101785862 B CN101785862 B CN 101785862B CN 2010101077727 A CN2010101077727 A CN 2010101077727A CN 201010107772 A CN201010107772 A CN 201010107772A CN 101785862 B CN101785862 B CN 101785862B
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Abstract
The invention belongs to the technical field of carrying out drug controllable release by using infrared light triggering, in particular to an infrared light triggering controllable drug carrier and a preparation method thereof based on an up-conversion material. A core shell structure of the controllable drug carrier consists of an up-conversion nanometer material doped with rare earth ions and a mesoporous material containing an azo derivative. The azo derivative is used as a photosensitive group to realize the controllable release of the infrared light triggering controllable drug. As calculated by weight percentage, the mesoporous material containing the azo derivative accounts for 10%-90% relative to the mass of the drug carrier, wherein the molar content of the azo derivative in the mesoporous material is 10%-20%. Proved by an experiment, the rare earth up-conversion material and mesoporous material composite structure prepared by the invention can realize the drug release function under the control of infrared light.
Description
Technical field
The invention belongs to infrared light and trigger the technical field carry out drug controllable release, be specifically related to a kind of infrared light triggering controllable drug carrier based on up-conversion and preparation method thereof.
Background content
In recent years along with the development of nanosecond medical science; Drug controllable release has caused people's attention; Can make medicine in the specific time, be discharged in the environment through external trigger, realize intelligent medication, accomplish to control drug dose and administration time in real time according to therapeutic advance with controlled dosage; Not only can treat timely and effectively, and can reduce drug side effect and patient's Drug resistance patient.Triggering mode has temperature, pH, externally-applied magnetic field, ultrasound wave, light, organized enzyme etc.
At present light is triggered the research that discharges medicine and concentrate on, medicine is discharged from nano-medicament carrier with modes such as photodestruciton, light isomeries through being included in photosensitive group in the nano-medicament carrier to the reaction of light.Trigger light wavelength and be mostly ultraviolet light and visible light, penetration depth is little, can only arrive the surface of skin or organ, is difficult for arriving pathological tissues, has limited therapeutic effect, simultaneously normal structure is also had injury.
The wavelength that sees through of tissue is 800-1500nm, and as triggering light, penetration depth is big, can arrive biological intravital pathological tissues with infrared light.Rear-earth-doped up-conversion nano material can produce ultraviolet light, visible light under the exciting of infrared light, because its unique spectral characteristic and biocompatibility have potential application prospect aspect medical imaging, the photodynamics.Rear-earth-doped up-conversion nano material and nano-medicament carrier are integrally combined; Carry out infrared light and trigger drug controllable release down; Can carry out the treatment of the in-house degree of depth, improve therapeutic effect, reduce ultraviolet light simultaneously and trigger ultraviolet light pair cell and the injury of tissue in the drug release process.
Azo derivative has the character of light isomery, promptly is positioned at nitrogen-nitrogen two key both sides atomic group because space steric effect exists cis and transconfiguration, and both spatial volumes are different, and the spatial volume of transconfiguration is bigger.Under the excitation of different optical wavelength, two kinds of structures can be reversible change.The mesoporous material specific surface area is big, high adsorption capacity, and the aperture homogeneous has adjustability, and its inwall can be modified, and has biocompatibility, is important pharmaceutical carrier.With the mesoporous material is pharmaceutical carrier, modifies mesoporous material with azo derivative, under the light wave excitation of certain wavelength, through its photoisomerization, regulates the size of free space in the mesoporous material or the on off state of control hole, can realize light-operated drug release.
Jie Lu had reported with mesoporous SiO in 2007
2Be pharmaceutical carrier, utilize the photoisomerization of azo derivative, trigger with blue light and ultraviolet light; Realized light-operated drug release (Light-ActivatedNanoimpeller-Controlled Drug Release in Cancer Cells; Small 2008, vol.4,421-426).Spectral quality based on the rare earth up-conversion; With the azo derivative is photosensitive group; With mesoporous material as pharmaceutical carrier; Make the composite construction of rear-earth-doped up-conversion nano material and mesoporous material, can realize the drug controllable slow release under the infrared light triggering, tempting application prospect is arranged in the medical science diagnosis and treatment.
Summary of the invention
The purpose of this invention is to provide a kind of infrared light triggering controllable drug carrier and this preparation of drug carriers method based on up-conversion, the present invention can be through the external release of carrying out light-operated medicine in the deep layer position of biological tissue of controlling to infrared light.
