CN106046383A - Unimolecular star copolymer nano-particles and preparation method thereof - Google Patents
Unimolecular star copolymer nano-particles and preparation method thereof Download PDFInfo
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Abstract
The invention discloses unimolecular poly(lactide-co-caprolactone)-b-polyethylene glycol nano-particles and a preparation method thereof. The nano-particles are formed through self-assembling of poly(lactide-co-caprolactone)-b-polyethylene glycol star copolymers in a water solution, and the poly(lactide-co-caprolactone)-b-polyethylene glycol star copolymers are obtained after polyhydroxy polyhedral oligomeric silsesquioxane POSS-(OH)32 triggers copolymerization of lactide and caprolactone and then is coupled with terminal methoxy polyethylene glycol carboxylic acid. According to the unimolecular poly(lactide-co-caprolactone)-b-polyethylene glycol nano-particles, the particle size is between 15 nm and 20 nm, the nano-particles are stable in structure and good in biocompatibility, can be loaded with anti-cancer drugs and has application prospects in the field of drug carrier preparation.
Description
Technical field
Open a kind of unimolecule star copolymer nano-particle of the present invention and preparation method thereof, relates to bio-medical material skill
Art field.
Background technology
High polymer nano micelle has the bright outlook as chemotherapeutics carrier in treating malignant tumor field.Injection type
Nano-micelle with blood circulation, may pass through the barrier of bodily tissue, arrive tumor locus, make medicine discharge at lesions position,
It is greatly improved the bioavailability of medicine, and reduces toxic and side effects.Therefore research and develop compound with regular structure, size is controlled, targeting is defeated
Give, the nano-micelle pharmaceutical carrier of condition controlled release significant.Prepared by the self assembly of linear amphiphilic copolymer and receive
Rice glue bundle is current study hotspot, but polymolecular nano-micelle is unstable in weak solution, can be dissociated into without Drug loading capacity
Unimolecule.It addition, pure physics medicine carrying mode is unstable, have medicine reveal, prominent release, the problem such as drug effect reduction.
In recent years, star copolymer nano-micelle, due to its stability, is not affected by factors such as solution dilutions, is had simultaneously
There is narrow diameter distribution, easily modify, alleviate the prominent advantage such as release, attract attention.People successively select containing polyfunctional group
Little molecule, hyperbranched polyether, hyper-branched polyester Bolton H40, dendroid (or hyperbranched) polyamide-amide etc. is as kernel
Synthesis star-type polymer nano-micelle.
At present, researcher selects cage modle oligomeric silsesquioxanes (POSS) composite structure regularity polymer mostly.POSS
To be a class coupled thing by Si-O is inner skeleton, the nanoscale three-dimensional system of the organic group of external connection, a diameter of 1～3nm.
POSS, as the core of star-type polymer, has an advantage that 1. good biocompatibility；2. structure height is symmetrical, due to its rigidity
The mastery reaction of cage modle skeleton, makes synthesized unimolecule nano-micelle more stable；3. can functionalization be formed a plurality of further
The raising of arm, beneficially drug loading；4. stable performance, high temperature resistant, mechanical strength good；5. size is little, excretion is easy；6. letter is synthesized
List, condition are easily controlled, monodispersity is good.
In the synthesis of nano-medicament carrier, in order to ensure biocompatibility and the degradability of material, people usually select
Select polylactic acid as kernel.But pure polylactic acid crystal is relatively strong, not only degraded is slow, and is unfavorable for the raising of carrying drug ratio.For
Raising degradation rate, researchers select again the copolymer of polylactic acid and polyglycolic acid to replace pure polylactic acid, but copolymer
Compliance is poor, and the acidity of degradation product, glycolic acid is too strong, and human body is produced physiological side effects.
Therefore, strengthen the stability of nano-micelle, improve carrying drug ratio, it is achieved the control of nano particle diameter, reduce nanometer
The side effect of pharmaceutical carrier is the problem needing solution at present badly.
Summary of the invention
For solving the drawbacks described above of current nano-micelle, it is an object of the invention to provide a kind of unimolecule poly-(lactide-
Co-caprolactone)-b-Polyethylene Glycol nano-particle and preparation method thereof.
A kind of unimolecule poly-(the lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle that the present invention provides, by poly-(third
Lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer is in aqueous by being self-assembly of, and it is poly-that (lactide-co-is own
Lactone)-b-Polyethylene Glycol star copolymer is by polyhydroxy cage-type silsesquioxane POSS-(OH)32Cause lactide and caprolactone
After combined polymerization, then obtain with end methoxy poly (ethylene glycol) carboxylic acid coupling.
The preparation side of a kind of unimolecule poly-(the lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle that the present invention provides
Method, comprises the following steps:
1) poly-for cage modle eight aminopropyl silsesquioxane is reacted in organic solvent with (+)-2,3-Epoxy-1-propanol, then precipitated product,
Obtain polyhydroxy cage-type silsesquioxane POSS-(OH) after drying32；
2) with step 1) polyhydroxy cage-type silsesquioxane POSS-(OH) that obtains32As initiator, add catalyst,
Cause the ring-opening polymerisation of lactide and caprolactone, obtain star-like poly-(lactide-co-caprolactone)；
3) obtain holding the poly-second of methoxyl group two by end methoxy poly (ethylene glycol) and succinic anhydride ring-opening reaction in organic solvent
Polyol carboxylic acid, end methoxy poly (ethylene glycol) carboxylic acid and the step 2 that will obtain) star-like poly-(lactide-co-caprolactone) that obtain urging
Carry out under agent and dehydrant effect being esterified coupling reaction, obtain unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol
Star copolymer；
4) by step 3) unimolecule poly-(the lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer that obtains is dissolved in and having
Machine solvent, obtains solution, is added drop-wise in ultra-pure water by solution, dialyses after stirring in ultra-pure water, obtains poly-(the third friendship of unimolecule
Ester-co-caprolactone)-b-Polyethylene Glycol nano-particle.
