CN105233282B - A kind of multifunctional nano pharmaceutical composition and preparation method thereof - Google Patents
A kind of multifunctional nano pharmaceutical composition and preparation method thereof Download PDFInfo
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Abstract
The present invention provides a kind of multifunctional nano pharmaceutical composition and preparation method thereof, and the composition includes the active constituent of carrier and load on this carrier, and the carrier is the polymer that mPEG-PLGA and/or PEG-PLGA and porphyrins are covalently keyed；Active ingredient includes hydrophobic drug and hydrophilic medicament, and it is 50~1000nm particle that the active constituent of the preferably described carrier and load on this carrier, which forms nano-scale,；The multifunctional nano pharmaceutical composition has photo-thermal effect, so that, in conjunction with photo-thermal therapy, improving therapeutic efficiency on the basis of traditional chemical drug therapy, can be applied to tumor therapeutic agent.
Description
Technical field
The invention belongs to nano biological field of medicaments, and in particular to a kind of multifunctional nano pharmaceutical composition and its preparation side
Method.
Background technique
Nanometer medicine-carried system refers to the delivery system of partial size that drug and nano-carrier are formed between 1~1000nm,
Including nanosphere, nanocapsule, nanoparticle and nano liposomes etc..Nanometer medicine-carried system has compared with other medicines carrier
Significant advantage: (1) ultra micro small size can be not easy to be removed rapidly by phagocyte, be extended by the smallest capillary of human body
Retention time in the circulatory system；(2) the targets portions such as liver, spleen, lung, marrow, the lymph that reticuloendothelial system distribution is concentrated are reached
Position；(3) tissue space can be penetrated and is absorbed by cell, be conducive to Transdermal absorption and intracellular drug effect plays；(4) drug can embed
Or inside nanoparticles are bonded in, also adsorbable or coupling is on its surface；(5) biodegradable of nano material itself is utilized
Property, pH or temperature sensitivity etc. achieve the effect that drug controlled release；(6) it improves the bioavilability of drug and reduces poison pair
Effect etc..
Nanoparticle is common a kind of selection in nanometer medicine-carried system, generally serves as the Polymer-supported of pharmaceutical carrier
Drug, to obtain Nano-particulate medicinal composition.But the preparation method of presently disclosed Nano-particulate medicinal composition obtains
Nano-particulate medicinal composition mostly only load the Nano-particulate medicinal composition of medical compounds a kind of.Such nanoparticle
Medicine composite for curing mode is single, can not solve the problems, such as drug resistance and therapeutic effect is not good enough.It is cumbersome in order to avoid repeating
Administration, improves patient's compliance, needs in clinical practice single drug delivery system to possess Treated with Chemotherapeutic Drugs object and delivers simultaneously and light
The function of heat cure.
Summary of the invention
In view of the deficiencies of the prior art, the purpose of the present invention is to provide a kind of multifunctional nano pharmaceutical composition and its systems
Preparation Method.
Realize that the object of the invention technical solution is as follows:
A kind of multifunctional nano pharmaceutical composition, the active constituent including carrier and load on this carrier, wherein described
Carrier is mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or polyethylene glycol cream
The polymer that acid-glycolic block copolymer (PEG-PLGA) and porphyrins are covalently keyed；The active ingredient packet
Hydrophobic drug and hydrophilic medicament are included, the active constituent of the carrier and load on this carrier forms nano particle.It is preferred that
Ground, the nanoparticle size are 50~1000nm.It is further preferred that the nanoparticle size is 50nm~300nm.
The present invention also provides the preparation methods of above-mentioned multifunctional nano pharmaceutical composition comprising following steps:
By the mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or poly- second two
The polymer that alcohol-polylactic acid-glycollic acid block copolymer (PEG-PLGA) and porphyrins are covalently keyed is dissolved in and water
In the first unmixing organic solvent, the polymer solution of modified porphyrin is obtained；
The aqueous solution of the hydrophilic medicament is added into the polymer solution of the modified porphyrin, emulsifies, obtains colostrum；
Surfactant is added into the colostrum and is dissolved in the dewatering medicament of the second organic solvent, ultrasound, decompression
Remove organic solvent after centrifuge washing to get.
Multifunctional nano pharmaceutical composition provided by the invention can carry hydrophilic drugs and dewatering medicament simultaneously, carry medicine
Amount is high.The pharmaceutical composition is prepared using emulsification mechanism, obtained pharmaceutical composition sized nanostructures grade, and narrowly distributing.
Further, porphyrin covalent linkage mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/
Or on polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA), after being prepared into nanoparticle, there is photo-thermal effect,
So that, in conjunction with photo-thermal therapy, improving therapeutic efficiency on the basis of traditional chemical drug therapy, can be applied to cancer therapeutics
Object.
Detailed description of the invention
Fig. 1-4 is 1 experimental result picture of experimental example；Wherein:
It is living to MDA-MB-231 cell under different time that Fig. 1 shows the mPEG-PLGA- porphyrin nano particles of various concentration
The influence of property；
Fig. 2 indicates the influence of the adriamycin and taxol hybrid medicine of various concentration to MDA-MB-231 cell activity；
Fig. 3 indicates influence of the multifunctional nano pharmaceutical composition of the preparation of embodiment 1 to MDA-MB-231 cell activity；
After Fig. 4 indicates multifunctional nano pharmaceutical composition and cell culture 12h in embodiment 1, in the laser of 680nm
Irradiate influence of the 5min to MDA-MB-231 cell activity.