The present invention combines rear-earth-doped up-conversion nano material and the nano-medicament carrier that contains photosensitive group; Up-conversion absorbs long wavelength's infrared light; Energy transfer process according to active ions inside; Up-conversion sends short wavelength's ultraviolet light and visible light; The short-wavelength light that is sent is through the interior photosensitive group of mode activated nano pharmaceutical carrier that absorbs again or energy resonance transmits, and photosensitive group is controlled the release of nano-medicament carrier Chinese medicine with modes such as photodestruciton or light isomeries.
Infrared light triggering controllable drug carrier based on up-conversion of the present invention; Form nucleocapsid structure by rare earth ion doped up-conversion nano material and the mesoporous material that contains azo derivative; It is to be that photosensitive group realizes that infrared light triggers the controllable release of medicine with the azo derivative, and up-conversion nano material is nuclear, and the mesoporous material that contains azo derivative is a shell; Calculate by mass percentage; The mesoporous material that contains azo derivative accounts for 10%～90% of pharmaceutical carrier quality, and all the other are rare earth ion doped up-conversion, and wherein the molar content of azo derivative in mesoporous material is 10%～20%.
The up-conversion nano material that the present invention relates to comprises oxide Gd
2O
3, Y
2O
3, Lu
2O
3With fluoride CaF
2, BaF
2, LaF
3, YF
3, ZnF
2, NaYF
4, LiYF
4, KYF
4, BaYF
5, Ba
2YF
7Nanocrystalline.
In up-conversion, the Doped Rare Earth ion partly replaces oxide or fluoride cation, and the Doped Rare Earth ion comprises sensitizer and active ions two parts, with Er
3+(molar content of rare earth ion is 0.1%～5%), Tm
3+(molar content 0.1%～5%), Ho
3+(molar content is 0.1%～5%), Dy
3+(molar content is 0.1%～5%), Gd
3+(molar content is 0.1%～5%), Nd
3+In (molar content is 0.1%～10%) one or more are as active ions, with Yb
3+(in up-conversion, molar content is 5%～20%) is as sensitizer; Through comparison and optimized choice repeatedly, use Yb among the embodiment
3+(molar content is 20%) is as sensitizer and use Tm
3+(molar content is 1.5%) is as active ions.
Mesoporous material and the up-conversion that will contain azo derivative combines and obtains infrared light and trigger controlled pharmaceutical carrier, and mesoporous material comprises SiO
2, TiO
2It is C that the template that synthesize meso-porous material adopted has cationic surfactant
nH
2n+1N
+(CH
3)
3X
-, n=8～22, X=Cl, Br or OH; Dodecylbenzene sodium sulfonate, NH
2(CH
2)
nNH
2, (PEO-PPO-PEO adopts CTAB (CTAB) as template among the embodiment for n=12～22 and block copolymer.
The variation of azo derivative cis-trans structure has formed motor segment in the molecule.Modify SiO with micromolecular azo derivative (molecular dimension is less than 1nm)
2Or TiO
2The inwall of mesoporous material can form the nanometer propeller, realizes the release of mesoporous interior medicine; Modify the inlet of mesoporous material with the azo derivative of macromole (molecular dimension be about 1.2nm and more than), can play the effect of light valve, the suitable-anti-attitude of light isomery forms mesoporous open and close state, thereby realizes drug release.The micromolecule azo derivative that uses among the embodiment is AzoH, and the macromole azo derivative is AzoG1, and its molecular formula is distinguished as follows:
Based on the method for preparing of the infrared light triggering controllable drug carrier of up-conversion, its step is following:
A: prepare rare earth ion doped up-conversion nano material
B: the mesoporous material that the rare earth ion doped up-conversion nano material azo derivative of preparation nucleocapsid structure is modified
Can use micromolecular azo derivative to modify the hole inwall of mesoporous material, also can use the macromole azo derivative to modify the hole inlet of mesoporous material, both method for preparinies are distinguished to some extent, provide respectively below.