Further, in step 1) in, cage modle eight poly-aminopropyl silsesquioxane is 1 with the mol ratio of (+)-2,3-Epoxy-1-propanol:
16, organic solvent is dioxane or DMF (DMF), under agitation, reacts at 40～50 DEG C.
Further, in step 2) in, reacting at 120-145 DEG C, catalyst is zinc lactate, lactide and caprolactone
Mol ratio is 1:9-9:1.
Further, in step 2) in, polyhydroxy cage-type silsesquioxane POSS-(OH)32With lactide and caprolactone
The mass ratio of weight sum is 1:39-1:23.
Further, in step 2) in, the consumption of catalyst accounts for lactide and the 0.15% of caprolactone weight sum.
Further, in step 3) in, organic solvent is dioxane or DMF, and the number of end methoxy poly (ethylene glycol) is divided equally
Son amount is 700-800, and catalyst is DMAP (DMAP), and dehydrant is 3-dicyclohexyl carbodiimide (DCC),
Star-like poly-(lactide-co-caprolactone) is 1:2 with the mass ratio of end methoxy poly (ethylene glycol) carboxylic acid.
Further, in step 4) in, organic solvent is dioxane or DMF, is stirring 6-8h, then in ultra-pure water
Ultra-pure water is dialysed 3 days, changed a dialysis solution every 4 hours.
Further, poly-(lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle of the present invention is applied to prepare medicine
Thing carrier.
A kind of unimolecule poly-(the lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle that the present invention provides is preparing medicine
Application in thing carrier is as follows: is dissolved in organic solvent by breast cancer, obtains breast cancer solution, gathered by unimolecule
(lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle lyophilization, is then added in breast cancer solution, super
Pure water is dialysed, the breast cancer free to remove nano grain surface, obtain drug-loading nanoparticles.
Further, breast cancer is paclitaxel, and organic solvent is dioxane.
Further, the concentration of breast cancer is 1.5mg/mL, is degraded by drug-loading nanoparticles in the HCl of 1M, point
Analysis carrying drug ratio.
Further, polyhydroxy cage-type silsesquioxane POSS-(OH) is changed32Can with the mass ratio of lactide Yu caprolactone
The size of nano-particle is obtained with regulation.
Further, caprolactone composition is the most, and hydrophobicity is the strongest, and compliance is the best.
Polyhydroxy cage-type silsesquioxane POSS-(OH) in the present invention32Structural formula as follows:
The synthetic route chart of poly-(lactide-co-caprolactone)-b-ethylene glycol copolymer in the present invention one specific embodiment
As follows:
Use technique scheme, the beneficial effects of the present invention is:
1. synthesis of polyhydroxy cage-type silsesquioxane POSS-(OH)32, as nucleosynthesis star copolymer, cage model sesquialter
Siloxane structure is stable；Simultaneously because branched structure, intramolecular has cavity structure, is beneficial to improve drug loading rate.
2. using lactide and caprolactone copolymer as nano-particle internal layer, destroy the crystallinity of polylactide, increase
Segment compliance, decreases the toxic and side effects of catabolite.
3. zinc lactate is as the catalyst of lactide Yu caprolactone ring-opening polymerisation, good biocompatibility, it is to avoid stannum catalysis
The toxicity of agent.
4. unimolecule nano-particle is more stable in weak solution, as injection-type pharmaceutical carrier, can reduce the leakage of medicine.
Accompanying drawing explanation
Fig. 1 is polyhydroxy cage-type silsesquioxane POSS-(OH)32's1H-nuclear magnetic spectrogram；
Fig. 2 is the scanning electron microscope (SEM) photograph of poly-(lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle.
Detailed description of the invention
Below in conjunction with the accompanying drawings and embodiment, the detailed description of the invention of the present invention is described in further detail.Hereinafter implement
Example is used for illustrating the present invention, but is not limited to the scope of the present invention.
Embodiment 1:
Under room temperature, 18g deionized water, 8ml normal propyl alcohol, 2ml acetonitrile, 0.4ml tetraethyl ammonium hydroxide are added 100ml tri-
In mouth flask, stirring makes solution be sufficiently mixed.Then under violent stirring, slowly drip γ-aminopropyl three ethoxy of 44.2g
Base silane, dropping in 10 minutes is complete.Temperature is risen to 50 DEG C, after being down to 25 after reacting 24 hours.With oxolane, product is brilliant
Separate out to obtain white solid powder, then clean 3 sucking filtration with oxolane.Finally it is put in the vacuum tank of 100 DEG C drying.
8.88g (0.01mol) above-mentioned white powder is dissolved in dioxane, is made into the solution that concentration is 8.0wt%,
Then above-mentioned solution is slowly dropped in the (+)-2,3-Epoxy-1-propanol of 11.84g (0.16mol), stirring reaction 3 hours at 40～50 DEG C.
Use ether sedimentation product, be vacuum dried to obtain water white transparency solid, obtain polyhydroxy cage-type silsesquioxane POSS-(OH)32, Fig. 1
For polyhydroxy cage-type silsesquioxane POSS-(OH)32's1H-nuclear magnetic spectrogram, at chemical shift 0.3-0.8, proton peak is for connecting
The signal of methylene on α position on Si atom, chemical shift 1.5-1.7 is the proton peak of methylene on β position on connection Si atom,
Chemical shift 2.5-3.0 is to be connected in atom N the proton peak of methylene on α position, and chemical shift 3.5-3.8 is former for being connected to oxygen
Methylene on son and the peak of C-H.Result shows, (+)-2,3-Epoxy-1-propanol aminopropyl silsesquioxane poly-with cage modle eight is opened
Ring reacts, it was demonstrated that successfully synthesize polyhydroxy cage-type silsesquioxane.