Fig. 5 indicates the transmission electron microscope picture of multifunctional nano pharmaceutical composition prepared by embodiment 2.
Fig. 6 indicates the transmission electron microscope picture of the carrier in embodiment 4.
Fig. 7 indicates the grain size distribution of the carrier in embodiment 4.
Fig. 8 shows the fluorescence spectras of carrier and protoporphyrin in embodiment 4.
When Fig. 9 indicates that carrier, chlorin e 6 and the PBS buffer solution in embodiment 5 irradiate under 680nm laser irradiation
Between change curve with temperature.
Figure 10 indicates the abosrption spectrogram of carrier and modified porphyrin polymer in embodiment 4.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to the accompanying drawings and embodiments, right
The present invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, and
It is not used in the restriction present invention.
The present invention provides a kind of multifunctional nano pharmaceutical composition, including carrier and load on this carrier activity at
Point, wherein the carrier is mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or gathers
The polymer that ethylene glycol-polylactic acid-glycollic acid block copolymer (PEG-PLGA) and porphyrins are covalently keyed is (referred to as
MPEG-PLGA- porphyrin or PEG-PLGA- porphyrin)；The active ingredient includes hydrophobic drug and hydrophilic medicament, described
The active constituent of carrier and load on this carrier forms nano particle.Preferably, the nanoparticle size be 50~
1000nm.It is further preferred that the nanoparticle size is 50nm~300nm.
Preferably, the weight average molecular weight of PEG (polyethylene glycol) section of the mPEG-PLGA or PEG-PLGA be 1000~
10000。
Preferably, the weight average molecular weight of PLGA (polylactic acid-glycollic acid block copolymer) section is 5000~50000；
It is further preferred that the lactide of the PLGA and the molar ratio of glycolide are 50:50~90:10.
Preferably, (i.e. mPEG-PLGA and/or PEG-PLGA gather the carrier with what porphyrins were covalently keyed
Close object) it is react being prepared into the porphyrins containing carboxyl by the hydroxyl on mPEG-PLGA and/or PEG-PLGA
It arrives.
Preferably, the porphyrins are the porphyrin containing carboxyl, preferably protoporphyrin, haematoporphyrin, chlorin
One or more of e6 etc..
Preferably, the mass ratio of the carrier and the hydrophilic medicament is 10:1~150:1；The carrier is dredged with described
The mass ratio of water drug is 10:1~100:1.
Preferably, the hydrophilic medicament is one or more of doxorubicin hydrochloride, epirubicin hydrochloride etc.；More preferably
For doxorubicin hydrochloride.
Preferably, the hydrophobic drug is one or more of taxol, bortezomib, curcumin etc.；More preferably
For taxol.
The embodiment of the present invention also provides the preparation method of above-mentioned multifunctional nano pharmaceutical composition comprising following steps:
S01: by the mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or gather
Ethylene glycol-polylactic acid-glycollic acid block copolymer (PEG-PLGA) is dissolved in the polymer that porphyrins are covalently keyed
In first organic solvent unmixing with water, the polymer solution of modified porphyrin is obtained；
The aqueous solution of the hydrophilic medicament is added in the polymer solution of S02: Xiang Suoshu modified porphyrin, emulsifies, obtains just
Cream；
Surfactant is added in S03: Xiang Suoshu colostrum and is dissolved in the dewatering medicament of the second organic solvent, ultrasound,
Decompression removal organic solvent after centrifuge washing to get.
Above-mentioned preparation method, in which:
In step S01, first organic solvent is one of methylene chloride, chloroform, ethyl acetate etc. or several
Kind.
Preferably, the concentration of the polymer solution of the modified porphyrin is 5~50mg/mL；
Preferably, the mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or poly-
The polymer that ethylene glycol-polylactic acid-glycollic acid block copolymer (PEG-PLGA) is covalently keyed with porphyrins (carries
Body) it is react being prepared with the porphyrins containing carboxyl by the hydroxyl on mPEG-PLGA and/or PEG-PLGA
's.
Preferably, carrier (i.e. methoxy polyethylene glycol-polylactic acid-glycolic block copolymer and/or the poly- second two
The polymer that alcohol-polylactic acid-glycollic acid block copolymer and porphyrins are covalently keyed) preparation method include: by
Mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-glycolic block copolymer
It is dissolved in third organic solvent, obtains copolymer solution；Being added into the copolymer solution can be with hydroxyl on the copolymer
The porphyrins of reaction；Or it is additionally added catalyst, it is stirred to react.
Preferably, the third organic solvent be methylene chloride, chloroform, ethyl acetate, n,N-Dimethylformamide,
At least one of dimethyl sulfoxide；
Preferably, the porphyrins can be the porphyrin compound for being activated carboxyl, be also possible to pass through
The carboxyl porphyrin compound of activation of catalyst is added；I.e. catalyst by after the activated carboxylic of the porphyrins again with
The hydroxyl of mPEG-PLGA or PEG-PLGA reacts.It is further preferred that the catalyst is 1- (3- dimethylamino third
Base) in -3- ethyl carbodiimide, 4- (dimethylamino) pyridine, n-hydroxysuccinimide, dicyclohexylcarbodiimide etc. one
Kind is several.
