CN108187059A - A kind of stimuli responsive type amphipathic cyclodextrin polymers carrier, preparation and its application in sustained and controlled release medicament is prepared - Google Patents
A kind of stimuli responsive type amphipathic cyclodextrin polymers carrier, preparation and its application in sustained and controlled release medicament is prepared Download PDFInfo
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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Abstract
The invention belongs to field of pharmaceutical preparations, specifically disclose amphipathic cyclodextrin polymers pharmaceutical carrier, it is characterised in that：Using cyclodextrin as core, 6 modifications of at least one saccharide ring of cyclodextrin core are grafted with hydrophilic segment；2 of at least one saccharide ring and/or 3 are modified with hydrophobic chain segment.And to have the chemistry key connection water-wet side of stimulating responsive and cyclodextrin to tumor microenvironment, achieve the purpose that targeted release.In addition the invention also discloses the preparation method and application of the carrier.Amphipathic cyclodextrin drug-loading system prepared by this method has that grain size is suitable, form is uniform, and drugloading rate is big, and stimulating responsive is good, delays the advantages of controlled release properties are high.
Description
Technical field：
The invention belongs to field of pharmaceutical preparations；There is hydrophilic and hydrophobic pharmaceutical carrier more particularly to a kind of.
Background technology
Recently as environmental degradation, population growth, aging and living-pattern preservation, the incidence of cancer is in bright
Aobvious ascendant trend.According to 2017《China's tumour registration annual report》Data are shown, now averagely per minute daily just to have 7 people to be diagnosed
For cancer, 10000 person-times are made a definite diagnosis daily, the probability cancered in life of people is 36%.The anticarcinogen clinically applied now
Most of object is chemotherapeutics, and normal cell has also been substantially damaged while cancer cell is murdered, and causes drug effect low and has
Serious side effect.Therefore, invention now is a kind of has that specificity kills cancer cell and toxic side effect is low and can be with
The drug of slow release has become urgent problem to be solved.
In order to solve the problems, such as that anticancer drug side effect is larger, the prior art reports certain methods, for example, Publication No.
The Chinese patent literature of CN103396521A discloses a kind of amphipathic β-CD star-type polymers, has hydrophobic block and hydrophilic
Property block, it is characterised in that：Amphipathic β-CD the star-type polymers are using β-CD as core, on its 3~6 hydroxyls, even
Upper amphipathic nature polyalcohol forms three arms, four arms, five arms or the amphipathic β-CD star-type polymers of six arms；The amphipathic connected
The hydrophobic block for closing object is polymerized by acrylic acid (AA) and methyl methacrylate (MMA), and hydrophilic block is by N- ethylene
Base pyrrolidones (PNVP) is polymerized.Polymer pH is sensitive, can stimuli responsive type release hydrophobic drug, maximum carries medicine
Measure is 21.44%.Acrylic acid and methylmethacrylate polymer as hydrophobic side, acrylic acid and methacrylate polymer without
Poison, but monomer is toxic, this limits the application of this polymer on the one hand；And drugloading rate is little, results in the need for
Carrier is more, and potential toxicity is caused to increase.
For another example, the Chinese patent literature of Publication No. CN101284885A discloses a kind of based on amphipathic cyclodextrin polymerization
Object and preparation method thereof has water-wet side block and hydrophobic side block, it is characterised in that：Prepared amphipathic cyclodextrin polymerization
The water-wet side of object is polyethylene glycol (PEG), and hydrophobic side is the polylactide (PCL) that can be degraded, the two and cyclodextrin (CD) phase
Even, amphipathic cyclodextrin medicine-carried system (CD-PCL-PEG) is formed, is realized to hydrophobic anticancer drug adriamycin
It contains, is expected to cover drug toxicity, reduce toxic side effect, maximum drugloading rate is 20.1%.Amphipathic ring paste prepared by this method
Smart polymer can not stimuli responsive type release drug.
Although existing method is successfully prepared amphipathic cyclodextrin, and successfully mask the toxicity of anticancer drug,
But acrylic monomers is toxic, polyacrylic acid prepared therefrom is although nontoxic, but do not ensure that all acrylic acid into
Work(polymerize, so there are genotoxic potentials；In addition, also there are drugloading rate it is relatively low the problem of；The prior art needs one kind that can have
The carrier and preparation that good stimulating responsive, drugloading rate are high, nontoxic, slow controlled release properties are good.
Invention content
An object of the present disclosure is, provides a kind of amphipathic cyclodextrin polymers pharmaceutical carrier (also abbreviation of the invention
For carrier), it is intended to improve the drugloading rate of carrier.
It is a second object of the invention to provide a kind of preparation side of the amphipathic cyclodextrin polymers pharmaceutical carrier
Method.
Third purpose of the present invention is, provides a kind of application of the amphipathic cyclodextrin polymers pharmaceutical carrier, will
Itself and hydrophobic drug mix self assembly in water (present invention is also referred to as autohemagglutination), to obtain the drug system with slow controlled-release effect
Agent.
4th purpose of the invention is, provides and a kind of assembles to obtain by the amphipathic cyclodextrin polymers pharmaceutical carrier
Sustained-release preparation (present invention be also referred to as drug-loading system).
Amphipathic cyclodextrin polymers pharmaceutical carrier of the present invention, using cyclodextrin as core, cyclodextrin core
At least one saccharide ring 6- positions modification be grafted with hydrophilic segment；The 2- positions of at least one saccharide ring and/or 3- are modified with thin
Aqueous segment.
The present invention is innovatively using cyclodextrin as modification core, in the 6- positions of cyclodextrin modification hydrophilic segment, and
2- and/or 3- are modified with hydrophobic chain segment, the performance for the carrier that so can unexpectedly improve, lifting carrier
Drugloading rate.Meanwhile by taking it is in tumour medicine application aspect as an example, two can be controlled by adjusting the length of hydrophilic chain and hydrophobic chain
The grain size of parent's property cyclodextrin self-aggregate between 40~100nm, be conducive to by EPR effects (i.e. the Thief zone of solid tumor, length it is stagnant
Stay effect) drug-loading system is made to assemble in knub position, side effect is reduced, improves curative effect；Drug-loading system passes through stimulating responsive
It learns key to be connected, can specifically be discharged in tumor tissues, further reduce side effect.
The present invention proposes a kind of novel amphipathic cyclodextrin carrier and preparation method thereof, and this method is prepared amphipathic
Cyclodextrin drugloading rate can greatly improve, and size is suitable, and thorn can be realized to the reducing environment in tumor tissues microenvironment
Swash property release, greatly reduce its toxic side effect, increase curative effect.
Cyclodextrin of the present invention be preferably α-, γ-, beta-cyclodextrin；Particularly preferably beta-cyclodextrin.
The 6- positions of saccharide ring can modify hydrophilic segment.Further study show that promote the 6- positions modification hydrophily of saccharide ring
The quantity of segment helps further to improve the performance of carrier.
As preferred：The 6- positions of each saccharide ring of cyclodextrin are modified with hydrophilic segment.
In the present invention, hydrophilic segment is preferably the polymer segment with excellent hydrophilic.
