CN108017783A - Polymer with high potency drugs load performance and preparation method and application - Google Patents
Polymer with high potency drugs load performance and preparation method and application Download PDFInfo
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Abstract
The present invention provides a kind of polymer with high potency drugs load performance and preparation method and application, and the macromolecule is with poly-（Ethylene glycol）‑bPoly- [（N2 ethoxys）Asparagine] based on, and modify to obtain by phenyl boric acid, macromolecule material of main part is the polyethylene glycol and polyaminoacid for having good biocompatibility, the phenyl boric acid group of polyaminoacid side chain can reach efficient drug loading with the medicine containing amino by Coordination interaction, have the drugloading rate of superelevation to clinically common chemotherapeutics such as adriamycin, Epi-ADM, Irinotecan etc.（More than 50%）With the envelop rate close to 100%, and carrier micelle release with hydrogen peroxide response；The freeze-dried powder of carrier micelle has a good solubility in aqueous, and the particle diameter of formation is small and narrowly distributing；Prepare simply at the same time, easy to promote, there is huge development prospect in bio-medical material especially drug delivery field.
Description
Technical field
The present invention relates to small-molecule drug load and delivering field, and it is related to amino acid technical field, more particularly to has
Polymer of high potency drugs load performance and preparation method and application.
Background technology
High molecular nanometer medicine refers to utilize nanometer technology, small-molecule drug is wrapped in the macromolecule carrier of self assembly
Portion, it is nano level delivery system to prepare scale.Macromolecule carrier is typically amphiphatic polymer, it can be formed
Hydrophobic inner core is used to wrap up dewatering medicament, and hydrophilic shell can improve the water-soluble and internal stability of carrier micelle.High score
Sub- Nano medication can extend drug blood circulation time, pass through tumor locus " infiltration of enhancing and retention effect "（EPR is imitated
Should）Realize passive target, while the design of carrier can be utilized to realize the targeting conveying and control release of medicine, finally improve medicine
The effect of thing, simultaneously reduces toxicity.The Nano medication listing based on the high molecular material such as polyester or polyaminoacid at present
（Genexol-PM）Or it is in clinical investigation phase（NK105、NC6004、CT-2103）.And the country is on high molecular nanometer
The exploitation of medicine also has substantial amounts of relevant report, for example, a kind of polyaminoacid material, can wrap up adriamycin and improve its stabilization
Property；A kind of macromolecule can be with compound small molecule cis-platinum, and obtained compound has good dissolubility and biocompatibility.
Although high molecular nanometer medicine is quickly grown in recent years, successfully clinical conversion is still limited by a nanometer medicine for it
The various properties of thing in itself, such as drugloading rate, envelop rate, dissolubility and release performance.At present, many high molecular nanometer medicines are all
It is to be prepared using self-assembling methods such as nanoprecipitations.However, high molecular material be generally difficult to obtain by these methods it is very high
Drugloading rate and envelop rate.Wherein, the aggregation that interaction too strong between medicine is induced is to cause a master of the above results
Want reason.Interaction between drug molecule is reduced by rational structure design or is improved between medicine and macromolecule carrier
Interaction potentially contribute to realize efficient drug loading.There is document report to reduce medicine point by small molecule dimer
Rapid aggregation behavior between son, and the medicine for being used for realization superelevation supports, but this method synthesis step is complicated, should in clinic
There is very big difficulty in used time.
The content of the invention
The present invention provides a kind of high molecular material, especially the high molecular material side chain to contain phenyl boric acid group, can be with
Realized by coordination to efficiently supporting containing amino medicine, and the structure designed has hydrogen peroxide response, can be with
Realize carrying medicament specificity release.
The present invention adopts the following technical scheme that：
A kind of polymer, has formula（I）Shown structure；
Formula（I）In, R1Selected from hydrogen, alkyl or substitution alkyl；
R2Selected from-NH- or-R5(CH2)rNH-, wherein, R5For-O- ,-OCONH- ,-OCO- ,-NHCOO- or-NHCO-, 1≤r≤
10；
R3Selected from hydrogen or following group：
R3 `Selected from hydrogen or following group：
R4Selected from hydrogen or hydrophobic grouping；
20≤n≤500；5≤m≤200.
