CN106928462A - A kind of PLA-PEG-PLA dendritics - Google Patents
A kind of PLA-PEG-PLA dendritics Download PDFInfo
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Abstract
The invention discloses a kind of PLA PEG PLA dendritics, preparation method and applications.Preparation method of the present invention is simple, and due to its special molecular structure, the winding degree of segment is far above linear polymer to the hydrophobic segment of the dendritic for obtaining in micella core, and medicine is embedded in and is wherein less susceptible to dissolution, thus can improve the stability of carrier micelle；The end group quantity of poplar bundles structure is apparently higher than linear polymer therefore also more obvious than linear polymer for the effect of terminal groups modification；Closely, particle diameter is smaller, it is easier to play EPR effects, preferable to tumour tumor tissue targeting for the micellar structure that the polymer of poplar bundles is formed.Dendritic of the invention can be applied as pharmaceutical carrier in pharmaceutical preparation is prepared.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, and in particular to say, be related to a kind of PLA-PEG-PLA dendritics,
Preparation method and applications.
Background technology
Polymer micelle is a kind of Nano medication controlled release system mainly for insoluble drug developed in recent years.Polymerization
Thing micelle administration system can significantly improve the solubility of medicine；Medicine toxicity is reduced, so as to improve therapeutic dose；Medicine
It is wrapped in core, drug degradation can be avoided to inactivate；Micella particle diameter very little, generally in below l00nm, can hide in netted
The phagocytosis of dermal system (RES), extension body circulation time, is reached to tumour quilt by strengthening osmotic effect (EPR effects)
Moving-target to effect, so as to improve therapeutic effect.Up to now, form the most important material of micella and be still amphipathic block
Copolymer.Copolymer hydrophobic side is inside in micella, and water-wet side is outside, in typical nucleocapsid structure, and hydrophobic kernel master
To be used for solubilized insoluble drug.
For this Nano medication controlled release system of micella, core is high polymer adjuvant, high polymer adjuvant and medicine in carrier micelle
Between interaction largely determine property inside and outside the glue bundle body, while largely affecting drug effect
And toxicity.However, up to now, in the drug delivery system of FDA approval listings, really by human body inspection simultaneously
It is proved to the synthesis high polymer adjuvant with tight security and there was only polyethylene glycol (PEG) and poly (lactide-co-glycolide)
(PLGA) two class.This two family macromolecule and its copolymer also make in other a large amount of ongoing clinical trials as auxiliary material
With.It is generally acknowledged that PEG by RE, therefore can will not in vivo assemble；And PLGA final catabolite is two
Carbonoxide and water, also do not poison to human body.It is presently used for being studied most extensively in the high polymer adjuvant for prepare micella, application
Most ripe is the block copolymer (mPEG-PLA) of methoxy poly (ethylene glycol) and poly- meso-lactide.
MPEG-PLA copolymers are not that pharmacopeia records composition.The difference of molecular weight and mPEG/PLA ratios according to PEG,
The copolymer of different structure and molecular weight can be formed.This analog copolymer have it is amphipathic, when in the solution formed micella when,
Micella periphery is hydrophilic mPEG segments, and kernel is hydrophobic PLA segments, using this property of copolymer material
Solubilising can be carried out to some insoluble drugs.MPEG-PLA biocompatibilities are good, and building-up process is simple, easy,
Itself is biodegradable, and lactic acid and PEG are degraded in vivo, and the two can be expelled directly out in vitro.Research shows：mPEG-PLA
Non-carcinogenesis, without genotoxicity, without teratogenesis, without mutagenicity, can be smoothly with original shape from RE.
At present, the polymer micelle drug delivery system with mPEG-PLA as carrier is more ripe, and is taken in laboratory stage
Certain progress was obtained, but the example of clinical conversion is still few, so far without such micellar preparation of FDA approval listings.
Maximum of which reason is very unstable (especially internal stability is worse) mPEG-PLA micellas.For example with mPEG-PLA
Even if being the docetaxel micella of carrier under relatively low concentration (2mg/ml), 6 hours are that drug precipitation occurs at room temperature,
Research finds：This micella is rapid after entering in vivo to disintegrate, and medicine is tied with the albumen (such as albumin) in blood immediately
Close and then transported toward tissue, therefore the enhancing osmotic effect (EPR effects) of micella cannot be played.
