CN108530642A - Miscellaneous arm star amphiphilic macromolecular material of biodegradable three block and preparation method thereof - Google Patents
Miscellaneous arm star amphiphilic macromolecular material of biodegradable three block and preparation method thereof Download PDFInfo
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Abstract
The invention discloses miscellaneous arm star amphiphilic macromolecular materials of a kind of biodegradable three block and preparation method thereof, with poly glycol monomethyl ether, L lactides, glycolide, ε caprolactones, the cyclic esters such as trimethylene carbonate and δ valerolactones are raw material, using the synthesis strategy of " core first ", poly glycol monomethyl ether terminal hydroxy group is modified first with benzyloxymethyl ethylene oxide, again using benzyloxymethyl ethylene oxide as initiator, cause different monomers ring-opening polymerisation successively, having finally obtained tool, there are three types of the miscellaneous arm Regular Star Polymers materials of three block of different macromolecular chains composition, a kind of miscellaneous arm star amphiphilic macromolecular medicine carrying material of biodegradable three block with higher researching value and application value is provided for Nano medication Transmission system.
Description
Technical field
The invention belongs to biomedical materials and biomedical engineering technology field, are related to biodegradable how miscellaneous arm star
Amphiphilic macromolecular material and its preparation.
Background technology
In recent ten years, the solution serious toxic side effect of chemotherapy that develops into of Nano medication Transmission system provides possibility,
Biodegradated polymer materal has become a kind of important Nano medication load due to its good degradability and biocompatibility
Body.General macromolecule medicine carrying material is that have shell core knot through what is be self-assembly of by amphiphilic (hydrophily and lipophile) macromolecule
The nano-particle of structure, chemotherapeutics can be supported in the hydrophobic core of high molecular material.Macromolecule medicine carrying material can not only be escaped
Human endothelium's network (Reticulo-endothelial System, RES) swallows, while can also utilize tumor tissues
The high-permeability and retention effect (Enhanced Permeability And retention effect, EPR) of blood vessel are passive
Targeting gathers tumor tissues, to reduce the dosage and number of chemotherapeutics, reduces toxic side effect, improves curative effect.Three
Functional group point of the miscellaneous arm star amphiphilic macromolecular material of block because of its unique material morphology, lower viscosity, higher density
Cloth, smaller hydrodynamic radius, higher stability and higher drugloading rate and as research macromolecule medicine carrying material it is new
Hot spot, but because its unique chemical constitution causes its preparation difficulty big compared with traditional Linear block amphiphilic macromolecular material.
Due to identical in arm number, miscellaneous arm Regular Star Polymers material of the preparation containing at least two identical macromolecule arms
The difficulty of material is less than the difficulty prepared per the entirely different Regular Star Polymers material of arm, therefore the miscellaneous arm star prepared at present is high
Molecular material is mostly the miscellaneous arm Regular Star Polymers material at least containing two identical macromolecule arms.Application No. is
The patent application document of CN201310685017.0 discloses a kind of thermosensitive miktoarm star high molecular emulsifier and its preparation side
Method polymerize (Reversible Addition- using the synthetic method of " core after first arm " by reversible addion-fragmentation chain transfer
Fragmentation Chain Transfer Polymerization, RAFT) method, by thermoresponsive linear arms and
Water soluble polymer linear arms are prepared for having the core of Thermo-sensitive to be crosslinked miscellaneous arm macromolecule emulsifier by heteropolymerization crosslinking agent；
Although what is prepared is 10 arm Regular Star Polymers materials, what be there are in fact is still that (thermal sensitivity is high for two kinds of macromolecule arm
Molecule linear arms and water soluble polymer linear arms), each type macromolecule arm quantity is five.Application No. is
CN201310085237.X patent application documents disclose the miscellaneous arm star polymer of the crosslinked multiple response of a seed nucleus and its preparation
Method polymerize (Reversible Addition- using the synthetic method of " core first " by reversible addion-fragmentation chain transfer
Fragmentation Chain Transfer Polymerization, RAFT) method, using crosslinking agent as core, temperature-responsive
Under initiator effect, polymerization obtains that there is temperature-responsive and the core of pH responses to be crosslinked miscellaneous arm star for arm and pH responses arm
Macromolecule (arm number is 6-10), but what be there are in fact is still two kinds of macromolecule arm (temperature-responsive arm and pH responses
Property arm).
And in the patent of a small number of Regular Star Polymers materials for preparing and being different from per arm, mostly contain and biological can not drop
The case where macromolecular chain of solution, such as application No. is CN200410017531.8 patent application documents, to disclose a kind of (ABC) S types miscellaneous
Arm star polymer and preparation method thereof, using the synthetic method of " core after first arm ", by there are three three kinds of different macromolecule arms and tools
Lysine of functional group or derivatives thereof couples obtain one by one；On the one hand its used undesirable bio-compatible of macromolecule arm
Property, makes it have biological non-biodegradable, this will limit its application in Nano medication Transmission system field, on the other hand due to
It needs first to be modified macromolecule arm using " core after first arm " synthesis strategy, again then be coupled to lysine or its
On derivative, preparation process is relatively cumbersome.
Invention content
The purpose of the present invention be intended to for the above-mentioned prior art in deficiency, providing one kind for Nano medication Transmission system can
The biodegradable miscellaneous arm star amphiphilic macromolecular material of three block, is made of the macromolecular chain of three sections of different structure units.
Another object of the present invention is intended to provide a kind of miscellaneous amphiphilic high score of arm star of above-mentioned biodegradable three block
The preparation method of sub- material, to simplify preparation flow, shorten the production cycle.
The miscellaneous arm star amphiphilic macromolecular material of biodegradable three block of the present invention, chemical constitution are as follows：
In formula, A chains are poly glycol monomethyl ether, and the homopolymer or total that B chains, C chains are different Biodegradable polyesters
Polymers.The B chains, C chains cause ring-opening polymerization by hydroxyl and are grafted on A chains.It is provided by the invention biodegradable
The miscellaneous arm star amphiphilic macromolecular material of three block, the miscellaneous arm star structure for having three polymer chain structure units different,
There is lower critical materials concentration and higher drugloading rate after forming micella in water；Poly glycol monomethyl ether simultaneously, for parent
Water chain；B chains, C chains be by the cyclic esters such as L- lactides, glycolide, 6-caprolactone, trimethylene carbonate, δ-valerolactone extremely
A kind of few monomer ring-opening polymerisation forms, and is hydrophobic chain, to assign high molecular material amphiphatic property, therefore the macromolecule material
Material is a kind of with high stability, high drug load, the macromolecule medicine carrying material compared with small particle.