(a) the rare earth ion doped up-conversion nano material micromolecule azo derivative of preparation nucleocapsid structure is modified the SiO of hole inwall
2Mesoporous material
The micromolecule azo derivative, isocyanates propyl-triethoxysilicane (ICPES) that (1) will contain hydroxyl is by mass ratio 100～200: 1 is dissolved in the dry ethanol of 10～30mL, at 80～90 ℃, N jointly
2Under reacted 4～8 hours, add ethyl orthosilicate (TEOS) again, the volume ratio of TEOS and ICPES is 1～5: 1;
(2) rare earth ion doped up-conversion nano material is dissolved in 1～10mL chloroform; Mass concentration is 1～30g/mol; Then with the template aqueous solution of 3～20mL, molar concentration 0.1～1M; Stir to clarify, with the NaOH aqueous solution dilution of 30～100mL, molar concentration 0.1～0.5M;
(3) solution of step (1) with step (2) is mixed, 80 ℃ were stirred 1～10 hour, cooling, centrifugal, clean with ethanol; Then precipitate is suspended in 10～60mL methanol solution; Add 1～3mL concentrated hydrochloric acid, 60 ℃ of heating 1～10 hour, cooling, precipitate were through centrifugal, washing, 60 ℃ of vacuum dryings 2～20 hours; Promptly obtain infrared light triggering controllable drug carrier based on up-conversion; It is a nucleocapsid structure, is nuclear with rare earth ion doped up-conversion nano material, and the mesoporous material of modifying the hole inwall with the micromolecule azo derivative is a shell;
(b) the rare earth ion doped up-conversion nano material macromole azo derivative of preparation nucleocapsid structure is modified the SiO of hole inlet
2Mesoporous material
(1) rare earth ion doped up-conversion nano material is dissolved in 1～10mL chloroform; Mass concentration is 1～30g/mol; Template aqueous solution with 3～20mL, molar concentration 0.1～1M stirs to clarify, with the NaOH aqueous solution dilution of 30～100mL, molar concentration 0.1～0.5M;
(2) in above-mentioned solution, add 0.5～5mLTEOS, 80 ℃ were stirred 1～10 hour, cooling, centrifugal, with ethanol clean, 2～20 hours, 500～800 ℃ sintering of 60 ℃ of vacuum dryings 3～10 hours, obtain the up-conversion nano material mesoporous material of nucleocapsid structure;
(3) the above-mentioned product with 10～100mg is suspended in the ICPES toluene solution of 5～20mL, molar concentration 1～20mM 80 ℃, N
2Refluxed 5～20 hours, filtration, dry toluene washing, the toluene solution of the macromole azo derivative of adding 10～50mL, molar concentration 1～10mM, 80 ℃, N
2Refluxed 5～20 hours; Filter, dry toluene washing, 60 ℃ of vacuum dryings 6～24 hours; Promptly obtain infrared light triggering controllable drug carrier based on up-conversion; It is a nucleocapsid structure, is nuclear with rare earth ion doped up-conversion nano material, and the mesoporous material that the macromole azo derivative is modified the hole inlet is a shell;
The pharmaceutical carrier of 1～30mg step B preparation was immersed in the aqueous solution of drug model that 5～20mL, molar concentration are 0.5～5mM 2～48 hours; The washing of centrifugal, deionization, 60 ℃ of vacuum dryings 5～24 hours can be loaded into drug model in the prepared infrared light triggering controllable drug carrier based on up-conversion of the present invention.
When mesoporous material and the up-conversion that will contain azo derivative combines, can also before two kinds of materials combine, up-conversion be modified or modification, improve the dissolubility of up-conversion nano material, improve the up-conversion nano material luminous efficiency.
Adopt method for coating that modification is carried out on rear-earth-doped up-conversion nano material surface in the present invention; The method that relates to has (1) to use the polymer with coordination atom O or N (like the polyethylene pyrrolin; Polyethylene Glycol; Nucleocapsid sugar, CTAB) or surfactant (like CTAB, oleic acid) coating up-conversion nano material, SiO is used in (2)
2Or TiO
2Layer coats up-conversion nano material, (3) use with the up-conversion nano material matrix phase with but the material that do not contain active ions coats up-conversion nano material, form the structure of active nucleus inertia shell, only be mixed with sensitizer Yb in the inertia shell
3+Or doped with sensitized agent Yb not
3+(molar content is 5%～20%).The modification material therefor is different, and the method for preparing of up-conversion can be different.Preparation Method that obtain through refining the front is one of them, and concrete method for preparing provides in an embodiment.Through comparison and optimized choice repeatedly, use (1) CTAB to coat three kinds of embodiments that up-conversion nano material (2) oleic acid coats up-conversion nano material (3) active nucleus inertia shell structure among the embodiment.
Carry out light-operated drug release experiment: choosing the dyestuff rhodamine B is drug model, rhodamine B is loaded in the material of rare earth up-conversion and mesoporous material nucleocapsid structure, material is deposited in the deionized water, with 980nm laser diode irradiation sample.Use 10mW, the aqueous solution above the 530nm light source irradiation precipitate at set intervals; Excite rhodamine B in the aqueous solution; The luminous intensity of rhodamine B maximum emission wavelength 575nm in the aqueous solution above the measurement precipitate; The relative intensity of fluorescence of meter record rhodamine B, thus the rhodamine B relative quantity that is discharged detected.