It is further preferred that the mPEG-PLGA and/or PEG-PLGA adds when being reacted with the porphyrins
Enter organic base as acid binding agent, to improve reaction efficiency.The acid binding agent is preferably triethylamine, N, in N- diisopropylethylamine etc.
One or more.
Preferably, the molar ratio of the mPEG-PLGA and/or PEG-PLGA and porphyrins is 1:10~10:1,
The molar ratio of the catalyst and mPEG-PLGA and/or PEG-PLGA are 5:1~1:5.Preferably, the catalyst is 1- (3-
Dimethylaminopropyl) -3- ethyl carbodiimide, 4- (dimethylamino) pyridine, n-hydroxysuccinimide, dicyclohexyl carbon two
One or more of imines.
Preferably, the time that the mPEG-PLGA and/or PEG-PLGA is reacted with the porphyrins is usual
Greater than 6h, to improve reaction efficiency.
Preferably, by filtering and thoroughly after the mPEG-PLGA and/or PEG-PLGA is reacted with porphyrins
The Methods For Purification of analysis, and the carrier (i.e. mPEG-PLGA and/or PEG-PLGA and porphyrin chemical combination are obtained by freeze-drying
The polymer that object is covalently keyed).
In step S02, the mass ratio of the carrier and the hydrophilic medicament is 10:1~150:1, the hydrophily medicine
The volume ratio of the polymer solution of object aqueous solution and the modified porphyrin is 1:5~1:100.The emulsification can by concussion,
The methods of ultrasound is realized.
In step S03, the surfactant is polyvinyl alcohol, propylene glycol block polyether F68, Tween 80, sapn and ten
One or more of dialkyl sulfonates；Preferably polyvinyl alcohol.
Preferably, mass concentration of the surfactant in the colostrum is 0.5%~3%.
Preferably, the mass ratio of the carrier (polymer of the i.e. described modified porphyrin) and the dewatering medicament be 10:1~
100:1.
Second organic solvent be preferably methylene chloride, chloroform, n,N-Dimethylformamide, dimethyl sulfoxide,
One or more of ethyl acetate etc..
The condition of the ultrasound is 3~10min of ultrasound under 100~300W power.
Further, in order to guarantee the stability and dispersibility of multifunctional nano pharmaceutical composition obtained, by ultrasonic institute
It obtains product to be added drop-wise to dropwise in the polyvinyl alcohol water solution that mass ratio is 0.1%~1%, depressurizes and remove again after 30~60min of stirring
Organic solvent is removed, is centrifuged, with deionized water centrifuge washing 2~3 times again.Specifically, the speed of the centrifuge washing be 10000~
15000rpm。
The study found that passing through the multifunctional nano drug for changing carrier and the available different drugloading rates of the mass ratio of drug
Composition, as shown in table 1, under identical preparation condition, with the raising of polymer and drug quality ratio, drugloading rate decline.
It is therefore preferred that the mass ratio of the carrier and hydrophilic medicament and hydrophobic drug is 20:(1~2): (1~2)；Into one
Preferably, the hydrophilic medicament is doxorubicin hydrochloride to step, and the hydrophobic drug is taxol；It is highly preferred that the carrier
It is 20:1.5:1 with the mass ratio of doxorubicin hydrochloride and taxol.
Table 1
Mass ratio refers to mPEG-PLGA- porphyrin carrier or PEG-PLGA- porphyrin carrier and doxorubicin hydrochloride and purple in table 1
The mass ratio of China fir alcohol.
Below to carrier of the present invention (i.e. described mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer
(mPEG-PLGA) and/or polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) and porphyrins it is covalent
The polymer of key connection) and preparation method thereof be further described.
Carrier of the present invention also can be used as a nanometer photo-thermal therapy reagent.In carrier of the present invention, porphyrin passes through covalent
The degradable polymer of key connection will not discharge in cyclic process, and the carrier is by emulsification-solidification method preparation, when stablizing
Between it is long, the carrier can also contain drug in forming process, in photo-thermal therapy reagent have certain application potential.
Carrier of the present invention is by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA)
And/or polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) polymerize with what porphyrins were covalently keyed
Object.
Preferably, the carrier is nano particle；It is further preferred that the nanoparticle size is 50~1000nm；
It is highly preferred that the nanoparticle size is 50nm~300nm.
Preferably, the weight average molecular weight of PEG (polyethylene glycol) section of the mPEG-PLGA or PEG-PLGA be 1000~
10000。
Preferably, PLGA (polylactic acid-glycollic acid block copolymer) the section weight average molecular weight is 5000~50000；Into
Preferably, the lactide of the PLGA and the molar ratio of glycolide are 50:50~90:10 to one step.
Preferably, the polymer that the mPEG-PLGA and/or PEG-PLGA and porphyrins are covalently keyed be by
What the hydroxyl on mPEG-PLGA and/or PEG-PLGA and the porphyrins containing carboxyl were prepared.
Preferably, the porphyrins are the porphyrin containing carboxyl, preferably protoporphyrin, haematoporphyrin, chlorin
One or more of e6 etc..
