CN105233282A - Multifunctional nano-drug composition and preparation method thereof - Google Patents
Multifunctional nano-drug composition and preparation method thereof Download PDFInfo
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- CN105233282A CN105233282A CN201510762348.9A CN201510762348A CN105233282A CN 105233282 A CN105233282 A CN 105233282A CN 201510762348 A CN201510762348 A CN 201510762348A CN 105233282 A CN105233282 A CN 105233282A
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Abstract
The invention provides a multifunctional nano-drug combination and a preparation method thereof. The combination comprises a carrier and active ingredients loaded on the carrier, wherein the carrier is a polymer formed by mPEG-PLGA and/or PEG-PLGA and a porphyrin compound through covalent-bond connection, and the active ingredients include hydrophobic and hydrophilic drugs. Preferentially, the carrier and the active ingredients loaded on the carrier form particles with the nano size of 50-1000 nm. The multifunctional nano-drug combination has photo-thermal effect so that the treatment efficiency can be improved based on traditional chemotherapy in combination with photo-thermal therapy, and the multifunctional nano-drug combination can be applied to cancer therapy drugs.
Description
Technical field
The invention belongs to nano biological field of medicaments, be specifically related to a kind of multifunctional nano pharmaceutical composition and preparation method thereof.
Background technology
Nanometer medicine-carried system refers to that particle diameter that medicine and nano-carrier formed is between the delivery system of 1 ~ 1000nm, comprises nanosphere, nanocapsule, nanoparticle and nanometer liposome etc.Nanometer medicine-carried system, compared with other medicines carrier, has significant advantage: (1) ultra micro small size, by the blood capillary that human body is minimum, is not easily removed rapidly by phagocyte, extends the retention time in blood circulation; (2) target site such as liver, spleen, lung, bone marrow, lymph that reticuloendothelial system distribution is concentrated is arrived; (3) can penetrate tissue gap by Cell uptake, be conducive to drug effect in Transdermal absorption and cell and play; (4) medicine can embed or be bonded in inside nanoparticles, and also adsorbable or coupling is on its surface; (5) utilize the biodegradability of nano material itself, pH or temperature sensitivity etc., reach the effect of drug controlled release; (6) improve the bioavailability of medicine and reduce toxic and side effects etc.
Nanoparticle is that one conventional in nanometer medicine-carried system is selected, and generally serves as the Polymer-supported medicine of pharmaceutical carrier, obtains Nano-particulate medicinal composition.But the Nano-particulate medicinal composition that the preparation method of disclosed Nano-particulate medicinal composition obtains at present mostly is the Nano-particulate medicinal composition of a kind of medical compounds of a load.This kind of Nano-particulate medicinal composition therapeutic modality is single, cannot solve drug resistance problem and therapeutic effect is not good enough.In order to avoid repeating loaded down with trivial details administration, improving patient's compliance, needing single drug-supplying system to have Treated with Chemotherapeutic Drugs thing in clinical practice and send the function with photo-thermal therapy simultaneously.
Summary of the invention
For the deficiencies in the prior art, the object of the present invention is to provide a kind of multifunctional nano pharmaceutical composition and preparation method thereof.
Realize the object of the invention technical scheme as follows:
A kind of multifunctional nano pharmaceutical composition, comprise carrier and load active component on this carrier, wherein, described carrier is the polymer that mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) are connected with porphyrins covalent bond; Described active ingredient comprises hydrophobic drug and hydrophilic medicament, and described carrier and load active component on this carrier forms nano-particle.Preferably, described nanoparticle size is 50 ~ 1000nm.Further preferably, described nanoparticle size is 50nm ~ 300nm.
The present invention also provides the preparation method of above-mentioned multifunctional nano pharmaceutical composition, and it comprises the steps:
Described mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or polymer that polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) is connected with porphyrins covalent bond are dissolved in water in immiscible first organic solvent, obtain the polymer solution of modified porphyrin;
In the polymer solution of described modified porphyrin, add the aqueous solution of described hydrophilic medicament, emulsifying, obtains colostrum;
Add surfactant to described just Ruzhong and be dissolved in the described dewatering medicament of the second organic solvent, ultrasonic, centrifuge washing after decompression removal organic solvent, to obtain final product.
Multifunctional nano pharmaceutical composition provided by the invention, can carry hydrophilic drugs and dewatering medicament, drug loading is high simultaneously.This pharmaceutical composition adopts emulsification mechanism preparation, the pharmaceutical composition sized nanostructures level obtained, and narrowly distributing.Further, porphyrin covalent linkage is on mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA), after being prepared into nanoparticle, there is photo-thermal effect, make on the basis of traditional chemical Drug therapy, in conjunction with photo-thermal therapy, improve therapeutic efficiency, can be applicable to anti-tumor medicine.
Accompanying drawing explanation
Fig. 1-4 is experimental example 1 experimental result picture; Wherein:
Fig. 1 represents the mPEG-PLGA-porphyrin nano granule of variable concentrations under different time to the impact of MDA-MB-231 cytoactive;
Fig. 2 represents that the amycin of variable concentrations and paclitaxel hybrid medicine are on the impact of MDA-MB-231 cytoactive;
Fig. 3 represents that multifunctional nano pharmaceutical composition prepared by embodiment 1 is on the impact of MDA-MB-231 cytoactive;
After Fig. 4 represents multifunctional nano pharmaceutical composition in embodiment 1 and cell culture 12h, at the laser illumination 5min of 680nm on the impact of MDA-MB-231 cytoactive.