Description of drawings
Fig. 1: rare earth ion doped up-conversion La
0.785Yb
0.2Tm
0.015F
3X-ray diffractogram.
The specific embodiment
Below in conjunction with embodiment the present invention is done further elaboration, selected up-conversion nano material and nano-medicament carrier in the embodiments of the invention just are used for the specific embodiment of the present invention of explaining, rather than will limit the invention with this.
Embodiment 1:
The Yb that the CTAB of nucleocapsid structure coats
3+And Tm
3+The YF of codope
3Up-conversion AzoH modifies the mesoporous SiO of hole inwall
2Pharmaceutical carrier
1. sample preparation
(1) preparation CTAB (CTAB) coats Yb
3+And Tm
3+The YF of codope
3Up-conversion nano material
CTAB 2.4g, Ketohexamethylene 25.5mL, n-amyl alcohol 1.5mL mix, and vigorous stirring is up to clarifying (solution A is made into two parts in this ratio), 0.785La: 0.2Yb in molar ratio: 0.15Tm weighing Y
2O
30.2655g, Yb
2O
30.1182g, Tm
2O
30.0087g, being dissolved in 60mL, mass percent and being in 7% the dilute hydrochloric acid, the solvent of evaporating surplus forms the solution of 3mL, mixes with solution A, and strong agitation forms little micellar solution B to clarifying; 40% hydrofluoric acid solution 3mL mixes the little micellar solution C of formation with another part solution A, solution C is slowly splashed in the solution B, after the strong agitation; Solution is transferred in the agitated reactor of 75mL, 130 ℃ were reacted 12 hours, and cooling, precipitate clean through centrifugal, ethanol; Three times repeatedly; 60 ℃ of vacuum dryings 6 hours, under argon gas atmosphere, 600 ℃ of annealing 6 hours, obtain the rare earth ion doped up-conversion Y of 130mg
1.57Yb
0.4Tm
0.03F
3, wherein the molar content of Yb is 20%, the molar content of Tm is 1.5%.The XRD diffraction spectrogram shows that nanoparticle is six side's phases, and granularity is about 30nm, is dissolved in the chloroform.
(2) Y of preparation nucleocapsid structure
1.57Yb
0.4Tm
0.03F
3AzoH modifies the SiO of hole inwall
2Mesoporous material
Dry ethanol 10ml, AzoH 0.284 gram, isocyanates propyl-triethoxysilicane (ICPES) 1.42mL mix homogeneously are at 80 ℃ of following N
2Reaction is 4 hours in the atmosphere, drips the 1mL ethyl orthosilicate again, obtains solution D.The rare earth ion doped up-conversion nano material that obtains in the 50mg step 1 is dissolved in the 2.0mL chloroform; Mix with aqueous solution (0.55M) 10ml of template CBTA; Strong agitation is to clarification; Constant temperature is 5 minutes under 80 ℃ of air atmospheres, with 90mL NaOH aqueous solution (0.13M) dilution, obtains aqueous solution E.Under strong agitation, solution D is added drop-wise in the solution E, 80 ℃ of reactions were stirred 3 hours, and cooling, centrifugal, precipitate clean with ethanol; Be suspended in the 50mL methanol solution, add the 0.5mL concentrated hydrochloric acid, 60 ℃ were heated 6 hours; Cooling, precipitate are through centrifugal, washed with de-ionized water; Three times repeatedly,, obtain the 1.1g infrared light triggering controllable drug carrier 60 ℃ of vacuum dryings 6 hours.Little angle XRD records mesoporous SiO
2The d spacing be 2.3nm, transmission electron microscope observing is to SiO
2Thickness be 50nm.
2. infrared light triggers the drug release experiment
(1) loading of drug model
The 20mg infrared light triggering controllable drug carrier was immersed in drug model dyestuff rhodamine B aqueous solution (1mM) 12 hours; Centrifugal, precipitate is used deionized water rinsing, and is ultrasonic, repeats 3 times; 60 ℃ of vacuum dryings 6 hours, obtain the infrared light triggering controllable drug carrier that 15mg is loaded with drug model.
(2) light triggers the release of dye molecule
10mg is loaded with the infrared light triggering controllable drug carrier of drug model; Be deposited on the quartz test tube bottom; Add the 10mL deionized water,, use 10mW, the aqueous solution above the 530nm light source irradiation precipitate at set intervals with 100mW, 980nm laser diode irradiation precipitate; Receive the luminous intensity of rhodamine B maximum emission wavelength 575nm in the aqueous solution above the precipitate, the relative luminous intensity of meter record rhodamine B.