The present invention also provides the preparation methods of above-mentioned carrier comprising following steps:
S011: by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or poly- second two
Alcohol-polylactic acid-glycollic acid block copolymer (PEG-PLGA) is dissolved in third organic solvent, obtains copolymer solution；
The porphyrins that can be reacted with hydroxyl on polymer are added in S012: Xiang Suoshu copolymer solution；Or
It is additionally added catalyst, is stirred to react, the polymer of modified porphyrin is obtained.
Preferably, the preparation method of the carrier further includes step S013: the polymer of the modified porphyrin is prepared into
Nano particle；Preferably, the nanoparticle size is 50~1000nm.
In above-mentioned preparation method:
In step S011, the third organic solvent can be that can dissolve the organic molten of mPEG-PLGA or PEG-PLGA
Agent；Preferably one of methylene chloride, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate etc. or several
Kind.
In step S012, the hydroxyl of mPEG-PLGA or PEG-PLGA are reacted with porphyrins, are formed covalent
The polymer of key connection.The porphyrins can be the porphyrin compound for being activated carboxyl, be also possible to pass through
The carboxyl porphyrin compound of activation of catalyst is added；I.e. catalyst by after the activated carboxylic of the porphyrins again with
The hydroxyl of mPEG-PLGA or PEG-PLGA reacts.
Preferably, the catalyst is 1- (3- dimethylaminopropyl) -3- ethyl carbodiimide, 4- (dimethylamino) pyrrole
One or more of pyridine, n-hydroxysuccinimide, dicyclohexylcarbodiimide etc..
It is further preferred that in step S012, the hydroxyl of mPEG-PLGA or PEG-PLGA and the porphyrins
Organic base is added when being reacted as acid binding agent, to improve reaction efficiency.The acid binding agent is preferably triethylamine, N, and N- bis- is different
One or more of propylethylamine etc..
Preferably, the molar ratio of the mPEG-PLGA or PEG-PLGA and porphyrins is 1:10~10:1, institute
The molar ratio for stating catalyst and mPEG-PLGA or PEG-PLGA is 5:1~1:5.
Preferably, the time that mPEG-PLGA or PEG-PLGA is reacted with the porphyrins is typically larger than
6h, to improve reaction efficiency.
Preferably, by filtering and thoroughly after the mPEG-PLGA or PEG-PLGA is reacted with porphyrins
The Methods For Purification of analysis, and the polymer of modified porphyrin is obtained by freeze-drying.
In step S013, by the polymer of the modified porphyrin be prepared into nano particle method can for emulsification-solidification method,
The prior arts conventional method such as nanoprecipitation method, emulsion solvent evaporation technique；Preferably, emulsion solvent evaporation technique preparation is selected,
The nanoparticle structure obtained in this way is more fine and close and stablizes, and photo-thermal effect is more preferable.
The technical scheme of the invention is further explained by means of specific implementation.Those skilled in the art should be bright
, the described embodiments are merely helpful in understanding the present invention, should not be regarded as a specific limitation of the invention.
Dynamic light scattering is carried out to multifunctional nano pharmaceutical composition obtained in following embodiment and carrier
(Zetasizer NanoZS), transmission electron microscope (U.S. FEI, Tecnai G2 20S-TWIN, 200kV), the light transmittance (U.S.
Perkin Elmer, Lambda 950UV-spectrophotometer), fluorescence analysis (U.S. Perkin Elmer, LS-55)
And photo-thermal effect measurement.
Embodiment 1
By 1- (3- dimethylaminopropyl) -3- second of the protoporphyrin of mPEG-PLGA, 50nmol of 100nmol, 50nmol
The N of base carbodiimide, 4- (dimethylamino) pyridine of 25nmol and 50 μ L, N- diisopropylethylamine is in 10mL anhydrous methylene chloride
Middle mixing, argon gas protection is lower to react at room temperature 48h, and product is dialysed for 24 hours, and freeze-drying obtains mPEG-PLGA- porphyrin carrier；
20mg mPEG-PLGA- porphyrin is dissolved in 1mL methylene chloride, 0.2mL doxorubicin hydrochloride aqueous solution is added
Then the polyvinyl alcohol water solution of 2mL2% is added in (7.5mg/mL), ultrasound 3min after mixing, the concussion that is vortexed is uniformly mixed, and adds
Enter the taxol (5mg/mL) that 0.2mL is dissolved in methylene chloride, then after ultrasonic emulsification 8min, mixture is slowly added into
10min is stirred in the polyvinyl alcohol of 10mL0.3%.It is evaporated under reduced pressure with Rotary Evaporators, after the methylene chloride in removing solution,
13000rpm is centrifuged 10min, then with deionized water centrifuge washing, obtains the multifunctional nano pharmaceutical composition.
Embodiment 2
100nmol of mPEG-PLGA, 100nmol chlorin e 6,50nmol 1- (3- dimethylaminopropyl) -3-
Ethyl carbodiimide, 25nmol 4- (dimethylamino) pyridine and 50 μ L triethylamines mix in 10mL anhydrous methylene chloride, argon gas
Protection is lower to react at room temperature 48h, and product dialysis 48h is freeze-dried, obtains mPEG-PLGA- chlorin e 6.