The preparation method of the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block of the present invention, with L- third
The cyclic ester monomers such as lactide, glycolide, 6-caprolactone, trimethylene carbonate, δ-valerolactone and poly glycol monomethyl ether
(mPEG) it is used as raw material, using the strategy of " core first ", biodegradable miscellaneous arm star is made with the method for ring-opening polymerization
Shape high score material.Poly glycol monomethyl ether and benzyloxymethyl reacting ethylene oxide first, benzyloxymethyl ethylene oxide open loop grafting
Onto poly glycol monomethyl ether hydroxyl, to carry out terminal groups modification to poly glycol monomethyl ether, it is grafted to poly glycol monomethyl ether
On benzyloxymethyl ethylene oxide cause successively the first monomer (or the monomer composition being made of the first monomer and second comonomer),
Ring-opening polymerization occurs for Third monomer (or monomer composition by Third monomer and the 4th monomer composition), embedding to obtain three
The miscellaneous arm star amphiphilic macromolecular material of section；It is as follows：
(1) terminal groups modification of mPEG
Under nitrogen protection, by the organic solution of the poly glycol monomethyl ether of a concentration of 0.05~0.27g/mL and benzyloxy first
Hexadecyl ethylene oxide is mixed to get the first mixed liquor, and then under ice bath, stirring condition, three second are instilled into the first mixed liquor of gained
Gained reaction system is stirred to react 1~3 day by the organic solution of amine after being added dropwise in 25~50 DEG C；After reaction, it rotates
Gained reaction solution to viscous pasty state obtains the first viscous mixture, then the first viscous mixture is instilled in the second organic solvent and is sunk
It forms sediment, gained sediment obtains solid powder through filtering, being dried in vacuo；Poly glycol monomethyl ether, benzyloxy first in the reaction system
The molar ratio of hexadecyl ethylene oxide and triethylamine is 1:(1~10):(1~10)；
(2) A-B di-block copolymers are prepared
By step (1) obtained solid product and the first monomer or the monomer composition being made of the first monomer and second comonomer
It is added in closed reaction vessel, then the stannous octoate toluene that dropwise addition weight concentration is 0.05~2% into closed reaction vessel is molten
Liquid, then vacuum drying removes toluene, and is stirred to react 1~3 day in 90~200 DEG C；After reaction, products therefrom is dissolved in
In third organic solvent, then acquired solution is rotated to viscous pasty state and obtains the second viscous mixture, it is sticky mixed by second later
It closes and is precipitated in object the 4th organic solvent of instillation, gained sediment obtains solid powder through filtering, being dried in vacuo；The step (1)
Obtained solid product and the first monomer are (1~10) by the monomer composition weight ratio that the first monomer and second comonomer form:
(10~1), the stannous octoate toluene solution weight be step (1) obtained solid product and the first monomer or by the first monomer and
The 0.01~1% of the monomer composition weight of second comonomer composition；
(3) B terminal hydroxy groups are protected
Under ice bath, stirring condition, to the step of a concentration of 0.08~0.25g/mL (2) obtained solid product it is organic molten
Gained reaction system, is stirred to react 1~3 day by the organic solution that chloroacetic chloride is instilled in liquid after being added dropwise in 25~50 DEG C；Instead
After answering, revolving gained reaction solution to viscous pasty state obtains third viscous mixture, then third viscous mixture is instilled the
It is precipitated in six organic solvents, gained sediment obtains solid powder through filtering, being dried in vacuo；Step (2) in the reaction system
The molar ratio of obtained solid product and chloroacetic chloride is 1:(1~10)；
(4) B-A-OH is prepared
By the organic solution of (3) obtained solid product the step of a concentration of 0.067~0.3g/mL and a concentration of 0.002~
The organic dispersions of the palladium carbon of 0.06g/mL are added in reaction kettle, and 2~5atm hydrogen is passed through into reaction kettle, and stirring is anti-later
It answers 1~3 day, filters out the palladium carbon in gained reaction solution after reaction, and reaction solution is obtained into solid through being spin-dried for, being dried in vacuo
Powder；The palladium carbon dosage is the 0.5~10% of step (3) obtained solid products weight；
(5) B-A-C triblock copolymers are prepared
By step (4) obtained solid product, Third monomer or monomer composition by Third monomer and the 4th monomer composition
It is added in closed reaction vessel, then the stannous octoate toluene that dropwise addition weight concentration is 0.05~2% into closed reaction vessel is molten
Liquid, then vacuum drying removes toluene, and is stirred to react 1~3 day in 90~200 DEG C；After reaction, products therefrom is dissolved in
In third organic solvent, then acquired solution is rotated to viscous pasty state and obtains the 4th viscous mixture, it is sticky mixed by the 4th later
It closes and is precipitated in object the 4th organic solvent of instillation, gained sediment is purified to obtain the miscellaneous arm star parents of biodegradable three block
Property high molecular material；Step (4) the obtained solid product and Third monomer or the list by Third monomer and the 4th monomer composition
Body composition weight ratio is (1~10)：(10:1), the stannous octoate toluene solution weight is step (4) obtained solid product
With Third monomer or by the 0.01~1% of Third monomer and the monomer composition weight of the 4th monomer composition.
The preparation method of the above-mentioned miscellaneous arm star amphiphilic macromolecular material of biodegradable three block, the step (1)
Purpose be to be modified to poly glycol monomethyl ether end group, the present invention in using benzyloxymethyl ethylene oxide to polyethyleneglycol
Methyl ether end group is modified, and ring-opening polymerization occurs for benzyloxymethyl ethylene oxide and poly glycol monomethyl ether, makes benzyloxymethyl
On ethylene oxide graft to poly glycol monomethyl ether terminal hydroxy group, using benzyloxymethyl ethylene oxide as three block macromolecular chain
Core, while benzyloxymethyl ethylene oxide causes the first monomer as initiator and (or is made of the first monomer and second comonomer successively
Monomer composition) or Third monomer (or monomer composition by Third monomer and the 4th monomer composition) occur polymerisation.
In step (1), the organic solution preparation process of the poly glycol monomethyl ether is：Under nitrogen protection, by vacuum drying gained
Poly glycol monomethyl ether, which is dissolved in the first organic solvent, obtains the organic solution of poly glycol monomethyl ether；The triethylamine it is organic
Solution is to be uniformly mixed to obtain with the first organic solvent by triethylamine, and the volume ratio of triethylamine and the first organic solvent is 1：(2.4
~26.8)；First organic solvent is one kind in dichloromethane, chloroform, dimethylformamide, tetrahydrofuran；Described
Two organic solvents are ether or petroleum ether, in order to keep the first viscous mixture precipitation complete, the second organic solvent and first sticky
Volume of mixture ratio >=10:1.
The preparation method of the above-mentioned miscellaneous arm star amphiphilic macromolecular material of biodegradable three block, the step (2)
Purpose be after benzyloxymethyl ethylene oxide is reacted with poly glycol monomethyl ether under the initiation of products therefrom terminal hydroxyl,
Make the first monomer (or the monomer composition being made of the first monomer and second comonomer) that ring-opening polymerization occur, obtains A-B two
Block copolymer.In order to avoid the influence of water, by step (1) obtained solid product, first monomer or by the first monomer and second
After the monomer composition of monomer composition is added in closed reaction vessel, prior to 50~120 DEG C at be dried in vacuo 1~5h, then be added dropwise
Stannous octoate toluene solution.The third organic solvent is one in dichloromethane, chloroform, dimethylformamide, tetrahydrofuran
Kind, dosage is to keep products therefrom dissolving complete；4th organic solvent is one kind in methanol, ether, petroleum ether；In order to
Keep the second viscous mixture precipitation complete, the 4th organic solvent and the second viscous mixture volume ratio >=10:1.