The pharmaceutical carrier of table 1: embodiment 1 preparation is discharged into the time dependent data of luminous relative intensity of the rhodamine B in the aqueous solution under infrared light triggers
| Light application time (minute) | 0 | 10 | 20 | 30 |
| Luminous relative intensity ( ＊10 3) | 0.30 | 4.2 | 4.8 | 5.2 |
Pharmaceutical carrier also can partly be revealed the dyestuff rhodamine B in aqueous solution under the irradiation of no infrared light, but its quantity much smaller than infrared light the release amount of medicine under light-operated, so we reach a conclusion: prepared rare earth up-conversion and SiO in the present embodiment
2The mesoporous material composite construction can be realized the drug release function under the infrared light control.
Embodiment 2:
The NaYF of nucleocapsid shell structure
4: 20%Yb
3+, 1.5%Tm
3+NaYF
4AzoH modifies the SiO of hole inwall
2Mesoporous pharmaceutical carrier
1. sample preparation
(1) prepares the Yb of nucleocapsid structure with thermal decomposition method
3+And Tm
3+Codope NaYF
4NaYF
4Up-conversion nano material
Sodium trifluoroacetate 2.72g, trifluoracetic acid yttrium 3.338g, trifluoracetic acid ytterbium 0.1026g and trifluoracetic acid thulium 0.0763g are dissolved in the 10mL oleyl amine, strong agitation under 110 ℃, under the argon 30 minutes, obtain lurid settled solution.Continuation slowly is heated to 300 ℃ with solution, reacts 30 minutes, splashes into the 5mL oleyl amine solution that contains sodium trifluoroacetate (1M), trifluoracetic acid yttrium (0.5M); Stirred 10 minutes, and dropped to room temperature fast, centrifugal; Precipitate is used washing with alcohol; Three times repeatedly, 60 ℃ of vacuum dryings 24 hours obtain the up-conversion nano material NaY of 1.72g nucleocapsid structure
0.785Yb
0.2Tm
0.015F
4, wherein the molar content of Yb is 20%, the molar content of Tm is 1.5%.
(2) NaYF of preparation nucleocapsid shell structure
4: 20%Yb
3+, 1.5%Tm
3+NaYF
4AzoH modifies the SiO of hole inlet
2Mesoporous material: the preparation process is identical with embodiment 1.
2. infrared light triggers the drug release experiment: test process and embodiment 1 are same, and experimental result sees the following form 2
The pharmaceutical carrier of table 2: embodiment 2 preparations triggers the time dependent data of luminous relative intensity that are discharged into the rhodamine B in the aqueous solution at infrared light
| Light application time (minute) | 0 | 10 | 20 | 30 |
| Luminous relative intensity ( ＊10 3) | 0.30 | 4.4 | 5.0 | 5.5 |
Embodiment 3:
The Yb that the oleic acid of nucleocapsid structure coats
3+And Tm
3+Codope Lu
2O
3AzoG1 modifies the mesoporous SiO of hole inlet
2Pharmaceutical carrier
1. sample preparation
(1) prepares the Lu that oleic acid coats Yb and Tm codope with solvent-thermal method
2O
3Up-conversion nano material
0.785Lu: 0.2Yb in molar ratio: 0.015Tm weighing Lu
2O
30.2554g, Yb
2O
30.0788g, Tm
2O
30.0058g, adding 40mL, mass percent and be in 7% the dilute hydrochloric acid, unnecessary solvent is removed in heating for dissolving and evaporation; Add 2.6g sodium acetate, 40mL ethylene glycol and 5mL oleic acid, after stirring to clarify, solution is transferred in the agitated reactor of 50mL; 180 ℃ of reactions 6 hours, cooling, centrifugal, precipitate are used washing with alcohol, three times repeatedly; 60 ℃ of vacuum dryings 6 hours, obtain 0.12g Lu
1.57Yb
0.4Tm
0.03O
3Up-conversion nano material, wherein the molar content of Yb is 20%, the molar content of Tm is 1.5%.
(2) macromole azo molecules AzoG1's is synthetic
With 269mg 4-(4 '-hydrogen-oxygen benzeneazo) phenethanol, 450mg F-G1-Br (syntheticly see document J.Am.Chem.Soc.1990,112,7638-7647), 55mL acetone, 62g hexaoxacyclooctadecane-6-6,244g K
2CO
3Mix, after 24 hours, remove and desolvate in the argon gas atmosphere refluxed.Product is extracted in water and chloroform are biphase, and the water layer after the extraction is further used chloroform extraction, triplicate, and the gained chloroformic solution dewaters with sodium sulfate.Crude product after desolventizing passes through SiO
2Silicagel column is further purified, and gets 458mg AzoG1, productive rate 74%.
