CN103479598A - Preparation method for polyethylene glycol-polyester triblock copolymer drug-loaded nano-micelle - Google Patents
Preparation method for polyethylene glycol-polyester triblock copolymer drug-loaded nano-micelle Download PDFInfo
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Abstract
The invention provides a preparation method for a polyethylene glycol-polyester triblock copolymer drug-loaded nano-micelle. The method comprises the following steps: adding a mixture of a micromolecular drug and an organic solvent into a polyethylene glycol-polyester triblock copolymer drop by drop so as to obtain a mixed solution; and adding ultrapure water drop by drop when the mixed solution undergoes primary stirring, then subjecting the mixed solution to secondary stirring, carrying out dialysis to remove the organic solvent and then carrying out freeze-drying so as to obtain the drug-loaded nano-micelle. According to the invention, the preparation method for the polyethylene glycol-polyester triblock copolymer drug-loaded nano-micelle has the advantages of simple operation and mild conditions; generated nano-micelle particles are in a good monodisperse state; the core of the prepared nano-micelle can wrap micromolecular drugs with poor water solubility, and encapsulation efficiency and dissolvability of the drugs are substantially improved; and the prepared polyethylene glycol-polyester triblock copolymer drug-loaded nano-micelle has a stable structure and a small particle size and is easy to preserve.
Description
Technical field
The present invention relates to field of polymer technology, particularly the preparation method of polyethylene glycol-ester triblock copolymer medicament-carried nano micelle.
Background technology
Macromolecule carrier medicament is emerging medicine-feeding technology along with materia medica research, biomaterial science and clinical medical development.Low-molecule drug has the advantages such as curative effect is high, easy to use, but also has very large side effect simultaneously.Usually, low-molecule drug enters in human body by oral or injection, and accretion rate is fast, and the half-life is short, lacks selectivity.The macromolecule that macromolecule carrier medicament refers to itself does not have pharmacological action, do not react with medicine yet is as the carrier of medicine, hydrogen bonded faint between dependence and medicine forms, or by polycondensation reaction, low-molecule drug is connected to the class medicine obtained on main polymer chain.Wherein macromolecular compound serves as the transmission system of low-molecule drug.
Can increase the action time of medicine with macromolecular material as the carrier of small-molecule drug, improve the selectivity of medicine, reduce the toxicity of small-molecule drug, accurate positioning.What develop rapidly in the recent period is the macromolecule carrier of micron and nanoscale, as: nano-micelle, vesicle and nano-particle etc., this family macromolecule carrier can effectively be distributed to drug molecule wherein, utilizes the various response modes of carrier, realizes the conveying of medicine and control discharging.
Wherein, nano-micelle can wrap drug molecule, and the stability of nano-micelle directly affects the performance of carrier micelle.At present, the preparation method of nano-micelle mainly contains: self-assembly method, dialysis, chemical bond method and electrostatic interaction method etc., but these methods existent defect all.Nano-micelle prepared by self-assembly method, material only relies on the non-covalent bonds such as Van der Waals force, hydrogen bond or electrostatic force to connect between layers, so the mechanical stability of nano-micelle is poor, and efficiency is low.The chemical bond method needs suitable functional group just can be reacted, comparatively strict for the selection of macromolecular material and small-molecule drug.Dialysis and electrostatic interaction method, be not suitable on a large scale and produce.
Therefore, the preparation method of carrier micelle also is subject to certain restrictions.
Summary of the invention
The technical problem that the present invention solves is to provide a kind of preparation method of polyethylene glycol-ester triblock copolymer medicament-carried nano micelle, simple to operate, be easy to industrialization, the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle envelop rate obtained is high, Stability Analysis of Structures.
The invention discloses a kind of preparation method of polyethylene glycol-ester triblock copolymer medicament-carried nano micelle, comprise the following steps:
(A) mixture of small-molecule drug and organic solvent is added drop-wise in polyethylene glycol-ester triblock copolymer, obtains mixed solution;
(B) drip ultra-pure water when described mixed solution being stirred for the first time, after continuing to stir for the second time, organic solvent is removed in dialysis and lyophilizing obtains medicament-carried nano micelle;
Described polyethylene glycol-ester triblock copolymer as shown in the formula (I),
Wherein ,-R-is
or
M is the degree of polymerization, 10≤m≤250; N is the degree of polymerization, 10≤n≤220.
Preferably, in described step (A), described small-molecule drug is methotrexate, 5-fluorouracil, cyclophosphamide, daunorubicin, amycin, epirubicin, pirarubicin, camptothecin or Ramulus et folium taxi cuspidatae class.
Preferably, in described step (A), the concentration of described small-molecule drug in organic solvent is 0.1～10mg/mL.
Preferably, in described step (A), the mass ratio of described small-molecule drug and polyethylene glycol-ester triblock copolymer is 0.01～1.
Preferably, the described speed stirred for the first time is 100～2000rpm.
Preferably, the speed of described dropping ultra-pure water is 0.05～5mL/min.
Preferably, the volume ratio of the consumption of described ultra-pure water and consumption of organic solvent is 0.01～20.
Preferably, described organic solvent is oxolane, Isosorbide-5-Nitrae-dioxane, dimethyl sulfoxide or DMF.
Compared with prior art, the present invention's nano-micelle of polyethylene glycol-ester triblock copolymer medicine carrying that adopted the nanometer sedimentation to prepare.The mixture that is about to small-molecule drug and organic solvent is added drop-wise in polyethylene glycol-ester triblock copolymer, stir, obtain mixed solution, when being stirred, described mixed solution drips ultra-pure water, continue to stir for the second time, organic solvent is removed in dialysis and lyophilizing obtains obtaining medicament-carried nano micelle after medicament-carried nano micelle.The method prepares polyethylene glycol-ester triblock copolymer medicament-carried nano micelle, simple to operate, mild condition, the nano-micelle particle generated can present good monodisperse status, and the nano-micelle kernel for preparing of the method can the poor small-molecule drug of coated water-soluble, and greatly improve envelop rate and the dissolubility of medicine, the medicament-carried nano micelle Stability Analysis of Structures of gained, particle diameter is little, and is easy to preserve.
The accompanying drawing explanation
Fig. 1 is the nuclear magnetic resonance map of polyethylene glycol-ester triblock copolymer in chloroform that embodiment 9 obtains;
Fig. 2 is the nuclear magnetic resonance map of polyethylene glycol-ester triblock copolymer in chloroform that embodiment 19 obtains;
Fig. 3 is the nano-micelle particle size distribution figure that embodiment 37～39,62 and 84 obtains;
The nano-micelle particle size distribution figure obtained that Fig. 4 is embodiment 43～45 preparations;
The particle size distribution figure of the nano-micelle of the variable concentrations that Fig. 5 is 50～52 preparations;
The transmission electron microscope picture of the nano-micelle that Fig. 6 is embodiment 62 preparations;
Fig. 7 is the influence curve figure of the nano-micelle that obtains of embodiment 47,57 and 79 to the MCF-7 cell survival rate;
The particle size distribution figure of the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle that Fig. 8 is embodiment 87～89 preparations;
The particle size distribution figure of polyethylene glycol-ester triblock copolymer medicament-carried nano micelle within 3 week that Fig. 9 is embodiment 87～89 preparations.
The specific embodiment
In order further to understand the present invention, below in conjunction with embodiment, the preferred embodiment of the invention is described, but should be appreciated that these are described is for further illustrating the features and advantages of the present invention, rather than limiting to the claimed invention.