In above-mentioned technical proposal, the alkyl is the alkyl of C1 ~ C40；In the substitution alkyl, substituent is sulfydryl, sugar
Residue, aldehyde radical, carboxyl, vinyl, alkynyl, succimide, maleimide, biotin, RGD classes small peptide, LHRH class small peptides
Or folic acid；The hydrophobic grouping is alkyl, benzyl, cholesterol formoxyl, acetyl group, cholic acid group or the deoxycholic acid of C4 ~ C20
Base.
In high molecular material provided by the invention based on polyaminoacid, it is preferred that the poly- amino containing phenyl boric acid structure
Acid fragment ratio in total polyaminoacid is not less than 20%；It is furthermore preferred that the group ratio of phenyl boric acid structure 40%~60% it
Between；The ratio is too low or too high may influence drug carrying ability or material solubility property.
Preferably, 40≤n≤250；M is the degree of polymerization of aspartic acid fragment in main chain, it is preferred that 10≤m≤50.
In preferable technical solution, R1For methyl；R2For-NH-；R4For acetyl group, polymer has formula at this time（I-a）'s
Structure：
R3Selected from hydrogen or following group：
R3 `Selected from hydrogen or following group：
。
The high polymer based on amino acid that the present invention designs, by introducing phenyl boric acid group in the high molecular side base, makes
It can strengthen the stability of carrier and medicine in self assembling process with the medicine containing amino by coordination, reduce small
The aggregation of molecular medicine, to realize efficient drug loading；The phenyl boric acid group particularly preferably designed has hydrogen peroxide response,
It can realize that medicine-carried system is discharged in tumor locus specificity；Current high molecular material is solved during Nano medication is prepared
Existing medicine is reunited the problem of low with drugloading rate.
The present invention also provides one kind to have formula（Ⅰ）The preparation method of the polymer of structure, includes the following steps：
（1）With formula（II）Or formula（III）The compound of structure is reacted in organic solvent with shielded amino acid monomer, is obtained
To the polymer with protection group；The amino acid monomer is carboxylic acid anhydrides in γ-benzyl-L-aspartate ester-N-；
（2）The polymer with protection group and monoethanolamine are reacted, obtained with formula（IV）The copolymer of structure, is poly-
（Ethylene glycol）-b- poly- [（N- 2- ethoxys）- asparagine] copolymer；
（3）There is formula by described in（IV）The copolymer of structure and there is formula（V）The small molecule reaction of structure, obtains with formula（VI）
The intermediate of structure；Finally, there is formula（VI）The intermediate of structure is obtained with formula by dialysis（Ⅰ）The polymer of structure；Tool
Body is with formula（VI）The intermediate of structure hydrolyzes in dialysis procedure and finally obtains formula（Ⅰ）The polymer of structure.
The present invention also provides a kind of preparation method of polymer lyophilized powder, include the following steps：
（1）With formula（II）Or formula（III）The compound of structure is reacted in organic solvent with shielded amino acid monomer, is obtained
To the polymer with protection group；The amino acid monomer is carboxylic acid anhydrides in γ-benzyl-L-aspartate ester-N-；
（2）The polymer with protection group and monoethanolamine are reacted, obtained with formula（IV）The copolymer of structure, is poly-
（Ethylene glycol）-b- poly- [（N- 2- ethoxys）- asparagine] copolymer；
（3）There is formula by described in（IV）The copolymer of structure and there is formula（V）The small molecule reaction of structure, obtains with formula（VI）
The intermediate of structure；Finally, there is formula（VI）The intermediate of structure obtains polymer lyophilized powder by dialysis, freeze-drying；Tool
Body is with formula（VI）The intermediate of structure hydrolyzes in dialysis procedure and finally obtains formula（Ⅰ）The polymer of structure.