(3) Lu of preparation nucleocapsid structure
0.785Yb
0.2Tm
0.015O
3AzoG1 modifies the mesoporous SiO of hole inlet
2Material
The nanoparticle that obtains in the 50mg step (1) is dissolved in the 1.0mL chloroform, mixes with 10mL CBTA aqueous solution (0.55M), after the strong agitation clarification, at 80 ℃ chloroform is vapored away, NaoH aqueous solution (0.13M) dilution with 90mL obtains solution A.Under strong agitation, the 1mL ethyl orthosilicate is added drop-wise in the solution A, 80 ℃ were stirred down after 3 hours, and cooling, centrifugal, precipitate are used washing with alcohol, 60 ℃ of vacuum dryings 6 hours, 550 ℃ of sintering 5 hours, obtained the Lu of 0.1g nucleocapsid structure
0.785Yb
0.2Tm
0.015O
3Mesoporous SiO
2Material.
The above-mentioned product of 50mg is suspended in the 5mL ICPES toluene solution (10mM) N
2Atmosphere, 80 ℃ of refluxed 12 hours are filtered, after precipitate repeatedly washs with dry toluene, are added in the toluene solution (1mM) of AzoG1 N
2Atmosphere, 80 ℃ of refluxed 12 hours are filtered, precipitate washs with dry toluene, 60 ℃ of vacuum dryings 6 hours, obtain the Lu of 25mg nucleocapsid structure
0.785Yb
0.2Tm
0.015O
3AzoG1 modifies the mesoporous SiO of hole inlet
2Material is an infrared light triggering controllable drug carrier.
2. infrared light triggers the drug release experiment: test process and embodiment 1 are same, and experimental result sees the following form 3
The pharmaceutical carrier of table 3: embodiment 3 preparations triggers the time dependent data of luminous relative intensity that are discharged into the rhodamine B in the aqueous solution at infrared light
| Light application time (minute) | 0 | 10 | 20 | 30 |
| Luminous relative intensity ( ＊10 3) | 0.31 | 12 | 15 | 18 |
Embodiment 4:
The Yb of nucleocapsid structure
3+And Tm
3+Codope Lu
2O
3The AzoG1 of hollow modifies the mesoporous SiO of hole inlet
2Pharmaceutical carrier
1. sample preparation
(1) prepares Yb and the Tm codope Lu that polyethylene pyrrolin (PVP-K30) coats with solvent-thermal method
2O
3Up-conversion nano material
0.785Lu: 0.2Yb in molar ratio: 0.015Tm weighing Lu
2O
30.2554g, Yb
2O
30.0788g, Tm
2O
30.0058g, the dilute hydrochloric acid of adding 40mL 7%, unnecessary solvent is removed in heating for dissolving and evaporation; Add 2.6g sodium acetate, 40mL ethylene glycol and 0.556g PVP, after stirring to clarify, solution is transferred in the agitated reactor of 50mL; 180 ℃ of reactions 6 hours, cooling, centrifugal, precipitate are used washing with alcohol, three times repeatedly; 60 ℃ of vacuum dryings 6 hours, obtain 0.24g Lu
1.57Yb
0.4Tm
0.03O
3Up-conversion nano material, wherein the molar content of Yb is 20%, the molar content of Tm is 1.5%.
(2) Lu of preparation nucleocapsid structure
0.785Yb
0.2Tm
0.015O
3The mesoporous SiO of hollow
2Material
The last conversion particles that obtains in the 50mg step (1) is dispersed in the mixed liquor of 200mL ethanol, 40mL deionized water, 6mL ammonia, dropwise adds 0.15mLTEOS, stirring at room 8 hours, the centrifuged deposit thing is dispersed in 2mL H again
2In the mixed liquor of O, 10mL ethanol, 0.72mL ammonia; Drip the mixed liquor of 0.25mL TEOS and 0.05mL octadecyltriethoxy silane (C18TMS) again, stirring at room 6 hours, the centrifuged deposit thing is scattered in the 10mL water; Change in the agitated reactor of 25mL, 130 ℃ were reacted 12 hours again.Cooling, precipitate clean through centrifugal, ethanol, three times repeatedly, after 6 hours, 550 ℃ of calcinings 6 hours, obtain the Lu of 42mg nucleocapsid structure at 60 ℃ of vacuum dryings
1.57Yb
0.4Tm
0.03O
3The mesoporous SiO of hollow
2Material.