Further study show that the hydrophilic segment is polyethylene glycol hydrophilic segment.One side of polyethylene glycol water-wet side
Face can improve the water solubility of drug, on the one hand be conducive to identification and destruction that medicine-carried system hides vivo immuning system, can
Effectively extend the circulation time of medicine-carried system in vivo, improve bioavilability.
In the present invention, the structural formula of the polyethylene glycol hydrophilic segment is, for example ,-PEG-O-CH3。
Further preferably, the molecular weight of polyethylene glycol hydrophilic segment is 200~8000.
As preferred：The hydrophilic segment and the 6- positions of cyclodextrin are keyed by stimuli responsive type chemical combination；It is described
Stimuli responsive type chemical combination key be pH stimuli responsive chemical combination key, thermal stimulus responds chemical combination key or redox stimuli responsive chemical combination
The one or more of key.
Further preferably, redox stimuli responsive chemical combination key is disulfide bond.It that is to say hydrophilic segment through disulfide bond
It is connected on the 6- positions primary carbon of cyclodextrin saccharide ring.
The present inventor contributes to further the study found that the 2- positions of increase saccharide ring and the quantity of the hydrophobic chain segment of 3-
It is cooperateed with hydrophilic segment, helps further to promote the obtained effect of carrier, for example, the load for the carrier being obviously improved
Dose eases up controlled release properties.
Further preferably, the 2- positions of each saccharide ring of the cyclodextrin and/or 3- are modified with hydrophobic chain segment.Namely
It is that the 2- positions of 7 saccharide rings of the cyclodextrin are modified with hydrophobic chain segment with 3-, in total 14 reaction sites.
Still more preferably, in the amphipathic cyclodextrin polymers pharmaceutical carrier, the 6- positions in each saccharide ring are modified
There is hydrophilic segment；2- positions in each saccharide ring are modified with hydrophobic chain segment with 3-.In this way, contribute to hydrophilic by 6
Property and 2, the cooperation of the hydrophobicity of 3, collaboration improves the obtained performance of carrier.
The hydrophobic chain segment can be selected well-known to those skilled in the art with hydrophobic group.
In the present invention, preferably by hydrophobic chain segment modification on 2- and/or 3- secondary hydroxyls；It that is to say, use is hydrophobic
Property segment substitute H on 2- and/or 3- secondary hydroxyls.
As preferred：The hydrophobic chain segment is the alkyl segment of C1~C20；Or for halogen, C1~C6 alkane
The alkyl segment of C1~C20 of at least one of base, C1~C6 alkoxies, benzyl substituent group substitution.C1~the C20's
Alkylene or alkynes base of the alkyl segment for the alkyl of the carbon number or containing unsaturated bond.
Further preferably, the hydrophobic chain segment is the straight chain of C5~C20 or branched saturated hydrocarbon group segment；More into one
Step is preferably straight chain saturation alkane base segment.The study found that the hydrophobic segment of preferred segment and the hydrophilic segment collaboration of the present invention,
It can help to collaboration and promote drugloading rate.
Further preferably, the hydrophobic segment is dodecyl.Further preferred hydrophobic segment can cooperate with the present invention
Hydrophilic segment, cooperate with and drugloading rate be promoted to 40%.
In the present invention, in a kind of most preferred amphipathic cyclodextrin polymers pharmaceutical carrier, the 6- positions in each saccharide ring are repaiied
It is decorated with PEG hydrophilic segments；2- positions in each saccharide ring and 3- are modified with dodecyl, and (structural formula is shown in formula 1, in flower bunch type
Poly structure；Hydrophilic segment and hydrophobic segment is not entirely shown in formula 1).In this way, contribute to the hydrophily by 6 and 2,3
Hydrophobicity coordinates, and collaboration improves the obtained performance of carrier, hence it is evident that the drugloading rate of lifting carrier.
The present invention also provides a kind of preparation of the amphipathic cyclodextrin polymers pharmaceutical carrier, including following step
Suddenly：
Step (a)：The protection of 6 hydroxyls of cyclodextrin
6 primary alconols of cyclodextrin are protected to obtain with 6 protected cyclodextrin of hydroxyl for a；
Step (b)：2 and/or 3 hydroxyls of cyclodextrin it is hydrophobically modified；
A is taken to be reacted under alkali with the source materials of hydrophobic chain segment, 2 is obtained by the reaction and/or 3 hydroxyls is hydrophobically modified
Product b；
Step (c)：6 hydroxyls deprotection of product b
It takes b in acid condition, hydrolyzes, remove 6 primary hydroxyl protecting groups, obtain product c；
(d) product c is directly connected to hydrophilic segment or is keyed by stimuli responsive type chemical combination, and the load is made
Body.
In the present invention, by the preparation method, hydrophobicity base is modified at 2,3 in the case of being protected in advance at 6
Group then connects hydrophilic segment at 6 again, so can help to that the carrier with superperformance is made, in addition, by using
Hydrophilic segment is modified at 6, can select suitable stimuli responsive type according to drug type by stimuli responsive type chemical combination key
Key is closed, controlled release, the sustained release of the drug of load is realized, achievees the purpose that precisely to treat.
The study found that the amphipathic cyclodextrin synthesized by preparation method of the present invention can be by the tune of hydrophobic chain
It is whole to adjust the drugloading rate of pharmaceutical carrier and slow controlled-release effect.Have been found that the number of hydrophobic chain short (C0~C4) or connection
It is few, then it can largely effect on the drugloading rate of drug.
In the present invention, suitable primary hydroxyl blocking group is selected, coordinates the preparation process, make it can be selective
While reaction with 2,3- primary hydroxyls, steric hindrance can also be reduced as possible, reach and be completely replaced purpose, be completely replaced hydrophobic
Segment matches again with hydrophilic segment of the present invention, can make carrier can be by simple autohemagglutination with carrying medicament, can also be apparent
Collaboration promotes drugloading rate.
Preferably, in step (a), in organic solvent, primary hydroxyl protecting group, cyclodextrin and triethylamine are at 20~80 DEG C
72~120h of lower reaction protects 6 primary alconols of cyclodextrin, removes solvent, silica gel column chromatography or recrystallization purifying product later,
It is dried to obtain 6 protected cyclodextrin of hydroxyl.
Preferably, the material source of primary hydroxyl protecting group is triphenylchloromethane, tert-butyl chloro-silicane, to first
One or more of benzene sulfonyl chloride.The present inventor can control primary hydroxyl to replace completely the study found that by the protection material
Or part replaces.
In the present invention, in step (a), the molar ratio of cyclodextrin and primary hydroxyl protecting group is 1: 3~1: 14.
In the present invention, in step (b), what the alkali can be used that those skilled in the art can know can arbitrarily make secondary alcohol
Alkylated alkali；In the present invention, preferably sodium hydride.
The source materials of hydrophobic chain segment can be the alkyl of C1~C20 of 1- bromos；Preferably C5~C20's of 1- bromos
Alkyl；Further preferably Dodecyl Bromide hydrocarbon.