The preparation method of the above-mentioned miscellaneous arm star amphiphilic macromolecular material of biodegradable three block, the step (3)
Purpose be to protect B terminal hydroxy groups in A-B di-block copolymers that step (2) obtains so that only also by benzyloxy
The hydroxyl that original obtains causes Third monomer (or monomer composition by Third monomer and the 4th monomer composition) and ring-opening polymerisation occurs,
It avoids generating three block linear polymeric material there is a situation where polymerisation by B terminal hydroxy groups initiation monomer, so that it is guaranteed that
Obtain the miscellaneous arm Regular Star Polymers material of target product-ABC types.In the step (3), step (2) obtained solid product it is organic
Solution preparation process is：Under nitrogen protection, vacuum dried step (2) obtained solid is dissolved in the 5th organic solvent and is obtained
It arrives；The organic solution of step (3) chloroacetic chloride is to be uniformly mixed to obtain by chloroacetic chloride and the 5th organic solvent, chloroacetic chloride and the
Five organic solvent volume ratios are (1~17.5)：250；5th organic solvent be dichloromethane, chloroform, dimethylformamide,
One kind in tetrahydrofuran；6th organic solvent is one kind in methanol, ether, petroleum ether, in order to keep third sticky mixed
It is complete to close object precipitation, the 6th organic solvent and third viscous mixture volume ratio >=10:1.
The preparation method of the above-mentioned miscellaneous arm star amphiphilic macromolecular material of biodegradable three block, the step (4)
Purpose be the benzyloxy in A-B di-block copolymers being reduced into hydroxyl, in order to cause Third monomer (or by third list
The monomer composition of body and the 4th monomer composition) ring-opening polymerization occurs.The present invention is using hydrogen reduction method, step
(3) organic solution of obtained solid product is to be dissolved in the 7th organic solvent by vacuum dried step (3) obtained solid product
In obtain, the organic dispersions of palladium carbon, which are distributed to by palladium carbon in the 7th organic solvent, to be obtained；7th organic solvent is dichloro
One kind in methane, chloroform, dimethylformamide, tetrahydrofuran.
The preparation method of the above-mentioned miscellaneous arm star amphiphilic macromolecular material of biodegradable three block, the step (5)
Purpose be that the hydroxyl made of hydrogen reducing causes Third monomer or by Third monomer and the 4th monomer composition in step (4)
Ring-opening polymerisation occurs for monomer composition, obtains B-A-C three block radial copolymers.In order to avoid the influence of water, by step (4) institute
After obtaining solid product, Third monomer or closed reaction vessel being added by Third monomer and the monomer composition of the 4th monomer composition,
It is dried in vacuo 1~5h at prior to 50~120 DEG C, then stannous octoate toluene solution is added dropwise.The third organic solvent is dichloromethane
One kind in alkane, chloroform, dimethylformamide, tetrahydrofuran, dosage are to keep products therefrom dissolving complete；Described 4th is organic
Solvent is one kind in methanol, ether, petroleum ether；In order to keep the 4th viscous mixture precipitation complete, the 4th organic solvent
With the 4th viscous mixture volume ratio >=10:1.In order to improve the purity of products therefrom, need to by dope gained sediment
It is purified, concrete mode is：Gained sediment is dissolved in tetrahydrofuran first, then instills acquired solution under stirring
In water, continue stirring and be precipitated completely to impurity, be centrifuged off impurity not soluble in water, gained supernatant is freeze-dried, and obtain can
The biodegradable miscellaneous arm star amphiphilic macromolecular material of three block；The dosage of the tetrahydrofuran is that gained precipitation is made to have dissolved
Entirely；The water and tetrahydrofuran volume ratio >=10:1.Purified obtained product is spongy solid, which is
The freeze-drying micella of the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block, micella have more as medicine-carried system
Low critical materials concentration and higher drugloading rate can effectively avoid liver, spleen etc. since its size is similar to virus and lipoprotein
Netted dermal system swallows, and the long period is present in blood circulation, discharges drug, therefore extends drug to a certain extent and exist
Internal half-life period.
The preparation method of the above-mentioned miscellaneous arm star amphiphilic macromolecular material of biodegradable three block, the step (2)
Must be carried out in the closed reaction vessel of anaerobic with the reaction vessel used in step (5), can also may be used with selective polymerization pipe
To select autoclave；According to polymerization pipe, needed after removing toluene in step (2) and step (5), by polymerization pipe into
Row tube sealing, then reaction is stirred under the conditions of being placed in 90~200 DEG C.
The preparation method of the above-mentioned miscellaneous arm star amphiphilic macromolecular material of biodegradable three block, described first is single
Body, second comonomer, Third monomer and the 4th monomer are L- lactides, glycolide, 6-caprolactone, trimethylene carbonate, δ-penta
One kind in lactone, and the first monomer is different monomers from Third monomer.
The preparation method of the above-mentioned miscellaneous arm star amphiphilic macromolecular material of biodegradable three block, in each step
First organic solvent, third organic solvent and the 5th organic solvent are identical or different, and second organic solvent, the 4th have
Solvent and the 6th organic solvent are identical or different.
The preparation method of the above-mentioned miscellaneous arm star amphiphilic macromolecular material of biodegradable three block relates in each step
And to be stirred to react, can its purpose is to make reaction solution be sufficiently mixed, can pass through magnetic agitation (before reactions will
Magnetic stick is positioned in reaction vessel) it realizes.
The preparation method of the above-mentioned miscellaneous arm star amphiphilic macromolecular material of biodegradable three block, step (1) and step
Suddenly in (3), catalyst is instilled under condition of ice bath, its purpose is to reduce initial reaction rate, side reaction is prevented to reach
The purpose of generation.
Compared with prior art, the invention has the advantages that：
1, the miscellaneous arm star amphiphilic macromolecular material of three block provided by the invention, is by the height of three sections of different structure units
The miscellaneous arm star structure of three block of strand (A chains, B chains and C chains) composition, wherein A chains are poly glycol monomethyl ether, are had hydrophilic
Property；B chains and C chains by the cyclic esters such as L- lactides, glycolide, 6-caprolactone, trimethylene carbonate and delta-lactone homopolymer or
Copolymer has hydrophobicity, and B chains are different from C chains, while A, B, C are biodegradable high molecular material, to be to receive
Rice drug delivery system provides a kind of miscellaneous arm star of biodegradable three block with higher researching value and application value
Shape amphiphilic macromolecular medicine carrying material；
2, the preparation method of the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block provided by the invention, is adopted
With the synthesis strategy of " core first ", the upper benzyloxymethyl ethylene oxide of grafting is modified to poly glycol monomethyl ether terminal hydroxy group first,
Using benzyloxymethyl ethylene oxide as core, while it is poly- to cause different monomers open loop as initiator successively for benzyloxymethyl ethylene oxide
It closes, having finally obtained tool, there are three types of the miscellaneous arm Regular Star Polymers materials of three block of different macromolecular chains composition；Compared to existing
The synthesis strategy of " core after first arm ", simplifies preparation flow, shortens the production cycle, to reduce synthesis cost；
3, the preparation method of the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block provided by the invention,
Before second is caused monomer ring-opening polymerisation, monomer polymerization products therefrom terminal hydroxy group first is caused to first time and is protected, is avoided
The case where monomer polymerization is caused by the terminal hydroxy group of products therefrom macromolecular chain and generates three block linear polymeric material, to protect
Demonstrate,prove the correctness of final goal product structure.