(3) Lu of preparation nucleocapsid structure
0.785Yb
0.2Tm
0.015O
3The AzoG1 of hollow modifies the mesoporous SiO of hole inlet
2Material
The nanoparticle that obtains in the 50mg above-mentioned steps is suspended in the 5mL ICPES toluene solution (10mM) N
280 ℃ of backflows of atmosphere were filtered, are repeatedly washed with dry toluene after 12 hours, put into the toluene solution (1mM) of AzoG1, at N
2Atmosphere, 80 ℃ refluxed 12 hours, filtered, used exsiccant toluene wash, and vacuum drying obtains the pharmaceutical carrier that the 30mg infrared light can trigger.
2. infrared light triggers the drug release experiment: test process and embodiment 1 are same, and experimental result sees the following form 4
The pharmaceutical carrier of table 4: embodiment 4 preparations triggers the time dependent data of luminous relative intensity that are discharged into the rhodamine B in the aqueous solution at infrared light
| Light application time (minute) | 0 | 10 | 20 | 30 |
| Luminous relative intensity ( ＊10 3) | 0.31 | 10 | 13 | 16 |
Claims (5)
1. infrared light triggering controllable drug carrier based on up-conversion; It is characterized in that: form nucleocapsid structure by rare earth ion doped up-conversion nano material and the mesoporous material that contains azo derivative; It is to be that photosensitive group realizes that infrared light triggers the controllable release of medicine with the azo derivative; Up-conversion nano material is nuclear, and the mesoporous material that contains azo derivative is a shell, calculates by mass percentage; The mesoporous material that contains azo derivative accounts for 10%～90% of pharmaceutical carrier quality, and wherein the molar content of azo derivative in mesoporous material is 10%～20%;
Up-conversion nano material is Gd
2O
3, Y
2O
3, Lu
2O
3, CaF
2, BaF
2, LaF
3, YF
3, ZnF
2, NaYF
4, LiYF
4, KYF
4, BaYF
5Or Ba
2YF
7Nanocrystalline;
The Doped Rare Earth ion partly replaces oxide or fluoride cation, and the Doped Rare Earth ion comprises sensitizer and active ions two parts, with Er
3+, Tm
3+, Ho
3+, Dy
3+, Gd
3+, Nd
3+In one or more as active ions, with Yb
3+As sensitizer;
Sensitizer Yb in up-conversion
3+Molar content be 5%～20%, active ions Er
3+Molar content be 0.1%～5%, Tm
3+Molar content 0.1%～5%, Ho
3+Molar content be 0.1%～5%, Dy
3+Molar content be 0.1%～5%, Gd
3+Molar content be 0.1%～5%, Nd
3+Molar content be 0.1%～10%;
Mesoporous material is SiO
2
The structural formula of azo derivative is as follows,
2. the method for preparing of the described a kind of infrared light triggering controllable drug carrier based on up-conversion of claim 1, its step is following:
A: prepare rare earth ion doped up-conversion nano material;
B: preparation is a nuclear with rare earth ion doped up-conversion nano material, and the mesoporous material that the micromolecule azo derivative is modified the hole inwall is the core-shell material of shell
The micromolecule azo derivative AzoH, isocyanates propyl-triethoxysilicane ICPES that (1) will contain hydroxyl is by mass ratio 100～200: 1 is dissolved in the dry ethanol of 10～30mL, at 80～90 ℃, N jointly
2Under reacted 4～8 hours, add ethyl orthosilicate TEOS again, the volume ratio of TEOS and ICPES is 1～5: 1;
(2) rare earth ion doped up-conversion nano material is dissolved in 1～10mL chloroform; Mass concentration is 1～30g/mol; Then with the template aqueous solution of 3～20mL, molar concentration 0.1～1M; Stir to clarify, with the NaOH aqueous solution dilution of 30～100mL, molar concentration 0.1～0.5M;
(3) solution of step (1) with step (2) is mixed, 80 ℃ were stirred 1～10 hour, cooling, centrifugal, clean with ethanol; Then precipitate is suspended in 10～60mL methanol solution; Add 1～3mL concentrated hydrochloric acid, 60 ℃ of heating 1～10 hour, cooling, precipitate were through centrifugal, washing, 60 ℃ of vacuum dryings 2～20 hours; Promptly obtain infrared light triggering controllable drug carrier based on up-conversion; It is a nucleocapsid structure, is nuclear with rare earth ion doped up-conversion nano material, and the mesoporous material of modifying the hole inwall with the micromolecule azo derivative is a shell;
Up-conversion nano material is Gd
2O
3, Y
2O
3, Lu
2O
3, CaF
2, BaF
2, LaF
3, YF
3, ZnF
2, NaYF
4, LiYF
4, KYF
4, BaYF
5Or Ba
2YF
7Nanocrystalline;
The Doped Rare Earth ion partly replaces oxide or fluoride cation, and the Doped Rare Earth ion comprises sensitizer and active ions two parts, with Er
3+, Tm
3+, Ho
3+, Dy
3+, Gd
3+, Nd
3+In one or more as active ions, with Yb
3+As sensitizer;
Sensitizer Yb in up-conversion
3+Molar content be 5%～20%, active ions Er
3+Molar content be 0.1%～5%, Tm
3+Molar content 0.1%～5%, Ho
3+Molar content be 0.1%～5%, Dy
3+Molar content be 0.1%～5%, Gd
3+Molar content be 0.1%～5%, Nd
3+Molar content be 0.1%～10%.