20mg mPEG-PLGA- chlorin e 6 is dissolved in 1mL methylene chloride, it is water-soluble that 0.2mL doxorubicin hydrochloride is added
Then the polyvinyl alcohol water solution of 10mL2% is added in liquid (5mg/mL), ultrasound 5min after mixing, the concussion that is vortexed is uniformly mixed, and adds
Enter the taxol (5mg/mL) that 0.2mL is dissolved in methylene chloride, then after ultrasonic emulsification 8min, be evaporated under reduced pressure with Rotary Evaporators,
After removing the methylene chloride in solution, 13000rpm is centrifuged 10min, then with deionized water centrifuge washing, obtains described multi-functional
Nano medication composition.
Embodiment 3
100nmol of PEG-PLGA, 100nmol haematoporphyrin, 300nmol n-hydroxysuccinimide, 300nmol bis-
Carbodicyclo hexylimide reacts at room temperature 48h, crosses filtered product dialysis 48h, and freeze-drying obtains PEG-PLGA- porphyrin.
20mg mPEG-PLGA- chlorin e 6 is dissolved in 1mL ethyl acetate, 0.2mL epirubicin hydrochloride water is added
The propylene glycol block of solution (5mg/mL), ultrasound 5min after mixing, polyvinyl alcohol and 10mL2% that 10mL2% is then added is poly-
Ether F68 aqueous solution, the concussion that is vortexed are uniformly mixed, and the taxol (1mg/mL) that 0.2mL is dissolved in methylene chloride are added, then ultrasound cream
It after changing 8min, is evaporated under reduced pressure with Rotary Evaporators, after the methylene chloride in removing solution, 13000rpm is centrifuged 10min, then spends
Ionized water centrifuge washing obtains the multifunctional nano pharmaceutical composition.
Embodiment 4
A kind of carrier, for by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) with
The nano particle that the polymer that porphyrins are covalently keyed is formed.The carrier can be used as a nanometer photo-thermal therapy reagent.
The preparation method of the carrier includes:
1) mPEG-PLGA of 100nmol is dissolved in 10mL anhydrous methylene chloride, obtains polymer solution；
2) protoporphyrin of 50nmol, the 1- (3- dimethylaminopropyl)-of 50nmol are added into resulting polymers solution
The N of 3- ethyl carbodiimide, 4- (dimethylamino) pyridine of 25nmol and 50 μ L, N- diisopropylethylamine room under protection of argon gas
Temperature reaction 48h；For 24 hours by products therefrom filtering, dialysis, freeze-drying obtains mPEG-PLGA- porphyrin；
3) gained mPEG-PLGA- porphyrin is dissolved in methylene chloride, mPEG-PLGA- porphyrin concentration is 20mg/mL, ultrasound
15min is to being completely dissolved；0.2mL deionized water and the mPEG-PLGA- porphyrin solution of 1.0mL are taken, with cell ultrasonication machine cream
Change 3min, obtains Water-In-Oil colostrum；Colostrum is added in PVA (polyvinyl alcohol) aqueous solution of 3mL, the concussion that is vortexed is uniformly mixed,
Then ultrasonic emulsification 5min obtains W/O/W emulsion；It is evaporated under reduced pressure using Rotary Evaporators, the dichloromethane in removing solution
Alkane obtains the carrier.
Embodiment 5
A kind of carrier, for by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) with
The nano particle that the polymer that porphyrins are covalently keyed is formed.The carrier can be used as a nanometer photo-thermal therapy reagent.
The preparation method of the carrier includes:
100nmol of mPEG-PLGA, 100nmol chlorin e 6,50nmol 1- (3- dimethylaminopropyl) -3-
Ethyl carbodiimide, 25nmol 4- (dimethylamino) pyridine and 50 μ L triethylamines mix in 10mL anhydrous methylene chloride, argon gas
Protection is lower to react at room temperature 48h, and product dialysis 48h is freeze-dried, obtains mPEG-PLGA- chlorin e 6.
7.5mg mPEG-PLGA- chlorin e 6 is dissolved in 1.5mL acetone, ultrasonic 15min is to being completely dissolved.In magnetic
Above-mentioned solution is added drop-wise in the deionized water of 10mL with the speed of 30 μ L/min under power stirring.Continue to stir 30min, solidification is received
Rice grain.It is evaporated under reduced pressure using Rotary Evaporators, the organic solvent in removing solution, obtains the carrier.
Embodiment 6
A kind of carrier, for by polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) and porphyrin chemical combination
The nano particle that the polymer that object is covalently keyed is formed.The carrier can be used as a nanometer photo-thermal therapy reagent.
The preparation method of the carrier includes:
100nmol of PEG-PLGA, 100nmol haematoporphyrin, 300nmol n-hydroxysuccinimide, 300nmol bis-
Carbodicyclo hexylimide reacts at room temperature 48h, crosses filtered product dialysis 48h, and freeze-drying obtains PEG-PLGA- porphyrin.
20mg PEG-PLGA- porphyrin is dissolved in 1mL methylene chloride, ultrasonic 15min is to being completely dissolved.10mLPVA is added
(1%) solution, the concussion that is vortexed are uniformly mixed it, emulsify 5min using high-speed shearing machine, emulsify power 6,000rmp, obtain water
Packet oil emulsion.It is evaporated under reduced pressure using Rotary Evaporators, the organic solvent in removing solution, obtains the carrier.
Embodiment 7
A kind of carrier, for by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) with
The nano particle that the polymer that porphyrins are covalently keyed is formed.The carrier can be used as a nanometer photo-thermal therapy reagent.