Fig. 5 represents the transmission electron microscope picture of multifunctional nano pharmaceutical composition prepared by embodiment 2.
Fig. 6 represents the transmission electron microscope picture of the carrier in embodiment 4.
Fig. 7 represents the grain size distribution of the carrier in embodiment 4.
Fig. 8 represents the fluorescence spectrum figure of carrier in embodiment 4 and protoporphyrin.
Fig. 9 represents the change curve of carrier, chlorin e 6 and PBS buffer solution irradiation time and temperature under 680nm laser irradiates in embodiment 5.
Figure 10 represents the abosrption spectrogram of carrier in embodiment 4 and modified porphyrin polymer.
Detailed description of the invention
In order to make object of the present invention, technical scheme and advantage clearly understand, below in conjunction with drawings and Examples, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
The invention provides a kind of multifunctional nano pharmaceutical composition, comprise carrier and load active component on this carrier, wherein, described carrier is the polymer (being called for short mPEG-PLGA-porphyrin or PEG-PLGA-porphyrin) that mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) are connected with porphyrins covalent bond; Described active ingredient comprises hydrophobic drug and hydrophilic medicament, and described carrier and load active component on this carrier forms nano-particle.Preferably, described nanoparticle size is 50 ~ 1000nm.Further preferably, described nanoparticle size is 50nm ~ 300nm.
Preferably, the weight average molecular weight of PEG (Polyethylene Glycol) section of described mPEG-PLGA or PEG-PLGA is 1000 ~ 10000.
Preferably, the weight average molecular weight of described PLGA (polylactic acid-glycollic acid block copolymer) section is 5000 ~ 50000; Further preferably, the lactide of described PLGA and the molar ratio of Acetic acid, hydroxy-, bimol. cyclic ester are 50:50 ~ 90:10.
Preferably, described carrier (i.e. mPEG-PLGA and/or PEG-PLGA be connected with porphyrins covalent bond polymer) is undertaken reacting preparing by the hydroxyl on mPEG-PLGA and/or PEG-PLGA and the porphyrins containing carboxyl.
Preferably, described porphyrins is the porphyrin containing carboxyl, is preferably one or more in protoporphyrin, hemoporphyrin, chlorin e 6 etc.
Preferably, the mass ratio of described carrier and described hydrophilic medicament is 10:1 ~ 150:1; The mass ratio of described carrier and described dewatering medicament is 10:1 ~ 100:1.
Preferably, described hydrophilic medicament is one or more in doxorubicin hydrochloride, epirubicin hydrochloride etc.; Be more preferably doxorubicin hydrochloride.
Preferably, described hydrophobic drug is one or more in paclitaxel, bortezomib, curcumin etc.; Be more preferably paclitaxel.
The embodiment of the present invention also provides the preparation method of above-mentioned multifunctional nano pharmaceutical composition, and it comprises the steps:
S01: described mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or polymer that polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) is connected with porphyrins covalent bond are dissolved in water in immiscible first organic solvent, obtain the polymer solution of modified porphyrin;
S02: the aqueous solution adding described hydrophilic medicament in the polymer solution of described modified porphyrin, emulsifying, obtains colostrum;
S03: add surfactant to described just Ruzhong and be dissolved in the described dewatering medicament of the second organic solvent, ultrasonic, centrifuge washing after decompression removal organic solvent, to obtain final product.
Above-mentioned preparation method, wherein:
In step S01, described first organic solvent is one or more in dichloromethane, chloroform, ethyl acetate etc.
Preferably, the concentration of the polymer solution of described modified porphyrin is 5 ~ 50mg/mL;
Preferably, the polymer (i.e. carrier) that described mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) are connected with porphyrins covalent bond is undertaken reacting preparing by the hydroxyl on mPEG-PLGA and/or PEG-PLGA and the porphyrins containing carboxyl.
Preferably, the preparation method of described carrier (i.e. the polymer that MPEG-PLA-glycolic block copolymer and/or polyethylene glycol-polylactic acid-glycolic block copolymer are connected with porphyrins covalent bond) comprising: mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-glycolic block copolymer are dissolved in the 3rd organic solvent, obtain copolymer solution; Add in described copolymer solution can with the porphyrins of hydroxyl reaction on described copolymer; Or also add catalyst, stirring reaction.
Preferably, described 3rd organic solvent is at least one in dichloromethane, chloroform, ethyl acetate, DMF, dimethyl sulfoxide;
Preferably, described porphyrins can be by the porphyrin compound of activated carboxyl, also can be the carboxyl porphyrin compound by adding catalyst activation; Namely catalyst by after the activated carboxylic of described porphyrins again with the hydroxyl reaction of mPEG-PLGA or PEG-PLGA.Further preferably, described catalyst is one or more in 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, 4-(dimethylamino) pyridine, N-hydroxy-succinamide, dicyclohexylcarbodiimide etc.