Description of the drawings
Fig. 1 is the synthetic route that the present invention prepares the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block
Figure.
Fig. 2 is the core of the miscellaneous arm star amphiphilic macromolecular material of PCL-PEG-PLLA biodegradation three blocks obtained by embodiment
Magnetic spectrum figure.
Fig. 3 is the row of the miscellaneous arm star amphiphilic macromolecular material of PCL-PEG-PLLA biodegradation three blocks obtained by embodiment
Anti-coagulating action glue chromatogram.
Specific implementation mode
Clear, complete description is carried out to the technical solution of various embodiments of the present invention below with reference to attached drawing, it is clear that retouched
A part of the embodiment that embodiment is only the present invention is stated, instead of all the embodiments.Based on the embodiments of the present invention, originally
Field those of ordinary skill obtained all other embodiment without making creative work, belongs to this hair
Bright protected range.
The synthetic route provided by the invention for preparing the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block
Figure is as shown in Figure 1, poly glycol monomethyl ether and benzyloxymethyl reacting ethylene oxide, benzyloxymethyl ethylene oxide open loop first is grafted
Onto poly glycol monomethyl ether hydroxyl, to carry out terminal groups modification to poly glycol monomethyl ether, it is grafted to poly glycol monomethyl ether
On benzyloxymethyl ethylene oxide cause successively the first monomer (or the monomer composition being made of the first monomer and second comonomer),
Ring-opening polymerization occurs for Third monomer (or monomer composition by Third monomer and the 4th monomer composition), embedding to obtain three
The miscellaneous arm star amphiphilic macromolecular material of section.With reference to 1 to 4 pair of above-mentioned miscellaneous arm star of biodegradable three block of embodiment
The preparation process of amphiphilic macromolecular material carries out clear, complete description.
Embodiment 1
Manufactured in the present embodiment is the miscellaneous arm star amphiphilic macromolecular material of PCL-PEG-PLLA biodegradation three blocks, system
It is standby that steps are as follows：
(1) terminal groups modification of mPEG
First lead to 5 minutes nitrogen, then under nitrogen protection, the polyethyleneglycol first after 6g is dried in vacuo into branch mouth bottle
Ether (Mn=2000) is added in branch mouth bottle, and 30ml dichloromethane is added, and stirring obtains the two of poly glycol monomethyl ether to dissolving
Chloromethanes solution；Backward poly glycol monomethyl ether dichloromethane solution in be added 2.29mL benzyloxymethyl ethylene oxide mixing
The first mixed liquor is obtained, then under the conditions of ice bath, magnetic agitation, the dichloromethane of triethylamine is instilled into the first mixed liquor of gained
Alkane solution (is uniformly mixed by 4.17mL triethylamines and 10mL dichloromethane and is obtained), and branch mouth bottle is moved into 30 DEG C of oil after being added dropwise
In bath, magnetic agitation is reacted 3 days；After reaction, revolving gained reaction solution to viscous pasty state obtains the first viscous mixture, then
First viscous mixture 15mL is instilled in 200mL ether and is precipitated, gained sediment obtains 5.9g whites through filtering, being dried in vacuo
Solid powder；
(2) PCL-mPEG di-block copolymers are prepared
3g steps (1) obtained solid product and 3g 6-caprolactones are added in polymerization pipe, are dried in vacuo in 80 DEG C of oil baths
Then 1h removes oil bath, then the stannous octoate toluene solution that 0.6mg weight concentrations are 0.1wt% is added dropwise into polymerization pipe, so
Vacuum drying removes toluene afterwards, and by polymerization pipe tube sealing, and magnetic agitation is reacted 2 days in 120 DEG C of oil baths；After reaction, will
Products therefrom is dissolved in 100mL dichloromethane, then acquired solution is rotated to viscous pasty state and obtains the second viscous mixture, by
The total 5mL of two viscous mixtures, which is instilled in 150mL methanol, to be precipitated, and gained sediment obtains 5.8 white solids through filtering, being dried in vacuo
Powder；
(3) PCL terminal hydroxy groups in PCL-mPEG are protected
First lead to 5 minutes nitrogen into branch mouth bottle, then under nitrogen protection, obtained by step (2) vacuum dried 5g
Solid (molecular weight is 4000 or so) is added in branch mouth bottle, and 20mL chloroforms are added, and stirring to dissolving obtains solid obtained by step (2)
The chloroformic solution of body；Under the conditions of ice bath, magnetic agitation, acetyl is instilled into the chloroformic solution of step (2) obtained solid product
The chloroformic solution (be uniformly mixed and obtained by 0.1mL chloroacetic chlorides and 20mL chloroforms) of chlorine, moves into branch mouth bottle in 25 after being added dropwise
It is reacted 3 days in DEG C oil bath；After reaction, revolving gained reaction solution to viscous pasty state obtains third viscous mixture, then by the
The total 20mL of three viscous mixtures is instilled in 350mL ether and is precipitated, and gained sediment is solid through filtering, being dried in vacuo to obtain 4.6g whites
Body powder；
(4) PCL-mPEG-OH is prepared
3g steps (3) obtained solid is dissolved in 10mL dichloromethane, while 0.3g palladium carbons are evenly spread into 10mL
In dichloromethane, then the dichloromethane dispersion liquid of the dichloromethane solution of step (3) obtained solid and palladium carbon is added to instead
It answers in kettle, it is 3atm that pressure in hydrogen to kettle is passed through into reaction kettle, puts reaction kettle stirred as on magnetic stirring apparatus later
Reaction 1 day filters out the palladium carbon in gained reaction solution, and reaction solution is obtained 2.7g through being spin-dried for, being dried in vacuo after reaction
White solid powder；
(5) it is the miscellaneous arm star amphiphilic macromolecular material of PCL-PEG-PLLA biodegradation three blocks to prepare
2g steps (4) obtained solid product and 1g L- lactides are added in polymerization pipe, then are added dropwise into polymerization pipe
0.3mg weight concentrations are the stannous octoate toluene solution of 0.1wt%, and then vacuum drying removes toluene, by polymerization pipe tube sealing, and
Magnetic agitation is reacted 2 days in 120 DEG C of oil baths；After reaction, obtained solid is dissolved in 100mL dichloromethane, then by institute
Solution rotates to viscous pasty state and obtains the 4th viscous mixture, will the total 8mL of the 4th viscous mixture instill it is heavy in 200mL methanol
It forms sediment, gained sediment is finally dissolved in 30mL tetrahydrofurans, instill acquired solution in 2000mL water under stirring, continue
Stirring is precipitated completely to impurity, is centrifuged off impurity not soluble in water, and gained supernatant is freeze-dried to obtain 2.6g whites sea
Continuous shape solid, the as described miscellaneous arm Regular Star Polymers material.