The embodiment of the invention discloses a kind of preparation method of polyethylene glycol-ester triblock copolymer medicament-carried nano micelle, comprise the following steps:
(A) mixture of small-molecule drug and organic solvent is added drop-wise in polyethylene glycol-ester triblock copolymer, obtains mixed solution;
(B) drip ultra-pure water when described mixed solution being stirred for the first time, after continuing to stir for the second time, organic solvent is removed in dialysis and lyophilizing obtains medicament-carried nano micelle;
Described polyethylene glycol-ester triblock copolymer as shown in the formula (I),
Wherein ,-R-is
or
M is the degree of polymerization, 10≤m≤250, preferred 40≤m≤200, preferred 60≤m≤150; N is the degree of polymerization, 10≤n≤220, preferred 30≤n≤20, preferred 60≤n≤150.
The present invention has selected the nanometer sedimentation to prepare polyethylene glycol-ester triblock copolymer medicament-carried nano micelle, simple to operate, mild condition, nano-micelle kernel prepared by the method can the poor small-molecule drug of coated water-soluble, and greatly improve envelop rate and the dissolubility of medicine, the medicament-carried nano micelle Stability Analysis of Structures of gained, particle diameter is little, and is easy to preserve.The present invention preferably controls the particle diameter of great medicament-carried nano micelle by the conditions such as speed, ultra-pure water addition and mixing speed that change the dropping ultra-pure water in preparation process, and the ratio of adjustment medicine and polyethylene glycol-ester triblock copolymer, select best medicine carrying condition.At first the present invention is added drop-wise to the mixture of small-molecule drug and organic solvent in polyethylene glycol-ester triblock copolymer, obtains mixed solution.Because the final micelle formed can be wrapped in inside by small-molecule drug, described small-molecule drug is preferably methotrexate, 5-fluorouracil, cyclophosphamide, daunorubicin, amycin, epirubicin, pirarubicin, camptothecin or Ramulus et folium taxi cuspidatae class, more preferably 10-hydroxycamptothecine, amycin or Docetaxel.Described organic solvent is preferably oxolane, Isosorbide-5-Nitrae-dioxane, dimethyl sulfoxide or DMF, more preferably oxolane.Described polyethylene glycol-ester triblock copolymer as shown in the formula (I),
Wherein ,-R-is
or
M is the degree of polymerization, preferred 40≤m≤200, preferred 60≤m≤150; N is the degree of polymerization, 10≤n≤220, preferred 30≤n≤20, preferred 60≤n≤150.
The polyethylene glycol polymeric that described polyethylene glycol-ester triblock copolymer is preferably 1000～40000 by lactide or caprolactone and molecular weight obtains; Described lactide is D-lactide or L-lactide.Its preparation method is specially:
Under the anhydrous and oxygen-free condition, by Polyethylene Glycol, esters monomer, add in ampulla, add a certain amount of toluene after azeotropic water removing, volume of toluene (mL) consumption is 10 times of esters monomer weight (g), injects the toluene solution of 0.1mol/L stannous octoate with syringe, the volumetric usage of stannous octoate and the mol ratio of esters monomer are 1/1000, put into 120 ℃ of oil baths and react 24h.After completion of the reaction, with a large amount of ether sedimentations, the amount ratio of ether and toluene is 10/1, buchner funnel filters, and products therefrom dissolves with chloroform again, then uses the ether sedimentation, buchner funnel filters products therefrom dry 24h in vacuum, has both obtained polyethylene glycol-ester triblock copolymer.
In the described process for preparing polyethylene glycol-ester triblock copolymer, the initiator of preferably selecting is caused, and described initiator is preferably Polyethylene Glycol, and the molecular weight of described Polyethylene Glycol is preferably 4000.The number-average molecular weight of the polyester block obtained is preferably 2000～30000.
In the present invention, the mixture of described small-molecule drug and organic solvent is uniform solution, preferably through stirring, within 4～6 hours, obtains, and the concentration of described small-molecule drug in organic solvent is preferably 0.1～10mg/mL, more preferably 0.4～8mg/mL.The mixture of described small-molecule drug and organic solvent is added drop-wise in polyethylene glycol-ester triblock copolymer, obtain mixed solution, the mass ratio of described small-molecule drug and polyethylene glycol-ester triblock copolymer is preferably 0.01～1, and more preferably 0.05～0.5.Because described polyethylene glycol-ester triblock copolymer can be selected the not esters monomer of isomorphism type in preparation process, therefore it is when preparing mixed solution with described mixture, also can select and there is the not polyethylene glycol-ester triblock copolymer of isomorphism type segment and mixed, between the segment of left-handed and dextrorotation, can interact, making it is to have three-dimensional compound action forming micelle, thereby improves envelop rate and the dissolubility of medicine.There is the not mass ratio of the polyethylene glycol-ester triblock copolymer of isomorphism type segment and be preferably 1:1.After preferably in the mixture of described small-molecule drug and organic solvent is added drop-wise to polyethylene glycol-ester triblock copolymer, stirred; The time of described stirring is preferably 1～3 hour.
After obtaining mixed solution, drip ultra-pure water when described mixed solution is stirred for the first time, after continuing to stir for the second time, organic solvent is removed in dialysis and lyophilizing obtains medicament-carried nano micelle.The device that drips ultra-pure water is preferably syringe pump, and the speed of described dropping ultra-pure water is preferably 0.05～5mL/min, more preferably 0.1～3mL/min.The consumption of described ultra-pure water and the volume ratio of consumption of organic solvent are preferably 0.01～20, more preferably 0.1～10.Drip ultra-pure water when described mixed liquor stirs for the first time, the described speed stirred for the first time is preferably 100～2000rpm, more preferably 800～1500rpm.After dripping end, continue to stir for the second time, organic solvent is removed in dialysis and lyophilizing obtains medicament-carried nano micelle, described preferably 8～12 hours time of stirring for the second time.The described speed stirred for the second time is preferably identical with the speed stirred for the first time.In order to improve the purity of the medicament-carried nano micelle obtained, preferably after stirring for the second time, in ultra-pure water, to be dialysed, dialysis time is preferably 20～30 hours, changes water more than 5 times, and dialysis preferably adopts the bag filter that MWCO is 3500.For the ease of preserving, the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle obtained can also be carried out to lyophilizing.
The particle diameter of the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle that utilizes Dynamic Light Scattering Determination to obtain, 3 week of METHOD FOR CONTINUOUS DETERMINATION, result shows, its change of size trend is basically identical, hence one can see that, polyethylene glycol-ester triblock copolymer medicament-carried nano micelle Stability Analysis of Structures prepared by the method for the invention.
The method prepares polyethylene glycol-ester triblock copolymer medicament-carried nano micelle, simple to operate, mild condition, the nano-micelle particle generated can present good monodisperse status, and the nano-micelle kernel for preparing of the method can the poor small-molecule drug of coated water-soluble, and greatly improve envelop rate and the dissolubility of medicine, the medicament-carried nano micelle Stability Analysis of Structures of gained, particle diameter is little, and is easy to preserve.
In order further to understand the present invention, below in conjunction with embodiment, the preparation method of polyethylene glycol-ester triblock copolymer medicament-carried nano micelle provided by the invention is described, protection scope of the present invention is not limited by the following examples.
The preparation of polyethylene glycol-(D-lactide) triblock copolymer that the Polyethylene Glycol of different number-average molecular weights causes
Polyethylene Glycol (PEG) 1.67g, 6.67g, 13.33g, 16.67g, 33.33g, 66.57g that to take respectively molecular weight be 1000,4000,8000,10000,20000,40000 put into reaction bulb, azeotropic water removing, add dextrorotation lactide (DLA) 12g under the anhydrous and oxygen-free environment, ventilation, 10 times of 120mL that volume of toluene (mL) consumption is esters monomer weight (g), the volumetric usage of stannous octoate and the mol ratio of esters monomer are 1/1000, inject the toluene solution 1mL of 0.1mol/L stannous octoate with syringe, put into 120 ℃ of oil baths and react 24h.After completion of the reaction, treat that solution is cooling, with the sedimentation while stirring of 1200mL ether, the amount ratio of ether and toluene is 10/1, and buchner funnel filters, and products therefrom dissolves with chloroform again, use the ether sedimentation, buchner funnel filters the dry 24h of products therefrom cold well in vacuum desiccator again, both different
The polyethylene glycol-of number-average molecular weight (D-lactide) triblock copolymer.