Present invention also offers the preparation method of intermediate, include the following steps：
（1）With formula（II）Or formula（III）The compound of structure is reacted in organic solvent with shielded amino acid monomer, is obtained
To the polymer with protection group；The amino acid monomer is carboxylic acid anhydrides in γ-benzyl-L-aspartate ester-N-；Polymerization is anti-
After the completion of answering, the end-blocking such as acetic anhydride, chloroacetic chloride, cholesterol formyl chloride is added（R4）, preferably blocked with acetic anhydride；
（2）The polymer with protection group and monoethanolamine are reacted, obtained with formula（IV）The copolymer of structure, is poly-
（Ethylene glycol）-b- poly- [（N- 2- ethoxys）- asparagine] copolymer；
（3）There is formula by described in（IV）The copolymer of structure and there is formula（V）The small molecule reaction of structure, obtains with formula（VI）
The intermediate of structure.
Compound structure of the present invention is as follows：
Formula（IV）
Formula（V）
R6For hydrogen or following group：
R6 `For hydrogen or following group：
In above-mentioned technical proposal, step（1）In, the organic solvent is n,N-Dimethylformamide or N, N- dimethyl formyl
Amine and dichloromethane mixture；The reaction preferably carries out in anhydrous conditions.
In above-mentioned technical proposal, step（3）In, there is formula（IV）The copolymer of structure and there is formula（V）Small point of structure
Son reaction carries out in a solvent, and the solvent is n,N-Dimethylformamide and/or dimethyl sulfoxide (DMSO)；The reaction is preferably in nothing
Carried out under water condition；Preferably, the reaction is in organic base（Such as 4-dimethylaminopyridine）In the presence of carry out.
The present invention also provides one kind to carry medicine complexes micelle, including with formula（Ⅰ）The polymer and active medicine of structure, institute
State medicine of the active medicine preferably with amino, such as adriamycin, Epi-ADM, Irinotecan.
The present invention also provides the preparation method of above-mentioned load medicine complexes micelle, is nanoprecipitation method, mainly including following step
Suddenly：Active medicine has formula with above-mentioned（I）The polymer of structure is dissolved in N,N-dimethylformamide, dimethyl sulfoxide (DMSO) or tetrahydrochysene
In the organic solvents such as furans, aqueous medium is then instilled, then dialysis removes organic solvent and ultimately forms load in aqueous
Medicine complexes micelle.Preferably, it is described that there is formula（I）The polymer of structure and the mass ratio of active medicine are（1~20）:1, this
The envelop rate for inventing obtained carrier micelle is not less than 80%.
There is formula present invention also offers above-mentioned（I）Application of the polymer of structure in antitumor drug is prepared, or
Application as active drug carrier.
Present invention also offers application of the complexes micelle in antitumor drug is prepared of above-mentioned load medicine.
The intermediate and the intermediate prepared present invention also offers the preparation method of above-mentioned intermediate is anti-in preparation
Application in tumour medicine, or the application in active drug carrier is prepared.
In conclusion the present invention provides a kind of high molecular material with excellent drug carrying ability, the macromolecule be with
Formula（I）The polymer of shown structure, can be used for biomaterial especially drug delivery field.The macromolecule is with poly-（Second two
Alcohol）-b- poly- [（N- 2- ethoxys）- asparagine] based on, preferably modify to obtain by phenyl boric acid.Macromolecule main body has good
Good biocompatibility, the phenyl boric acid group of its side chain can reach efficient medicine with the medicine containing amino by coordination
Load.Preliminary Results of the present invention show the material to clinically common chemotherapeutics such as adriamycin, Epi-ADM, Yi Li
There is the drugloading rate of superelevation for health etc.（More than 50%）With the envelop rate close to 100%, and insoluble drug release has tumor microenvironment
Response.The macromolecule is prepared simply, easy to promote, has huge application in biomaterial especially Nano medication field
Prospect.