Although micella is received significant attention as a kind of promising slightly solubility anticancer drug carrier of comparing, it is with mPEG-PLA
The unstability (especially performance in vivo) of the micella of auxiliary material causes that the EPR effects of this nanometer formulation cannot be played, it is impossible to
Target administration is realized, therefore drug effect is also difficult to improve.On the other hand, at this stage, the micella prospect of active targeting is not found pleasure in
See.Therefore, developing thought more feasible for mPEG-PLA micellas at this stage is to improve the stability of micella, especially
Internal stability, had both retained the excellent biocompatibility of the macromolecule, while improving carrier by playing micella EPR effects
Targeting, and then improve drug effect.Therefore, people have done substantial amounts of effort.As patent 201010001047 discloses one kind
In micellar solution add amino acid improve micella stability method, and as auxiliary additive aminoacid ingredient whether
Into whether still keeping the stability of micella unknown by the dilution of blood after in vivo, therefore the internal effect for using
And it is indefinite；Whether the amino acid of addition produces influence to equally exist uncertainty the performance of drug effect as non-inert composition.
There is research to think together to be embedded in taxol and docetaxel the steady of micella is remarkably improved in block copolymer micelle in addition
It is qualitative, but this combination drug micella, clinically using accreditation is more difficult to get, internal stability is unknown at present.
In sum, the exploitation of micellar preparation faces larger difficulty, on the one hand, be clinically proven it is safe for medicine
The selection of the high polymer adjuvant of release system is extremely limited, and develops a kind of brand-new novel high polymer auxiliary material and undoubtedly face huge
Risk.Secondly, the drug effect for being seen in all kinds of micellar preparations of report is difficult to be obviously improved compared with conventional formulation, for example South Korea three
Though the taxol micella Genexol PM for supporting society's research and development complete the clinical trial of three phases in the U.S., because drug effect is not obvious, so far
FDA listing approvals are not obtained.3rd, the micella auxiliary material versatility that report is seen at present is poor, and a kind of usual auxiliary material can only pin
Micella is formed to one or two kind of effective ingredient, its popularization and application is have impact on.
The content of the invention
In order to solve the above problems, the present invention is carried based on the mPEG-PLA block copolymers with generally acknowledged security
For a kind of new PLA-PEG-PLA dendritics, preparation method and applications.
The present invention provides a kind of PLA-PEG-PLA dendritics, and molecular structural formula is as follows：
Wherein：R4 is the polylactide segment of hydrophobic group end-blocking.
In above-mentioned dendritic, the R4 is the polylactide segment of hydrophobic group end-blocking, and its molecular formula isWherein Y is hydrophobic group.
In the present invention, the selected hydrophobic group Y of terminal groups modification aspect mainly considers three effects of aspect：First, energy
Enough increase the hydrophobicity of hydrophobic segment in high polymer adjuvant, so as to improve parcel ability of the micella to medicine.Due to
End terminal hydroxy group has between certain hydrophily, and hydrophobic medicine such as docetaxel and is difficult to be formed in mPEG-PDLLA
Stronger active force, influence micella is to the bag core of medicine, and passing through grafted hydrophobic end group can significantly improve its hydrophobicity；
Second, by improving drug molecule and block copolymer in hydrophobic chain segment compatibility, increase drug molecule and hydrophobic chain
Active force, makes drug molecule be difficult dissolution in micelle inner core；3rd, can form intermolecular force, including hydrogen bond,
Conjugation, so as to help that medicine is wrapped in the kernel of micella, further increases the stability of micella.
In above-mentioned dendritic, described hydrophobic group Y includes any one of following radicals：Alkyl, tertiary fourth
Oxygen carbonyl, benzyl, fluorenylmethyloxycarbonyl or phenyl ring.Preferably, it is fluorenylmethyloxycarbonyl or phenyl ring.