The miscellaneous arm star amphiphilic macromolecular material of PCL-PEG-PLLA biodegradation three blocks that the present embodiment is obtained into
Row nuclear magnetic resonance tests (test condition 400MHz1H NMR,CDCl3For solvent), obtained nuclear magnetic spectrogram as shown in Fig. 2, from
As can be seen that chemical shift belongs to the hydrogen atom of poly glycol monomethyl ether segment in the proton peak of 3.35 and 3.7ppm in Fig. 2,
The proton peak of PCL segments appears at 1.4,1.7,2.3 and 4.1ppm；The proton peak of PLLA segments appears in 1.6 and 5.2ppm
Place.The molecular weight that above-mentioned high molecular material is calculated according to proton peak integral area is the PCL-PEG-PLLA molecules of 5979 and design
Amount 6000 is very close, it can be seen that, the 1 miscellaneous arm Regular Star Polymers material of gained of embodiment meets target product.
The miscellaneous arm star amphiphilic macromolecular material of PCL-PEG-PLLA biodegradation three blocks obtained by the present embodiment is carried out
The test of molecular weight distribution, gained exclusion Gel chromatogram is as shown in figure 3, as can be seen from the figure its PDI (Polymer
Dispersity index) it is 1.21, illustrate that molecular weight distribution is very narrow, the performances such as drugloading rate and grain size to high molecular material
Influence very little.
Embodiment 2
Manufactured in the present embodiment is the miscellaneous arm star amphiphilic macromolecular material of PCL-PEG-PGA biodegradation three blocks, system
It is standby that steps are as follows：
(1) terminal groups modification of mPEG
First lead to 10 minutes nitrogen, then under nitrogen protection, the polyethyleneglycol after 8g is dried in vacuo into branch mouth bottle
Methyl ether (Mn=2000) is added in branch mouth bottle, and 30ml chloroforms are added, and stirring obtains the chloroform of poly glycol monomethyl ether to dissolving
Solution；Backward poly glycol monomethyl ether chloroformic solution in 0.61mL benzyloxymethyl ethylene oxide is added to be mixed to get first mixed
Close liquid, then under the conditions of ice bath, magnetic agitation, into the first mixed liquor of gained instill triethylamine chloroformic solution (by
0.56mL triethylamines and 15mL chloroforms, which are uniformly mixed, to be obtained), branch mouth bottle is moved into 50 DEG C of oil baths after being added dropwise, magnetic agitation
Reaction 1 day；After reaction, revolving gained reaction solution to viscous pasty state obtains the first viscous mixture, then sticky mixed by first
It closes and is precipitated in the total 20mL instillations 500mL ether of object, gained sediment obtains 7.7g white solid powders through filtering, being dried in vacuo；
(2) PCL-mPEG di-block copolymers are prepared
4g steps (1) obtained solid product and 40g 6-caprolactones are added in polymerization pipe, vacuum is dry in 120 DEG C of oil baths
Then dry 1h removes oil bath, then the stannous octoate toluene solution that 0.44g weight concentrations are 0.05wt% is added dropwise into polymerization pipe,
Then vacuum drying removes toluene, and by polymerization pipe tube sealing, and magnetic agitation is reacted 1 day in 200 DEG C of oil baths；After reaction,
Products therefrom is dissolved in 600mL dichloromethane, then acquired solution is rotated to viscous pasty state and obtains the second viscous mixture, it will
The total 50mL of second viscous mixture, which is instilled in 750mL ether, to be precipitated, and gained sediment obtains 41.8 whites through filtering, being dried in vacuo
Solid powder；
(3) PCL terminal hydroxy groups in PCL-mPEG are protected
First lead to 10 minutes nitrogen into branch mouth bottle, then under nitrogen protection, by step (2) institute vacuum dried 4.4g
It obtains solid (molecular weight is 22000 or so) to be added in branch mouth bottle, and 30mL DMF is added, stirring to dissolving obtains step (2) institute
Obtain the DMF solution of solid；Under the conditions of ice bath, magnetic agitation, second is instilled into the DMF solution of step (2) obtained solid product
The DMF solution (be uniformly mixed and obtained by 0.14mL chloroacetic chlorides and 10mL DMF) of acyl chlorides, after being added dropwise by branch mouth bottle move into
It is reacted 3 days in 40 DEG C of oil baths；After reaction, revolving gained reaction solution to viscous pasty state obtains third viscous mixture, then will
The total 10mL of third viscous mixture, which is instilled in 150mL ether, to be precipitated, and gained sediment obtains 4.2g whites through filtering, being dried in vacuo
Solid powder；
(4) PCL-mPEG-OH is prepared
4g steps (3) obtained solid is dissolved in 50mL dichloromethane, while 0.2g palladium carbons are evenly spread into 10mL
In dichloromethane, then the dichloromethane dispersion liquid of the dichloromethane solution of step (3) obtained solid and palladium carbon is added to instead
It answers in kettle, it is 2atm that hydrogen to air pressure is passed through into reaction kettle, later by reaction kettle as being stirred to react 3 on magnetic stirring apparatus
It, filters out the palladium carbon in gained reaction solution, and reaction solution is consolidated through being spin-dried for, being dried in vacuo obtaining 3.9g whites after reaction
Body powder；
(5) the miscellaneous arm star amphiphilic macromolecular material of PCL-PEG-PGA biodegradation three blocks is prepared
3g steps (4) obtained solid product and 3g glycolides are added in polymerization pipe, then 0.06g weights are added dropwise into polymerization pipe
The stannous octoate toluene solution of a concentration of 0.05wt% is measured, then vacuum drying removes toluene, by polymerization pipe tube sealing, and in 200
Magnetic agitation is reacted 1 day in DEG C oil bath；After reaction, obtained solid is dissolved in 150mL dichloromethane, then by acquired solution
Revolving to viscous pasty state obtains the 4th viscous mixture, and the total 18mL of the 4th viscous mixture is instilled in 250mL ether and is precipitated, most
Gained sediment is dissolved in 60mL tetrahydrofurans afterwards, instills acquired solution in 600mL water under stirring, continues stirring extremely
Impurity is precipitated completely, is centrifuged off impurity not soluble in water, and the freeze-dried 5.7g white sponges that obtain of gained supernatant are consolidated
Body, the as described miscellaneous arm Regular Star Polymers material.