Brief description of the drawings
Fig. 1 is the block copolymer mPEG with protection group prepared by embodiment 1113-b-PBLA21With deuterated trifluoroacetic acid
Hydrogen nuclear magnetic resonance spectrogram during as solvent；
Fig. 2 is formula prepared by embodiment 1（IV）The block copolymer mPEG of structure113-b-PHEA21With deuterated trifluoroacetic acid and deuterium
Dai Shui is as mixed solvent（v:v=1:9）When hydrogen nuclear magnetic resonance spectrogram；
Fig. 3 is formula prepared by embodiment 2（V）The hydrogen nuclear magnetic resonance spectrogram when small molecule of structure is using deuterochloroform as solvent；
Fig. 4 is formula prepared by embodiment 3（VI）The nuclear-magnetism when precursor material of structure is using deuterated dimethyl sulfoxide as solvent is total to
Shake hydrogen spectrogram；
Fig. 5 is formula prepared by embodiment 3（I）The hydrogen nuclear magnetic resonance when macromolecule of structure is using deuterated dimethyl sulfoxide as solvent
Spectrogram；
Fig. 6 is 4 Chinese style of embodiment（I）The drugloading rate and envelop rate of the macromolecule loading adriamycin micella of structure；
Fig. 7 is the micella particle diameter distribution that drugloading rate prepared by embodiment 4 is 33.4%；
Fig. 8 be embodiment 4 prepare drugloading rate be 33.4% micella under different hydrogen peroxide concentrations drug release patterns；
Fig. 9 is formula prepared by embodiment 3（I）Toxicity test result figure of the macromolecule of structure to NIH/3T3 cells；
Figure 10 be embodiment 4 prepare adriamycin drugloading rate be 33.4% micella to HeLa cell proliferation inhibitions.
Embodiment
For a further understanding of the present invention, the preferred embodiment of the invention is described with reference to embodiment, these
Description is simply further explanation the features and advantages of the present invention, rather than limiting to the claimed invention.
Formula（I）Method for producing polymer according to the following steps：
In anhydrous N,N-dimethylformamide and dichloromethane in the mixed solvent（v:V is 1:9）, using with formula（II）, formula
（III）Polyethylene glycol in primary amine groups trigger γ-benzyl-L-aspartate ester-N- in carboxylic acid anhydrides polymerization, finished in reaction
Excessive acetic anhydride end-blocking can be added afterwards, obtains the polymer with protection group, then in n,N-Dimethylformamide and second
Hydramine reacts, and obtains formula（IV）The copolymer of structure.
It is described that there is formula in the polymer process with protection group is prepared（II）Or formula（III）The compound of structure with
The molar ratio of carboxylic acid anhydride monomer is preferably 1 in the γ-benzyl-L-aspartate ester-N-：5 ~ 200, more preferably 1：10~
50；The temperature of the reaction is preferably 20 DEG C ~ 30 DEG C；The time of the reaction is preferably 48h ~ 96h.
In the above-mentioned polymer with protection group and monoethanolamine reaction process, protection group removes simultaneously under the action of organic base
Further act on, obtained with formula with monoethanolamine（IV）The copolymer of structure.The temperature of wherein described reaction is preferably 30 DEG C ~
40 DEG C, the time of the stirring reaction is preferably 12h ~ 24h, and the solvent of the reaction is preferably n,N-Dimethylformamide.Instead
After answering, settled with excess diethyl ether, obtain formula after filtration, washing and drying（IV）The copolymer of structure.
Formula in order to obtain（IV）The lyophilized co-polymer powder end of structure, above-mentioned sedimentation products are dissolved with n,N-Dimethylformamide,
Dialyse 24h ~ 72h in pure water, and water is changed 6 ~ 15 times in dialysis procedure, is freeze-dried, obtains with formula（IV）The copolymer of structure
Freeze-dried powder.
Formula（V）The synthesis of the small molecule of structure is carried out according to method as follows.Simple, by 4- methylol phenyl boric acids
Pinacol ester and N, N'- carbonyl dimidazoles are mixed in anhydrous methylene chloride, and abundant washing and drying, drains solvent after reaction
Obtain formula（V）The small molecule of structure.
Formula（IV）The copolymer of structure and（V）The small molecule reaction of structure, obtains（VI）The intermediate of structure.Reaction is preferred
Carried out in anhydrous n,N-Dimethylformamide, add 4-dimethylaminopyridine（DMAP）Catalyst as reaction.It is described to stir
The temperature for mixing reaction is preferably 40 DEG C ~ 60 DEG C.The time of the stirring reaction is preferably 48h ~ 96h.Reaction finishes, and obtains（VI）
The intermediate of structure.The intermediate need not be further purified, and can directly add distilled water dialysis, in the process pinacol quilt
Hydrolysis removing, formula is obtained after lyophilized（I）The macromolecule of structure.