In above-mentioned dendritic, total number average molecular weight is 2000-60000, and the number-average molecular weight of wherein PEG chain segment is
1000-10000。
The present invention also provides a kind of preparation method of above-mentioned PLA-PEG-PLA dendritics, comprises the following steps as follows：
(1) synthesis end group branch polyethylene glycol G4-PEG-G4
By NHS-PEG-NHS and 4 generation poplar bundles polyester G4-NH2After being dissolved in organic solvent, triethylamine TEA is added
Reaction is stirred at room temperature, the white powder material after reactant ether precipitation is G4-PEG-G4；Wherein：
NHS-PEG-NHS、G4-NH2It is 1 with the mol ratio of TEA：(1-5：(0.1-5)；
(2) 32 branch polyethylene glycols PEG-G4- (OH) of hydroxyl are contained32Synthesis
G4-PEG-G4 is dissolved in Organic Alcohol, is dividedly in some parts Dowex H+ exchanger resins, is filtered to remove after room temperature reaction 12h
Resin, the white powdery solids after solution ether precipitation are PEG-G4- (OH)32；
(3) dumbbell shape block copolymer PLAnSynthesis
By DL- lactides and PEG-G4- (OH)32It is added in dry polymerization bottle, with lactide molar ratio 0.05-0.5%
SnOCt2As catalyst, by reactant in the 6-24h that is polymerized at 130-150 DEG C, product chlorine after vacuum sealing polymerization bottle
Imitative dissolving, gained white solid is subject copolymers dumbbell shape block copolymer PLA after methanol extractionn。
(4) end capping reaction
By dumbbell shape block copolymer PLAnReacted with hydrophobic end-capping reagent, by obtaining target after purification
PLA-PEG-PLA dendritics.
Further, the present invention also provides a kind of above-mentioned PLA-PEG-PLA dendritics and is being prepared as pharmaceutical carrier
Application in pharmaceutical preparation.
The beneficial effects of the present invention are：The hydrophobic segment of poplar bundles is due to its special molecular structure, chain in micella core first
The winding degree of section is far above linear polymer, and medicine is embedded in and is wherein less susceptible to dissolution, thus can improve the steady of carrier micelle
It is qualitative；The end group quantity of poplar bundles structure is apparently higher than linear polymer therefore also more poly- than linear for the effect of terminal groups modification
Compound is obvious；Closely, particle diameter is smaller, it is easier to play EPR effects for the micellar structure that the polymer of poplar bundles is formed, to swollen
Knurl tumor tissue targeting is preferable.
Brief description of the drawings
Fig. 1 is the chemical equation schematic diagram for synthesizing PLA-PEG-PLA dendritic steps.
Fig. 2 is G4-PEG-G41H NMR spectras.
Fig. 3 is PEG-G4- (OH)32's1H NMR spectras.
Fig. 4 is dumbbell shape block copolymer (PLAn)1H NMR spectras.
Fig. 5 is that embodiment 2 surveys the taxol micella grain size distribution for obtaining, and particle diameter is 25.4 ± 4.5nm
Fig. 6 is that embodiment 3 surveys the taxol micella grain size distribution for obtaining, and particle diameter is 25.6 ± 4.6nm.
Fig. 7 is that embodiment 4 surveys the docetaxel micella grain size distribution for obtaining, and particle diameter is 24.1 ± 4.4nm.
Fig. 8 is adriamycin micella grain size distribution, and particle diameter is 26.2 ± 4.5nm.
Fig. 9 is curcumin micella grain size distribution, and particle diameter is 24.9 ± 4.6nm.
Figure 10 is micella stability contrast schematic diagram.
Figure 11 is that tumor Volume Changes figure is shown.
Specific embodiment
In PLA-PEG-PLA dendritics of the invention, the quantity of poplar bundles hydroxyl can be 16,32 or 64
Individual, response path is essentially identical.
Embodiment 1 synthesizes 32 PLA-PEG-PLA dendritics of hydroxyl
Its specific reactive mode is as shown in Figure 1.
(1) synthesis NHS blocks polyethylene glycol (NHS-PEG-NHS)
Carboxy polyethylene glycol (molecular weight is 2000) 10g is dissolved in 50mL anhydrous methylene chlorides, adds 1.16g N hydroxyls
Succinimide (NHS, 10mmol), 2.08g carbodicyclo hexylimides (DCC), 0.12g dihydromethyl propionic acids
(bis-MPA), and 1.1g 4- dimethylamino pyridine-p- toluene fulfonates (DPTS), stirring reaction 48h is obtained at room temperature
Reaction solution.After reacting liquid filtering is removed into insoluble matter, pour into 1L ether and precipitate, sediment is redissolved in organic molten
Agent, such as tetrahydrofuran, ethyl acetate, dichloromethane or chloroform etc., the water insoluble impurity that then removal side reaction is produced,
It is preferred that using centrifugal separation, after being deposited in ether again by sediment removing and by clear liquid, white powder is vacuum dried to obtain
Solid is NHS and blocks polyethylene glycol (NHS-PEG-NHS).