In round-bottomed flask add polyhydroxy cage-type silsesquioxane 0.3g, D, L-lactide 1.44g (0.01mol) and
10.26g (0.09mol) caprolactone and zinc lactate 0.0176g.Evacuation-inflated with nitrogen, circulates three times, stirs under 135 DEG C of oil baths
Melted 5min, then reacts 24h at 135 DEG C.The product dichloromethane obtained is dissolved, then precipitates with normal hexane, weight
Multiple three times, obtaining weak yellow liquid, vacuum drying obtains star-like poly-(lactide-co-caprolactone)；
The end methoxy poly (ethylene glycol) 80g that number-average molecular weight is 700～800 is dissolved in dioxane, adds succinic anhydride
10g, obtains after reacting 8 hours holding methoxy poly (ethylene glycol) carboxylic acid at 45 DEG C, and it is standby that solution is cooled to room temperature.
In 100mL round-bottomed flask, add star-like poly-(lactide-co-caprolactone) obtained above 2.4g, hold methoxyl group
Polyethylene carboxylic acid 4.8g, add DMAP (DMAP) 1.5g, 1,3-dicyclohexyl carbodiimide (DCC)
1.8g, carries out being esterified coupling reaction, obtains unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer.
Poly-for unimolecule (lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer is dissolved in DMF wiring solution-forming, with note
Emitter sucks this solution, is slowly dropped in ultra-pure water, loads in bag filter, dialyse 3 days in ultra-pure water after stirring 6 hours,
Within every 4 hours, change dialysis solution.By the nanoparticles solution lyophilization in bag filter, obtain unimolecule poly-(lactide-co-oneself
Lactone)-b-Polyethylene Glycol nano-particle.Fig. 2 is the scanning electricity of poly-(lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle
Mirror figure.
Paclitaxel is dissolved in 5mL dioxane, is made into the solution that concentration is 1.5mg/mL, add 20mg freezing and do
Poly-(lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle after dry, dialyses 8 hours, to remove nanometer in ultra-pure water
The paclitaxel that particle surface is free, obtains drug-loading nanoparticles.Drug-loading nanoparticles is degraded in the HCl solution of 1M, analyzes
The concentration of paclitaxel, it is 14.8% that analysis obtains carrying drug ratio.
Embodiment 2:
Under room temperature, 18g deionized water, 8ml normal propyl alcohol, 2ml acetonitrile, 0.4ml tetraethyl ammonium hydroxide are added 100ml tri-
In mouth flask, stirring makes solution be sufficiently mixed.Then under violent stirring, slowly drip γ-aminopropyl three ethoxy of 44.2g
Base silane, dropping in 10 minutes is complete.Temperature is risen to 40 DEG C, after reacting 24 hours, is down to 25 DEG C.With oxolane, product is brilliant
Separate out to obtain white solid powder, then clean 3 sucking filtration with oxolane.Finally it is put in the vacuum tank of 100 DEG C drying.
8.88g (0.01mol) above-mentioned white powder is dissolved in dioxane, is made into the solution that concentration is 8.0wt%,
Then above-mentioned solution is slowly dropped in the (+)-2,3-Epoxy-1-propanol of 11.84g (0.16mol), stirring reaction 3 hours at 40～50 DEG C.
Use ether sedimentation product, be then vacuum dried to obtain water white transparency solid, obtain polyhydroxy cage-type silsesquioxane POSS-(OH)32。
Polyhydroxy cage-type silsesquioxane 0.3g, D, L-lactide 2.88g and 9.12g caprolactone is added in round-bottomed flask
With zinc lactate 0.0176g.Evacuation-inflated with nitrogen, circulates three times, and the melted 5min of stirring under 120 DEG C of oil baths, then at 120 DEG C
Lower reaction 24h.The product dichloromethane obtained is dissolved, then precipitates with normal hexane, in triplicate, obtain weak yellow liquid,
Vacuum drying obtains star-like poly-(lactide-co-caprolactone)；
The end methoxy poly (ethylene glycol) 80g that number-average molecular weight is 700～800 is dissolved in dioxane, adds succinic anhydride
10g, obtains after reacting 8 hours holding methoxy poly (ethylene glycol) carboxylic acid at 45 DEG C, and it is standby that solution is cooled to room temperature.
In 100mL round-bottomed flask, add star-like poly-(lactide-co-caprolactone) obtained above 2.4g, hold methoxyl group
Polyethylene carboxylic acid 4.8g, add DMAP (DMAP) 1.5g, 1,3-dicyclohexyl carbodiimide (DCC)
1.8g, carries out being esterified coupling reaction, obtains unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer.
Poly-for unimolecule (lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer is dissolved in dioxane and is made into molten
Liquid, sucks this solution with syringe, is slowly dropped in ultra-pure water, loads in bag filter, after stirring 6 hours in ultra-pure water thoroughly
Analyse 3 days, within every 4 hours, change dialysis solution.By the nanoparticles solution lyophilization in bag filter, obtain unimolecule poly-(lactide-
Co-caprolactone)-b-Polyethylene Glycol nano-particle.
Embodiment 3:
Under room temperature, 18g deionized water, 8ml normal propyl alcohol, 2ml acetonitrile, 0.4ml tetraethyl ammonium hydroxide are added 100ml tri-
In mouth flask, stirring makes solution be sufficiently mixed.Then under violent stirring, slowly drip γ-aminopropyl three ethoxy of 44.2g
Base silane, dropping in 10 minutes is complete.Temperature is risen to 50 DEG C, after reacting 24 hours, is down to 25 DEG C.With oxolane, product is brilliant
Separate out to obtain white solid powder, then clean 3 sucking filtration with oxolane.Finally it is put in the vacuum tank of 100 DEG C drying.
8.88g (0.01mol) above-mentioned white powder is dissolved in dioxane, is made into the solution that concentration is 8.0wt%,
Then above-mentioned solution is slowly dropped in the (+)-2,3-Epoxy-1-propanol of 11.84g (0.16mol), stirring reaction 3 hours at 40～50 DEG C.