Further preferably, organic base is added as acid binding agent when described mPEG-PLGA and/or PEG-PLGA and described porphyrins react, to improve reaction efficiency.Described acid binding agent is preferably one or more in triethylamine, DIPEA etc.
Preferably, the mol ratio of described mPEG-PLGA and/or PEG-PLGA and porphyrins is 1:10 ~ 10:1, and the mol ratio of described catalyst and mPEG-PLGA and/or PEG-PLGA is 5:1 ~ 1:5.Preferably, described catalyst is one or more in 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, 4-(dimethylamino) pyridine, N-hydroxy-succinamide, dicyclohexylcarbodiimide.
Preferably, the time that described mPEG-PLGA and/or PEG-PLGA and described porphyrins carry out reacting is greater than 6h usually, to improve reaction efficiency.
Preferably, by the Methods For Purification filtered and dialyse after described mPEG-PLGA and/or PEG-PLGA and porphyrins react, and obtain described carrier (i.e. mPEG-PLGA and/or PEG-PLGA be connected with porphyrins covalent bond polymer) by lyophilization.
In step S02, the mass ratio of described carrier and described hydrophilic medicament is 10:1 ~ 150:1, and the volume ratio of the polymer solution of described hydrophilic medicament aqueous solution and described modified porphyrin is 1:5 ~ 1:100.Described emulsifying can pass through method realizations such as shaking, ultrasonic.
In step S03, described surfactant is one or more in polyvinyl alcohol, propylene glycol block polyether F68, Tween 80, span and dodecyl sodium sulfate; Be preferably polyvinyl alcohol.
Preferably, described surfactant is 0.5% ~ 3% in the mass concentration in described just Ruzhong.
Preferably, described carrier (i.e. the polymer of described modified porphyrin) is 10:1 ~ 100:1 with the mass ratio of described dewatering medicament.
Described second organic solvent is preferably one or more in dichloromethane, chloroform, DMF, dimethyl sulfoxide, ethyl acetate etc.
Described ultrasonic condition is ultrasonic 3 ~ 10min under 100 ~ 300W power.
Further, in order to ensure stability and the dispersibility of obtained multifunctional nano pharmaceutical composition, ultrasonic products therefrom being dropwise added drop-wise to mass ratio is in the polyvinyl alcohol water solution of 0.1% ~ 1%, after stirring 30 ~ 60min, decompression removes organic solvent again, centrifugal, with deionized water centrifuge washing 2 ~ 3 times again.Particularly, the speed of described centrifuge washing is 10000 ~ 15000rpm.
Research finds, can obtain the multifunctional nano pharmaceutical composition of different drug loading by changing carrier and the mass ratio of medicine, as shown in table 1, and under identical preparation condition, along with polymer and the raising of drug quality ratio, its drug loading declines.Therefore, preferably, the mass ratio of described carrier and hydrophilic medicament and hydrophobic drug is 20:(1 ~ 2): (1 ~ 2); Further preferably, described hydrophilic medicament is doxorubicin hydrochloride, and described hydrophobic drug is paclitaxel; More preferably, the mass ratio of described carrier and doxorubicin hydrochloride and paclitaxel is 20:1.5:1.
Table 1
In table 1, mass ratio refers to the mass ratio of mPEG-PLGA-porphyrin carrier or PEG-PLGA-porphyrin carrier and doxorubicin hydrochloride and paclitaxel.
Below carrier of the present invention (i.e. the polymer that described mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) are connected with porphyrins covalent bond) and preparation method thereof is further described.
Carrier of the present invention also can be used as nanometer photo-thermal therapy reagent.In carrier of the present invention, the degradable polymer that porphyrin is connected by covalent bond, can not discharge in cyclic process, described carrier is by emulsifying-solidification method preparation, stabilization time is long, described carrier can also in forming process bag medicine carrying thing, in photo-thermal therapy reagent, there is certain application potential.
Carrier of the present invention is the polymer be connected with porphyrins covalent bond by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA).
Preferably, described carrier is nano-particle; Further preferably, described nanoparticle size is 50 ~ 1000nm; More preferably, described nanoparticle size is 50nm ~ 300nm.
Preferably, the weight average molecular weight of PEG (Polyethylene Glycol) section of described mPEG-PLGA or PEG-PLGA is 1000 ~ 10000.
Preferably, described PLGA (polylactic acid-glycollic acid block copolymer) section weight average molecular weight is 5000 ~ 50000; Further preferably, the lactide of described PLGA and the molar ratio of Acetic acid, hydroxy-, bimol. cyclic ester are 50:50 ~ 90:10.
Preferably, the polymer that described mPEG-PLGA and/or PEG-PLGA is connected with porphyrins covalent bond is prepared by the hydroxyl on mPEG-PLGA and/or PEG-PLGA and the porphyrins containing carboxyl.
Preferably, described porphyrins is the porphyrin containing carboxyl, is preferably one or more in protoporphyrin, hemoporphyrin, chlorin e 6 etc.
The present invention also provides the preparation method of above-mentioned carrier, and it comprises the steps:
S011: mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) are dissolved in the 3rd organic solvent, obtain copolymer solution;
S012: add in described copolymer solution can with the porphyrins of hydroxyl reaction on polymer; Or also add catalyst, stirring reaction, obtain the polymer of modified porphyrin.