The preparation method of the carrier includes:
100nmol of mPEG-PLGA, 50nmol protoporphyrin, 50nmol 1- (3- dimethylaminopropyl) -3- ethyl
Carbodiimide, 25nmol 4- (dimethylamino) pyridine and 50 μ L N, N- diisopropylethylamine mix in 10mL anhydrous methylene chloride
It closes, argon gas protection is lower to react at room temperature 48h, and product is dialysed for 24 hours, and freeze-drying obtains mPEG-PLGA- porphyrin.
MPEG-PLGA- porphyrin is dissolved in methylene chloride, concentration 20mg/mL, ultrasonic 15min are to being completely dissolved.It takes
0.2mL deionized water and 1.0mLmPEG-PLGA- porphyrin solution emulsify 3min with cell ultrasonication machine, obtain Water-In-Oil colostrum.
Colostrum is added in 3mLPVA aqueous solution, the concussion that is vortexed is uniformly mixed, and then it is multiple to obtain W/O/W by ultrasonic emulsification 5min
Cream.It is evaporated under reduced pressure using Rotary Evaporators, the methylene chloride in removing solution, obtains the carrier.
Embodiment 8
A kind of carrier, for by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and
The polymer shape that polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) and porphyrins are covalently keyed
At nano particle.The carrier can be used as a nanometer photo-thermal therapy reagent.
The preparation method of the carrier includes:
1) mPEG-PLGA of 120nmol and PEG-PLGA are dissolved in 15mL anhydrous methylene chloride, obtain polymer solution；
Wherein, the ratio of mPEG-PLGA and PEG-PLGA is 1: 1；
2) protoporphyrin of 60nmol, the 1- (3- dimethylaminopropyl)-of 60nmol are added into resulting polymers solution
The N of 3- ethyl carbodiimide, 4- (dimethylamino) pyridine of 30nmol and 60 μ L, N- diisopropylethylamine room under protection of argon gas
Temperature reaction 48h；For 24 hours by products therefrom filtering, dialysis, freeze-drying obtains mPEG-PLGA- porphyrin and PEG-PLGA- porphyrin；
3) gained mPEG-PLGA- porphyrin and PEG-PLGA- porphyrin are dissolved in methylene chloride, mPEG-PLGA- porphyrin and
PEG-PLGA- porphyrin concentration is respectively 12mg/mL, and ultrasonic 15min is to being completely dissolved；Take 0.2mL deionized water and 1.0mL
MPEG-PLGA- porphyrin and PEG-PLGA- porphyrin solution emulsify 3min with cell ultrasonication machine, obtain Water-In-Oil colostrum；It will be first
Cream is added in PVA (polyvinyl alcohol) aqueous solution of 3mL, and the concussion that is vortexed is uniformly mixed, and then ultrasonic emulsification 5min obtains water packet
Water-In-Oil emulsion；It is evaporated under reduced pressure using Rotary Evaporators, the methylene chloride in removing solution, obtains the carrier.
Embodiment 9
A kind of carrier, for by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and
The polymer shape that polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) and porphyrins are covalently keyed
At nano particle.The carrier can be used as a nanometer photo-thermal therapy reagent.
The preparation method of the carrier includes:
1) mPEG-PLGA of 120nmol and PEG-PLGA are dissolved in 15mL anhydrous methylene chloride, obtain polymer solution；
Wherein, the ratio of mPEG-PLGA and PEG-PLGA is 1: 1；
2) chlorin e 6 of 60nmol, 1- (the 3- dimethylamino third of 60nmol are added into resulting polymers solution
Base) -3- ethyl carbodiimide, 4- (dimethylamino) pyridine of 30nmol and 60 μ L N, N- diisopropylethylamine argon gas protect
Lower room temperature reaction 48h；For 24 hours by products therefrom filtering, dialysis, freeze-drying obtains mPEG-PLGA- porphyrin and PEG-PLGA- porphin
Quinoline；
3) gained mPEG-PLGA- porphyrin and PEG-PLGA- porphyrin are dissolved in methylene chloride, mPEG-PLGA- porphyrin and
PEG-PLGA- porphyrin concentration is respectively 12mg/mL, and ultrasonic 15min is to being completely dissolved；Take 0.2mL deionized water and 1.0mL
MPEG-PLGA- porphyrin and PEG-PLGA- porphyrin solution emulsify 3min with cell ultrasonication machine, obtain Water-In-Oil colostrum；It will be first
Cream is added in the mixed aqueous solution of PVA (polyvinyl alcohol) and F68 (polyoxyethylene poly-oxygen propylene aether block copolymer) of 3mL,
The concussion that is vortexed is uniformly mixed, and then ultrasonic emulsification 5min obtains W/O/W emulsion；It is evaporated under reduced pressure, removed using Rotary Evaporators
The methylene chloride in solution is removed, the carrier is obtained.
Experimental example 1
Multifunctional nano pharmaceutical composition made from embodiment 1 is diluted with PBS, with adriamycin and taxol drug
Gross mass meter is configured to the various concentration that concentration is respectively 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL
Medical fluid.It is 1.5:1 with the two mass ratio, being diluted to total concentration is respectively 10 meanwhile by adriamycin and taxol wiring solution-forming
The medical fluid of the various concentration of μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL is as control.With simple
MPEG-PLGA- porphyrin polymer nano particle is as control.