The present inventor surprisingly also found, in step (b), except good collaboration alkylating reagent (hydrophobic segment source materials)
Outside type, alkali is required to be added portionwise with hydrophobic chain segment, contribute to solve this field be difficult to solve be difficult to complete long-chain
Alkylated technical problem, contributes to hydrophobic chain segment to replace secondary hydroxyl entirely.
The method that is added portionwise is, for example, that sodium hydride and bromoalkane are respectively classified into 2~3 parts, first adds a hydrogen
Change sodium, reaction more than 4h adds a bromoalkane, after reacting 2~4d, repeats this step, until reaction terminates.
The present invention also provides：Irritation response chemical combination key is disulfide bond, and the preparation method of the carrier is：
(1) protection of 6 hydroxyls of cyclodextrin
In organic solvent, primary hydroxyl protecting group, cyclodextrin and triethylamine react 72~120 hours at 20~80 DEG C,
6 primary alconols of cyclodextrin are protected, solvent, silica gel column chromatography or recrystallization method purified product is removed later, is dried to obtain 6 hydroxyls
Protected cyclodextrin a；
(2) cyclodextrin 2, the alkylation of 3 hydroxyls
Take a first fully reacted in organic solvent with sodium hydride, add in bromoalkane later, at 0~50 DEG C reaction 2~
5d is quenched, and removes solvent, gel chromatography separation method purified product, dry b；
(3) 6 hydroxyl deprotection of cyclodextrin
It takes b in acid condition, hydrolyzes, remove primary hydroxyl protecting group, ammonium hydroxide neutralizes the complete acid of unreacted, and removal is molten
Agent obtains crude product, and vacuum drying obtains product c；
(4) iodo of 6 hydroxyls of cyclodextrin
C reacts 18~36h with triphenyl phosphorus, elemental iodine in anhydrous organic solvent at 60~90 DEG C, cuts half solvent,
PH value is adjusted to 9~10 with sodium methoxide, and with a large amount of methanol extractions, methanol is washed three times, is obtained product, is dried to obtain d；
(5) 6 hydroxy thiols of cyclodextrin
D reacts 16~28h with thiocarbamide at 60~100 DEG C in organic solvent, removes organic solvent, adds in appropriate bases
Aqueous solution, 0.5~1.5h of back flow reaction after reaction solution cooling, adjust pH and are less than 7, extracted with dichloromethane, saturated salt solution
It washes, removes solvent, obtain product e.
(6) bromo of poly glycol monomethyl ether
Poly glycol monomethyl ether reacts 18~28h with phosphorus tribromide in anhydrous organic solvent at 0~30 DEG C, later will be anti-
Liquid is answered to be slowly dropped in water, adds in dichloromethane extraction, then neutrality is washed to saturated salt solution, it is dry, use rotary evaporation
Instrument removes dichloromethane solvent, obtains bromo poly glycol monomethyl ether f.
(7) poly glycol monomethyl ether is Thiolation
F reacts 16~28h in anhydrous organic solvent with thiocarbamide at 60~100 DEG C, removes organic solvent, adds in appropriate
The aqueous solution of alkali, 0.5~1.5h of back flow reaction after reaction solution cooling, adjust pH and are less than 7, extracted with dichloromethane, saturated common salt
Washing removes solvent, obtains Thiolation poly glycol monomethyl ether g.
(8) synthesis of amphipathic cyclodextrin flower bunch type polymer drug carrier
G, final amphipathic cyclodextrin h is fully obtained by the reaction in e in an oxidizing environment.
In the present invention, by the preferred preparation method, hydrophobic segment and hydrophilic segment can be overcome to mismatch, cause to carry
The technical issues of dose is not high realizes the complete modification of required segment, makes the hydrophilic and hydrophobic load medicine for matching, promoting drug
Amount.
Preferably, in step (1), primary hydroxyl protecting group is by triphenylchloromethane, tert-butyl chloro-silicane, to toluene
The offer of one or more of sulfonic acid chloride.In the present invention, select suitable primary hydroxyl blocking group, make its can selectively with
While primary hydroxyl reacts, steric hindrance can also be reduced as possible so that it can replace completely；Or increase steric hindrance, make it not exclusively
Replace primary hydroxyl.I.e. the selection of blocking group has key effect to the substitution completely of control primary hydroxyl or part substitution.
The molar ratio of cyclodextrin and primary hydroxyl protecting group is 1: 3~1: 14.
Preferably, in step (2), the chemical formula of bromoalkane is R1-Br.The R1Alkyl for C1~12；More into one
Step is preferably the linear paraffin base of C5~12.Preferred R1, help to cooperate with the hydrophilic segment, promote drugloading rate.
A and bromoalkane, the molar ratio of sodium hydride (that is to say 1: 7: 7~1: 60: 60：1: 7~60: 7~60).It is anti-herein
Ying Zhong, bromoalkane needs to add in batches with sodium hydride, to achieve the purpose that bromoalkane is fully reacted with cyclodextrin.Reaction time extends
Contribute to the full substitution of cyclodextrin secondary hydroxyl.The ratio of three and the selection of reaction time, charging process, brominated alkanes are determined jointly
Determine the substitution degree of secondary hydroxyl.
The method that is added portionwise is, for example, that sodium hydride and bromoalkane are respectively classified into 2~3 parts (for example, dividing equally),
A sodium hydride is first added, reaction more than 4h adds a bromoalkane, after reacting 2~4d, repeats this step, until reaction
Terminate.For example, first by a and 1/3 part of more than sodium hydride 4h (such as 12~for 24 hours), subsequent 1~4d of bromoalkane of 1/3 part of addition
Afterwards, the 2nd 1/3 part of more than sodium hydride 4h is added after reaction again, after then adding 1/3 part of 1~4d of bromoalkane again, finally again
Remaining more than sodium hydride 4h is added, adds remaining bromoalkane, until reaction terminates.
The reaction total time of step (2) is preferably 3~9d.
Preferably, the acid described in step (3) is one or more of tetrafluoro boric acid, tetrabutyl ammonium fluoride, acetic acid.
In step (3), adding in the amount of acid needs excess.
Preferably, the molar ratio of c and elemental iodine, triphenyl phosphorus is 1: 7: 7~1: 28: 28 (1: 7~28: 7 in step (4)
~28).The reaction carries out in anhydrous conditions.
Preferably, step (5) and alkali described in (7) be sodium hydroxide, one or more of potassium hydroxide, sodium methoxide.
In step (5) and (7), the molar ratio of reactant and thiocarbamide is 1: 3~1: 30.
Preferably, in step (6) molar ratio of poly glycol monomethyl ether and phosphorus tribromide 1: 2~1: 5.
Preferably, the oxidation environment described in step (8) is to add oxygen into reaction solution or add in contain peroxidating
The aqueous solution of hydrogen connects air and heats to realize.
The molar ratio of g and e is 1: 7~1: 21.Under the range, contribute to the hydrophilic chain being made and hydrophobic segment matches
Section, and then help to promote the obtained drugloading rate of carrier.
Preferably, in step (1)~(8), organic solvent used be selected from n,N-Dimethylformamide, dichloromethane,
One or more of methanol, ethyl alcohol, dimethyl sulfoxide (DMSO).