The present invention has formula in preparation（I）During the macromolecule of structure, with γ-benzyl-L-aspartate ester-N-
Carboxylic acid anhydrides is raw material, and carboxylic acid anhydrides source in this amino acid-N- is not particularly limited, and is referred to following methods preparation：
L-Aspartic acid and phenmethylol react under the action of the concentrated sulfuric acid, post-treated to obtain γ-benzyl-L- asparagus fern ammonia
Acid esters, the γ-benzyl-L-aspartate ester with it is double（Trichloromethyl）Carbonic ester（Triphosgene）Reaction, obtains γ-benzene first
Carboxylic acid anhydrides in base-L-Aspartic acid ester-N-.
The above-mentioned compound structure that is related to is as follows：
Formula（II）
Formula（III）
Formula（IV）
Formula（V）
R6For hydrogen or following group：
R6 `For hydrogen or following group：
For a further understanding of the present invention, with reference to embodiment to polymer provided by the invention and its load medicine complexes micelle
Preparation method is described in detail, but protection scope of the present invention is not limited by the following examples.
Embodiment 1
It is 5000 to have formula to add into dry reaction bulb 5.00g number-average molecular weights（II）The polyethyleneglycol first of structure
Ether, with 80mL dry toluenes at 130 DEG C after azeotropic water removing 3h, the remaining toluene of decompressing and extracting；Obtained solid is dissolved in
In the dichloromethane of 20mL dryings, the first solution is obtained；Carboxylic acid anhydrides in 5.50g γ-benzyl-L-aspartate ester-N- is molten
Solution obtains the second solution in the 5mL n,N-Dimethylformamide dried and the in the mixed solvent of 50mL dichloromethane；In blanket of nitrogen
In enclosing, the first solution is mixed with the second solution, the stirring reaction 48h under room temperature, nitrogen protective condition；Then 10mL second is added
Acid anhydrides the reaction was continued 24h.After reaction, decompression pumps most of solvent, then is settled with ether, filters, and after dry, obtains
It is γ-benzyl-L-aspartate ester, protection group is benzyl to the block copolymer with protection group.Obtained band is protected
The block copolymer of base carries out nuclear magnetic resonance spectroscopy, as a result referring to Fig. 1, the results showed that γ-benzyl-L-aspartate ester gathers
Right is 21, which is denoted as mPEG113-b-PBLA21, its structure is as follows：
Take the mPEG that 5.00g is obtained113-b-PBLA21It is dissolved at 35 DEG C in the n,N-Dimethylformamide of 45mL dryings,
4mL monoethanolamines are added, stirring reaction 24h, product is settled with ether, filters, wash, using n,N-Dimethylformamide after drying
Dissolve, dialyse 72h in pure water, water is changed in dialysis procedure 10 times, and then freeze-drying obtains block copolymer.
Nuclear magnetic resonance spectroscopy is carried out to obtained block copolymer, Fig. 2 is the block copolymer of the preparation of embodiment 1 with deuterated
Hydrogen nuclear magnetic resonance spectrogram when trifluoroacetic acid and deuterated water are as solvent, the results showed that, the block copolymer tool that embodiment 1 obtains
There is formula（IV）Structure, wherein, R1It is methyl；R2For-NH-；R3For hydrogen；R4It is acetyl group；The yield of the block copolymer is
70%, wherein, n=113, m=21, are denoted as mPEG113-b-PHEA21, its concrete structure is as follows：
。
Embodiment 2
In the round-bottomed flask of a drying, 7.2g 4- methylol phenyl boric acid pinacol esters and 10.3g carbonyl dimidazoles are added, are added
Enter the dissolving of 50mL anhydrous methylene chlorides, react at room temperature 12h.The dilution of 500mL ethyl acetate is added into system after reaction, according to
It is secondary to use distilled water and saturated common salt water washing organic layer, then by organic layer with anhydrous MgSO4It is dried overnight.It is removed under reduced pressure organic
Solvent finally obtains 7.6g formulas（V）The small molecule of structure.Nuclear magnetic resonance spectroscopy is carried out to obtained block copolymer, Fig. 3 is real
Hydrogen nuclear magnetic resonance spectrogram when applying the small molecule of the preparation of example 2 using deuterated dimethyl sulfoxide as solvent, the results showed that successfully synthesis should
Small molecule, its concrete structure are as follows：
Formula（V）.