(2) synthesis end group branch polyethylene glycol (G4-PEG-G4)
(G4-NH2 is closed 3.47g (0.34mmol) NHS-PEG-NHS and 4.37g (2.04mmol) 4 generations poplar bundles polyester
Into method bibliography Macromolecules 2002；35:8307 methods synthesize) be dissolved in after 25mL anhydrous methylene chlorides plus
Enter 1mL (7.33mmol) triethylamine and reaction 48h is stirred at room temperature.Reactant ether precipitation after white powder material be
G4-PEG-G4.Resulting G4-PEG-G4 is carried out into magnetic resonance detection, testing conditions are：Bruker 400M nuclear-magnetisms
Resonance instrument, to hold liquid, TMS is internal standard, hydrogen spectrum to deuterochloroform.The collection of illustrative plates for obtaining is as shown in Fig. 2 can from a peaks and b peaks
Will become apparent from successfully being grafted to the structure of poplar bundles the two ends of polyethylene glycol.
(3) the 32 branch polyethylene glycol of hydroxyl (PEG-G4- (OH) are contained32) synthesis
1.05gG4-PEG-G4 is dissolved in 75mL methyl alcohol, is dividedly in some parts 0.5 gram of -1 gram of Dowex H+ exchanger resin, room temperature
Resin is filtered to remove after reaction 12h, the white powdery solids after solution ether precipitation are PEG-G4- (OH)32。
By resulting PEG-G4- (OH)32Magnetic resonance detection is carried out, testing conditions are：Bruker 400M nuclear magnetic resonance
Instrument, to hold liquid, TMS is internal standard, hydrogen spectrum to deuterochloroform.The collection of illustrative plates for obtaining is as shown in figure 3, it can be seen that branch in Fig. 3
Change body structure surface terminal hydroxy group deprotection complete.
(4) dumbbell shape block copolymer (PLAn) synthesis
(PLAn) the single lactide segment of representative in formula the degree of polymerization.The product n=10 therein that following step is obtained.
1gDL- lactides (6.94mmol) and 1g PEG-G4- (OH)32It is added in dry polymerization bottle, adds 5mg
SnOct2Used as catalyst, by reactant in the 12h that is polymerized at 130 DEG C after vacuum sealing polymerization bottle, product chloroform dissolves,
Gained white solid is subject copolymers after methanol extraction, and its number-average molecular weight is 4000.
By resulting (PLAn) magnetic resonance detection is carried out, testing conditions are：Bruker 400M NMRs, it is deuterated
Chloroform is solvent, and tetramethylsilane (tetramethylsilane, abbreviation TMS) is NMR internal standards, measures its nuclear magnetic resonance
Hydrogen spectrum includes following characteristics peak, and the visible characteristic peak for representing polylactide, can be shown in Table at 3.6ppm at 1.6,5.2ppm
Show the characteristic peak of polyethylene glycol, the visible characteristic peak for representing poplar bundles polyester construction at 1.1ppm and 4.2-4.4ppm.
The collection of illustrative plates for arriving such as Fig. 4, it can clearly be seen that the characteristic absorption of PEG and PLA in Fig. 4.
(5) end capping reaction
The dumbbell shape block copolymer of reacting dose and hydrophobic end-capping reagent are reacted, is total to by obtaining target macromolecule after purification
Polymers, the molecular formula of copolymer is as follows：
Wherein R4 is the polylactide segment of hydrophobic group end-blocking, and number average molecular weight is 1000-50000.
The benzyl end-capped copolymer of embodiment 2 wraps up taxol
Poplar bundles LA-PEG-PLA dendritic 5g and 2g chlorobenzoyl chlorides obtained by the first step are added into round bottom to burn
In bottle, 100 DEG C of reaction 6h are heated under nitrogen protection, product is dissolved after being cooled to room temperature with dichloromethane, after ether precipitation
It had both been the copolymer auxiliary material B z endcapped mPEG-PLA of benzyl end-blocking to obtain white powdery solids.
By the polymer auxiliary material 1g and appropriate taxol co-dissolve of the benzyl end-blocking obtained by above-mentioned steps in ethyl acetate,
50 DEG C of rotary evaporations remove solvent, and after adding the dissolving of 50ml waters for injection, solution is filtered to remove not through 0.22 μm of pvdf membrane
Wrapped taxol, the taxol micelle freeze-drying powder that the subsequent solution is freezed.The freeze-dried powder determines particle diameter after redissolving
25.4nm (see Fig. 5 grain size distributions).
By adjusting the input quantity of input taxol, the micelle freeze-drying powder that content of taxol is not waited can be obtained.Every 100 parts
Copolymer can at most wrap up 85 parts of taxols, and copolymer is 100 with the part by weight of taxol：1~85.