Use ether sedimentation product, be then vacuum dried to obtain water white transparency solid, obtain polyhydroxy cage-type silsesquioxane POSS-(OH)32。
Polyhydroxy cage-type silsesquioxane 0.3g, D, L-lactide 4.32g and 7.98g caprolactone is added in round-bottomed flask
With zinc lactate 0.0176g.Evacuation-inflated with nitrogen, circulates three times, and the melted 5min of stirring under 145 DEG C of oil baths, then at 145 DEG C
Lower reaction 24h.The product dichloromethane obtained is dissolved, then precipitates with normal hexane, in triplicate, obtain weak yellow liquid,
Vacuum drying obtains star-like poly-(lactide-co-caprolactone)；
The end methoxy poly (ethylene glycol) 80g that number-average molecular weight is 700～800 is dissolved in DMF, addition succinic anhydride 10g, 45
Obtaining after reacting 8 hours at DEG C holding methoxy poly (ethylene glycol) carboxylic acid, it is standby that solution is cooled to room temperature.
In 100mL round-bottomed flask, add star-like poly-(lactide-co-caprolactone) obtained above 2.4g, hold methoxyl group
Polyethylene carboxylic acid 4.8g, add DMAP (DMAP) 1.5g, 1,3-dicyclohexyl carbodiimide (DCC)
1.8g, carries out being esterified coupling reaction, obtains unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer.
Poly-for unimolecule (lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer is dissolved in dioxane and is made into molten
Liquid, sucks this solution with syringe, is slowly dropped in ultra-pure water, loads in bag filter, after stirring 6 hours in ultra-pure water thoroughly
Analyse 3 days, within every 4 hours, change dialysis solution.By the nanoparticles solution lyophilization in bag filter, obtain unimolecule poly-(lactide-
Co-caprolactone)-b-Polyethylene Glycol nano-particle.
Embodiment 4:
Under room temperature, 18g deionized water, 8ml normal propyl alcohol, 2ml acetonitrile, 0.4ml tetraethyl ammonium hydroxide are added 100ml tri-
In mouth flask, stirring makes solution be sufficiently mixed.Then under violent stirring, slowly drip γ-aminopropyl three ethoxy of 44.2g
Base silane, dropping in 10 minutes is complete.Temperature is risen to 40 DEG C, after reacting 24 hours, is down to 25 DEG C.With oxolane, product is brilliant
Separate out to obtain white solid powder, then clean 3 sucking filtration with oxolane.Finally it is put in the vacuum tank of 100 DEG C drying.
8.88g (0.01mol) above-mentioned white powder is dissolved in dioxane, is made into the solution that concentration is 8.0wt%,
Then above-mentioned solution is slowly dropped in the (+)-2,3-Epoxy-1-propanol of 11.84g (0.16mol), stirring reaction 3 hours at 40～50 DEG C.
Use ether sedimentation product, be then vacuum dried to obtain water white transparency solid, obtain polyhydroxy cage-type silsesquioxane POSS-(OH)32。
Polyhydroxy cage-type silsesquioxane 0.3g, D, L-lactide 5.76g and 6.84g caprolactone is added in round-bottomed flask
With zinc lactate 0.0176g.Evacuation-inflated with nitrogen, circulates three times, and the melted 5min of stirring under 145 DEG C of oil baths, then at 145 DEG C
Lower reaction 24h.The product dichloromethane obtained is dissolved, then precipitates with normal hexane, in triplicate, obtain weak yellow liquid,
Vacuum drying obtains star-like poly-(lactide-co-caprolactone)；
The end methoxy poly (ethylene glycol) 80g that number-average molecular weight is 700～800 is dissolved in dioxane, adds succinic anhydride
10g, obtains after reacting 8 hours holding methoxy poly (ethylene glycol) carboxylic acid at 45 DEG C, and it is standby that solution is cooled to room temperature.
In 100mL round-bottomed flask, add star-like poly-(lactide-co-caprolactone) obtained above 2.4g, hold methoxyl group
Polyethylene carboxylic acid 4.8g, add DMAP (DMAP) 1.5g, 1,3-dicyclohexyl carbodiimide (DCC)
1.8g, carries out being esterified coupling reaction, obtains unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer.
Poly-for unimolecule (lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer is dissolved in dioxane and is made into molten
Liquid, sucks this solution with syringe, is slowly dropped in ultra-pure water, loads in bag filter, after stirring 6 hours in ultra-pure water thoroughly
Analyse 3 days, within every 4 hours, change dialysis solution.By the nanoparticles solution lyophilization in bag filter, obtain unimolecule poly-(lactide-
Co-caprolactone)-b-Polyethylene Glycol nano-particle.
Embodiment 5:
Under room temperature, 18g deionized water, 8ml normal propyl alcohol, 2ml acetonitrile, 0.4ml tetraethyl ammonium hydroxide are added 100ml tri-
In mouth flask, stirring makes solution be sufficiently mixed.Then under violent stirring, slowly drip γ-aminopropyl three ethoxy of 44.2g
Base silane, dropping in 10 minutes is complete.Temperature is risen to 45 DEG C, after reacting 24 hours, is down to 25 DEG C.With oxolane, product is brilliant
Separate out to obtain white solid powder, then clean 3 sucking filtration with oxolane.Finally it is put in the vacuum tank of 100 DEG C drying.
8.88g (0.01mol) above-mentioned white powder is dissolved in dioxane, is made into the solution that concentration is 8.0wt%,
Then above-mentioned solution is slowly dropped in the (+)-2,3-Epoxy-1-propanol of 11.84g (0.16mol), stirring reaction 3 hours at 40～50 DEG C.
Use ether sedimentation product, be then vacuum dried to obtain water white transparency solid, obtain polyhydroxy cage-type silsesquioxane POSS-(OH)32。
Polyhydroxy cage-type silsesquioxane 0.3g, D, L-lactide 7.20g and 5.70g caprolactone is added in round-bottomed flask
With zinc lactate 0.0176g.Evacuation-inflated with nitrogen, circulates three times, and the melted 5min of stirring under 135 DEG C of oil baths, then at 135 DEG C
Lower reaction 24h.The product dichloromethane obtained is dissolved, then precipitates with normal hexane, in triplicate, obtain weak yellow liquid,
Vacuum drying obtains star-like poly-(lactide-co-caprolactone)；
The end methoxy poly (ethylene glycol) 80g that number-average molecular weight is 700～800 is dissolved in dioxane, adds succinic anhydride
10g, obtains after reacting 8 hours holding methoxy poly (ethylene glycol) carboxylic acid at 45 DEG C, and it is standby that solution is cooled to room temperature.