3. the method for preparing of a kind of infrared light triggering controllable drug carrier based on up-conversion as claimed in claim 2 is characterized in that: use CTAB or NaYF
4Up-conversion is modified or modification.
4. the method for preparing of the described a kind of infrared light triggering controllable drug carrier based on up-conversion of claim 1, its step is following:
A: prepare rare earth ion doped up-conversion nano material;
B: preparation is a nuclear with rare earth ion doped up-conversion nano material, and the mesoporous material that the macromole azo derivative is modified the hole inlet is the core-shell material of shell
(1) rare earth ion doped up-conversion nano material is dissolved in 1～10mL chloroform; Mass concentration is 1～30g/mol; Template aqueous solution with 3～20mL, molar concentration 0.1～1M stirs to clarify, with the NaOH aqueous solution dilution of 30～100mL, molar concentration 0.1～0.5M;
(2) in above-mentioned solution, add 0.5～5mL TEOS; 80 ℃ were stirred 1～10 hour; Cooling, centrifugal, with ethanol clean, 2～20 hours, 500～800 ℃ sintering of 60 ℃ of vacuum dryings 3～10 hours, obtaining with the up-conversion nano material is nuclear, mesoporous material is the core-shell material of shell;
(3) the above-mentioned product with 10～100mg is suspended in the ICPES toluene solution of 5～20mL, molar concentration 1～20mM 80 ℃, N
2Refluxed 5～20 hours, filtration, dry toluene washing, the toluene solution of the macromole azo derivative AzoG1 of adding 10～50mL, molar concentration 1～10mM, 80 ℃, N
2Refluxed 5～20 hours; Filter, dry toluene washing, 60 ℃ of vacuum dryings 6～24 hours; Promptly obtain infrared light triggering controllable drug carrier based on up-conversion; It is a nucleocapsid structure, is nuclear with rare earth ion doped up-conversion nano material, and the mesoporous material that the macromole azo derivative is modified the hole inlet is a shell;
Up-conversion nano material is Gd
2O
3, Y
2O
3, Lu
2O
3, CaF
2, BaF
2, LaF
3, YF
3, ZnF
2, NaYF
4, LiYF
4, KYF
4, BaYF
5Or Ba
2YF
7Nanocrystalline;
The Doped Rare Earth ion partly replaces oxide or fluoride cation, and the Doped Rare Earth ion comprises sensitizer and active ions two parts, with Er
3+, Tm
3+, Ho
3+, Dy
3+, Gd
3+, Nd
3+In one or more as active ions, with Yb
3+As sensitizer;
Sensitizer Yb in up-conversion
3+Molar content be 5%～20%, active ions Er
3+Molar content be 0.1%～5%, Tm
3+Molar content 0.1%～5%, Ho
3+Molar content be 0.1%～5%, Dy
3+Molar content be 0.1%～5%, Gd
3+Molar content be 0.1%～5%, Nd
3+Molar content be 0.1%～10%.
5. the method for preparing of a kind of infrared light triggering controllable drug carrier based on up-conversion as claimed in claim 4 is characterized in that: use oleic acid or polyethylene pyrrolin that up-conversion is modified or modification.
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| CN109232776A (en) * | 2017-07-10 | 2019-01-18 | 四川大学 | Photoinitiator compound based on up-conversion and its preparation method and application |
| CN108192590B (en) * | 2017-12-10 | 2020-06-16 | 湖北工业大学 | Preparation method of polyazobenzene multifunctional nanoparticles based on rare earth up-conversion material |
| CN109498807B (en) * | 2018-08-15 | 2021-09-14 | 西安电子科技大学 | Up-conversion nanoparticle oxygen-independent photodynamic diagnosis and treatment probe and preparation method thereof |
| CN110075306B (en) * | 2019-04-28 | 2020-11-06 | 大连理工大学 | Preparation method of near-infrared light-controlled visible drug carrier |
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