Embodiment 3
Formula in order to obtain（I）High molecular material, added into dry reaction bulb in 2.00g embodiments 1 prepare there is formula
（IV）The block copolymer of structure, 1.0g formulas（V）The small molecule and DMAP of structure（412mg）, vacuumize 12h.Then add
The n,N-Dimethylformamide dissolving of 10mL dryings, the stirring reaction 12h under 50 DEG C, nitrogen protective condition.After reaction, use
Excessive ether is settled, and is washed, and is filtered, and after dry, obtains intermediate.Nuclear-magnetism is carried out to obtained midbody polymer to be total to
Vibration analysis, as a result referring to Fig. 4, the results showed that, phenyl boric acid group is successfully grafted on macromolecule.Obtained intermediate has formula
（VI）Structure, wherein, R1It is methyl；R2For-NH-；R6For phenyl boric acid group, the ratio shared by phenyl boric acid group is 48%；R4It is
Acetyl group；Obtained intermediate concrete structure is as follows：
Above-mentioned intermediate is dissolved in water, dialyse 72h in rear pure water, water is changed in dialysis procedure 10 times, obtains with formula（I-a）
The polymer of structure, finally freeze-drying obtain freeze-dried powder, and nuclear magnetic resonance spectroscopy is carried out to obtained material（Fig. 5）, as a result table
Bright pinacol is by complete hydrolysis.
R3For following group：
N=113, m=21.
Embodiment 4
The formula that will be obtained in embodiment 3（I-a）The polymer 20mg and different quality of structure（4th, 10,13.3 or 20mg）Salt
Sour adriamycin is dissolved in 0.5mL n,N-Dimethylformamide, and equivalent is added in course of dissolution as the three of 1.5 times of doxorubicin hydrochloride
Ethamine, be sufficiently mixed in 37 DEG C of shaking table 3 it is small when, be then slowly dropped into the ultra-pure water quickly stirred（2mL）, it is added dropwise
After continue to stir 3h, dialyse in pure water 12h, water is changed in dialysis procedure 5 times, and load adriamycin is obtained finally by freeze-drying
Composite micelle.
Using ultraviolet-visible spectrum, adriamycin contains in the carrier micelle that the absorption measurement embodiment 4 of 480 nm obtains
Amount, the loading of the adriamycin in micella is calculated by the following formula（DLC）And envelop rate（DLE）：
DLC=(gross mass of quality/micella of medicine in micella) × 100%
DLE=(quality of the quality of medicine/input medicine in micella) × 100%
Fig. 6 is the drugloading rate of carrier micelle and collecting for envelop rate prepared for embodiment 4, the results show that formula（I）The height of structure
Molecule can almost quantify load adriamycin, and envelop rate is close to 100%.
The micella of different drugloading rates is redissolved in PBS（pH=7.4）, concentration to 0.1mg/mL, utilizes dynamic light scattering point
Analysis, measures the hydrodynamics particle diameter of micella, and as a result referring to Fig. 7, Fig. 7 is the load medicine glue that drugloading rate prepared by embodiment 4 is 33.4%
The hydrodynamics distribution map of beam, the results showed that micella particle diameter is evenly distributed between 18nm ~ 48nm.Other different drugloading rates
Micella particle diameter is also in 100 below nm, and narrow distribution.
Embodiment 5
The formula that will be obtained in embodiment 3（I-a）The polymer 20mg and different quality of structure（4th, 10,13.3 or 20mg）Salt
Sour Epi-ADM is dissolved in 0.5mL n,N-Dimethylformamide, and it is 1.5 times of Farmorubine Hydrochloride that equivalent is added in course of dissolution
Triethylamine, be sufficiently mixed in 37 DEG C of shaking table 3 it is small when, be then slowly dropped into the ultra-pure water quickly stirred（2mL）, it is added dropwise
After continue to stir 3h, dialyse in pure water 12h, water is changed in dialysis procedure 5 times, finally by freeze-drying obtain load table Ah
The composite micelle of mycin.