In 100mL round-bottomed flask, add star-like poly-(lactide-co-caprolactone) obtained above 2.4g, hold methoxyl group
Polyethylene carboxylic acid 4.8g, add DMAP (DMAP) 1.5g, 1,3-dicyclohexyl carbodiimide (DCC)
1.8g, carries out being esterified coupling reaction, obtains unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer.
Poly-for unimolecule (lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer is dissolved in dioxane and is made into molten
Liquid, sucks this solution with syringe, is slowly dropped in ultra-pure water, loads in bag filter, after stirring 6 hours in ultra-pure water thoroughly
Analyse 3 days, within every 4 hours, change dialysis solution.By the nanoparticles solution lyophilization in bag filter, obtain unimolecule poly-(lactide-
Co-caprolactone)-b-Polyethylene Glycol nano-particle.
Embodiment 6:
Under room temperature, 18g deionized water, 8ml normal propyl alcohol, 2ml acetonitrile, 0.4ml tetraethyl ammonium hydroxide are added 100ml tri-
In mouth flask, stirring makes solution be sufficiently mixed.Then under violent stirring, slowly drip γ-aminopropyl three ethoxy of 44.2g
Base silane, dropping in 10 minutes is complete.Temperature is risen to 50 DEG C, after reacting 24 hours, is down to 25 DEG C.With oxolane, product is brilliant
Separate out to obtain white solid powder, then clean 3 sucking filtration with oxolane.Finally it is put in the vacuum tank of 100 DEG C drying.
8.88g (0.01mol) above-mentioned white powder is dissolved in dioxane, is made into the solution that concentration is 8.0wt%,
Then above-mentioned solution is slowly dropped in the (+)-2,3-Epoxy-1-propanol of 11.84g (0.16mol), stirring reaction 3 hours at 40～50 DEG C.
Use ether sedimentation product, be then vacuum dried to obtain water white transparency solid, obtain polyhydroxy cage-type silsesquioxane POSS-(OH)32。
Polyhydroxy cage-type silsesquioxane 0.3g, D, L-lactide 8.64g and 4.56g caprolactone is added in round-bottomed flask
With zinc lactate 0.0176g.Evacuation-inflated with nitrogen, circulates three times, and the melted 5min of stirring under 135 DEG C of oil baths, then at 135 DEG C
Lower reaction 24h.The product dichloromethane obtained is dissolved, then precipitates with normal hexane, in triplicate, obtain weak yellow liquid,
Vacuum drying obtains star-like poly-(lactide-co-caprolactone)；
The end methoxy poly (ethylene glycol) 80g that number-average molecular weight is 700～800 is dissolved in dioxane, adds succinic anhydride
10g, obtains after reacting 8 hours holding methoxy poly (ethylene glycol) carboxylic acid at 45 DEG C, and it is standby that solution is cooled to room temperature.
In 100mL round-bottomed flask, add star-like poly-(lactide-co-caprolactone) obtained above 2.4g, hold methoxyl group
Polyethylene carboxylic acid 4.8g, add DMAP (DMAP) 1.5g, 1,3-dicyclohexyl carbodiimide (DCC)
1.8g, carries out being esterified coupling reaction, obtains unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer.
Poly-for unimolecule (lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer is dissolved in dioxane and is made into molten
Liquid, sucks this solution with syringe, is slowly dropped in ultra-pure water, loads in bag filter, after stirring 6 hours in ultra-pure water thoroughly
Analyse 3 days, within every 4 hours, change dialysis solution.By the nanoparticles solution lyophilization in bag filter, obtain unimolecule poly-(lactide-
Co-caprolactone)-b-Polyethylene Glycol nano-particle.
Embodiment 7:
Under room temperature, 18g deionized water, 8ml normal propyl alcohol, 2ml acetonitrile, 0.4ml tetraethyl ammonium hydroxide are added 100ml tri-
In mouth flask, stirring makes solution be sufficiently mixed.Then under violent stirring, slowly drip γ-aminopropyl three ethoxy of 44.2g
Base silane, dropping in 10 minutes is complete.Temperature is risen to 50 DEG C, after reacting 24 hours, is down to 25 DEG C.With oxolane, product is brilliant
Separate out to obtain white solid powder, then clean 3 sucking filtration with oxolane.Finally it is put in the vacuum tank of 100 DEG C drying.
8.88g (0.01mol) above-mentioned white powder is dissolved in dioxane, is made into the solution that concentration is 8.0wt%,
Then above-mentioned solution is slowly dropped in the (+)-2,3-Epoxy-1-propanol of 11.84g (0.16mol), stirring reaction 3 hours at 40～50 DEG C.
Heating under reduced pressure removes solvent, is then vacuum dried to obtain water white transparency solid, obtains polyhydroxy cage-type silsesquioxane POSS-
(OH)32。
Oneself is interior to add polyhydroxy cage-type silsesquioxane 0.3g, D, L-lactide 10.08g and 3.42g in round-bottomed flask
Ester and zinc lactate 0.0176g.Evacuation-inflated with nitrogen, circulates three times, and the melted 5min of stirring under 135 DEG C of oil baths, then 135
24h is reacted at DEG C.The product dichloromethane obtained is dissolved, then precipitates with normal hexane, in triplicate, obtain light yellow liquid
Body, vacuum drying obtains star-like poly-(lactide-co-caprolactone)；
The end methoxy poly (ethylene glycol) 80g that number-average molecular weight is 700～800 is dissolved in dioxane, adds succinic anhydride
10g, obtains after reacting 8 hours holding methoxy poly (ethylene glycol) carboxylic acid at 45 DEG C, and it is standby that solution is cooled to room temperature.
In 100mL round-bottomed flask, add star-like poly-(lactide-co-caprolactone) obtained above 2.4g, hold methoxyl group
Polyethylene carboxylic acid 4.8g, add DMAP (DMAP) 1.5g, 1,3-dicyclohexyl carbodiimide (DCC)
1.8g, carries out being esterified coupling reaction, obtains unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer.