Preferably, the preparation method of described carrier also comprises step S013: the polymer of described modified porphyrin is prepared into nano-particle; Preferably, described nanoparticle size is 50 ~ 1000nm.
In above-mentioned preparation method:
In step S011, described 3rd organic solvent can for dissolving the organic solvent of mPEG-PLGA or PEG-PLGA; Be preferably one or more in dichloromethane, chloroform, DMF, dimethyl sulfoxide, ethyl acetate etc.
In step S012, hydroxyl and the porphyrins of mPEG-PLGA or PEG-PLGA react, and form the polymer that covalent bond connects.Described porphyrins can be by the porphyrin compound of activated carboxyl, also can be the carboxyl porphyrin compound by adding catalyst activation; Namely catalyst by after the activated carboxylic of described porphyrins again with the hydroxyl reaction of mPEG-PLGA or PEG-PLGA.
Preferably, described catalyst is one or more in 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, 4-(dimethylamino) pyridine, N-hydroxy-succinamide, dicyclohexylcarbodiimide etc.
Further preferably, in step S012, add organic base as acid binding agent when the hydroxyl of mPEG-PLGA or PEG-PLGA and described porphyrins react, to improve reaction efficiency.Described acid binding agent is preferably one or more in triethylamine, DIPEA etc.
Preferably, the mol ratio of described mPEG-PLGA or PEG-PLGA and porphyrins is 1:10 ~ 10:1, and the mol ratio of described catalyst and mPEG-PLGA or PEG-PLGA is 5:1 ~ 1:5.
Preferably, the time that mPEG-PLGA or PEG-PLGA and described porphyrins carry out reacting is greater than 6h usually, to improve reaction efficiency.
Preferably, by the Methods For Purification filtered and dialyse after described mPEG-PLGA or PEG-PLGA and porphyrins react, and the polymer of modified porphyrin is obtained by lyophilization.
In step S013, the method polymer of described modified porphyrin being prepared into nano-particle can be the prior art conventional methods such as emulsifying-solidification method, nanoprecipitation method, emulsion solvent evaporation technique; Preferably, select emulsion solvent evaporation technique to prepare, the nanoparticle structure obtained like this is more fine and close and stable, and photo-thermal effect is better.
Technical scheme of the present invention is further illustrated below by detailed description of the invention.Those skilled in the art should understand, described embodiment is only help to understand the present invention, should not be considered as concrete restriction of the present invention.
Dynamic light scattering (ZetasizerNanoZS), transmission electron microscope (U.S. FEI are carried out to the multifunctional nano pharmaceutical composition obtained in following examples and carrier, TecnaiG220S-TWIN, 200kV), light transmittance (U.S. PerkinElmer, Lambda950UV-spectrophotometer), fluorescence analysis (U.S. PerkinElmer, LS-55) and photo-thermal effect measure.
Embodiment 1
By 1-(3-the dimethylaminopropyl)-3-ethyl carbodiimide of the protoporphyrin of mPEG-PLGA, 50nmol of 100nmol, 50nmol, 4-(dimethylamino) pyridine of 25nmol and the N of 50 μ L, N-diisopropylethylamine mixes in 10mL anhydrous methylene chloride, room temperature reaction 48h under argon shield, product dialysis 24h, lyophilization, obtains mPEG-PLGA-porphyrin carrier;
20mgmPEG-PLGA-porphyrin is dissolved in 1mL dichloromethane, add 0.2mL doxorubicin hydrochloride aqueous solution (7.5mg/mL), ultrasonic 3min after mixing, then the polyvinyl alcohol water solution of 2mL2% is added, vortex concussion mix homogeneously, add the paclitaxel (5mg/mL) that 0.2mL is dissolved in dichloromethane, then after ultrasonic emulsification 8min, mixture slowly joins in the polyvinyl alcohol of 10mL0.3% and stirs 10min.After the dichloromethane in Rotary Evaporators reduction vaporization, removing solution, the centrifugal 10min of 13000rpm, then use deionized water centrifuge washing, obtain described multifunctional nano pharmaceutical composition.
Embodiment 2
100nmolofmPEG-PLGA, 100nmol chlorin e 6,50nmol1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, 25nmol4-(dimethylamino) pyridine and 50 μ L triethylamines mix in 10mL anhydrous methylene chloride; room temperature reaction 48h under argon shield; product dialysis 48h; lyophilization, obtains mPEG-PLGA-chlorin e 6.
20mgmPEG-PLGA-chlorin e 6 is dissolved in 1mL dichloromethane, add 0.2mL doxorubicin hydrochloride aqueous solution (5mg/mL), ultrasonic 5min after mixing, then the polyvinyl alcohol water solution of 10mL2% is added, vortex concussion mix homogeneously, add the paclitaxel (5mg/mL) that 0.2mL is dissolved in dichloromethane, then after ultrasonic emulsification 8min, after the dichloromethane in Rotary Evaporators reduction vaporization, removing solution, the centrifugal 10min of 13000rpm, use deionized water centrifuge washing again, obtain described multifunctional nano pharmaceutical composition.
Embodiment 3
100nmolofPEG-PLGA, 100nmol hemoporphyrin, 300nmolN-N-Hydroxysuccinimide, 300nmol dicyclohexylcarbodiimide, room temperature reaction 48h, cross filtered product dialysis 48h, lyophilization, obtains PEG-PLGA-porphyrin.