Number-average molecular weight and the reaction yield of polyethylene glycol-(D-lactide) triblock copolymer of table 1 embodiment 1～6 preparation
In table 1, number-average molecular weight M
nthe number-average molecular weight of polyethylene glycol-(D-lactide) triblock copolymer caused for the Polyethylene Glycol of different number-average molecular weights, by
1h NMR measures and obtains.
Embodiment 7～10
The preparation of polyethylene glycol-(D-lactide) triblock copolymer of the different polymerization degree that Polyethylene Glycol causes
Polyethylene Glycol (PEG) 4g, 6g, 8g, 12g that to take respectively molecular weight be 4000 put into reaction bulb, azeotropic water removing, add dextrorotation lactide (DLA) 12g under the anhydrous and oxygen-free environment, ventilation, 10 times of 120mL that volume of toluene (mL) consumption is esters monomer weight (g), the volumetric usage of stannous octoate and the mol ratio of esters monomer are 1/1000, inject the toluene solution 1mL of 0.1mol/L stannous octoate with syringe, put into 120 ℃ of oil baths and react 24h.After completion of the reaction, treat that solution is cooling, with the sedimentation while stirring of 1200mL ether, the amount ratio of ether and toluene is 10/1, buchner funnel filters, and products therefrom dissolves with chloroform again, then uses the ether sedimentation, buchner funnel filters the dry 24h of products therefrom cold well in vacuum desiccator, obtains polyethylene glycol-(D-lactide) triblock copolymer of the different polymerization degree of Polyethylene Glycol initiation.
Number-average molecular weight and the reaction yield of polyethylene glycol-(D-lactide) triblock copolymer of table 2 embodiment 7～10 preparations
In table 2, number-average molecular weight M
nthe number-average molecular weight of polyethylene glycol-(D-lactide) triblock copolymer of the different polymerization degree caused for Polyethylene Glycol, by
1h NMR measures and obtains.
The nuclear magnetic resonance map of polyethylene glycol-(D-lactide) triblock copolymer of embodiment 9 preparations is referring to Fig. 1, and Fig. 1 is that Fig. 1 is the nuclear magnetic resonance map of polyethylene glycol-ester triblock copolymer in chloroform that embodiment 9 obtains.In Fig. 1, being attributed to of each peak: 1.6ppm(S, 3H, HO-CH (CH
3) OC (O)) 3.68ppm(S, 2H, CH
2cH
2o)), 5.2ppm(S, 3H, HO-CH (CH
3) OC (O)).Fig. 1 shows that polyethylene glycol-(D-lactide) triblock copolymer of embodiment 9 preparations has formula (I) structure.
Embodiment 11～16
The preparation of polyethylene glycol-(L-lactide) triblock copolymer that the Polyethylene Glycol of different number-average molecular weights causes
Taking respectively molecular weight is 1000, 4000, 8000, 10000, 20000, 40000 Polyethylene Glycol (PEG) 1.67g, 6.67g, 13.33g, 16.67g, 33.33g, 66.57g put into reaction bulb, azeotropic water removing, add levorotatory lactide (LLA) 12g under the anhydrous and oxygen-free environment, ventilation, volume of toluene (mL) consumption is 10 times of esters monomer weight (g), be 120mL, the volumetric usage of stannous octoate and the mol ratio of esters monomer are 1/1000, inject the toluene solution 1mL of 0.1mol/L stannous octoate with syringe, put into 120 ℃ of oil baths and react 24h.After completion of the reaction, treat that solution is cooling, with the sedimentation while stirring of 1200mL ether, the amount ratio of ether and toluene is 10/1, buchner funnel filters, and products therefrom dissolves with chloroform again, then uses the ether sedimentation, buchner funnel filters the dry 24h of products therefrom cold well in vacuum desiccator, both polyethylene glycol-(L-lactide) triblock copolymer of Polyethylene Glycol initiation of different number-average molecular weights.
Number-average molecular weight and the reaction yield of polyethylene glycol-(L-lactide) triblock copolymer that the Polyethylene Glycol of table 3 embodiment 11～16 preparations causes
In upper table, number-average molecular weight M
nthe number-average molecular weight of polyethylene glycol-(L-lactide) triblock copolymer caused for the Polyethylene Glycol of different number-average molecular weights, by
1h NMR measures and obtains.
Embodiment 17～20
The preparation of polyethylene glycol-(L-lactide) triblock copolymer that the Polyethylene Glycol of different number-average molecular weights causes.
Polyethylene Glycol (PEG) 4g, 6g, 8g, 12g that to take respectively molecular weight be 4000 put into reaction bulb, azeotropic water removing, add levorotatory lactide (LLA) 12g under the anhydrous and oxygen-free environment, ventilation, volume of toluene (mL) consumption is 10 times of esters monomer weight (g), i.e. 120mL, and the volumetric usage of stannous octoate and the mol ratio of esters monomer are 1/1000, inject the toluene solution 1mL of 0.1mol/L stannous octoate with syringe, put into 120 ℃ of oil baths and react 24h.After completion of the reaction, treat that solution is cooling, with the sedimentation while stirring of 1200mL ether, the amount ratio of ether and toluene is 10/1, buchner funnel filters, and products therefrom dissolves with chloroform again, then uses the ether sedimentation, buchner funnel filters the dry 24h of products therefrom cold well in vacuum desiccator, obtains polyethylene glycol-(L-lactide) triblock copolymer of the Polyethylene Glycol initiation of different number-average molecular weights.
Number-average molecular weight and the reaction yield of polyethylene glycol-(L-lactide) triblock copolymer of table 4 embodiment 17～20 preparations
In table 4, number-average molecular weight M
nthe number-average molecular weight of polyethylene glycol-(L-lactide) triblock copolymer caused for the Polyethylene Glycol of different number-average molecular weights, by
1h NMR measures and obtains.
The nuclear magnetic resonance map of polyethylene glycol-(L-lactide) triblock copolymer of embodiment 19 preparations is referring to Fig. 2, and Fig. 2 is the nuclear magnetic resonance map of polyethylene glycol-ester triblock copolymer in chloroform that embodiment 19 obtains.In Fig. 2, being attributed to of each peak: 1.6ppm(S, 3H, HO-CH (CH
3) OC (O)) 3.68ppm(S, 2H, CH
2cH
2o)), 5.2ppm(S, 3H, HO-CH (CH
3) OC (O)).Fig. 2 shows that polyethylene glycol-(L-lactide) triblock copolymer of embodiment 19 preparations has formula (I) structure.
Embodiment 21～26
The preparation of poly-(6-caprolactone) triblock copolymer that the Polyethylene Glycol of different number-average molecular weights causes
Polyethylene Glycol (PEG) 1.67g, 6.67g, 13.33g, 16.67g, 33.33g, 66.57g that to take respectively molecular weight be 1000,4000,8000,10000,20000,40000 put into reaction bulb, azeotropic water removing, add caprolactone 12g under the anhydrous and oxygen-free environment, ventilation, 10 times of 120mL that volume of toluene (mL) consumption is own lactone monomer weight (g), the volumetric usage of stannous octoate and oneself mol ratio of interior alicyclic monomer are 1/1000, inject the toluene solution 1mL of 0.1mol/L stannous octoate with syringe, put into 120 ℃ of oil baths and react 24h.After completion of the reaction, treat that solution is cooling, with the sedimentation while stirring of 1200mL ether, the amount ratio of ether and toluene is 10/1, buchner funnel filters, and products therefrom dissolves with chloroform again, then uses the ether sedimentation, buchner funnel filters the dry 24h of products therefrom cold well in vacuum desiccator, obtains polyethylene glycol-(6-caprolactone) triblock copolymer of different number-average molecular weights.