Embodiment 3
Manufactured in the present embodiment is the miscellaneous arm star amphiphilic macromolecular material of PVL-PEG-PLLA biodegradation three blocks, system
It is standby that steps are as follows：
(1) terminal groups modification of mPEG
First lead to 3 minutes nitrogen, then under nitrogen protection, the polyethyleneglycol first after 5g is dried in vacuo into branch mouth bottle
Ether (Mn=5000) is added in branch mouth bottle, and 100ml tetrahydrofurans are added, and stirring obtains poly glycol monomethyl ether to dissolving
Tetrahydrofuran solution；Backward poly glycol monomethyl ether tetrahydrofuran solution in that 1.52mL benzyloxymethyl ethylene oxide is added is mixed
Conjunction obtains the first mixed liquor, and then under the conditions of ice bath, magnetic agitation, the tetrahydrochysene of triethylamine is instilled into the first mixed liquor of gained
Tetrahydrofuran solution (is uniformly mixed by 1.39mL triethylamines and 10mL tetrahydrofurans and is obtained), and branch mouth bottle is moved into 25 DEG C after being added dropwise
In oil bath, magnetic agitation is reacted 2 days；After reaction, revolving gained reaction solution to viscous pasty state obtains the first viscous mixture,
The total 7mL of the first viscous mixture is instilled in 200mL petroleum ethers again and is precipitated, gained sediment is obtained through filtering, being dried in vacuo
4.9g white solid powder；
(2) PVL-mPEG di-block copolymers are prepared
4g steps (1) obtained solid product and 0.8g δ-valerolactones are added in polymerization pipe, vacuum is dry in 50 DEG C of oil baths
Then dry 5h removes oil bath, then the stannous octoate toluene solution that 0.48mg weight concentrations are 2wt% is added dropwise into polymerization pipe, so
Vacuum drying removes toluene afterwards, and by polymerization pipe tube sealing, and magnetic agitation is reacted 3 days in 90 DEG C of oil baths；After reaction, by institute
It obtains product to be dissolved in 200mL tetrahydrofurans, then acquired solution is rotated to viscous pasty state and obtains the second viscous mixture, by second
The total 10mL of viscous mixture, which is instilled in 200mL methanol, to be precipitated, and gained sediment obtains 7.9 white solids through filtering, being dried in vacuo
Powder；
(3) PVL terminal hydroxy groups in PVL-mPEG are protected
First lead to 3 minutes nitrogen into branch mouth bottle, then under nitrogen protection, obtained by step (2) vacuum dried 3g
Solid (molecular weight is 6000 or so) is added in branch mouth bottle, and 30mL chloroforms are added, and stirring to dissolving obtains solid obtained by step (2)
The chloroformic solution of body；Under the conditions of ice bath, magnetic agitation, acetyl is instilled into the chloroformic solution of step (2) obtained solid product
The chloroformic solution (be uniformly mixed and obtained by 0.04mL chloroacetic chlorides and 10mL chloroforms) of chlorine, moves into branch mouth bottle in 50 after being added dropwise
It is reacted 1 day in DEG C oil bath；After reaction, revolving gained reaction solution to viscous pasty state obtains third viscous mixture, then by the
The total 10mL of three viscous mixtures is instilled in 100mL methanol and is precipitated, and gained sediment is solid through filtering, being dried in vacuo to obtain 2.8g whites
Body powder；
(4) PVL-mPEG-OH is prepared
2g steps (3) obtained solid is dissolved in 30mL DMF, while 0.01g palladium carbons are evenly spread into 5mL DMF
In, then the DMF dispersion liquids of the DMF solution of step (3) obtained solid and palladium carbon are added in reaction kettle, are led into reaction kettle
It is 5atm to enter hydrogen to air pressure, and reaction kettle is filtered out institute after reaction as being stirred to react on magnetic stirring apparatus 2 days later
The palladium carbon in reaction solution is obtained, and reaction solution is obtained into 1.8g white solid powders through being spin-dried for, being dried in vacuo；
(5) it is the miscellaneous arm star amphiphilic macromolecular material of PVL-PEG-PLLA biodegradation three blocks to prepare
1g steps (4) obtained solid product and 0.1g L- lactides are added in polymerization pipe, then are added dropwise into polymerization pipe
0.11mg weight concentrations are the stannous octoate toluene solution of 2wt%, and then vacuum drying removes toluene, by polymerization pipe tube sealing, and
Magnetic agitation is reacted 3 days in 90 DEG C of oil baths；After reaction, obtained solid is dissolved in 100mL tetrahydrofurans, then by gained
Solution rotates to viscous pasty state and obtains the 4th viscous mixture, and the total 8mL of the 4th viscous mixture is instilled in 80mL methanol and is precipitated,
Gained sediment is finally dissolved in 20mL tetrahydrofurans, acquired solution is instilled in 800mL water under stirring, continues to stir
It is precipitated completely to impurity, is centrifuged off impurity not soluble in water, gained supernatant is freeze-dried to obtain 2.4g white sponges
Solid, the as described miscellaneous arm Regular Star Polymers material.
Embodiment 4
Manufactured in the present embodiment is the miscellaneous arm star amphiphilic macromolecular material of PCL-PEG-PLGA biodegradation three blocks, system
It is standby that steps are as follows：
(1) terminal groups modification of mPEG
First lead to 5 minutes nitrogen, then under nitrogen protection, the polyethyleneglycol first after 6g is dried in vacuo into branch mouth bottle
Ether (Mn=2000) is added in branch mouth bottle, and 75ml chloroforms are added, and to dissolving, the chloroform for obtaining poly glycol monomethyl ether is molten for stirring
Liquid；Backward poly glycol monomethyl ether chloroformic solution in be added 3.66mL benzyloxymethyl ethylene oxide be mixed to get the first mixing
Liquid instills the chloroformic solution of triethylamine into the first mixed liquor of gained (by 2.08mL then under the conditions of ice bath, magnetic agitation
Triethylamine and 5mL chloroforms, which are uniformly mixed, to be obtained), branch mouth bottle is moved into 30 DEG C of oil baths after being added dropwise, magnetic agitation reaction 2
It；After reaction, revolving gained reaction solution to viscous pasty state obtains the first viscous mixture, then the first viscous mixture is total to
16mL is instilled in 250mL ether and is precipitated, and gained sediment obtains 5.9g white solid powders through filtering, being dried in vacuo；
(2) PCL-mPEG di-block copolymers are prepared
5g steps (1) obtained solid product and 5g 6-caprolactones are added in polymerization pipe, are dried in vacuo in 90 DEG C of oil baths
Then 2h removes oil bath, then the stannous octoate toluene solution that 0.05g weight concentrations are 1wt% is added dropwise into polymerization pipe, then
Vacuum drying removes toluene, and by polymerization pipe tube sealing, and magnetic agitation is reacted 2 days in 150 DEG C of oil baths；After reaction, by institute
It obtains product to be dissolved in 250mL dichloromethane, then acquired solution is rotated to viscous pasty state and obtains the second viscous mixture, by second
The total 15mL of viscous mixture, which is instilled in 3500mL ether, to be precipitated, and gained sediment obtains 4.8 white solids through filtering, being dried in vacuo
Powder；
(3) PCL terminal hydroxy groups in PCL-mPEG are protected
First lead to 3 minutes nitrogen into branch mouth bottle, then under nitrogen protection, obtained by step (2) vacuum dried 4g
Solid (molecular weight is 4000 or so) is added in branch mouth bottle, and 50mL chloroforms are added, and stirring to dissolving obtains solid obtained by step (2)
The chloroformic solution of body；Under the conditions of ice bath, magnetic agitation, acetyl is instilled into the chloroformic solution of step (2) obtained solid product