Breast cancer cell MDA-MB-231 is cultivated, temperature is 37 DEG C, will be in the MDA-MB-231 cell of logarithmic growth phase
96 well culture plates are inoculated in by the density in 1000/hole respectively, after 12 hours, are separately added into medical fluid and the zero load of various concentration
Polymer, parallel 6 hole of every kind of concentration.The DMEM culture medium containing 10 weight % fetal calf serums is respectively adopted, every hole adds 100 μ L,
Culture is measured cell activity using MTS reagent box for 24 hours and after 48h.Concrete operations fully according to kit explanation into
Row.
It is as shown in Figure 1, Figure 2, Figure 3 and Figure 4 for the experimental result of the effect of vigor of tumour cell.Fig. 1 is mPEG-
Influence (the nano particle the preparation method is the same as that of Example 1 step of the PLGA- porphyrin nano particle to MDA-MB-231 cell activity
1) preparation method of Nano medication composition in, not drug containing), Fig. 2 is drug molecule adriamycin and taxol to MDA-MB-
The influence of 231 cell activity, Fig. 3 indicate that multifunctional nano pharmaceutical composition prepared by embodiment 1 is living to MDA-MB-231 cell
The influence of property.After multifunctional nano pharmaceutical composition prepared by Fig. 4 expression embodiment 1 is to MDA-MB-231 cell culture 12h,
Under the laser (radium will prestige, Beijing) of 680nm, 1W/cm is utilized2Laser the cell activity after 5min is irradiated to it.
From experimental result as can be seen that mPEG-PLGA- porphyrin nano particle does not have MDA-MB-231 tumour cell substantially
The killing cell ability of lethal effect, medicine-carried nano particles is directly proportional to concentration, identical dense in drug from time effect
Under the conditions of degree, nanoparticle inhibits the degree of cell activity to enhance than effect for 24 hours after 48h effect, described pharmaceutical composition performance
The effect of sustained release out.Due to protoporphyrin in nanometer photo-thermal therapy reagent high aggregation, with good light thermal property, because
This is outside plus under the irradiation of laser, and material warms enhance the therapeutic effect of chemotherapeutics, and cell survival rate reduces (Fig. 3 and figure
4)。
Experimental example 2
To transmission electron microscope (U.S. FEI, the TecnaiG2 20S- of multifunctional nano pharmaceutical composition made from embodiment 2
TWIN, 200kV) measurement, as shown in figure 5, the size of the multifunctional nano drug is in 100nm.
Experimental example 3
Fig. 6 is the transmission electron microscope picture of carrier prepared by embodiment 4, as can be seen that the size of nano particle from electron microscope
In 100nm or so, almost spherical.Using the particle diameter distribution for the carrier that laser particle analyzer measurement embodiment 4 obtains, as shown in fig. 7,
The average grain diameter of nano particle is 150nm or so, also further confirms that the carrier has good dispersibility.To embodiment 4
The carrier of acquisition and simple protoporphyrin carry out fluorescence analysis, and such as Fig. 8, the carrier fluorescence quenching is very serious as the result is shown,
Illustrate protoporphyrin high aggregation in nano particle, this is also that it has the reason of good light thermal property.
In addition, the carrier and chlorin e 6 and PBS buffer solution to the preparation of embodiment 5 carry out photo-thermal effect measurement,
Under the laser (radium will prestige, Beijing) of 680nm, 1W/cm is utilized2Laser it is irradiated, and using thermal imaging system (Ti27,
Fluke temperature assessment) is carried out, as the result is shown as shown in figure 9, the carrier has good light thermal property as shown in Figure 9.Benefit
Spectral scan is carried out with polymer of the ultraviolet specrophotometer to carrier and modified porphyrin that embodiment 4 obtains, as a result such as Figure 10
It is shown, the carrier compared to modified porphyrin polymer occur red shift, therefore, the carrier can effectively absorb near infrared light with
For photo-thermal therapy.
Carrier made from embodiment 4-9 is prepared into multifunctional nano drug by the method similar with embodiment 1-3 respectively
Composition, effect are suitable with multifunctional nano pharmaceutical composition prepared by embodiment 1-3.As space is limited, it is only exemplified by portion herein
Divide most convincing test example.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, fall within the scope of the claimed invention without departing from theon the basis of the spirit of the present invention.