Preferably, in step (1)~(8), signified anhydrous and oxygen-free reaction system is with indifferent gas such as nitrogen or argon gas
It is completed under body atmosphere.
Also a kind of application of the amphipathic cyclodextrin polymers pharmaceutical carrier of the present invention, the amphipathic ring is pasted
Smart polymer drug carrier, hydrophobic drug and organic solvent mix to obtain dispersion liquid, and water is added in dispersion liquid, carry out from group
Dress, obtaining load has the sustained release preparation of hydrophobic drug.
Preferably, the grain size of the amphipathic cyclodextrin polymers pharmaceutical carrier is preferably 40~100nm.The grain size model
Under enclosing, be conducive to promote the obtained effect of sustained release preparation, less side effect；For example, if load is antitumor drug, at this
Be conducive to make drug-loading system in tumour position by EPR effects (i.e. the Thief zone of solid tumor, long retention effect) under the carrier of grain size
Aggregation is put, reduces side effect, improves curative effect.
Further preferably, the grain size of the amphipathic cyclodextrin polymers pharmaceutical carrier is preferably 40~50nm.This is excellent
The performance for selecting the carrier under range is more excellent.
The inventors discovered that by autohemagglutination method of the present invention, help further to promote drugloading rate, reduce drug-eluting.
The present inventor is the study found that by carrier of the present invention and autohemagglutination method, in addition to it can be obviously improved drug loading,
It is also avoided that dash forward and applies effect, there is excellent sustained release performance.
The hydrophobic drug can be arbitrary non-aqueous compound medicine.
Can suitable stimuli responsive chemical combination key be selected according to the effect partial of hydrophobic drug, so as to make the drug of load
It is discharged in drug effect site selective, castering action effect.
Preferably, the hydrophobic drug is hydrophobic anticancer drug.Preferably, it is loaded for hydrophobic anticancer drug
Carrier stimuli responsive chemical combination key be redox stimuli responsive chemical combination key；Further preferably disulfide bond.
Be preferred for the carrier of hydrophobicity tumour medicine load, the hydroxyl connection polyethylene glycol of 6 as water-wet side, 2,
3 hydroxyls connect carbochain as hydrophobic side；Polyethylene glycol is with cyclodextrin by having reduction stimulating responsive or DH stimulations to ring
The chemical combination key connection of answering property, can orient scission of link under tumor tissues microenvironment.Amphipathic cyclodextrin molecule can be certainly in water phase
It is assembled into that outer layer is hydrophilic, the hydrophobic spherical medicine-carried system of internal layer can carry hydrophobic anticancer drug in hydrophobic pocket.The present invention
In, the drugloading rate of the carrier is big, and good biocompatibility has no toxic side effect, and can be oriented under tumor tissues microenvironment
Release, delay the good amphipathic cyclodextrin flower bunch type polymer drug carrier of controlled release properties.Drug after load can be in tumour
Targeted release in tissue microenvironment, slow controlled release properties are good, Small side effects, and drug effect is high.
In the present invention, by the autohemagglutination of the carrier, hydrophobic, outer hydrophilic ball shape structure in formation, so as to which ring is pasted
The hydrophobic pocket of essence expands, and increases the amount of containing of hydrophobic drug.In addition, disulfide bond or acyl are introduced on amphipathic cyclodextrin molecule
The reduction-oxidations such as hydrazone key respond or the chemical combination key of pH response types, can be allowed to the targeted release anticancer under tumor tissues microenvironment
Drug, the content of dispersion that this measure had both increased cancerous tissue also reduce side effect of the carrier medicament in normal structure.
Preferably, the hydrophobic anticancer drug is 5 FU 5 fluorouracil, doxorubicin hydrochloride, hydroxycamptothecin, Changchun
One or more of new alkali, taxol.
Application of the present invention, the pharmaceutical carrier are sufficiently stirred mixed with hydrophobic anticancer drug in organic solvent
It is even, it is slowly dropped into deionized water later, removes solvent after self assembly, it is dry, that is, form amphipathic cyclodextrin ball-type autohemagglutination
Polymer drug-carried system (present invention is also referred to as sustained release preparation).
In the present invention, existing method can be used, obtained drug-loading system is carried out to carry medicine test.For example, by amphipathic ring
Dextrin medicine-carried system is dissolved in methanol solution, and ultrasound measures its UV absorption in certain wave strong point, obtains drugloading rate.
The present invention also provides a kind of sustained-release preparations of dewatering medicament, assemble to obtain using the application process,
Including the spherical particle being self-assembly of by several amphipathic cyclodextrin polymers pharmaceutical carriers, the outer layer of the spherical particle is grafted
There is the hydrophilic segment；The hydrophobic drug of spherical particle inner cavity chamber load, and its inner surface is modified with hydrophobic chain segment.
Using hydrophilic segment as PEG, hydrophobic chain segment is for dodecyl, hydrophobic drug is that antitumor drug is
Example, structural formula are shown in formula 2：
The grain size of amphipathic cyclodextrin ball-type autohemagglutination system prepared by the present invention can pass through EPR effects in 40~100nm
Further assemble in tumor tissues, reach better therapeutic effect.Amphipathic cyclodextrin drug-loading system prepared by this method has
Uniform particle sizes, form is controllable, and drugloading rate is big, and stimulating responsive is good, delays the advantages of controlled release properties are high.
Sustained release preparation of the present invention, drugloading rate may be up to 40%.
Advantageous effect
Amphipathic cyclodextrin flower bunch type polymer drug carrier synthesized by the present invention, be by cyclodextrin be core, chemistry
It modifies：On the one hand the introducing of hydrophobic alkyl group is the hydrophobic side as amphipathic nature polyalcohol, on the one hand can expand simultaneously again
The hydrophobic pocket of large cyclodextrin, further increases drugloading rate；The introducing of stimuli responsive type chemical combination key disulfide bond again can be in tumor group
Directional fracture in the reducing environment in microenvironment is knitted, the spherical self-aggregate that amphipathic cyclodextrin is formed is destroyed, releases medicine out
Come.Not only side effect in the normal tissue can have been reduced but also the drug effect in tumor tissues can be improved.The introducing of polyethylene glycol, one
Aspect acts as the hydrophilic radical of amphipathic cyclodextrin, is on the one hand the toxic side effect for reducing material, can also extend it
Circulation time in vivo.The grain size of amphipathic cyclodextrin drug-loading system prepared by this method is conducive between 40~100nm
Drug-loading system is made to assemble in knub position by EPR effects (i.e. the Thief zone of solid tumor, long retention effect), be further reduced pair
Effect improves curative effect；The drugloading rate of the drug-loading system (present invention is also referred to as sustained release preparation) of the present invention can reach 40%.Grain size is equal
Even, form is controllable, and drugloading rate is big, and stimulating responsive is good, and it is high to delay controlled release properties.
Description of the drawings
Fig. 1 is the polymer drug-carried system transmittance electron microscope of amphipathic cyclodextrin ball-type autohemagglutination made from embodiment 1, can by figure
Know, the size of ball-type autopolymer of the invention is and uniform in size in 40nm~50nm or so.