20mgmPEG-PLGA-chlorin e 6 is dissolved in 1mL ethyl acetate, add 0.2mL epirubicin hydrochloride aqueous solution (5mg/mL), ultrasonic 5min after mixing, then the polyvinyl alcohol of 10mL2% and the propylene glycol block polyether F68 aqueous solution of 10mL2% is added, vortex concussion mix homogeneously, add the paclitaxel (1mg/mL) that 0.2mL is dissolved in dichloromethane, then after ultrasonic emulsification 8min, use Rotary Evaporators reduction vaporization, after dichloromethane in removing solution, the centrifugal 10min of 13000rpm, use deionized water centrifuge washing again, obtain described multifunctional nano pharmaceutical composition.
Embodiment 4
A kind of carrier, it is the nano-particle formed by the polymer that mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) is connected with porphyrins covalent bond.This carrier can be used as nanometer photo-thermal therapy reagent.
The preparation method of this carrier comprises:
1) mPEG-PLGA of 100nmol is dissolved in 10mL anhydrous methylene chloride, obtains polymer solution;
2) in resulting polymers solution, add DIPEA room temperature reaction 48h under argon shield of the protoporphyrin of 50nmol, 1-(3-the dimethylaminopropyl)-3-ethyl carbodiimide of 50nmol, 4-(dimethylamino) pyridine of 25nmol and 50 μ L; Filtered by products therefrom, dialyse 24h, lyophilization, obtains mPEG-PLGA-porphyrin;
3) be dissolved in dichloromethane by gained mPEG-PLGA-porphyrin, mPEG-PLGA-porphyrin concentration is 20mg/mL, and ultrasonic 15min is to dissolving completely; Get the mPEG-PLGA-porphyrin solution of 0.2mL deionized water and 1.0mL, with cell ultrasonication machine emulsifying 3min, obtain Water-In-Oil colostrum; Joined by colostrum in PVA (polyvinyl alcohol) aqueous solution of 3mL, vortex concussion mix homogeneously, then ultrasonic emulsification 5min obtains W/O/W emulsion; Utilize the dichloromethane in Rotary Evaporators reduction vaporization, removing solution, obtain described carrier.
Embodiment 5
A kind of carrier, it is the nano-particle formed by the polymer that mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) is connected with porphyrins covalent bond.This carrier can be used as nanometer photo-thermal therapy reagent.
The preparation method of this carrier comprises:
100nmolofmPEG-PLGA, 100nmol chlorin e 6,50nmol1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, 25nmol4-(dimethylamino) pyridine and 50 μ L triethylamines mix in 10mL anhydrous methylene chloride; room temperature reaction 48h under argon shield; product dialysis 48h; lyophilization, obtains mPEG-PLGA-chlorin e 6.
Be dissolved in by 7.5mgmPEG-PLGA-chlorin e 6 in 1.5mL acetone, ultrasonic 15min is to dissolving completely.Under magnetic stirring above-mentioned solution is added drop-wise in the deionized water of 10mL with the speed of 30 μ L/min.Continue to stir 30min, curing nano granule.Utilize the organic solvent in Rotary Evaporators reduction vaporization, removing solution, obtain described carrier.
Embodiment 6
A kind of carrier, it is the nano-particle formed by the polymer that polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) is connected with porphyrins covalent bond.This carrier can be used as nanometer photo-thermal therapy reagent.
The preparation method of this carrier comprises:
100nmolofPEG-PLGA, 100nmol hemoporphyrin, 300nmolN-N-Hydroxysuccinimide, 300nmol dicyclohexylcarbodiimide, room temperature reaction 48h, cross filtered product dialysis 48h, lyophilization, obtains PEG-PLGA-porphyrin.
Be dissolved in by 20mgPEG-PLGA-porphyrin in 1mL dichloromethane, ultrasonic 15min is to dissolving completely.Add 10mLPVA (1%) solution, vortex concussion makes its mix homogeneously, and utilize high-speed shearing machine emulsifying 5min, emulsifying power 6,000rmp, obtains oil-in-water emulsion.Utilize the organic solvent in Rotary Evaporators reduction vaporization, removing solution, obtain described carrier.
Embodiment 7
A kind of carrier, it is the nano-particle formed by the polymer that mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) is connected with porphyrins covalent bond.This carrier can be used as nanometer photo-thermal therapy reagent.
The preparation method of this carrier comprises:
100nmolofmPEG-PLGA, 50nmol protoporphyrin, 50nmol1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, 25nmol4-(dimethylamino) pyridine and 50 μ LN; N-diisopropylethylamine mixes in 10mL anhydrous methylene chloride; room temperature reaction 48h under argon shield; product dialysis 24h; lyophilization, obtains mPEG-PLGA-porphyrin.
Be dissolved in dichloromethane by mPEG-PLGA-porphyrin, concentration is 20mg/mL, and ultrasonic 15min is to dissolving completely.Get 0.2mL deionized water and 1.0mLmPEG-PLGA-porphyrin solution, with cell ultrasonication machine emulsifying 3min, obtain Water-In-Oil colostrum.Joined by colostrum in 3mLPVA aqueous solution, vortex concussion mix homogeneously, then ultrasonic emulsification 5min obtains W/O/W emulsion.Utilize the dichloromethane in Rotary Evaporators reduction vaporization, removing solution, obtain described carrier.