Fig. 5 is the taxol micella grain size distribution that the present embodiment actual measurement is obtained, and particle diameter is 25.4 ± 4.5nm
Particle diameter distribution is homogeneous.
Embodiment 3Fmoc group end cappings wrap up taxol
1.84g Fmoc lysines add triethylamine 0.7ml, solution to be cooled to -10 DEG C after being dissolved in 10ml anhydrous ethyl acetates,
Add pivalyl chloride 0.61ml that 0 DEG C of reaction 2h is warming up under stirring, then heat to room temperature and react 1h again, filtering removal is not
Molten thing, obtains white solid and is dissolved in 5ml dry methylene chlorides after filtrate rotary evaporation removal solvent, adds triethylamine 0.7ml,
4- pyrollidinopyridine 74mg, solution adds the PLA-PEG-PLA dendritics 1g after being cooled to 0 DEG C, reaction
Room temperature continuation reaction 24h obtains Fmoc terminated polymer Fmoc-Lys endcapped mPEG-PLA after 2h.
The Fmoc terminated polymers 1g that above-mentioned steps are obtained is dissolved in ethanol, 45 DEG C of rotary evaporation removals with appropriate taxol
Solvent, after adding the dissolving of 50ml waters for injection, liquid is filtered to remove not wrapped taxol through 0.22 μm of pvdf membrane, with
Taxol micelle freeze-drying powder is freezed to obtain afterwards.The freeze-dried powder determines particle diameter after redissolving be 25.6nm.
By adjusting the input quantity of input taxol, the micelle freeze-drying powder that content of taxol is not waited can be obtained.Every 100 parts
Copolymer can at most wrap up 100 parts of taxols, and copolymer is 100 with the part by weight of taxol：1~100.
Fig. 6 is the taxol micella grain size distribution that the present embodiment actual measurement is obtained, and particle diameter is 25.6 ± 4.6nm.
Embodiment 4, Boc- phenylalanines end-blocking parcel docetaxel
1.33g Boc- phenylalanines add triethylamine 0.7ml, solution to be cooled to -10 DEG C after being dissolved in 10ml anhydrous ethyl acetates,
Add pivalyl chloride 0.61ml that 0 DEG C of reaction 2h is warming up under stirring, then heat to room temperature and react 1h again, filtering removal is not
Molten thing, obtains white solid and is dissolved in 5ml dry methylene chlorides after filtrate rotary evaporation removal solvent, adds triethylamine 0.7ml,
Pyrollidinopyridine 74mg, solution adds the PLA-PEG-PLA dendritics 1g after being cooled to 0 DEG C, reaction
Room temperature continuation reaction 24h obtains Boc- phenylalanine terminated polymer Boc-Phe endcapped mPEG-PLA after 2h.
The Boc- phenylalanines end-blocking high polymer adjuvant 1g that above-mentioned steps are obtained and appropriate docetaxel are dissolved in ethyl acetate,
40 DEG C of rotary evaporations remove solvent, add 50ml waters for injection dissolving medicine, solution to be filtered to remove through 0.22 μm of pvdf membrane
Not wrapped medicine, then freezes to obtain docetaxel micelle freeze-drying powder.Fig. 7 is the docetaxel that the present embodiment actual measurement is obtained
Micella grain size distribution, particle diameter is 24.1 ± 4.4nm.The freeze-dried powder determines particle diameter after redissolving be 24.1nm.Thrown by adjusting
Enter the input quantity of taxol, the micelle freeze-drying powder that content of taxol is not waited can be obtained.Every 100 parts of copolymers can at most be wrapped
50 parts of docetaxels are wrapped up in, copolymer is 100 with the part by weight of docetaxel：1~50.
Embodiment 5：Parcel adriamycin
20mg ADMhs are dissolved in 1ml chloroforms, add 0.5ml triethylamine lucifuges to add embodiment after 12h is stirred at room temperature
The high-molecular copolymer 100mg of 3 gained, (molecular cut off is 3000) dialysis 24h in bag filter is transferred to by above-mentioned solution
Freeze afterwards and obtain micella adriamycin micelle freeze-drying powder.
By adjusting the input quantity of input adriamycin, the micelle freeze-drying powder that doxorubicin content is not waited can be obtained.Every 100 parts
Copolymer can at most wrap up 33 parts of adriamycins, and copolymer is 100 with the part by weight of adriamycin：1~33.