Using ultraviolet-visible spectrum in the carrier micelle that the absorption measurement embodiment 5 of 480 nm obtains Epi-ADM
Content, drugloading rate and envelop rate calculation formula reference implementation example 4.The results show that formula（I）The macromolecule of structure can almost quantify
Load Epi-ADM, the envelop rate of medicine is close to 100%.
The micella of different drugloading rates is redissolved in PBS（pH=7.4）, concentration to 0.1mg/mL, utilizes dynamic light scattering point
Analysis, the results showed that all carrier micelle hydrodynamics particle diameters are in 100 below nm, and narrow distribution.
Embodiment 6
The formula that will be obtained in embodiment 3（I-a）The polymer 20mg and different quality of structure（4th, 10,13.3 or 20mg）Salt
Sour Irinotecan is dissolved in 0.5mL n,N-Dimethylformamide, and it is 1.5 times of irinotecan hydrochloride that equivalent is added in course of dissolution
Triethylamine, be sufficiently mixed in 37 DEG C of shaking table 3 it is small when, be then slowly dropped into the ultra-pure water quickly stirred（2mL）, it is added dropwise
After continue to stir 3h, dialyse in pure water 12h, water is changed in dialysis procedure 5 times, and load Yi Li is obtained finally by freeze-drying
For the composite micelle of health.
Using ultraviolet-visible spectrum in the carrier micelle that the absorption measurement embodiment 6 of 360 nm obtains Irinotecan
Content, drugloading rate and envelop rate calculation formula reference implementation example 4.The results show that formula（I）The macromolecule of structure can almost quantify
Irinotecan is loaded, the envelop rate of medicine is more than 90%.
The micella of different drugloading rates is redissolved in PBS（pH=7.4）, concentration to 0.1mg/mL, utilizes dynamic light scattering point
Analysis, the results showed that all carrier micelle hydrodynamics particle diameters are in 100 below nm, and narrow distribution.
Embodiment 7
The composite micelle that drugloading rate prepared by the embodiment 4 of 5mg is 33.4% is taken to be dissolved in the phosphorus that the pH value of 5mL 0.01M is 7.4
In hydrochlorate buffer solution, wherein containing 0.5% Tween 80, the bag filter that molecular cut off is 3500 is then transferred to, uses 45mL
Corresponding buffer solution is dialysed, and is dialysed and is carried out in the constant temperature oscillation case that temperature is 37 DEG C, rotating speed is 100, when specific
Between sample 4mL, and supplement the buffer solution of respective amount；Using ultraviolet-visible spectrum 480nm absorption measurement release liquid it is dense
Degree, obtains cumulative percentage release as time increased variation relation, releasing result are as shown in Figure 8.Releasing result shows to carry
Insoluble drug release is slow under normal physiological conditions for medicine micella, and medicine can be released quickly under the conditions of 100 μM of hydrogen peroxide
Put.It is such the result shows that carrier micelle release tool since the content of tumor tissues and intracellular hydrogen peroxide ratio normal structure is high
There is the response of tumor tissues microenvironment, have more preferable specificity when applying in vivo.
Embodiment 8
The polymeric material toxicity of preparation is investigated using MTT cell toxicity tests, is comprised the following steps that：
1st, logarithmic phase NIH/3T3 cells are collected, are inoculated with 96 orifice plates, contain 100 μ L in every hole（~ 7000）Cell；37
DEG C, saturated humidity, 5% CO224 h are cultivated in cell incubator；
2nd, nutrient solution is discarded after 24 h, the formula for embodiment 3 being prepared with culture medium（I-a）The polymer dilution of structure is dense to difference
Degree, adds in 96 orifice plates, and 200 μ L, every kind of 3 multiple holes of concentration are added per hole；At 37 DEG C, saturated humidity, 5% CO2Cell culture
48 h are cultivated in case；
3rd, after 48h, the 3- that 20 μ L concentration are 5mg/mL is added per hole（4,5- dimethylthiazoles -2）- 2,5- dimethyl tetrazoles
Bromide（MTT）Solution, continues to cultivate 4h；Culture is terminated, sucks nutrient solution in hole, 200 μ L dimethyl sulfoxide (DMSO)s, low speed are added per hole
10min is vibrated, absorption value of each hole at 492nm is detected with microplate reader, the cell survival rate under each concentration is calculated.