Poly-for unimolecule (lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer is dissolved in dioxane and is made into molten
Liquid, sucks this solution with syringe, is slowly dropped in ultra-pure water, loads in bag filter, after stirring 6 hours in ultra-pure water thoroughly
Analyse 3 days, within every 4 hours, change dialysis solution.By the nanoparticles solution lyophilization in bag filter, obtain unimolecule poly-(lactide-
Co-caprolactone)-b-Polyethylene Glycol nano-particle.
Embodiment 8:
Under room temperature, 18g deionized water, 8ml normal propyl alcohol, 2ml acetonitrile, 0.4ml tetraethyl ammonium hydroxide are added 100ml tri-
In mouth flask, stirring makes solution be sufficiently mixed.Then under violent stirring, slowly drip γ-aminopropyl three ethoxy of 44.2g
Base silane, dropping in 10 minutes is complete.Temperature is risen to 50 DEG C, after reacting 24 hours, is down to 25 DEG C.With oxolane, product is brilliant
Separate out to obtain white solid powder, then clean 3 sucking filtration with oxolane.Finally it is put in the vacuum tank of 100 DEG C drying.
8.88g (0.01mol) above-mentioned white powder is dissolved in dioxane, is made into the solution that concentration is 8.0wt%,
Then above-mentioned solution is slowly dropped in the (+)-2,3-Epoxy-1-propanol of 11.84g (0.16mol), stirring reaction 3 hours at 40～50 DEG C.
Heating under reduced pressure removes solvent, is then vacuum dried to obtain water white transparency solid, obtains polyhydroxy cage-type silsesquioxane POSS-
(OH)32。
Oneself is interior to add polyhydroxy cage-type silsesquioxane 0.3g, D, L-lactide 11.52g and 2.28g in round-bottomed flask
Ester and zinc lactate 0.0176g.Evacuation-inflated with nitrogen, circulates three times, and the melted 5min of stirring under 135 DEG C of oil baths, then 135
24h is reacted at DEG C.The product dichloromethane obtained is dissolved, then precipitates with normal hexane, in triplicate, obtain light yellow liquid
Body, vacuum drying obtains star-like poly-(lactide-co-caprolactone)；
The end methoxy poly (ethylene glycol) 80g that number-average molecular weight is 700～800 is dissolved in dioxane, adds succinic anhydride
10g, obtains after reacting 8 hours holding methoxy poly (ethylene glycol) carboxylic acid at 45 DEG C, and it is standby that solution is cooled to room temperature.
In 100mL round-bottomed flask, add star-like poly-(lactide-co-caprolactone) obtained above 2.4g, hold methoxyl group
Polyethylene carboxylic acid 4.8g, add DMAP (DMAP) 1.5g, 1,3-dicyclohexyl carbodiimide (DCC)
1.8g, carries out being esterified coupling reaction, obtains unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer.
Poly-for unimolecule (lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer is dissolved in dioxane and is made into molten
Liquid, sucks this solution with syringe, is slowly dropped in ultra-pure water, loads in bag filter, after stirring 6 hours in ultra-pure water thoroughly
Analyse 3 days, within every 4 hours, change dialysis solution.By the nanoparticles solution lyophilization in bag filter, obtain unimolecule poly-(lactide-
Co-caprolactone)-b-Polyethylene Glycol nano-particle.
Embodiment 9:
Under room temperature, 18g deionized water, 8ml normal propyl alcohol, 2ml acetonitrile, 0.4ml tetraethyl ammonium hydroxide are added 100ml tri-
In mouth flask, stirring makes solution be sufficiently mixed.Then under violent stirring, slowly drip γ-aminopropyl three ethoxy of 44.2g
Base silane, dropping in 10 minutes is complete.Temperature is risen to 50 DEG C, after reacting 24 hours, is down to 25 DEG C.With oxolane, product is brilliant
Separate out to obtain white solid powder, then clean 3 sucking filtration with oxolane.Finally it is put in the vacuum tank of 100 DEG C drying.
8.88g (0.01mol) above-mentioned white powder is dissolved in dioxane, is made into the solution that concentration is 8.0wt%,
Then above-mentioned solution is slowly dropped in the (+)-2,3-Epoxy-1-propanol of 11.84g (0.16mol), stirring reaction 3 hours at 40～50 DEG C.
Heating under reduced pressure removes solvent, is then vacuum dried to obtain water white transparency solid, obtains polyhydroxy cage-type silsesquioxane POSS-
(OH)32。
Oneself is interior to add polyhydroxy cage-type silsesquioxane 0.3g, D, L-lactide 12.96g and 1.14g in round-bottomed flask
Ester and zinc lactate 0.0176g.Evacuation-inflated with nitrogen, circulates three times, and the melted 5min of stirring under 135 DEG C of oil baths, then 135
24h is reacted at DEG C.The product dichloromethane obtained is dissolved, then precipitates with normal hexane, in triplicate, obtain light yellow liquid
Body, vacuum drying obtains star-like poly-(lactide-co-caprolactone)；
The end methoxy poly (ethylene glycol) 80g that number-average molecular weight is 700～800 is dissolved in dioxane, adds succinic anhydride
10g, obtains after reacting 8 hours holding methoxy poly (ethylene glycol) carboxylic acid at 45 DEG C, and it is standby that solution is cooled to room temperature.
In 100mL round-bottomed flask, add star-like poly-(lactide-co-caprolactone) obtained above 2.4g, hold methoxyl group
Polyethylene carboxylic acid 4.8g, add DMAP (DMAP) 1.5g, 1,3-dicyclohexyl carbodiimide (DCC)
1.8g, carries out being esterified coupling reaction, obtains unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer.
Poly-for unimolecule (lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer is dissolved in dioxane and is made into molten
Liquid, sucks this solution with syringe, is slowly dropped in ultra-pure water, loads in bag filter, after stirring 6 hours in ultra-pure water thoroughly
Analyse 3 days, within every 4 hours, change dialysis solution.By the nanoparticles solution lyophilization in bag filter, obtain unimolecule poly-(lactide-
Co-caprolactone)-b-Polyethylene Glycol nano-particle.