The chloroformic solution (be uniformly mixed and obtained by 0.7mL chloroacetic chlorides and 10mL chloroforms) of chlorine, moves into branch mouth bottle in 35 after being added dropwise
It is reacted 2 days in DEG C oil bath；After reaction, revolving gained reaction solution to viscous pasty state obtains third viscous mixture, then by the
The total 8mL of three viscous mixtures is instilled in 150mL methanol and is precipitated, and gained sediment is solid through filtering, being dried in vacuo to obtain 3.7g whites
Body powder；
(4) PCL-mPEG-OH is prepared
3g steps (3) obtained solid is dissolved in 40mL DMF, while 0.3g palladium carbons are evenly spread into 5mL DMF
In, then the DMF dispersion liquids of the DMF solution of step (3) obtained solid and palladium carbon are added in reaction kettle, are led into reaction kettle
It is 4atm to enter hydrogen to pressure, and reaction kettle is filtered out institute after reaction as being stirred to react on magnetic stirring apparatus 1 day later
The palladium carbon in reaction solution is obtained, and reaction solution is obtained into 2.9g white solid powders through being spin-dried for, being dried in vacuo；
(5) the miscellaneous arm star amphiphilic macromolecular material of PCL-PEG-PLGA biodegradation three blocks is prepared
2.5g steps (4) obtained solid product, 1.5g glycolides and 3.5g L- lactides are added in polymerization pipe, then to
The stannous octoate toluene solution that 0.0375g weight concentrations are 1wt% is added dropwise in polymerization pipe, then vacuum drying removes toluene, will
Polymerization pipe tube sealing, and magnetic agitation is reacted 2 days in 150 DEG C of oil baths；After reaction, obtained solid is dissolved in 150mL dichloros
In methane, then acquired solution is rotated to viscous pasty state and obtains the 4th viscous mixture, by the total 20mL drops of the 4th viscous mixture
Enter and precipitated in 200mL ether, gained sediment is finally dissolved in 60mL tetrahydrofurans, instills acquired solution under stirring
In 1800mL water, continues stirring and be precipitated completely to impurity, be centrifuged off impurity not soluble in water, gained supernatant is freeze-dried
7.2g white sponge solids are obtained, the as described miscellaneous arm Regular Star Polymers material.
Claims (10)
1. a kind of miscellaneous arm star amphiphilic macromolecular material of biodegradable three block, it is characterised in that chemical constitution is as follows：
In formula, A chains are poly glycol monomethyl ether, B chains, the homopolymer or copolymer that C chains are Biodegradable polyester, and the B
Chain and homopolymer or copolymer that C chains are different Biodegradable polyesters.
2. the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block according to claim 1, it is characterised in that
The B chains, C chains are by least one of L- lactides, glycolide, 6-caprolactone, trimethylene carbonate, δ-valerolactone monomer
Ring-opening polymerisation forms.
3. the preparation method of the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block described in claim 1, special
Sign is that steps are as follows：
(1) terminal groups modification of mPEG
Under nitrogen protection, by the organic solution and benzyloxy first of the poly glycol monomethyl ether that mass concentration is 0.05~0.27g/mL
Hexadecyl ethylene oxide is mixed to get the first mixed liquor, and then under ice bath, stirring condition, three second are instilled into the first mixed liquor of gained
Gained reaction system is stirred to react 1~3 day by the organic solution of amine after being added dropwise in 25~50 DEG C；After reaction, it rotates
Gained reaction solution to viscous pasty state obtains the first viscous mixture, then the first viscous mixture is instilled in the second organic solvent and is sunk
It forms sediment, gained sediment obtains solid powder through filtering, being dried in vacuo；Poly glycol monomethyl ether, benzyloxy first in the reaction system
The molar ratio of hexadecyl ethylene oxide and triethylamine is 1:(1~10):(1~10)；
(2) A-B di-block copolymers are prepared
The monomer composition formed by step (1) obtained solid product and the first monomer or by the first monomer and second comonomer is added
In closed reaction vessel, then the stannous octoate toluene solution that weight concentration is 0.05~2% is added dropwise into closed reaction vessel, so
Vacuum drying removes toluene afterwards, and is stirred to react 1~3 day in 90~200 DEG C；After reaction, products therefrom is dissolved in third
In organic solvent, then acquired solution is rotated to viscous pasty state and obtains the second viscous mixture, later by the second viscous mixture
It instills in the 4th organic solvent and precipitates, gained sediment obtains solid powder through filtering, being dried in vacuo；Obtained by the step (1)
Solid product and the first monomer are (1~10) by the monomer composition weight ratio that the first monomer and second comonomer form:(10~
1), the stannous octoate toluene solution weight is for step (1) obtained solid product and first monomer or by the first monomer and second
The 0.01~1% of the monomer composition weight of monomer composition；
(3) B terminal hydroxy groups are protected
Under ice bath, stirring condition, into the organic solution of (2) obtained solid product the step of a concentration of 0.08~0.25g/mL
Gained reaction system, is stirred to react 1~3 day by the organic solution for instilling chloroacetic chloride after being added dropwise in 25~50 DEG C；Reaction knot
Shu Hou, revolving gained reaction solution to viscous pasty state obtains third viscous mixture, then third viscous mixture instillation the 6th is had
It is precipitated in solvent, gained sediment obtains solid powder through filtering, being dried in vacuo；In the reaction system obtained by step (2)
The molar ratio of solid product and chloroacetic chloride is 1:(1~10)；
(4) B-A-OH is prepared
By the organic solution of (3) obtained solid product the step of a concentration of 0.067~0.3g/mL and a concentration of 0.002~
The organic dispersions of the palladium carbon of 0.06g/mL are added in reaction kettle, and 2-5atm hydrogen is passed through into reaction kettle, and stirring is anti-later
It answers 1~3 day, filters out the palladium carbon in gained reaction solution after reaction, and reaction solution is obtained into solid through being spin-dried for, being dried in vacuo
Powder；The palladium carbon dosage is the 0.5~10% of step (3) obtained solid products weight；
(5) B-A-C triblock copolymers are prepared
It is added by step (4) obtained solid product, Third monomer or by Third monomer and the monomer composition of the 4th monomer composition
In closed reaction vessel, then the stannous octoate toluene solution that weight concentration is 0.05~2% is added dropwise into closed reaction vessel, so
Vacuum drying removes toluene afterwards, and is stirred to react 1~3 day in 90~200 DEG C；After reaction, products therefrom is dissolved in third
In organic solvent, then acquired solution is rotated to viscous pasty state and obtains the 4th viscous mixture, later by the 4th viscous mixture
It instills in the 4th organic solvent and precipitates, gained sediment is purified to obtain the miscellaneous amphiphilic height of arm star of biodegradable three block
Molecular material；Step (4) the obtained solid product and Third monomer or the monomer group by Third monomer and the 4th monomer composition
Polymer weight ratio is (1~10)：(10:1), the stannous octoate toluene solution weight is step (4) obtained solid product and the
Three monomers or by the 0.01~1% of Third monomer and the monomer composition weight of the 4th monomer composition.