Fig. 2 is amphipathic cyclodextrin polymers pharmaceutical carrier nucleus magnetic hydrogen spectrum figure made from embodiment 1.Polyethylene glycol and ring paste
For the ownership of the hydrogen of essence between 3.38~3.83ppm, the ownership of the hydrogen of dodecyl (removes-CH in 1.26ppm3With α-H),
1.68ppm (α-H) and 0.88ppm (- CH3), ratio 1358: 231: 28: 42, this spectrogram can illustrate the primary hydroxyl of cyclodextrin
(6-) and secondary hydroxyl (2,3-) are completely substituted.
Fig. 3 is amphipathic cyclodextrin polymers pharmaceutical carrier nucleus magnetic hydrogen spectrum figure made from embodiment 3.Polyethylene glycol and ring paste
For the ownership of the hydrogen of essence between 3.38~3.66ppm, the ownership of the hydrogen of dodecyl (removes-CH in 1.26ppm3With α-H),
1.68ppm (α-H) and 0.88ppm (- CH3), ratio 1358: 112: 21: 14, this spectrogram can illustrate the primary hydroxyl of cyclodextrin
It is fully substituted, but secondary hydroxyl is only partly replaced.
Fig. 4 is the nucleus magnetic hydrogen spectrum figure of cyclodextrin pharmaceutical carrier made from comparative example (comparative example 1).Poly- second two
The ownership of the hydrogen of alcohol and cyclodextrin is between 3.24~3.75ppm.Show that the primary hydroxyl of cyclodextrin is substituted in figure.
Fig. 5 is Examples 1 to 3 and the polymer drug-carried system of comparative example amphipathic cyclodextrin ball-type autohemagglutination in different rings
Under border, the cumulative release figure of drug controlled release (drug is by taking adriamycin as an example).
In Fig. 5, be labeled with DTT is the release figure added in after reducing agent dithiothreitol (DTT), and does not represent DTT's
It is the release figure for not adding in reducing agent.DOX's is tired in the as Examples 1 to 3 and comparative example of 8 kinds of icon representations in figure
Product release figure.
As shown in Figure 5, the medicine-carried system that prepared by embodiment 1 is in the presence of having reducing agent dithiothreitol (DTT), drug release
Speed significantly rises, existing for no DTT under the conditions of, drug release is seldom.This has absolutely proved the amphipathic cyclodextrin of the present invention
The polymer drug-carried system controlled-release effect of ball-type autohemagglutination is fine.Hydrophobic side in embodiment 2 is ethyl, hydrophobic relative to embodiment 1
End shortens, and causes hydrophobic part is opposite to weaken, small to the load capacity of drug, and can cause burst release.Water delivery chain in embodiment 3 is only
It is the hydroxyl of part substituted cyclodextrin 2,3, it is comparatively, small to the load capacity of drug.Case is compared, because without hydrophobic
End, cyclodextrin is hydrophobic with respect to polyethylene glycol, can form less stable from poly polymer, cause burst effect more obvious.
Specific embodiment
With reference to specific embodiment, the present invention is described in detail, but is not the limitation present invention.
Embodiment 1
(1) protection of 6 hydroxyls of cyclodextrin
In DMF, tert-butyl chloro-silicane 14.5g, cyclodextrin 9g and triethylamine 5mL react 96 hours at 30 DEG C,
Protect 6 primary alconols of cyclodextrin, vacuum distillation later removes solvent, silica gel column chromatography methanol and dichloromethane gradient come
Purified product, vacuum drying obtain tertiary butyl dimethyl Si cyclodextrin a；
(2) cyclodextrin 2, the alkylation of 3 hydroxyls
The a of 2g is taken first to be reacted in anhydrous DMF with sodium hydride 0.5g fully for 24 hours, adds in bromododecane 0.21mL later,
3d is reacted at 30 DEG C；The sodium hydride of 0.5g is added in anhydrous DMF again, reaction for 24 hours, adds in bromododecane later
0.21mL reacts 2d at 30 DEG C.It is quenched with methanol, vacuum distillation removes solvent, with gel chromatography separation method purified product, very
Sky is dried to obtain the tertiary butyl dimethyl Si cyclodextrin b of 12 alkane substitution；
(3) 6 hydroxyl deprotection of cyclodextrin
The b of 2g is taken to be hydrolyzed under excessive tetrabutyl ammonium fluoride aqueous solution, removes fert-butyidimethylsilyl, ammonium hydroxide neutralizes not anti-
The acid answered removes solvent, obtains crude product, be dried in vacuo, obtain product c to neutrality；
(4) iodo of 6 hydroxyls of cyclodextrin
The c of 2g is taken to be reacted for 24 hours at 70 DEG C with triphenyl phosphorus 6.47g, elemental iodine 6.74g in anhydrous DMF, vacuum distillation subtracts
Fall half solvent, adjust pH value to 9 with sodium methoxide, with a large amount of methanol extractions, methanol is washed three times, is obtained product, is dried to obtain d；
(5) 6 hydroxy thiols of cyclodextrin
The d of 2g is taken to react 28h at 90 DEG C with thiocarbamide 0.57g in DMF, vacuum distillation removes DMF, adds in appropriate hydrogen-oxygen
Change sodium water solution, back flow reaction 1h after reaction solution cooling, adjusts pH with aqueous potassium hydrogen sulfate and is less than 7, extracted with dichloromethane
It takes, saturated common salt washing removes solvent, obtains product e.
(6) bromo of poly glycol monomethyl ether
5g poly glycol monomethyl ethers 2000 is taken to be reacted for 24 hours at 20 DEG C in anhydrous methylene chloride with phosphorus tribromide 1mL, later
Reaction solution is slowly dropped in water, adds in dichloromethane extraction, then neutrality is washed to saturated salt solution, it is dry, with rotation
Evaporimeter removes dichloromethane solvent, obtains bromo poly glycol monomethyl ether f.
(7) poly glycol monomethyl ether is Thiolation
The f and thiocarbamide 5.7g of 5g is taken to be reacted for 24 hours at 70 DEG C in anhydrous DMF, vacuum distillation removes organic solvent, adds in
The aqueous solution of appropriate bases, 0.5~1.5h of back flow reaction after reaction solution cooling, adjust pH and are less than 7, extracted with dichloromethane, saturation
Salt is washed, and vacuum distillation removal solvent obtains Thiolation poly glycol monomethyl ether g.
(8) synthesis of amphipathic cyclodextrin flower bunch type polymer drug carrier
Take the g of the e and 0.7g of 0.1g that final two are fully obtained by the reaction in DMSO solution existing for excess hydrogen peroxide
Parent's property cyclodextrin h.
(9) assembling of the polymer drug-carried system of amphipathic cyclodextrin ball-type autohemagglutination
The h of 10mg is sufficiently stirred mixing in DMSO with the adriamycin of 10mg, instills deionized water later, is uniformly mixed it
Solvent is removed afterwards, it is dry, that is, form amphipathic cyclodextrin medicine-carried system.
(10) measurement of drugloading rate
Amphipathic cyclodextrin medicine-carried system is dissolved in methanol solution, ultrasound measures its UV absorption at 490nm, obtains
Go out drugloading rate for 40% (quality/gross mass of adriamycin).