Fig. 8 is adriamycin micella grain size distribution, and particle diameter distribution is homogeneous, and particle diameter is 26.2 ± 4.5nm.
Embodiment 6：Parcel curcumin
20mg curcumins and the gained copolymer of 300mg embodiments 1 are dissolved in 5ml acetone, 45 DEG C of revolving removal solvent acetones
Curcumin micellar solution is obtained after adding the ultrapure water dissolves medicine films of 5ml afterwards,
By adjusting the input quantity of input curcumin, the micelle freeze-drying powder that turmeric cellulose content is not waited can be obtained.Every 100 parts
Copolymer can at most wrap up 20.5 parts of curcumins, and copolymer is 100 with the part by weight of curcumin：1~20.5.
As shown in figure 9, particle diameter distribution is homogeneous, particle diameter is 24.9 ± 4.6nm to the micella particle diameter distribution.
Experimental example 7, the contrast of micella stability
The carrier micelle that embodiment 2-4 is obtained, is redissolved using appropriate water for injection.Separately according to patent CN1197396A institutes
The method stated voluntarily prepares mPEG-PLA taxol micellas.The drug concentration unification of all solution is adjusted to 5mg/ml.So
Hyclone (concentration of last hyclone is 50%) is added afterwards, and micella change of size in 24h is recorded with dynamic light scattering,
As shown in Figure 10：
As shown in Figure 10, in the serum solution of high concentration, particle diameter does not almost have three kinds of micellas that prepared by embodiment 1-3 in 24h
Change, it is seen that its stability is very high.And mPEG-PLA micellas particle diameter in 6h has significantly become big, illustrate that its is steady
It is qualitative poor.
Experimental example 8, inhibiting tumor assay
With A549 adenocarcinomas of lung as model, the taxol micella for using embodiment 2 and embodiment 3 to prepare is medicine.Using city
Sell Genexol PM as a comparison.When tumour grows to about 150mm3When packet administration, every group of 6 nude mices, altogether administration
4 times, every 3 days once, measures gross tumor volume and records such as Figure 11：
As seen from Figure 11, tumor killing effect of the micella that embodiment 2 and embodiment 3 are obtained in the case where dosage is waited is significantly stronger than
MPEG-PLA- taxols micella (commercially available Genexol PM), significant difference p<0.01, illustrate the target of both micellas
Tropism is significantly higher than linear mPEG-PLA taxol micellas, with preferable application prospect.
Claims (4)
1. a kind of PLA-PEG-PLA dendritics, it is characterised in that molecular structural formula is as follows：
Wherein：R4 is the polylactide segment of hydrophobic group end-blocking.
2. dendritic as claimed in claim 1, it is characterised in that the polylactide segment of the hydrophobic group end-blocking
The molecular formula of R4 isWherein Y is hydrophobic group.
3. dendritic as claimed in claim 2, it is characterised in that described hydrophobic group Y is included in following radicals
Any one：Tertbutyloxycarbonyl, benzyl, fluorenylmethyloxycarbonyl or phenyl.
4. dendritic as claimed in claim 1, it is characterised in that total number average molecular weight is 2000-60000, wherein PEG
The number-average molecular weight of segment is 1000-10000.
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| CN111053946A (en) * | 2019-12-19 | 2020-04-24 | 南京智能高端装备产业研究院有限公司 | Bi-component tissue adhesive based on polysaccharide and hyperbranched polypeptide and preparation method thereof |
| CN115975182A (en) * | 2023-01-10 | 2023-04-18 | 深圳市乐土生物医药有限公司 | Amino acid copolymer and application thereof |
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| CN103772686A (en) * | 2012-10-26 | 2014-05-07 | 苏州雷纳药物研发有限公司 | Amphiphilic block copolymer and preparation method thereof, micelle drug delivery system formed by copolymer and anti-tumor drug |
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| CN103772686A (en) * | 2012-10-26 | 2014-05-07 | 苏州雷纳药物研发有限公司 | Amphiphilic block copolymer and preparation method thereof, micelle drug delivery system formed by copolymer and anti-tumor drug |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111053946A (en) * | 2019-12-19 | 2020-04-24 | 南京智能高端装备产业研究院有限公司 | Bi-component tissue adhesive based on polysaccharide and hyperbranched polypeptide and preparation method thereof |
| CN115975182A (en) * | 2023-01-10 | 2023-04-18 | 深圳市乐土生物医药有限公司 | Amino acid copolymer and application thereof |
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