Number-average molecular weight and the reaction yield of polyethylene glycol-(6-caprolactone) triblock copolymer of table 5 embodiment 21～26 preparations
In table 5, number-average molecular weight M
nthe number-average molecular weight of polyethylene glycol-(6-caprolactone) triblock copolymer caused for the Polyethylene Glycol of different number-average molecular weights, by
1h NMR measures and obtains.
Embodiment 27～30
The preparation of poly-(6-caprolactone) triblock copolymer that the Polyethylene Glycol of different number-average molecular weights causes
Polyethylene Glycol (PEG) 4g, 6g, 8g, 12g that to take respectively molecular weight be 4000 put into reaction bulb, azeotropic water removing, add own lactone 12g under the anhydrous and oxygen-free environment, ventilation, 10 times of 120mL that volume of toluene (mL) consumption is caprolactone monomer weight (g), the volumetric usage of stannous octoate and oneself mol ratio of interior alicyclic monomer are 1/1000, inject the toluene solution 1mL of 0.1mol/L stannous octoate with syringe, put into 120 ℃ of oil baths and react 24h.After completion of the reaction, treat that solution is cooling, with the sedimentation while stirring of 1200mL ether, the amount ratio of ether and toluene is 10/1, buchner funnel filters, and products therefrom dissolves with chloroform again, then uses the ether sedimentation, buchner funnel filters the dry 24h of products therefrom cold well in vacuum desiccator, obtains polyethylene glycol-(6-caprolactone) triblock copolymer of different number-average molecular weights.
Polyethylene glycol-(6-caprolactone) triblock copolymer of table 6 embodiment 27～30 preparations
In table 6, number-average molecular weight M
nthe number-average molecular weight of polyethylene glycol-(6-caprolactone) triblock copolymer of the different polymerization degree caused for Polyethylene Glycol, by
1h NMR measures and obtains
Embodiment 31～33
Get respectively polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 19 preparations, be dissolved in respectively oxolane, 1,4-dioxane, dimethyl sulfoxide, N, in dinethylformamide, concentration is 2.5mg/mL, stir 3h, syringe pump flow velocity 0.1mL/min, flow (mL) 25mL are set, the mixing speed 1000rpm of agitator is set.The polyester block copolymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, the bag filter that is 3500 with the MWCO 24h that dialyses in Milli-Q, change water more than 5 times.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
Embodiment 34～36
Get respectively polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 19 preparations, be prepared into respectively the tetrahydrofuran solution that concentration is 2mg/mL, 2.5mg/mL, 3mg/mL, stir 3h, syringe pump flow velocity 0.1mL/min, flow (mL) 25mL are set, the mixing speed 1000r/min of agitator is set.The polyester block copolymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
Embodiment 37～39
Get polyethylene glycol-(D-lactide) triblock copolymer of three parts of embodiment, 9 preparations, every part of 100mg, be dissolved in tetrahydrofuran solution, concentration is 2.5mg/mL, stir 3h, syringe pump flow velocity 0.1mL/min, flow (mL) 25mL are set, the mixing speed that agitator is set is respectively 500rpm, 1000rpm, 1500rpm.The polyester lactic acid block copolymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
Fig. 3 is the nano-micelle particle size distribution figure that embodiment 37～39,62 and 84 obtains, in Fig. 3,
the dynamic fluid mechanics radius distribution of the nano-micelle obtained for embodiment 37,
the dynamic fluid mechanics radius distribution of the nano-micelle obtained for embodiment 38,
the dynamic fluid mechanics radius distribution of the nano-micelle obtained for embodiment 39,
the dynamic fluid mechanics radius distribution of the nano-micelle obtained for embodiment 62,
the dynamic fluid mechanics radius distribution of the nano-micelle obtained for embodiment 84.
Get polyethylene glycol-(L-lactide) triblock copolymer of three parts of embodiment, 19 preparations, every part of 100mg, be dissolved in tetrahydrofuran solution, concentration is 2.5mg/mL, stir 3h, syringe pump flow velocity 0.1mL/min is set, flow (mL) is set as respectively 20mL, 25mL, 30mL, the mixing speed that agitator is set is 1000rpm.The polylactic-acid block copolymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
Embodiment 43～45
Get polyethylene glycol-(L-lactide) triblock copolymer of three parts of embodiment, 19 preparations, every part of 100mg, be dissolved in tetrahydrofuran solution, concentration is 2.5mg/mL, stir 3h, the syringe pump flow velocity is set and is respectively 0.1mL/min, 0.3mL/min, 0.5mL/min, flow (mL) is set as 25mL, and the mixing speed that agitator is set is 1000rpm.The polylactic-acid block copolymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
The nano-micelle particle size distribution figure obtained that Fig. 4 is embodiment 43～45 preparations, in Fig. 4,
the dynamic fluid mechanics radius distribution of the nano-micelle obtained for embodiment 43,
the dynamic fluid mechanics radius distribution of the nano-micelle obtained for embodiment 44,
the dynamic fluid mechanics radius distribution of the nano-micelle obtained for embodiment 45.
Embodiment 46～49
Take respectively polyethylene glycol-(D-lactide) the triblock copolymer 100mg of embodiment 1～4 preparation, be dissolved in tetrahydrofuran solution, concentration is 2.5mg/mL, stir 3h, it is that 0.1mL/min, flow (mL) are set as 25mL that the syringe pump flow velocity is set, and the mixing speed that agitator is set is 1000rpm.The polylactic-acid block copolymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
Embodiment 50～52
Take respectively polyethylene glycol-(D-lactide) the triblock copolymer 100mg of embodiment 7～9 preparations, be dissolved in tetrahydrofuran solution, concentration is 2.5mg/mL, stir 3h, the syringe pump flow velocity is set and is respectively 0.1mL/min, 0.3mL/min, 0.5mL/min, flow (mL) is set as 25mL, and the mixing speed that agitator is set is 1000rpm.The polylactic-acid block copolymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
The particle size distribution figure of the nano-micelle of the variable concentrations that Fig. 5 is embodiment 50～52 preparations, in Fig. 5,
the dynamic fluid mechanics radius distribution of the nano-micelle obtained for embodiment 50,
the dynamic fluid mechanics radius distribution of the nano-micelle obtained for embodiment 51,
the dynamic fluid mechanics radius distribution of the nano-micelle obtained for embodiment 52.
Embodiment 53～55
Get polyethylene glycol-(D-lactide) triblock copolymer of three parts of embodiment, 3 preparations, every part of 100mg, be dissolved in tetrahydrofuran solution, concentration is 2.5mg/mL, stir 3h, the syringe pump flow velocity is set and is respectively 0.1mL/min, 0.3mL/min, 0.5mL/min, flow (mL) is set as 25mL, and the mixing speed that agitator is set is 1000rpm.The polylactic-acid block copolymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
Embodiment 56～59
Take respectively polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 11～14 preparations, be dissolved in tetrahydrofuran solution, concentration is 2.5mg/mL, stir 3h, it is 0.1mL/min that the syringe pump flow velocity is set, flow (mL) is set as 25mL, and the mixing speed that agitator is set is 1000rpm.The polylactic-acid block copolymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
Embodiment 60～63
Take respectively polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 17～20 preparations, be dissolved in tetrahydrofuran solution, concentration is 2.5mg/mL, stir 3h, it is 0.1mL/min that the syringe pump flow velocity is set, flow (mL) is set as 25mL, and the mixing speed that agitator is set is 1000rpm.The polylactic-acid block copolymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
The transmission electron microscope picture of the nano-micelle that Fig. 6 is embodiment 62 preparations, as shown in Figure 6, described method has prepared nano-micelle.