(11) the slow controlled release research of drug
The polymer drug-carried system of amphipathic cyclodextrin ball-type autohemagglutination of 10mg is placed in the PBS of 2mL (or containing 10M DTT's
PBS it in), is put into bag filter, is placed in the bottle of the PBS buffer solutions (or PBS of the DTT containing 10M) containing 8mL again later
In, shaking table is put into, is discharged in 37 DEG C, is measured under taking outer layer PBS at the 490nm ultraviolet.Obtain adriamycin Cumulative release profile.
Embodiment 2
It is compared with embodiment 1, the main distinction is, hydrophobic segment is ethyl, and concrete operations are as follows：
(1) protection of 6 hydroxyls of cyclodextrin
In DMF, triphenylchloromethane 9g, cyclodextrin 5g and triethylamine 5mL react 96 hours at 70 DEG C, protect cyclodextrin
6 primary alconols, later vacuum distillation remove solvent, silica gel column chromatography methanol and dichloromethane gradient come purified product,
Vacuum drying obtains triphenyl methyl ether-cyclodextrin a；
(2) cyclodextrin 2, the alkylation of 3 hydroxyls
The a of 2g is taken first to be reacted in anhydrous DMF with sodium hydride 0.5g fully for 24 hours, bromoethane 0.15mL is added in later, 30
3d is reacted at DEG C；The sodium hydride of 0.5g is added in anhydrous DMF again, reaction for 24 hours, adds in bromoethane 0.15mL, at 30 DEG C later
Lower reaction 2d.It is quenched with methanol, vacuum distillation removes solvent, and with gel chromatography separation method purified product, vacuum drying obtains first
Oxygroup-triphenylmethoxy-cyclodextrin b；
(3)~(9) step repeats embodiment 1
(10) measurement of drugloading rate
Amphipathic cyclodextrin medicine-carried system is dissolved in methanol solution, ultrasound measures its UV absorption in certain wave strong point,
It is 25% to obtain drugloading rate.
(11) the slow controlled release research of drug
The PBS that the polymer drug-carried system of amphipathic cyclodextrin ball-type autohemagglutination of 5~10mg is placed in 2mL (or contains 10M
The PBS of DTT) in, it is put into bag filter, is placed in again later containing the small of 8mLPBS buffer solutions (or PBS containing 10M DTT)
Bottle in, be put into shaking table, discharged in 37 DEG C, take outer layer PBS locate to measure at a particular wavelength it is ultraviolet.Show that the accumulative of anticancer drug is released
Put curve.
Embodiment 3
It is compared with embodiment 1, the main distinction is, part 2,3- modification hydrophobic segments, and concrete operations are as follows：
(1) protection of 6 hydroxyls of cyclodextrin
In DMF, tert-butyl chloro-silicane 14.5g, cyclodextrin 9g and triethylamine 5mL react 96 hours at 70 DEG C,
Protect 6 primary alconols of cyclodextrin, vacuum distillation later removes solvent, silica gel column chromatography methanol and dichloromethane gradient come
Purified product, vacuum drying obtain tertiary butyl dimethyl Si cyclodextrin a；
(2) cyclodextrin 2, the alkylation of 3 hydroxyls
The a of 2g is taken first to be reacted in anhydrous DMF fully with sodium hydride 0.5g, adds in bromododecane 0.21mL later,
It reacts at 30 DEG C for 24 hours, is quenched with methanol, vacuum distillation removes solvent, with gel chromatography separation method purified product, is dried in vacuo
The tertiary butyl dimethyl Si cyclodextrin b replaced to 12 alkane；
(3) 6 hydroxyl deprotection of cyclodextrin
The b of 2g is taken to be hydrolyzed under excessive tetrabutyl ammonium fluoride aqueous solution, removes fert-butyidimethylsilyl, ammonium hydroxide neutralizes not anti-
The acid answered removes solvent, obtains crude product, be dried in vacuo, obtain product c to neutrality；
(4) iodo of 6 hydroxyls of cyclodextrin
The c of 2g is taken to be reacted for 24 hours at 70 DEG C with triphenyl phosphorus 3.24g, elemental iodine 3.37g in anhydrous DMF, vacuum distillation subtracts
Fall half solvent, adjust pH value to 9 with sodium methoxide, with a large amount of methanol extractions, methanol is washed three times, is obtained product, is dried to obtain d；
(5) 6 hydroxy thiols of cyclodextrin
The d of 2g is taken to react 28h at 90 DEG C with thiocarbamide 0.29g in DMF, vacuum distillation removes DMF, adds in appropriate hydrogen-oxygen
Change sodium water solution, back flow reaction 1h after reaction solution cooling, adjusts pH with aqueous potassium hydrogen sulfate and is less than 7, extracted with dichloromethane
It takes, saturated common salt washing removes solvent, obtains product e.
(6) bromo of poly glycol monomethyl ether
5g poly glycol monomethyl ethers 2000 is taken to be reacted for 24 hours at 20 DEG C in anhydrous methylene chloride with phosphorus tribromide 1mL, later
Reaction solution is slowly dropped in water, adds in dichloromethane extraction, then neutrality is washed to saturated salt solution, it is dry, with rotation
Evaporimeter removes dichloromethane solvent, obtains bromo poly glycol monomethyl ether f.
(7) poly glycol monomethyl ether is Thiolation
The f and thiocarbamide 5.7g of 5g is taken to be reacted for 24 hours at 70 DEG C in anhydrous DMF, vacuum distillation removes organic solvent, adds in
The aqueous solution of appropriate bases, 0.5~1.5h of back flow reaction after reaction solution cooling, adjust pH and are less than 7, extracted with dichloromethane, saturation
Salt is washed, and vacuum distillation removal solvent obtains Thiolation poly glycol monomethyl ether g.
(8) synthesis of amphipathic cyclodextrin flower bunch type polymer drug carrier
Take the g of the e and 0.7g of 0.1g that final two are fully obtained by the reaction in DMSO solution existing for excess hydrogen peroxide
Parent's property cyclodextrin h.
(9) assembling of the polymer drug-carried system of amphipathic cyclodextrin ball-type autohemagglutination
The h of 10mg is sufficiently stirred mixing in DMSO with the adriamycin of 10mg, is slowly dropped into deionized water later, and mixing is equal
Solvent is removed after even, it is dry, that is, form amphipathic cyclodextrin medicine-carried system.
(10) measurement of drugloading rate
Amphipathic cyclodextrin medicine-carried system is dissolved in methanol solution, ultrasound measures its UV absorption at 490nm, obtains
Go out drugloading rate for 29% (quality/gross mass of adriamycin).
(11) the slow controlled release research of drug
The polymer drug-carried system of amphipathic cyclodextrin ball-type autohemagglutination of 10mg is placed in the PBS of 2mL (or containing 10M DTT's
PBS it in), is put into bag filter, is placed in the bottle of the PBS buffer solutions (or PBS of the DTT containing 10M) containing 8mL again later
In, shaking table is put into, is discharged in 37 DEG C, is measured under taking outer layer PBS at the 490nm ultraviolet.Obtain adriamycin Cumulative release profile.