Embodiment 10:
Under room temperature, 18g deionized water, 8ml normal propyl alcohol, 2ml acetonitrile, 0.4ml tetraethyl ammonium hydroxide are added 100ml tri-
In mouth flask, stirring makes solution be sufficiently mixed.Then under violent stirring, slowly drip γ-aminopropyl three ethoxy of 44.2g
Base silane, dropping in 10 minutes is complete.Temperature is risen to 50 DEG C, after reacting 24 hours, is down to 25 DEG C.With oxolane, product is brilliant
Separate out to obtain white solid powder, then clean 3 sucking filtration with oxolane.Finally it is put in the vacuum tank of 100 DEG C drying.
8.88g (0.01mol) above-mentioned white powder is dissolved in dioxane, is made into the solution that concentration is 8.0wt%,
Then above-mentioned solution is slowly dropped in the (+)-2,3-Epoxy-1-propanol of 11.84g (0.16mol), stirring reaction 3 hours at 40～50 DEG C.
Heating under reduced pressure removes solvent, is then vacuum dried to obtain water white transparency solid, obtains polyhydroxy cage-type silsesquioxane POSS-
(OH)32。
Oneself is interior to add polyhydroxy cage-type silsesquioxane 0.4g, D, L-lactide 1.44g and 10.26g in round-bottomed flask
Ester and zinc lactate 0.0176g.Evacuation-inflated with nitrogen, circulates three times, and the melted 5min of stirring under 135 DEG C of oil baths, then 135
24h is reacted at DEG C.The product dichloromethane obtained is dissolved, then precipitates with normal hexane, in triplicate, obtain light yellow liquid
Body, vacuum drying obtains star-like poly-(lactide-co-caprolactone)；
The end methoxy poly (ethylene glycol) 80g that number-average molecular weight is 700～800 is dissolved in dioxane, adds succinic anhydride
10g, obtains after reacting 8 hours holding methoxy poly (ethylene glycol) carboxylic acid at 45 DEG C, and it is standby that solution is cooled to room temperature.
In 100mL round-bottomed flask, add star-like poly-(lactide-co-caprolactone) obtained above 2.4g, hold methoxyl group
Polyethylene carboxylic acid 4.8g, add DMAP (DMAP) 1.5g, 1,3-dicyclohexyl carbodiimide (DCC)
1.8g, carries out being esterified coupling reaction, obtains unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer.
Poly-for unimolecule (lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer is dissolved in dioxane and is made into molten
Liquid, sucks this solution with syringe, is slowly dropped in ultra-pure water, loads in bag filter, after stirring 6 hours in ultra-pure water thoroughly
Analyse 3 days, within every 4 hours, change dialysis solution.By the nanoparticles solution lyophilization in bag filter, obtain unimolecule poly-(lactide-
Co-caprolactone)-b-Polyethylene Glycol nano-particle.
Embodiment 11:
Under room temperature, 18g deionized water, 8ml normal propyl alcohol, 2ml acetonitrile, 0.4ml tetraethyl ammonium hydroxide are added 100ml tri-
In mouth flask, stirring makes solution be sufficiently mixed.Then under violent stirring, slowly drip γ-aminopropyl three ethoxy of 44.2g
Base silane, dropping in 10 minutes is complete.Temperature is risen to 50 DEG C, after reacting 24 hours, is down to 25 DEG C.With oxolane, product is brilliant
Separate out to obtain white solid powder, then clean 3 sucking filtration with oxolane.Finally it is put in the vacuum tank of 100 DEG C drying.
8.88g (0.01mol) above-mentioned white powder is dissolved in dioxane, is made into the solution that concentration is 8.0wt%,
Then above-mentioned solution is slowly dropped in the (+)-2,3-Epoxy-1-propanol of 11.84g (0.16mol), stirring reaction 3 hours at 40～50 DEG C.
Heating under reduced pressure removes solvent, is then vacuum dried to obtain water white transparency solid, obtains polyhydroxy cage-type silsesquioxane POSS-
(OH)32。
Oneself is interior to add polyhydroxy cage-type silsesquioxane 0.5g, D, L-lactide 1.44g and 10.26g in round-bottomed flask
Ester and zinc lactate 0.0176g.Evacuation-inflated with nitrogen, circulates three times, and the melted 5min of stirring under 135 DEG C of oil baths, then 135
24h is reacted at DEG C.The product dichloromethane obtained is dissolved, then precipitates with normal hexane, in triplicate, obtain light yellow liquid
Body, vacuum drying obtains star-like poly-(lactide-co-caprolactone)；
The end methoxy poly (ethylene glycol) 80g that number-average molecular weight is 700～800 is dissolved in dioxane, adds succinic anhydride
10g, obtains after reacting 8 hours holding methoxy poly (ethylene glycol) carboxylic acid at 45 DEG C, and it is standby that solution is cooled to room temperature.
In 100mL round-bottomed flask, add star-like poly-(lactide-co-caprolactone) obtained above 2.4g, hold methoxyl group
Polyethylene carboxylic acid 4.8g, add DMAP (DMAP) 1.5g, 1,3-dicyclohexyl carbodiimide (DCC)
1.8g, carries out being esterified coupling reaction, obtains unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer.
Poly-for unimolecule (lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer is dissolved in dioxane and is made into molten
Liquid, sucks this solution with syringe, is slowly dropped in ultra-pure water, loads in bag filter, after stirring 6 hours in ultra-pure water thoroughly
Analyse 3 days, within every 4 hours, change dialysis solution.By the nanoparticles solution lyophilization in bag filter, obtain unimolecule poly-(lactide-
Co-caprolactone)-b-Polyethylene Glycol nano-particle.