Embodiment 64～66
Get polyethylene glycol-(L-lactide) triblock copolymer of three parts of embodiment, 13 preparations, every part of 100mg, be dissolved in tetrahydrofuran solution, concentration is 2.5mg/mL, stir 3h, the syringe pump flow velocity is set and is respectively 0.1mL/min, 0.3mL/min, 0.5mL/min, flow (mL) is set as 25mL, flow (mL) is set as 25mL, and the mixing speed that agitator is set is 1000rpm.The polylactic-acid block copolymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
Embodiment 67～70
Take respectively polyethylene glycol-(6-caprolactone) the triblock copolymer 100mg of embodiment 21～24 preparations, be dissolved in tetrahydrofuran solution, concentration is 2.5mg/mL, stir 3h, it is 0.1mL/min that the syringe pump flow velocity is set, flow (mL) is set as 25mL, and the mixing speed that agitator is set is 1000rpm.The polycaprolactone block polymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
Embodiment 71～74
Take respectively polyethylene glycol-(6-caprolactone) the triblock copolymer 100mg of embodiment 27～30 preparations, be dissolved in tetrahydrofuran solution, concentration is 2.5mg/mL, stir 3h, it is 0.1mL/min that the syringe pump flow velocity is set, flow (mL) is set as 25mL, and the mixing speed that agitator is set is 1000rpm.The polycaprolactone block polymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
Embodiment 75～77
Get polyethylene glycol-(6-caprolactone) triblock copolymer of three parts of embodiment, 23 preparations, every part of 100mg, be dissolved in tetrahydrofuran solution, concentration is 2.5mg/mL, stir 3h, the syringe pump flow velocity is set and is respectively 0.1mL/min, 0.3mL/min, 0.5mL/min, flow (mL) is set as 25mL, flow (mL) is set as 25mL, and the mixing speed that agitator is set is 1000rpm.The polylactic-acid block copolymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
Embodiment 78～81
Polyethylene glycol-(D-lactide) triblock copolymer of embodiment 1～4 preparation is mixed with each 50mg of polyethylene glycol-(L-lactide) triblock copolymer of embodiment 11～14 preparations, be dissolved in tetrahydrofuran solution, concentration is 2.5mg/mL, stir 3h, it is 0.1mL/min that the syringe pump flow velocity is set, flow (mL) is set as 25mL, and the mixing speed that agitator is set is 1000rpm.The polycaprolactone block polymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
Embodiment 82～85
Polyethylene glycol-(D-lactide) triblock copolymer of embodiment 7～10 preparations is mixed with each 50mg of polyethylene glycol-(L-lactide) triblock copolymer of embodiment 17～20 preparations, be dissolved in tetrahydrofuran solution, concentration is 2.5mg/mL, stir 3h, it is 0.1mL/min that the syringe pump flow velocity is set, flow (mL) is set as 25mL, and the mixing speed that agitator is set is 1000rpm.The polycaprolactone block polymer solution dissolved is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution standardize solution, must there is bioactive nano-micelle after dialysis.
Embodiment 86
The toxicity test of nano-micelle in the MCF-7 cell that embodiment 47,57,79 is obtained:
The nano-micelle respectively embodiment 47,57,79 obtained and PEI are configured to the cell culture medium that concentration is respectively 0.01 μ g/mL, 0.025 μ g/mL, 0.05 μ g/mL and 0.10 μ g/mL.
At first, MCF-7 cell kind, in 96 well culture plates, is removed to culture medium after cultivation 24h, the cell culture medium of the nano-micelle that experimental group adds the embodiment 47,57,79 of above-mentioned each concentration to obtain, matched group adds the PEI of above-mentioned each concentration.Cultivate respectively after 72 hours and add MTT, absorb culture medium after 4h, add DMSO to measure the OD value at matched group and experimental group 490nm wavelength place on microplate reader.
Experimental result is referring to Fig. 7, and Fig. 7 is the influence curve figure of the nano-micelle that obtains of embodiment 47,57,79 to the MCF-7 cell survival rate, in Fig. 7,
the influence curve of the nano-micelle obtained for the embodiment 47 of variable concentrations to cell survival rate,
the influence curve of the nano-micelle obtained for the embodiment 57 of variable concentrations to cell survival rate,
the influence curve of the nano-micelle obtained for the embodiment 79 of variable concentrations to cell survival rate;
the PEI of variable concentrations is for the influence curve of cell survival rate.
As shown in Figure 7, in the concentration range of all tests, maximum concentration is 0.1mg L
-1nano-micelle cultivate 72h after, its cell survival rate is more than 80%.That is to say, nano-micelle has lower cytotoxicity, the biological compatibility carrier of conduct transmission bioactive substance that can be safe.
Embodiment 87～89
Polyglycol ether-polyester three-block copolymer is selected respectively polyethylene glycol-(D-lactide) the triblock copolymer 100mg of embodiment 9 preparations, polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 19 preparations, polyethylene glycol-(D-lactide) triblock copolymer of embodiment 9 preparations mixes with each 50mg of polyethylene glycol-(L-lactide) triblock copolymer of embodiment 19 preparations.
10-hydroxycamptothecine is dissolved in oxolane, the concentration of 10-hydroxycamptothecine is 0.4mg/mL, stir 5h, after dissolving, 10-hydroxycamptothecine-tetrahydrofuran solution is added drop-wise to the solution that the mass ratio that is configured to 10-hydroxycamptothecine and polyethylene glycol-ester triblock copolymer in load weighted polyethylene glycol-ester triblock copolymer is 1:5 and continues to stir 2h, syringe pump flow velocity 0.1mL/min is set, flow (mL) is set as the mixing speed 1000rpm that 25mL arranges agitator.The polyethylene glycol-ester triblock copolymer solution that is dissolved with 10-hydroxycamptothecine is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution lyophilizing, must there is bioactive polyethylene glycol-ester triblock copolymer medicament-carried nano micelle after dialysis.
Through calculating, the envelop rate of the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle that embodiment 87 obtains is 100%, and medicine carrying efficiency is 13.1%; The envelop rate of the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle that embodiment 88 obtains is 88%, and medicine carrying efficiency is 11.7%; The envelop rate of the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle that embodiment 89 obtains is 100%, and medicine carrying efficiency is 13.2%.
The particle size distribution figure of the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle that Fig. 8 is embodiment 87～89 preparations, described particle size distribution figure is recorded by dynamic light scattering (DLS).In Fig. 8,
the dynamic fluid mechanics radius distribution of the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle obtained for embodiment 87,
the dynamic fluid mechanics radius distribution of the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle obtained for embodiment 88,
the dynamic fluid mechanics radius distribution of the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle obtained for embodiment 89.
The particle size distribution figure of polyethylene glycol-ester triblock copolymer medicament-carried nano micelle within 3 week that Fig. 9 is embodiment 87～89 preparations, the particle size distribution of polyethylene glycol-ester triblock copolymer medicament-carried nano micelle when 1 week that a is embodiment 87～89 preparations, the particle size distribution of polyethylene glycol-ester triblock copolymer medicament-carried nano micelle when 1 week that b is embodiment 87～89 preparations, the particle size distribution of polyethylene glycol-ester triblock copolymer medicament-carried nano micelle when 1 week that c is embodiment 87～89 preparations
the dynamic fluid mechanics radius distribution of the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle obtained for embodiment 87,
the dynamic fluid mechanics radius distribution of the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle obtained for embodiment 88,
the dynamic fluid mechanics radius distribution of the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle obtained for embodiment 89.
As shown in Figure 9, the polyethylene glycol-ester triblock copolymer medicament-carried nano micelle good stability that prepared by the present invention.
Embodiment 90～92
Polyethylene glycol-ester triblock copolymer is selected respectively polyethylene glycol-(D-lactide) the triblock copolymer 100mg of embodiment 3 preparations, polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 13 preparations, polyethylene glycol-(D-lactide) triblock copolymer of embodiment 3 preparations mixes with each 50mg of polyethylene glycol-(L-lactide) triblock copolymer of embodiment 13 preparations.