Compare case (comparative example 1)
It is compared with embodiment, difference lies in be made the carrier only modified at 6 relatively such as the prior art, specifically
Operation is as follows：
(1) iodo of cyclodextrin primary hydroxyl
The cyclodextrin of 2g is taken to be reacted for 24 hours at 70 DEG C with triphenyl phosphorus 6.47g, elemental iodine 6.74g in anhydrous DMF, decompression
Distillation cuts half solvent, adjusts pH value to 9 with sodium methoxide, with a large amount of methanol extractions, methanol is washed three times, obtains product, dry
Obtain a；
(2) cyclodextrin primary hydroxyl is Thiolation
The a of 2g is taken to react 28h at 90 DEG C with thiocarbamide 0.57g in DMF, vacuum distillation removes DMF, adds in appropriate hydrogen-oxygen
Change sodium water solution, back flow reaction 1h after reaction solution cooling, adjusts pH with aqueous potassium hydrogen sulfate and is less than 7, extracted with dichloromethane
It takes, saturated common salt washing removes solvent, obtains product c.
(3) bromo of poly glycol monomethyl ether
5g poly glycol monomethyl ethers 2000 is taken to be reacted for 24 hours at 20 DEG C in anhydrous methylene chloride with phosphorus tribromide 1mL, later
Reaction solution is slowly dropped in water, adds in dichloromethane extraction, then neutrality is washed to saturated salt solution, it is dry, with rotation
Evaporimeter removes dichloromethane solvent, obtains bromo poly glycol monomethyl ether f.
(4) poly glycol monomethyl ether is Thiolation
The f and thiocarbamide 5.7g of 5g is taken to be reacted for 24 hours at 70 DEG C in anhydrous DMF, vacuum distillation removes organic solvent, adds in
The aqueous solution of appropriate bases, 0.5~1.5h of back flow reaction after reaction solution cooling, adjust pH and are less than 7, extracted with dichloromethane, saturation
Salt is washed, and vacuum distillation removal solvent obtains Thiolation poly glycol monomethyl ether g.
(5) synthesis of cyclodextrin pharmaceutical carrier
Take the g of the e and 0.7g of 0.05g that final ring is fully obtained by the reaction in DMSO solution existing for excess hydrogen peroxide
Dextrin polymer h.
(6) assembling of cyclodextrin drug-loading system
The h of 10mg is sufficiently stirred mixing in DMSO with the adriamycin of 10mg, is slowly dropped into deionized water later, and mixing is equal
Solvent is removed after even, it is dry, that is, form cyclodextrin medicine-carried system.
(7) measurement of drugloading rate
Cyclodextrin medicine-carried system is dissolved in methanol solution, ultrasound measures its UV absorption at 490nm, obtains load medicine
It measures as 21% (quality/gross mass of adriamycin).
(8) the slow controlled release research of drug
The polymer drug-carried system of amphipathic cyclodextrin ball-type autohemagglutination of 10mg is placed in the PBS of 2mL (or containing 10M DTT's
PBS it in), is put into bag filter, is placed in the bottle of the PBS buffer solutions (or PBS of the DTT containing 10M) containing 8mL again later
In, shaking table is put into, is discharged in 37 DEG C, is measured under taking outer layer PBS at the 490nm ultraviolet.Obtain adriamycin release profiles.
Claims (10)
1. amphipathic cyclodextrin polymers pharmaceutical carrier, it is characterised in that：Using cyclodextrin as core, cyclodextrin core is extremely
The 6- positions modification of a few saccharide ring is grafted with hydrophilic segment；The 2- positions of at least one saccharide ring and/or 3- are modified with hydrophobicity
Segment.
2. one kind amphipathic cyclodextrin polymers pharmaceutical carrier as described in claim 1, it is characterised in that：Each sugar of cyclodextrin
The 6- positions of ring are modified with hydrophilic segment.
3. amphipathic cyclodextrin polymers pharmaceutical carrier as claimed in claim 1 or 2, it is characterised in that：The hydrophily
The 6- of segment and cyclodextrin positions are keyed by stimuli responsive type chemical combination；The stimuli responsive type chemical combination key is pH stimuli responsives
Chemical combination key, thermal stimulus response chemical combination key or redox stimuli responsive chemical combination key；
Further preferably, redox stimuli responsive chemical combination key is disulfide bond.
4. such as claims 1 to 3 any one of them amphipathic cyclodextrin polymers pharmaceutical carrier, it is characterised in that：Described
Hydrophilic segment is polyethylene glycol hydrophilic segment；Preferably, the molecular weight of polyethylene glycol hydrophilic segment is 200~8000.
5. such as Claims 1 to 4 any one of them amphipathic cyclodextrin polymers pharmaceutical carrier, it is characterised in that：Described
The 2- positions of saccharide ring or/and 3- are modified with hydrophobic chain segment；Preferably, the 2- positions of each saccharide ring of the cyclodextrin and 3-
It is modified with hydrophobic chain segment.
6. the amphipathic cyclodextrin polymers pharmaceutical carrier as described in claim 1 or 5, it is characterised in that：The hydrophobicity
Segment is the alkyl segment of C1~C20；Or for at least one in halogen, C1~C6 alkyl, C1~C6 alkoxies, benzyl
The alkyl segment of C1~C20 of a substituent group substitution；Preferably, the hydrophobic chain segment is the straight chain or branch of C5~C20
Chain saturated hydrocarbyl segment；
The hydrophobic segment is modified on 2- and/or 3- secondary hydroxyls；Further preferably, the hydrophobic segment is 12
Alkyl.
7. a kind of preparation of claim 1~6 any one of them amphipathic cyclodextrin polymers pharmaceutical carrier, feature exist
In：Include the following steps：
Step (a)：The protection of 6 hydroxyls of cyclodextrin
6 primary alconols of cyclodextrin are protected to obtain with 6 protected cyclodextrin of hydroxyl for a；
Step (b)：2 and/or 3 hydroxyls of cyclodextrin it is hydrophobically modified；
A is taken to be reacted under alkali with the source materials of hydrophobic chain segment, 2 and/or the hydrophobically modified production of 3 hydroxyls is obtained by the reaction
Object b；
Step (c)：6 hydroxyls deprotection of product b
It takes b in acid condition, hydrolyzes, remove 6 primary hydroxyl protecting groups, obtain product c；
(d) product c is directly connected to hydrophilic segment or is keyed by stimuli responsive type chemical combination, and the carrier is made.