Claims (14)
1. a kind of multifunctional nano pharmaceutical composition, the active constituent including carrier and load on this carrier, wherein the load
Body is that mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-glycolic block are total
The polymer that polymers and porphyrins are covalently keyed；The active ingredient includes hydrophobic drug and hydrophilic medicament,
The active constituent of the carrier and load on this carrier forms nano particle；The nanoparticle size is 50~1000nm；
The porphyrins are the porphyrin containing carboxyl, are selected from one or more of protoporphyrin, haematoporphyrin, chlorin e 6；
The mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer or polyethylene glycol-polylactic acid-glycolic block copolymerization
The weight average molecular weight of the polyethylene glycol section of object is 1000~10000；The polylactic acid-glycollic acid block copolymer section is divided equally again
Son amount is 5000~50000；The lactide of the polylactic acid-glycollic acid block copolymer and the molar ratio of glycolide are 50:
50~90:10；
The preparation method of the multifunctional nano pharmaceutical composition includes the following steps:
S01: by the mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-second
The polymer that Alkyd Block Copolymer and porphyrins are covalently keyed is dissolved in the first organic solvent unmixing with water,
Obtain the polymer solution of modified porphyrin；
The aqueous solution of the hydrophilic medicament is added in the polymer solution of S02: Xiang Suoshu modified porphyrin, emulsifies, obtains colostrum；
Surfactant is added in S03: Xiang Suoshu colostrum and is dissolved in the dewatering medicament of the second organic solvent, ultrasound, decompression
Remove organic solvent after centrifuge washing to get；
Wherein, the mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-second
The preparation method for the polymer that Alkyd Block Copolymer and porphyrins are covalently keyed includes: by the poly- second two of mono methoxy
That glycolic block copolymer is dissolved in third is organic molten for alcohol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-
In agent, copolymer solution is obtained；The porphyrin that can be reacted with hydroxyl on the copolymer is added into the copolymer solution
Close object；Catalyst is added, organic base is added as acid binding agent, is stirred to react；The catalyst is 1- (3- dimethylamino third
Base) -3- ethyl carbodiimide, 4- (dimethylamino) pyridine, n-hydroxysuccinimide, one of dicyclohexylcarbodiimide
Or it is several；The acid binding agent is triethylamine, N, one or more of N- diisopropylethylamine；
Alternatively, the mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-second
The preparation method for the polymer that Alkyd Block Copolymer and porphyrins are covalently keyed includes: by the poly- second two of mono methoxy
That glycolic block copolymer is dissolved in third is organic molten for alcohol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-
In agent, copolymer solution is obtained；The porphyrin that can be reacted with hydroxyl on the copolymer is added into the copolymer solution
Close object；Organic base is added as acid binding agent, is stirred to react；The acid binding agent is triethylamine, N, one in N- diisopropylethylamine
Kind is several；The porphyrins are the porphyrin compounds for being activated carboxyl.
2. multifunctional nano pharmaceutical composition according to claim 1, which is characterized in that the nanoparticle size is
50nm~300nm.
3. multifunctional nano pharmaceutical composition according to claim 1 or 2, which is characterized in that the carrier and the parent
The mass ratio of aqueous pharmaceutical is 10:1~150:1；The mass ratio of the carrier and the dewatering medicament is 10:1~100:1.
4. multifunctional nano pharmaceutical composition according to claim 3, which is characterized in that the hydrophilic medicament is hydrochloric acid
One or more of adriamycin, epirubicin hydrochloride；The hydrophobic drug is taxol, in bortezomib, curcumin
It is one or more of.
5. multifunctional nano pharmaceutical composition according to claim 3, which is characterized in that the carrier and hydrophilic medicament
And the mass ratio of hydrophobic drug is 20:(1~2): (1~2).
6. multifunctional nano pharmaceutical composition according to claim 5, which is characterized in that the hydrophilic medicament is hydrochloric acid
Adriamycin, the hydrophobic drug are taxol, and the carrier is 20:1.5:1 with the mass ratio of doxorubicin hydrochloride and taxol.
7. the preparation method of any one of the claim 1-6 multifunctional nano pharmaceutical composition, which is characterized in that including as follows
Step:
S01: by the mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-second
The polymer that Alkyd Block Copolymer and porphyrins are covalently keyed is dissolved in the first organic solvent unmixing with water,
Obtain the polymer solution of modified porphyrin；
The aqueous solution of the hydrophilic medicament is added in the polymer solution of S02: Xiang Suoshu modified porphyrin, emulsifies, obtains colostrum；
Surfactant is added in S03: Xiang Suoshu colostrum and is dissolved in the dewatering medicament of the second organic solvent, ultrasound, decompression
Remove organic solvent after centrifuge washing to get.
8. preparation method according to claim 7, which is characterized in that in step S01, first organic solvent is dichloro
One or more of methane, chloroform, ethyl acetate；And/or
The third organic solvent is methylene chloride, chloroform, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide
At least one of.
9. preparation method according to claim 8, which is characterized in that in step S01, the polymer of the modified porphyrin is molten
The concentration of liquid is 5~50mg/mL.
10. preparation method according to claim 8, which is characterized in that the mono methoxy polyethylene glycol-polylactic acid-second
The molar ratio of Alkyd Block Copolymer and/or polyethylene glycol-polylactic acid-glycolic block copolymer and porphyrins is 1:
10~10:1, the catalyst and mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol
The molar ratio of lactic acid-ethanol block copolymer is 5:1~1:5.
11. preparation method according to claim 7, which is characterized in that hydrophilic medicament aqueous solution described in step S02 with
The volume ratio of the polymer solution of the modified porphyrin is 1:5~1:100.
12. preparation method according to claim 7, which is characterized in that in step S03, the surfactant is poly- second
One or more of enol, propylene glycol block polyether F68, Tween 80, sapn and dodecyl sodium sulfate.
13. preparation method according to claim 12, which is characterized in that in step S03, the surfactant is described
Mass concentration in colostrum is 0.5%~3%.
14. preparation method according to claim 12, which is characterized in that in step S03, second organic solvent is two
One or more of chloromethanes, chloroform, n,N-Dimethylformamide, dimethyl sulfoxide, ethyl acetate.
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