Embodiment 8
A kind of carrier, it is the nano-particle formed with the polymer that polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) is connected with porphyrins covalent bond by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA).This carrier can be used as nanometer photo-thermal therapy reagent.
The preparation method of this carrier comprises:
1) mPEG-PLGA and PEG-PLGA of 120nmol is dissolved in 15mL anhydrous methylene chloride, obtains polymer solution; Wherein, the ratio of mPEG-PLGA and PEG-PLGA is 1: 1;
2) in resulting polymers solution, add DIPEA room temperature reaction 48h under argon shield of the protoporphyrin of 60nmol, 1-(3-the dimethylaminopropyl)-3-ethyl carbodiimide of 60nmol, 4-(dimethylamino) pyridine of 30nmol and 60 μ L; Filtered by products therefrom, dialyse 24h, lyophilization, obtains mPEG-PLGA-porphyrin and PEG-PLGA-porphyrin;
3) be dissolved in dichloromethane by gained mPEG-PLGA-porphyrin and PEG-PLGA-porphyrin, mPEG-PLGA-porphyrin and PEG-PLGA-porphyrin concentration are respectively 12mg/mL, and ultrasonic 15min is to dissolving completely; Get mPEG-PLGA-porphyrin and the PEG-PLGA-porphyrin solution of 0.2mL deionized water and 1.0mL, with cell ultrasonication machine emulsifying 3min, obtain Water-In-Oil colostrum; Joined by colostrum in PVA (polyvinyl alcohol) aqueous solution of 3mL, vortex concussion mix homogeneously, then ultrasonic emulsification 5min obtains W/O/W emulsion; Utilize the dichloromethane in Rotary Evaporators reduction vaporization, removing solution, obtain described carrier.
Embodiment 9
A kind of carrier, it is the nano-particle formed with the polymer that polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) is connected with porphyrins covalent bond by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA).This carrier can be used as nanometer photo-thermal therapy reagent.
The preparation method of this carrier comprises:
1) mPEG-PLGA and PEG-PLGA of 120nmol is dissolved in 15mL anhydrous methylene chloride, obtains polymer solution; Wherein, the ratio of mPEG-PLGA and PEG-PLGA is 1: 1;
2) in resulting polymers solution, add DIPEA room temperature reaction 48h under argon shield of the chlorin e 6 of 60nmol, 1-(3-the dimethylaminopropyl)-3-ethyl carbodiimide of 60nmol, 4-(dimethylamino) pyridine of 30nmol and 60 μ L; Filtered by products therefrom, dialyse 24h, lyophilization, obtains mPEG-PLGA-porphyrin and PEG-PLGA-porphyrin;
3) be dissolved in dichloromethane by gained mPEG-PLGA-porphyrin and PEG-PLGA-porphyrin, mPEG-PLGA-porphyrin and PEG-PLGA-porphyrin concentration are respectively 12mg/mL, and ultrasonic 15min is to dissolving completely; Get mPEG-PLGA-porphyrin and the PEG-PLGA-porphyrin solution of 0.2mL deionized water and 1.0mL, with cell ultrasonication machine emulsifying 3min, obtain Water-In-Oil colostrum; Joined by colostrum in the PVA (polyvinyl alcohol) of 3mL and the mixed aqueous solution of F68 (polyoxyethylene poly-oxygen propylene aether block copolymer), vortex concussion mix homogeneously, then ultrasonic emulsification 5min obtains W/O/W emulsion; Utilize the dichloromethane in Rotary Evaporators reduction vaporization, removing solution, obtain described carrier.
Experimental example 1
Multifunctional nano pharmaceutical composition PBS obtained for embodiment 1 is diluted, in amycin and taxol drug gross mass, be mixed with concentration and be respectively 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, the medicinal liquid of the variable concentrations of 0.1 μ g/mL, 0.01 μ g/mL.Meanwhile, by amycin and paclitaxel wiring solution-forming, with the two mass ratio for 1.5:1, be diluted to total concentration and be respectively 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, the medicinal liquid of the variable concentrations of 0.1 μ g/mL, 0.01 μ g/mL in contrast.With simple mPEG-PLGA-porphyrin polymer nano-particle in contrast.
Cultivate breast cancer cell MDA-MB-231, temperature is 37 DEG C, and the MDA-MB-231 cell being in exponential phase is inoculated in 96 well culture plates by the density in 1000/hole, after 12 hours respectively, add the medicinal liquid of variable concentrations and unloaded polymer respectively, often kind of parallel 6 holes of concentration.Adopt the DMEM culture medium containing 10 % by weight hyclones respectively, every hole adds 100 μ L, after cultivating 24h and 48h, uses MTS test kit to measure cytoactive.Concrete operations are carried out according to the explanation of test kit completely.