10-hydroxycamptothecine is dissolved in oxolane, the concentration of 10-hydroxycamptothecine is 0.4mg/mL, stir 5h, after dissolving, 10-hydroxycamptothecine-tetrahydrofuran solution is added drop-wise in load weighted polyglycol ether-polyester three-block copolymer and is configured to 10-hydroxycamptothecine and polyglycol ether-polyester three-block copolymer quality and continues to stir 2h than the solution for 1:5, syringe pump flow velocity 0.1mL/min is set, flow (mL) is set as the mixing speed 1000rpm that 25mL arranges agitator.The polyethylene glycol-ester triblock copolymer solution that is dissolved with 10-hydroxycamptothecine is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution lyophilizing, must there is bioactive polyglycol ether-polyester three-block copolymer medicament-carried nano micelle after dialysis.
The envelop rate of the polyglycol ether that embodiment 90 obtains-polyester three-block copolymer medicament-carried nano micelle is 12.76%, and medicine carrying efficiency is 92.34%;
The envelop rate of the polyglycol ether that embodiment 91 obtains-polyester three-block copolymer medicament-carried nano micelle is 12.03%, and medicine carrying efficiency is 95.6%;
The envelop rate of the polyglycol ether that embodiment 92 obtains-polyester three-block copolymer medicament-carried nano micelle is 14.3%, and medicine carrying efficiency is 100%.
Embodiment 93～97
Take respectively polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 13 preparations.10-hydroxycamptothecine is dissolved in oxolane, the concentration of 10-hydroxycamptothecine is 0.4mg/mL, stir 5h, after dissolving, 10-hydroxycamptothecine-tetrahydrofuran solution is added drop-wise in load weighted polyglycol ether-polyester three-block copolymer, be configured to 10-hydroxycamptothecine and polyethylene glycol-ester triblock copolymer mass ratio is respectively 1:20,1:10,3:20,4:20, the solution of 5:20 continues to stir 2h, syringe pump flow velocity 0.1mL/min is set, flow (mL) is set as the mixing speed 1000rpm that 25mL arranges agitator.The polyethylene glycol-ester triblock copolymer solution that is dissolved with 10-hydroxycamptothecine is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution lyophilizing, must there is bioactive polyglycol ether-polyester three-block copolymer medicament-carried nano micelle after dialysis.
The envelop rate of the polyglycol ether that embodiment 93 obtains-polyester three-block copolymer medicament-carried nano micelle is 11.39%, and medicine carrying efficiency is 87.52%;
The envelop rate of the polyglycol ether that embodiment 94 obtains-polyester three-block copolymer medicament-carried nano micelle is 12.51%, and medicine carrying efficiency is 89.21%;
The envelop rate of the polyglycol ether that embodiment 95 obtains-polyester three-block copolymer medicament-carried nano micelle is 13.21%, and medicine carrying efficiency is 97.32%;
The envelop rate of the polyglycol ether that embodiment 96 obtains-polyester three-block copolymer medicament-carried nano micelle is 12.74%, and medicine carrying efficiency is 90.63%;
The envelop rate of the polyglycol ether that embodiment 97 obtains-polyester three-block copolymer medicament-carried nano micelle is 11.94%, and medicine carrying efficiency is 87.86%.
Embodiment 98～102
Take respectively polyethylene glycol-(D-lactide) the triblock copolymer 100mg of embodiment 6 preparations.10-hydroxycamptothecine is dissolved in oxolane, the concentration of 10-hydroxycamptothecine is 0.4mg/mL, stir 5h, after dissolving, 10-hydroxycamptothecine-tetrahydrofuran solution is added drop-wise in load weighted polyethylene glycol-ester triblock copolymer, be configured to 10-hydroxycamptothecine and polyethylene glycol-ester triblock copolymer mass ratio is respectively 1:20,1:10,3:20,4:20, the solution of 5:20 continues to stir 2h, syringe pump flow velocity 0.1mL/min is set, flow (mL) is set as the mixing speed 1000rpm that 25mL arranges agitator.The polyethylene glycol-ester triblock copolymer solution that is dissolved with 10-hydroxycamptothecine is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution lyophilizing, must there is bioactive polyglycol ether-polyester three-block copolymer medicament-carried nano micelle after dialysis.
The envelop rate of the polyglycol ether that embodiment 98 obtains-polyester three-block copolymer medicament-carried nano micelle is 12.17%, and medicine carrying efficiency is 86.24%;
The envelop rate of the polyglycol ether that embodiment 99 obtains-polyester three-block copolymer medicament-carried nano micelle is 12.84%, and medicine carrying efficiency is 91.63%;
The envelop rate of the polyglycol ether that embodiment 100 obtains-polyester three-block copolymer medicament-carried nano micelle is 13.42%, and medicine carrying efficiency is 98.87%;
The envelop rate of the polyglycol ether that embodiment 101 obtains-polyester three-block copolymer medicament-carried nano micelle is 12.76%, and medicine carrying efficiency is 91.22%;
The envelop rate of the polyglycol ether that embodiment 102 obtains-polyester three-block copolymer medicament-carried nano micelle is 12.16%, and medicine carrying efficiency is 87.26%.
Embodiment 103～107
Polyethylene glycol-(D-lactide) triblock copolymer of embodiment 9 preparation is mixed with each 50mg of polyethylene glycol-(L-lactide) triblock copolymer prepared by embodiment 19, prepare the polyglycol ether of 5 parts of identical described mixing-polyester three-block copolymer.10-hydroxycamptothecine is dissolved in oxolane, the concentration of 10-hydroxycamptothecine is 0.4mg/mL, stir 5h, after dissolving, 10-hydroxycamptothecine-tetrahydrofuran solution is added drop-wise in load weighted polyglycol ether-polyester three-block copolymer and is configured to 10-hydroxycamptothecine and is respectively 1:20 with polyglycol ether-polyester three-block copolymer quality ratio, 1:10,3:20,4:20, the solution of 5:20 continues to stir 2h, syringe pump flow velocity 0.1mL/min is set, flow (mL) is set as the mixing speed 1000rpm that 25mL arranges agitator.The polyethylene glycol-ester triblock copolymer solution that is dissolved with 10-hydroxycamptothecine is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution lyophilizing, must there is bioactive polyglycol ether-polyester three-block copolymer medicament-carried nano micelle after dialysis.
The envelop rate of the polyglycol ether that embodiment 103 obtains-polyester three-block copolymer medicament-carried nano micelle is 11.89%, and medicine carrying efficiency is 86.84%
The envelop rate of the polyglycol ether that embodiment 104 obtains-polyester three-block copolymer medicament-carried nano micelle is 12.51%, and medicine carrying efficiency is 92.52%;
The envelop rate of the polyglycol ether that embodiment 105 obtains-polyester three-block copolymer medicament-carried nano micelle is 13.42%, and medicine carrying efficiency is 98.62%;
The envelop rate of the polyglycol ether that embodiment 106 obtains-polyester three-block copolymer medicament-carried nano micelle is 12.35%, and medicine carrying efficiency is 94.23%;
The envelop rate of the polyglycol ether that embodiment 107 obtains-polyester three-block copolymer medicament-carried nano micelle is 11.72%, and medicine carrying efficiency is 88.24%.
Embodiment 108～110
Polyethylene glycol-ester triblock copolymer is selected respectively polyethylene glycol-(D-lactide) the triblock copolymer 100mg of embodiment 9 preparations, polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 19 preparations, polyethylene glycol-(D-lactide) triblock copolymer of embodiment 9 preparations mixes with each 50mg of polyethylene glycol-(L-lactide) triblock copolymer of embodiment 19 preparations.