4. the preparation method of the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block according to claim 3,
It is characterized in that in the step (1), the organic solution preparation process of the poly glycol monomethyl ether is：Under nitrogen protection,
Vacuum drying gained poly glycol monomethyl ether is dissolved in the first organic solvent and obtains the organic solution of poly glycol monomethyl ether；Institute
The organic solution for stating triethylamine is to be uniformly mixed to obtain with the first organic solvent by triethylamine, triethylamine and the first organic solvent
Volume ratio is 1：(2.4~26.8)；First organic solvent is in dichloromethane, chloroform, dimethylformamide, tetrahydrofuran
One kind；Second organic solvent is ether or petroleum ether.
5. the preparation method of the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block according to claim 3,
It is characterized in that in the step (2), by step (1) obtained solid product, first monomer or by the first monomer and second comonomer
After closed reaction vessel is added in the monomer composition of composition, prior to 50~120 DEG C at be dried in vacuo 1~5h, then sad Asia is added dropwise
Tin toluene solution；In the step (5), by step (4) obtained solid product, Third monomer or by Third monomer and the 4th monomer
After closed reaction vessel is added in the monomer composition of composition, prior to 50~120 DEG C at be dried in vacuo 1~5h, then sad Asia is added dropwise
Tin toluene solution.
6. the preparation method of the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block according to claim 5,
It is characterized in that the third organic solvent in the step (2) and step (5) is dichloromethane, chloroform, dimethylformamide, four
One kind in hydrogen furans, dosage are to keep products therefrom dissolving complete；4th organic solvent is methanol, ether, petroleum ether
In one kind.
7. the preparation method of the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block according to claim 3,
It is characterized in that in the step (3), the organic solution preparation process of step (2) obtained solid product is：Under nitrogen protection,
Vacuum dried step (2) obtained solid product is dissolved in the 5th organic solvent and is obtained；Step (3) chloroacetic chloride has
Machine solution is to be uniformly mixed to obtain by chloroacetic chloride and the 5th organic solvent, chloroacetic chloride and the 5th organic solvent volume ratio for (1~
17.5)：250；5th organic solvent is one kind in dichloromethane, chloroform, dimethylformamide, tetrahydrofuran；It is described
6th organic solvent is one kind in methanol, ether, petroleum ether.
8. the preparation method of the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block according to claim 3,
It is characterized in that in the step (4), the organic solution of step (3) obtained solid product is by vacuum dried step (3)
Obtained solid product, which is dissolved in the 7th organic solvent, to be obtained, and the organic dispersions of palladium carbon are distributed to by palladium carbon in the 7th organic solvent
It obtains；7th organic solvent is one kind in dichloromethane, chloroform, dimethylformamide, tetrahydrofuran.
9. the preparation method of the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block according to claim 3,
It is characterized in that in the step (5), the concrete mode to gained sediment purifying is：Gained sediment is dissolved in tetrahydrochysene first
Furans, then instill acquired solution in deionized water under stirring, continue stirring and be precipitated completely to impurity, is centrifuged off not
It is dissolved in the impurity of water, gained supernatant is freeze-dried to obtain the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block
Material；The dosage of the tetrahydrofuran is to keep gained sediment dissolving complete.
10. the preparation method of the miscellaneous arm star amphiphilic macromolecular material of biodegradable three block according to claim 3,
It is characterized in that first monomer, second comonomer, Third monomer and the 4th monomer be L- lactides, glycolide, 6-caprolactone,
One kind in trimethylene carbonate, δ-valerolactone, and the first monomer is different monomers from Third monomer.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113906057A (en) * | 2019-04-12 | 2022-01-07 | 密歇根大学董事会 | Triblock copolymer and nanofiber gelation microspheres comprising same |
| CN114349944A (en) * | 2020-10-13 | 2022-04-15 | 中石化南京化工研究院有限公司 | Polycaprolactone block copolymer and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1401567A1 (en) * | 2001-06-08 | 2004-03-31 | Labopharm Inc. | Unimolecular polymeric micelles with an ionizable inner core |
| CN1243779C (en) * | 2002-03-13 | 2006-03-01 | 北京键凯科技有限公司 | Hydrophili polymer derirative having Y shaped branch, its preparation method, combined object with medicine molecule and medical compositon containing combined object |
| EP1804849A1 (en) * | 2004-10-29 | 2007-07-11 | Abbott Cardiovascular Systems, Inc. | Poly(ester amide) filler blends for modulation of coating properties |
| CN101215377A (en) * | 2007-12-27 | 2008-07-09 | 中国科学院长春应用化学研究所 | Aliphatic polyester-polyamino acid Y-type three-arm block copolymers and synthetic method thereof |
-
2018
- 2018-02-16 CN CN201810152579.1A patent/CN108530642B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1401567A1 (en) * | 2001-06-08 | 2004-03-31 | Labopharm Inc. | Unimolecular polymeric micelles with an ionizable inner core |
| CN1243779C (en) * | 2002-03-13 | 2006-03-01 | 北京键凯科技有限公司 | Hydrophili polymer derirative having Y shaped branch, its preparation method, combined object with medicine molecule and medical compositon containing combined object |
| EP1804849A1 (en) * | 2004-10-29 | 2007-07-11 | Abbott Cardiovascular Systems, Inc. | Poly(ester amide) filler blends for modulation of coating properties |
| CN101215377A (en) * | 2007-12-27 | 2008-07-09 | 中国科学院长春应用化学研究所 | Aliphatic polyester-polyamino acid Y-type three-arm block copolymers and synthetic method thereof |
Non-Patent Citations (2)
| Title |
|---|
| ZHAOMIN TANG，等: "Redox-responsive star-shaped magnetic micelles with active-targeted and magnetic-guided functions for cancer therapy", 《ACTA BIOMATERIALIA》 * |
| 张译心，等: "基于PEG-PCL-PLLA杂臂星形高分子胶束的合成与性能", 《高分子材料科学与工程》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113906057A (en) * | 2019-04-12 | 2022-01-07 | 密歇根大学董事会 | Triblock copolymer and nanofiber gelation microspheres comprising same |
| CN113906057B (en) * | 2019-04-12 | 2023-10-20 | 密歇根大学董事会 | Triblock copolymers and nanofiber gelling microspheres comprising same |
| CN114349944A (en) * | 2020-10-13 | 2022-04-15 | 中石化南京化工研究院有限公司 | Polycaprolactone block copolymer and preparation method thereof |
| CN114349944B (en) * | 2020-10-13 | 2023-12-05 | 中石化南京化工研究院有限公司 | Polycaprolactone block copolymer and preparation method thereof |
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