For the effect of vigor of tumor cell experimental result as shown in Figure 1, Figure 2, Figure 3 and Figure 4.Fig. 1 is the preparation method of mPEG-PLGA-porphyrin nano granule on Nano medication compositions in the impact (preparation method of this nano-particle is with embodiment 1 step 1) of MDA-MB-231 cytoactive, not drug containing), Fig. 2 be drug molecule amycin and paclitaxel on the impact of MDA-MB-231 cytoactive, Fig. 3 represents that multifunctional nano pharmaceutical composition prepared by embodiment 1 is on the impact of MDA-MB-231 cytoactive.Fig. 4 represents that multifunctional nano pharmaceutical composition prepared by embodiment 1 is to after MDA-MB-231 cell culture 12h, under the laser instrument (radium will prestige, Beijing) of 680nm, utilizes 1W/cm
2laser the cytoactive after 5min is irradiated to it.
As can be seen from experimental result, mPEG-PLGA-porphyrin nano granule does not have lethal effect substantially to MDA-MB-231 tumor cell, the killer cell ability of medicine-carried nano particles is directly proportional to concentration, time effect, under medicine same concentrations condition, after 48h effect, the degree of nanoparticle T suppression cell activity strengthens than 24h effect, and described pharmaceutical composition shows the effect of sustained release.Because protoporphyrin is assembled at nanometer photo-thermal therapy reagent camber, it has good light thermal property, and therefore under the irradiation of additional laser, material warms, enhances the therapeutic effect of chemotherapeutics, and cell survival rate reduces (Fig. 3 and Fig. 4).
Experimental example 2
The multifunctional nano pharmaceutical composition obtained to embodiment 2 measures with transmission electron microscope (U.S. FEI, TecnaiG220S-TWIN, 200kV), and as shown in Figure 5, the size of this multifunctional nano medicine is at 100nm.
Experimental example 3
Fig. 6 is the transmission electron microscope picture of carrier prepared by embodiment 4, as can be seen from Electronic Speculum figure, the size of nano-particle at about 100nm, almost spherical.Utilize laser particle analyzer to measure the particle size distribution of the carrier that embodiment 4 obtains, as shown in Figure 7, the mean diameter of nano-particle is about 150nm, also confirms that described carrier has good dispersibility further.The carrier obtain embodiment 4 and simple protoporphyrin carry out fluorescence analysis, and as Fig. 8, it is very serious that result shows described carrier fluorescence quencher, and illustrate that protoporphyrin is assembled at nano-particle camber, this is also that it has the reason of good light thermal property.
In addition, the carrier prepare embodiment 5 and chlorin e 6 and PBS buffer solution carry out photo-thermal effect mensuration, under the laser instrument (radium will prestige, Beijing) of 680nm, utilize 1W/cm
2laser it is irradiated, and utilize thermal imaging system (Ti27, Fluke) to carry out temperature test and appraisal, as shown in Figure 9, carrier described in this has good light thermal property as shown in Figure 9 in result display.The carrier utilizing ultraviolet spectrophotometer to obtain embodiment 4 and the polymer of modified porphyrin carry out spectral scan, result as shown in Figure 10, this carrier compares the polymer generation red shift of modified porphyrin, and therefore, described carrier can effectively absorb near infrared light for photo-thermal therapy.
The carrier obtained by embodiment 4-9 is respectively prepared into multifunctional nano pharmaceutical composition by the method similar with embodiment 1-3, and multifunctional nano pharmaceutical composition prepared by its effect and embodiment 1-3 is suitable.As space is limited, the test example of part most cogency is only exemplified herein.
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (10)
1. a multifunctional nano pharmaceutical composition, comprise carrier and load active component on this carrier, wherein, described carrier is the polymer that mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-glycolic block copolymer are connected with porphyrins covalent bond; Described active ingredient comprises hydrophobic drug and hydrophilic medicament, and described carrier and load active component on this carrier forms nano-particle; Preferably, described nanoparticle size is 50 ~ 1000nm; Further preferably, described nanoparticle size is 50nm ~ 300nm.
2. multifunctional nano pharmaceutical composition according to claim 1, it is characterized in that, the weight average molecular weight of the Polyethylene Glycol section of described mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer or polyethylene glycol-polylactic acid-glycolic block copolymer is 1000 ~ 10000;
Preferably, the weight average molecular weight of described polylactic acid-glycollic acid block copolymer section is 5000 ~ 50000; Further preferably, the lactide of described polylactic acid-glycollic acid block copolymer and the molar ratio of Acetic acid, hydroxy-, bimol. cyclic ester are 50:50 ~ 90:10;
Preferably, described porphyrins is the porphyrin containing carboxyl, one or more more preferably in protoporphyrin, hemoporphyrin, chlorin e 6.
3. multifunctional nano pharmaceutical composition according to claim 1 and 2, is characterized in that, the mass ratio of described carrier and described hydrophilic medicament is 10:1 ~ 150:1; The mass ratio of described carrier and described dewatering medicament is 10:1 ~ 100:1;
Preferably, described hydrophilic medicament is one or more in doxorubicin hydrochloride, epirubicin hydrochloride; Described hydrophobic drug is one or more in paclitaxel, bortezomib, curcumin.
4. multifunctional nano pharmaceutical composition according to claim 3, is characterized in that, the mass ratio of described carrier and hydrophilic medicament and hydrophobic drug is 20:(1 ~ 2): (1 ~ 2);
Preferably, the mass ratio of described carrier and doxorubicin hydrochloride and paclitaxel is 20:1.5:1.