Dissolving polymer samples with oxolane (THF), with THF for flowing phase, flow 1.0mL/min, with polystyrene
For standard specimen, measured the number-average molecular weight (M of poly-(lactide-co-caprolactone)-b-Polyethylene Glycol by GPC methodn) and Weight-average molecular
Amount (Mw) and polydispersity coefficient (Mw/Mn), table 1 is poly-(lactide-co-caprolactone) poly-second of-b-synthesized in embodiment 1-9
The molecular weight determination of glycol.
The molecular weight determination of table 1 poly-(lactide-co-caprolactone)-b-Polyethylene Glycol
Claims (9)
1. unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle, it is characterised in that by poly-(the third friendship
Ester-co-caprolactone)-b-Polyethylene Glycol star copolymer in aqueous by being self-assembly of, described poly-(lactide-co-
Caprolactone)-b-Polyethylene Glycol star copolymer is by polyhydroxy cage-type silsesquioxane POSS-(OH)32Cause lactide interior with oneself
After ester combined polymerization, then obtain with end methoxy poly (ethylene glycol) carboxylic acid coupling.
2. the preparation method of unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle, it is characterised in that
Comprise the following steps:
1) poly-for cage modle eight aminopropyl silsesquioxane is reacted in organic solvent with (+)-2,3-Epoxy-1-propanol, then precipitated product, be dried
After obtain described polyhydroxy cage-type silsesquioxane POSS-(OH)32；
2) with step 1) described polyhydroxy cage-type silsesquioxane POSS-(OH) that obtains32As initiator, add catalyst,
Cause the ring-opening polymerisation of lactide and caprolactone, obtain star-like poly-(lactide-co-caprolactone)；
3) obtain holding methoxy poly (ethylene glycol) carboxylic by end methoxy poly (ethylene glycol) and succinic anhydride ring-opening reaction in organic solvent
Acid, by described end methoxy poly (ethylene glycol) carboxylic acid and step 2) described star-like poly-(lactide-co-caprolactone) that obtain in catalysis
Carry out under agent and dehydrant effect being esterified coupling reaction, obtain unimolecule poly-(lactide-co-caprolactone)-b-Polyethylene Glycol star
Type copolymer；
4) by step 3) described unimolecule poly-(the lactide-co-caprolactone)-b-Polyethylene Glycol star copolymer that obtains is dissolved in and having
Machine solvent, obtains solution, is added drop-wise in ultra-pure water by described solution, dialyses, obtain described unimolecule after stirring in ultra-pure water
Poly-(lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle.
3. the preparation of unimolecule poly-(the lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle described in a claim 2
Method, it is characterised in that: in step 1) in, described cage modle eight poly-aminopropyl silsesquioxane and described (+)-2,3-Epoxy-1-propanol mole
Ratio is 1:16, and described organic solvent is dioxane or DMF, under agitation, reacts at 40～50 DEG C.
4. the preparation of unimolecule poly-(the lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle described in a claim 2
Method, it is characterised in that: in step 2) in, at 120-145 DEG C react, described catalyst is zinc lactate, described lactide with
The mol ratio of described caprolactone is 1:9-9:1.
5. the preparation of unimolecule poly-(the lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle described in a claim 2
Method, it is characterised in that: in step 2) in, described polyhydroxy cage-type silsesquioxane POSS-(OH)32With lactide and caprolactone
The mass ratio of weight sum be 1:39-1:23.
6. the preparation of unimolecule poly-(the lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle described in a claim 2
Method, it is characterised in that: in step 2) in, the consumption of described catalyst accounts for described lactide and caprolactone weight sum
0.15%.
7. the preparation of unimolecule poly-(the lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle described in a claim 2
Method, it is characterised in that: in step 3) in, described organic solvent is dioxane or DMF, described end methoxy poly (ethylene glycol)
Number-average molecular weight is 700-800, and described catalyst is DMAP, and described dehydrant is that 3-dicyclohexyl carbonization two is sub-
Amine, described star-like poly-(lactide-co-caprolactone) is 1:2 with the mass ratio of described end methoxy poly (ethylene glycol) carboxylic acid.
8. the preparation of unimolecule poly-(the lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle described in a claim 2
Method, it is characterised in that: in step 4) in, described organic solvent is dioxane or DMF.
9. poly-(lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle described in a claim 1, it is characterised in that:
Described poly-(lactide-co-caprolactone)-b-Polyethylene Glycol nano-particle is applied to prepare pharmaceutical carrier.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107022068A (en) * | 2017-04-27 | 2017-08-08 | 山西大学 | ε caprolactones and L lactides catalyst for copolymerization and copolymerization process |
| CN107793573A (en) * | 2017-10-13 | 2018-03-13 | 江南大学 | A kind of preparation of the amphiphilic star copolymer nano-micelle of hydridization |
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| CN101503497A (en) * | 2009-03-02 | 2009-08-12 | 江南大学 | Preparation of star type block acid sensitive nano micelle |
| CN102558464A (en) * | 2010-12-10 | 2012-07-11 | 江南大学 | Preparation method of star block copolymer temperature-sensitive nanomicelle |
| CN103073730A (en) * | 2012-12-27 | 2013-05-01 | 清华大学深圳研究生院 | CA-(PLA-ran-PLC-b-PEC) periodic copolymer and preparation method and application thereof |
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| CN101125926A (en) * | 2007-07-30 | 2008-02-20 | 中国医学科学院生物医学工程研究所 | Terminal amido group start-type poly (lactic-co-glycolic acid)/polyglycol block copolymer, preparation method, medicament-carried nano micelle and application |
| CN101503497A (en) * | 2009-03-02 | 2009-08-12 | 江南大学 | Preparation of star type block acid sensitive nano micelle |
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| CN103073730A (en) * | 2012-12-27 | 2013-05-01 | 清华大学深圳研究生院 | CA-(PLA-ran-PLC-b-PEC) periodic copolymer and preparation method and application thereof |
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| CN107022068B (en) * | 2017-04-27 | 2019-05-17 | 山西大学 | 6-caprolactone and L- lactide catalyst for copolymerization and copolymerization process |
| CN107793573A (en) * | 2017-10-13 | 2018-03-13 | 江南大学 | A kind of preparation of the amphiphilic star copolymer nano-micelle of hydridization |
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