Methotrexate is dissolved in oxolane, the concentration of methotrexate is 0.4mg/mL, stir 5h, after dissolving, methotrexate-tetrahydrofuran solution is added drop-wise in load weighted polyglycol ether-polyester three-block copolymer and is configured to methotrexate and polyglycol ether-polyester three-block copolymer quality and continues to stir 2h than the solution that is respectively 1:5, syringe pump flow velocity 0.1mL/min is set, flow (mL) is set as the mixing speed 1000rpm that 25mL arranges agitator.The polyethylene glycol-ester triblock copolymer solution that is dissolved with methotrexate is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution lyophilizing, must there is bioactive polyglycol ether-polyester three-block copolymer medicament-carried nano micelle after dialysis.
The envelop rate of the polyglycol ether that embodiment 108 obtains-polyester three-block copolymer medicament-carried nano micelle is 22.21%, and medicine carrying efficiency is 89.93%;
The envelop rate of the polyglycol ether that embodiment 109 obtains-polyester three-block copolymer medicament-carried nano micelle is 22.27%, and medicine carrying efficiency is 90.42%;
The envelop rate of the polyglycol ether that embodiment 110 obtains-polyester three-block copolymer medicament-carried nano micelle is 24.52%, and medicine carrying efficiency is 100%.
Embodiment 111～113
Polyethylene glycol-ester triblock copolymer is selected respectively polyethylene glycol-(D-lactide) the triblock copolymer 100mg of embodiment 9 preparations, polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 19 preparations, polyethylene glycol-(D-lactide) triblock copolymer of embodiment 9 preparations mixes with each 50mg of polyethylene glycol-(L-lactide) triblock copolymer of embodiment 19 preparations.
Cyclophosphamide is dissolved in oxolane, the concentration of cyclophosphamide is 0.4mg/mL, stir 5h, after dissolving, cyclophosphamide-tetrahydrofuran solution is added drop-wise in load weighted polyglycol ether-polyester three-block copolymer and is configured to cyclophosphamide and polyglycol ether-polyester three-block copolymer quality and continues to stir 2h than the solution that is respectively 1:5, syringe pump flow velocity 0.1mL/min is set, flow (mL) is set as the mixing speed 1000rpm that 25mL arranges agitator.The polyethylene glycol-ester triblock copolymer solution that is dissolved with cyclophosphamide is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution lyophilizing, must there is bioactive year polyglycol ether-polyester three-block copolymer medicine nano-micelle after dialysis.
The envelop rate of the polyglycol ether that embodiment 111 obtains-polyester three-block copolymer medicament-carried nano micelle is 52.34%, and medicine carrying efficiency is 90.63%;
The envelop rate of the polyglycol ether that embodiment 112 obtains-polyester three-block copolymer medicament-carried nano micelle is 52.41%, and medicine carrying efficiency is 91.46%;
The envelop rate of the polyglycol ether that embodiment 113 obtains-polyester three-block copolymer medicament-carried nano micelle is 63.63%, and medicine carrying efficiency is 98.95%.
Embodiment 114～116
Polyethylene glycol-ester triblock copolymer is selected respectively polyethylene glycol-(D-lactide) the triblock copolymer 100mg of embodiment 9 preparations, polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 19 preparations, polyethylene glycol-(D-lactide) triblock copolymer of embodiment 9 preparations mixes with each 50mg of polyethylene glycol-(L-lactide) triblock copolymer of embodiment 19 preparations.
5-fluorouracil is dissolved in oxolane, the concentration of 5-fluorouracil is 0.4mg/mL, stir 5h, after dissolving, 5-fluorouracil-tetrahydrofuran solution is added drop-wise in load weighted polyglycol ether-polyester three-block copolymer and is configured to 5-fluorouracil and polyglycol ether-polyester three-block copolymer quality and continues to stir 2h than the solution that is respectively 1:5, syringe pump flow velocity 0.1mL/min is set, flow (mL) is set as the mixing speed 1000rpm that 25mL arranges agitator.The polyethylene glycol-ester triblock copolymer solution that is dissolved with 5-fluorouracil is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution lyophilizing, must there is bioactive polyglycol ether-polyester three-block copolymer medicament-carried nano micelle after dialysis.
The envelop rate of the polyglycol ether that embodiment 114 obtains-polyester three-block copolymer medicament-carried nano micelle is 43.34%, and medicine carrying efficiency is 84.52%;
The envelop rate of the polyglycol ether that embodiment 115 obtains-polyester three-block copolymer medicament-carried nano micelle is 45.63%, and medicine carrying efficiency is 84.63%;
The envelop rate of the polyglycol ether that embodiment 116 obtains-polyester three-block copolymer medicament-carried nano micelle is 51.37%, and medicine carrying efficiency is 95.47%.
Embodiment 117～119
Polyethylene glycol-ester triblock copolymer is selected respectively polyethylene glycol-(D-lactide) the triblock copolymer 100mg of embodiment 9 preparations, polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 19 preparations, polyethylene glycol-(D-lactide) triblock copolymer of embodiment 9 preparations mixes with each 50mg of polyethylene glycol-(L-lactide) triblock copolymer of embodiment 19 preparations.
Docetaxel is dissolved in oxolane, the concentration of Docetaxel is 0.4mg/mL, stir 5h, after dissolving, Docetaxel-tetrahydrofuran solution is added drop-wise in load weighted polyglycol ether-polyester three-block copolymer and is configured to Docetaxel and is respectively 1:20 with polyglycol ether-polyester three-block copolymer quality ratio, 1:10,3:20,4:20, the solution of 5:20 continues to stir 2h, syringe pump flow velocity 0.1mL/min is set, flow (mL) is set as the mixing speed 1000rpm that 25mL arranges agitator.The polyethylene glycol-ester triblock copolymer solution that is dissolved with Docetaxel is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution lyophilizing, must there is bioactive polyglycol ether-polyester three-block copolymer medicament-carried nano micelle after dialysis.
The envelop rate of the polyglycol ether that embodiment 117 obtains-polyester three-block copolymer medicament-carried nano micelle is 14.37%, and medicine carrying efficiency is 84.58%;
The envelop rate of the polyglycol ether that embodiment 118 obtains-polyester three-block copolymer medicament-carried nano micelle is 14.47%, and medicine carrying efficiency is 86.54%;
The envelop rate of the polyglycol ether that embodiment 119 obtains-polyester three-block copolymer medicament-carried nano micelle is 16.74%, and medicine carrying efficiency is 96.35%.
Polyethylene glycol-ester triblock copolymer is selected respectively polyethylene glycol-(D-lactide) the triblock copolymer 100mg of embodiment 9 preparations, polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 19 preparations, polyethylene glycol-(D-lactide) triblock copolymer of embodiment 9 preparations mixes with each 50mg of polyethylene glycol-(L-lactide) triblock copolymer of embodiment 19 preparations.
Daunorubicin is dissolved in oxolane, the concentration of daunorubicin is 0.4mg/mL, stir 5h, after dissolving, daunorubicin-tetrahydrofuran solution is added drop-wise in load weighted polyglycol ether-polyester three-block copolymer and is configured to daunorubicin and is respectively 1:20 with polyglycol ether-polyester three-block copolymer quality ratio, 1:10,3:20,4:20, the solution of 5:20 continues to stir 2h, syringe pump flow velocity 0.1mL/min is set, flow (mL) is set as the mixing speed 1000rpm that 25mL arranges agitator.The polyethylene glycol-ester triblock copolymer solution that is dissolved with daunorubicin is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution lyophilizing, must there is bioactive polyglycol ether-polyester three-block copolymer medicament-carried nano micelle after dialysis.
The envelop rate of the polyglycol ether that embodiment 120 obtains-polyester three-block copolymer medicament-carried nano micelle is 15.36%, and medicine carrying efficiency is 86.35%;
The envelop rate of the polyglycol ether that embodiment 121 obtains-polyester three-block copolymer medicament-carried nano micelle is 15.32%, and medicine carrying efficiency is 87.12%;
The envelop rate of the polyglycol ether that embodiment 122 obtains-polyester three-block copolymer medicament-carried nano micelle is 16.83%, and medicine carrying efficiency is 97.32%.