5. the preparation method of multifunctional nano pharmaceutical composition described in any one of claim 1-4, is characterized in that, comprise the steps:
S01: the polymer that described mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-glycolic block copolymer are connected with porphyrins covalent bond is dissolved in water in immiscible first organic solvent, obtains the polymer solution of modified porphyrin;
S02: the aqueous solution adding described hydrophilic medicament in the polymer solution of described modified porphyrin, emulsifying, obtains colostrum;
S03: add surfactant to described just Ruzhong and be dissolved in the described dewatering medicament of the second organic solvent, ultrasonic, centrifuge washing after decompression removal organic solvent, to obtain final product.
6. preparation method according to claim 5, is characterized in that, in step S01, described first organic solvent is one or more in dichloromethane, chloroform, ethyl acetate;
Preferably, the concentration of the polymer solution of described modified porphyrin is 5 ~ 50mg/mL;
Preferably, described mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-glycolic block copolymer comprise with the preparation method of the polymer that porphyrins covalent bond is connected: mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-glycolic block copolymer are dissolved in the 3rd organic solvent, obtain copolymer solution; Add in described copolymer solution can with the porphyrins of hydroxyl reaction on described copolymer; Or also add catalyst, stirring reaction;
Preferably, described 3rd organic solvent is at least one in dichloromethane, chloroform, ethyl acetate, DMF, dimethyl sulfoxide;
Preferably, described porphyrins is by the porphyrin compound of activated carboxyl; Or by adding the carboxyl porphyrin compound of catalyst activation; Further preferably, described catalyst is one or more in 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, 4-(dimethylamino) pyridine, N-hydroxy-succinamide, dicyclohexylcarbodiimide.
7. preparation method according to claim 6, it is characterized in that, when described mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-glycolic block copolymer and described porphyrins react, add organic base as acid binding agent; Described acid binding agent is preferably one or more in triethylamine, DIPEA.
8. preparation method according to claim 6, it is characterized in that, the mol ratio of described mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-glycolic block copolymer and porphyrins is 1:10 ~ 10:1, and the mol ratio of described catalyst and mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-glycolic block copolymer is 5:1 ~ 1:5; Preferably, described catalyst is one or more in 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, 4-(dimethylamino) pyridine, N-hydroxy-succinamide, dicyclohexylcarbodiimide.
9. preparation method according to claim 5, is characterized in that, the volume ratio of the polymer solution of the aqueous solution of hydrophilic medicament described in step S02 and described modified porphyrin is 1:5 ~ 1:100.
10. preparation method according to claim 5, is characterized in that, in step S03, described surfactant is one or more in polyvinyl alcohol, propylene glycol block polyether F68, Tween 80, span and dodecyl sodium sulfate;
Preferably, described surfactant is 0.5% ~ 3% in the mass concentration in described just Ruzhong;
Preferably, described second organic solvent is one or more in dichloromethane, chloroform, DMF, dimethyl sulfoxide, ethyl acetate.
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| CN105968370A (en) * | 2016-06-22 | 2016-09-28 | 国家纳米科学中心 | Triple disulfide-bond linked polyethylene glycol-polycaprolactone triblock copolymer as well as preparation method and application thereof |
| CN107970226A (en) * | 2017-12-27 | 2018-05-01 | 国家纳米科学中心 | A kind of nano-drug transporter and its preparation method and application |
| CN109134516A (en) * | 2018-08-27 | 2019-01-04 | 苏州大学 | A kind of dimer prodrug and a kind of light regulation Nano medication and application with tumor microenvironment response |
| CN111888342A (en) * | 2020-07-02 | 2020-11-06 | 南方医科大学南方医院 | Drug-loaded nano-composite and preparation method and application thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105968370A (en) * | 2016-06-22 | 2016-09-28 | 国家纳米科学中心 | Triple disulfide-bond linked polyethylene glycol-polycaprolactone triblock copolymer as well as preparation method and application thereof |
| CN105968370B (en) * | 2016-06-22 | 2019-05-24 | 国家纳米科学中心 | The polyethylene glycol polycaprolactone triblock polymer and its preparation method and application of triple disulfide bond connections |
| CN107970226A (en) * | 2017-12-27 | 2018-05-01 | 国家纳米科学中心 | A kind of nano-drug transporter and its preparation method and application |
| CN107970226B (en) * | 2017-12-27 | 2020-01-21 | 国家纳米科学中心 | Nano-carrier medicine and preparation method and application thereof |
| CN109134516A (en) * | 2018-08-27 | 2019-01-04 | 苏州大学 | A kind of dimer prodrug and a kind of light regulation Nano medication and application with tumor microenvironment response |
| CN109134516B (en) * | 2018-08-27 | 2022-02-11 | 苏州大学 | Dimer prodrug with tumor microenvironment response, light-controlled nano-drug and application |
| CN111888342A (en) * | 2020-07-02 | 2020-11-06 | 南方医科大学南方医院 | Drug-loaded nano-composite and preparation method and application thereof |
| CN111888342B (en) * | 2020-07-02 | 2022-03-15 | 南方医科大学南方医院 | Drug-loaded nano-composite and preparation method and application thereof |
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