8. the preparation of one kind amphipathic cyclodextrin polymers pharmaceutical carrier as claimed in claim 7, it is characterised in that：Irritation
It is disulfide bond to respond chemical combination key, and the preparation method of the carrier is：
(1) protection of 6 hydroxyls of cyclodextrin
In organic solvent, primary hydroxyl protecting group, cyclodextrin and triethylamine react 72~120h, protection ring paste at 20~80 DEG C
Smart 6 primary alconols, remove solvent later, obtain 6 protected cyclodextrin of hydroxyl as a；
(2) cyclodextrin 2, the alkylation of 3 hydroxyls
A is taken first fully to be reacted in organic solvent with sodium hydride, adds in bromoalkane later, 2~5d is reacted at 0~50 DEG C, is quenched
It goes out, removes solvent, gel chromatography separation method purified product is dried to obtain product b；
(3) 6 hydroxyl deprotection of cyclodextrin
It takes b in acid condition, hydrolyzes, remove primary hydroxyl protecting group, ammonium hydroxide neutralizes the complete acid of unreacted, removes solvent, obtains
To crude product, vacuum drying obtains product c；
(4) iodo of 6 hydroxyls of cyclodextrin
C reacts 18~36h with triphenyl phosphorus, elemental iodine in anhydrous organic solvent at 60~90 DEG C, cuts half solvent, uses first
Sodium alkoxide adjusts pH value to 9~10, and with a large amount of methanol extractions, methanol is washed three times, is obtained product, is dried to obtain d；
(5) 6 hydroxy thiols of cyclodextrin
D reacts 16~28h with thiocarbamide at 60~100 DEG C in organic solvent, removes organic solvent, adds in the water-soluble of appropriate bases
Liquid, 0.5~1.5h of back flow reaction after reaction solution cooling, adjust pH and are less than 7, extracted with dichloromethane, and saturated common salt washing is gone
Except solvent, product e is obtained；
(6) bromo of poly glycol monomethyl ether
Poly glycol monomethyl ether reacts 18~28h with phosphorus tribromide in anhydrous organic solvent at 0~30 DEG C, later by reaction solution
It is slowly dropped in water, adds in dichloromethane extraction, then neutrality is washed to saturated salt solution, it is dry, it is removed with Rotary Evaporators
Dichloromethane solvent is removed, obtains bromo poly glycol monomethyl ether f；
(7) poly glycol monomethyl ether is Thiolation
F reacts 16~28h in anhydrous organic solvent with thiocarbamide at 60~100 DEG C, removes organic solvent, adds in appropriate bases
Aqueous solution, 0.5~1.5h of back flow reaction after reaction solution cooling, adjust pH and are less than 7, extracted with dichloromethane, saturated salt solution
It washes, removes solvent, obtain Thiolation poly glycol monomethyl ether g；
(8) synthesis of amphipathic cyclodextrin flower bunch type polymer drug carrier
G, final amphipathic cyclodextrin h is fully obtained by the reaction in e in an oxidizing environment；
Preferably, in step (1), the molar ratio of cyclodextrin and primary hydroxyl protecting group is 1: 3~1: 14；Primary hydroxyl protecting group is three
One or more of phenyl chloromethanes, tert-butyl chloro-silicane, paratoluensulfonyl chloride；
Preferably, in step (2), the chemical formula of bromoalkane is R1- Br, the R1Alkyl for C5~12；A and bromoalkane,
The molar ratio of sodium hydride is 1: 7: 7~1: 60: 60；
Preferably, in step (2), bromoalkane and NaH are added in batches, and the method that is added portionwise is, by sodium hydride and bromo
Alkane is respectively classified into 2~3 parts, a sodium hydride of first addition, reaction more than 4h (preferably 12~for 24 hours) a bromoalkane is added,
After reacting 1~4d, this step is repeated, until reaction terminates；
Preferably, the acid described in step (3) is one or more of tetrafluoro boric acid, tetrabutyl ammonium fluoride, acetic acid；Add in acid
Amount needs excess；
Preferably, the molar ratio of c and elemental iodine, triphenyl phosphorus is 1: 7: 7~1: 28: 28 in step (4)；
Preferably, step (5) and alkali described in (7) be sodium hydroxide, one or more of potassium hydroxide, sodium methoxide；Reaction
The molar ratio of object and thiocarbamide is 1: 3~1: 30；
Preferably, in step (6) molar ratio of poly glycol monomethyl ether and phosphorus tribromide 1: 2~1: 5；
Preferably, the oxidation environment described in step (8) is that oxygen is added into reaction solution or is added in containing hydrogen peroxide
Aqueous solution connects air and heats to realize；The molar ratio of g and e is 1: 7~1: 21；
Preferably, in step (1)~(8), organic solvent used be independently chosen from n,N-Dimethylformamide, dichloromethane,
One or more of methanol, ethyl alcohol, dimethyl sulfoxide (DMSO)；
Preferably, in step (1)~(8), signified anhydrous and oxygen-free reaction system is with the inert gases atmosphere such as nitrogen or argon gas
Enclose lower completion.
9. a kind of application of claim 1~6 any one of them amphipathic cyclodextrin polymers pharmaceutical carrier, feature exist
In：Amphipathic cyclodextrin polymers pharmaceutical carrier, hydrophobic drug and the organic solvent are mixed into obtain dispersion liquid, disperseed
Water is added in liquid, carries out self assembly, obtaining load has the sustained release preparation of hydrophobic drug；
Preferably, the hydrophobic drug is hydrophobic anticancer drug；Further preferably 5 FU 5 fluorouracil, hydrochloric acid Ah mould
One or more of element, hydroxycamptothecin, vincristine, taxol；
Preferably, the grain size of the amphipathic cyclodextrin polymers pharmaceutical carrier is preferably 40~100nm.
10. a kind of sustained-release preparation of dewatering medicament, which is characterized in that assembled using the application process described in claim 9
Arrive, including the spherical particles being self-assembly of by several amphipathic cyclodextrin polymers pharmaceutical carriers, the spherical particles it is outer
Layer is grafted with the hydrophilic segment；Spherical particles inner cavity chamber load hydrophobic drug, and its inner surface be modified with it is hydrophobic
Property segment.
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| CN109821025A (en) * | 2019-01-21 | 2019-05-31 | 中南大学 | A kind of light and redox double stimuli responsive type amphiphilic polymer pharmaceutical carrier and its preparation method and application |
| CN113384713A (en) * | 2021-06-12 | 2021-09-14 | 南开大学 | Enzyme-responsive supramolecular nanoparticle controllable-release anticancer drug adriamycin system and preparation method thereof |
| CN115006549A (en) * | 2022-06-16 | 2022-09-06 | 湖南科技大学 | Preparation method of acid-sensitive cross-linked cyclodextrin nano-hydrogel drug delivery system with controllable particle size and controllable degradation |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109821025A (en) * | 2019-01-21 | 2019-05-31 | 中南大学 | A kind of light and redox double stimuli responsive type amphiphilic polymer pharmaceutical carrier and its preparation method and application |
| CN109821025B (en) * | 2019-01-21 | 2020-11-06 | 中南大学 | Light and redox dual-stimulus response type amphiphilic polymer drug carrier and preparation method and application thereof |
| CN113384713A (en) * | 2021-06-12 | 2021-09-14 | 南开大学 | Enzyme-responsive supramolecular nanoparticle controllable-release anticancer drug adriamycin system and preparation method thereof |
| CN115006549A (en) * | 2022-06-16 | 2022-09-06 | 湖南科技大学 | Preparation method of acid-sensitive cross-linked cyclodextrin nano-hydrogel drug delivery system with controllable particle size and controllable degradation |
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