Embodiment 123～125
Polyethylene glycol-ester triblock copolymer is selected respectively polyethylene glycol-(D-lactide) the triblock copolymer 100mg of embodiment 9 preparations, polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 19 preparations, polyethylene glycol-(D-lactide) triblock copolymer of embodiment 9 preparations mixes with each 50mg of polyethylene glycol-(L-lactide) triblock copolymer of embodiment 19 preparations.
Amycin is dissolved in oxolane, the concentration of amycin is 0.4mg/mL, stir 5h, after dissolving, amycin-tetrahydrofuran solution is added drop-wise in load weighted polyglycol ether-polyester three-block copolymer and is configured to amycin and is respectively 1:20,1:10 with polyglycol ether-polyester three-block copolymer quality ratio, 3:20,4:20, the solution of 5:20 continues to stir 2h, syringe pump flow velocity 0.1mL/min is set, flow (mL) is set as the mixing speed 1000rpm that 25mL arranges agitator.The polyethylene glycol-ester triblock copolymer solution that is dissolved with amycin is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution lyophilizing, must there is bioactive polyglycol ether-polyester three-block copolymer medicament-carried nano micelle after dialysis.
The envelop rate of the polyglycol ether that embodiment 123 obtains-polyester three-block copolymer medicament-carried nano micelle is 15.23%, and medicine carrying efficiency is 86.34%;
The envelop rate of the polyglycol ether that embodiment 124 obtains-polyester three-block copolymer medicament-carried nano micelle is 15.47%, and medicine carrying efficiency is 86.25%;
The envelop rate of the polyglycol ether that embodiment 125 obtains-polyester three-block copolymer medicament-carried nano micelle is 17.82%, and medicine carrying efficiency is 96.35%.
Embodiment 126～128
Polyethylene glycol-ester triblock copolymer is selected respectively polyethylene glycol-(D-lactide) the triblock copolymer 100mg of embodiment 9 preparations, polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 19 preparations, polyethylene glycol-(D-lactide) triblock copolymer of embodiment 9 preparations mixes with each 50mg of polyethylene glycol-(L-lactide) triblock copolymer of embodiment 19 preparations.
Epirubicin is dissolved in oxolane, the concentration of epirubicin is 0.4mg/mL, stir 5h, after dissolving, epirubicin-tetrahydrofuran solution is added drop-wise in load weighted polyglycol ether-polyester three-block copolymer and is configured to epirubicin and is respectively 1:20 with polyglycol ether-polyester three-block copolymer quality ratio, 1:10,3:20,4:20, the solution of 5:20 continues to stir 2h, syringe pump flow velocity 0.1mL/min is set, flow (mL) is set as the mixing speed 1000rpm that 25mL arranges agitator.The polyethylene glycol-ester triblock copolymer solution that is dissolved with epirubicin is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution lyophilizing, must there is bioactive polyglycol ether-polyester three-block copolymer medicament-carried nano micelle after dialysis.
The envelop rate of the polyglycol ether that embodiment 126 obtains-polyester three-block copolymer medicament-carried nano micelle is 15.78%, and medicine carrying efficiency is 86.34%;
The envelop rate of the polyglycol ether that embodiment 127 obtains-polyester three-block copolymer medicament-carried nano micelle is 15.62%, and medicine carrying efficiency is 85.96%;
The envelop rate of the polyglycol ether that embodiment 128 obtains-polyester three-block copolymer medicament-carried nano micelle is 17.35%, and medicine carrying efficiency is 97.42%.
Embodiment 129～131
Polyethylene glycol-ester triblock copolymer is selected respectively polyethylene glycol-(D-lactide) the triblock copolymer 100mg of embodiment 9 preparations, polyethylene glycol-(L-lactide) the triblock copolymer 100mg of embodiment 19 preparations, polyethylene glycol-(D-lactide) triblock copolymer of embodiment 9 preparations mixes with each 50mg of polyethylene glycol-(L-lactide) triblock copolymer of embodiment 19 preparations.
Pirarubicin is dissolved in oxolane, the concentration of pirarubicin is 0.4mg/mL, stir 5h, after dissolving, pirarubicin-tetrahydrofuran solution is added drop-wise in load weighted polyglycol ether-polyester three-block copolymer and is configured to pirarubicin and is respectively 1:20 with polyglycol ether-polyester three-block copolymer quality ratio, 1:10,3:20,4:20, the solution of 5:20 continues to stir 2h, syringe pump flow velocity 0.1mL/min is set, flow (mL) is set as the mixing speed 1000rpm that 25mL arranges agitator.The polyethylene glycol-ester triblock copolymer solution that is dissolved with pirarubicin is placed on agitator and stirs, with the syringe pump set, in solution, at the uniform velocity drip Milli-Q.Continue to stir 10h after drip finishing, with bag filter (MWCO=3500) 24h that dialyses, change water more than 5 times in Milli-Q.By the solution lyophilizing, must there is bioactive polyglycol ether-polyester three-block copolymer medicament-carried nano micelle after dialysis.
The envelop rate of the polyglycol ether that embodiment 129 obtains-polyester three-block copolymer medicament-carried nano micelle is 15.31%, and medicine carrying efficiency is 86.34%;
The envelop rate of the polyglycol ether that embodiment 130 obtains-polyester three-block copolymer medicament-carried nano micelle is 15.53%, and medicine carrying efficiency is 87.53%;
The envelop rate of the polyglycol ether that embodiment 131 obtains-polyester three-block copolymer medicament-carried nano micelle is 17.83%, and medicine carrying efficiency is 97.36%.
The explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.
To the above-mentioned explanation of the disclosed embodiments, make professional and technical personnel in the field can realize or use the present invention.Multiple modification to these embodiment will be apparent for those skilled in the art, and General Principle as defined herein can be in the situation that do not break away from the spirit or scope of the present invention, realization in other embodiments.Therefore, the present invention will can not be restricted to these embodiment shown in this article, but will meet the widest scope consistent with principle disclosed herein and features of novelty.
Claims (8)
1. the preparation method of a polyethylene glycol-ester triblock copolymer medicament-carried nano micelle comprises the following steps:
(A) mixture of small-molecule drug and organic solvent is added drop-wise in polyethylene glycol-ester triblock copolymer, obtains mixed solution;
(B) drip ultra-pure water when described mixed solution being stirred for the first time, after continuing to stir for the second time, organic solvent is removed in dialysis and lyophilizing obtains medicament-carried nano micelle;
Described polyethylene glycol-ester triblock copolymer as shown in the formula (I),
Wherein ,-R-is
or
M is the degree of polymerization, 10≤m≤250; N is the degree of polymerization, 10≤n≤220.
2. preparation method according to claim 1, it is characterized in that, in described step (A), described small-molecule drug is methotrexate, 5-fluorouracil, cyclophosphamide, daunorubicin, amycin, epirubicin, pirarubicin, camptothecin or Ramulus et folium taxi cuspidatae class.
3. preparation method according to claim 1, is characterized in that, in described step (A), the concentration of described small-molecule drug in organic solvent is 0.1～10mg/mL.
4. preparation method according to claim 1, is characterized in that, in described step (A), the mass ratio of described small-molecule drug and polyethylene glycol-ester triblock copolymer is 0.01～1.
5. preparation method according to claim 1, is characterized in that, the described speed stirred for the first time is 100～2000rpm.
6. preparation method according to claim 1, is characterized in that, the speed of described dropping ultra-pure water is 0.05～5mL/min.
7. preparation method according to claim 1, is characterized in that, the consumption of described ultra-pure water and the volume ratio of consumption of organic solvent are 0.01～20.
8. preparation method according to claim 1, is characterized in that, described organic solvent is oxolane, Isosorbide-5-Nitrae-dioxane, dimethyl sulfoxide or DMF.
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