Fig. 9 is formula prepared by embodiment 3（I-a）The polymer of structure investigates result figure to NIH/3T3 cytotoxicities, as a result
Show that cell survival rate is more than 80% at various concentrations, it was demonstrated that high molecular material prepared by the present invention has good safety
Property.
Embodiment 9
1st, logarithmic phase HeLa human cervical carcinoma cells are collected, are inoculated with 96 orifice plates, contain 100 μ L in every hole（~ 7000）Cell；
At 37 DEG C, saturated humidity, 5% CO224 h are cultivated in cell incubator；
2nd, nutrient solution is discarded after 24 h, the carrier micelle that the drugloading rate for embodiment 4 being prepared with culture medium is 33.4% is diluted to not
Same concentration, adds in 96 orifice plates, and 200 μ L, every kind of 3 multiple holes of concentration are added per hole；At 37 DEG C, saturated humidity, 5% CO2Cell
48 h are cultivated in incubator；
3rd, after 48h, the MTT solution that 20 μ L concentration are 5mg/mL is added per hole, continues to cultivate 4h；Culture is terminated, sucks in hole and trains
Nutrient solution, 200 μ L dimethyl sulfoxide (DMSO)s are added per hole, and low-speed oscillation 10min, absorption value of each hole at 492nm is detected with microplate reader,
The high molecular cell survival rate of each concentration is calculated.
Figure 10 is that the carrier micelle that drugloading rate prepared by embodiment 4 is 33.4% investigates HeLa cytotoxicities result figure, right
It is the pure medicine of adriamycin according to group.The result shows that the carrier micelle of preparation has good Cytostatic to tumor cell effect.
The present invention by improving the interaction between medicine and small molecule to high molecular rational modification, enhancing carrier and
Stability of the medicine in self assembling process, reduces the aggregation of small-molecule drug, to realize efficient drug loading, especially this
Complicated synthesis step is not required in the design of sample, in practicality advantageously.
The general principles defined herein can without departing from the spirit or scope of the present invention, in other realities
Apply in example and realize.Therefore, the present invention is not intended to be limited to the embodiments shown herein, and is to fit to public with institute herein
The consistent most wide scope of the principle and features of novelty opened.
Claims (10)
1. a kind of polymer, has formula（I）Shown structure；
Formula（I）In, R1Selected from hydrogen, alkyl or substitution alkyl；
R2Selected from-NH- or-R5(CH2)rNH-, wherein, R5For-O- ,-OCONH- ,-OCO- ,-NHCOO- or-NHCO-, 1≤r≤
10；
R3Selected from hydrogen or following group：
R3 `Selected from hydrogen or following group：
R4Selected from hydrogen or hydrophobic grouping；
20≤n≤500；5≤m≤200.
2. polymer according to claim 1, it is characterised in that the alkyl is the alkyl of C1 ~ C40；The substitution alkyl
In, substituent is sulfydryl, saccharide residue, aldehyde radical, carboxyl, vinyl, alkynyl, succimide, maleimide, biotin, RGD
Small peptide, LHRH small peptides or folic acid；The hydrophobic grouping is alkyl, benzyl, cholesterol formoxyl, acetyl group, the courage of C4 ~ C20
Acidic group or deoxycholic acid base.
3. polymer according to claim 1, it is characterised in that the group ratio of phenyl boric acid structure is not less than 20%.
4. the preparation method of polymer described in claim 1, it is characterised in that include the following steps：
（1）With formula（II）Or formula（III）The compound of structure is reacted in organic solvent with shielded amino acid monomer, is obtained
To the polymer with protection group；The amino acid monomer is carboxylic acid anhydrides in γ-benzyl-L-aspartate ester-N-；
（2）The polymer with protection group and monoethanolamine are reacted, obtained with formula（IV）The copolymer of structure；
（3）There is formula by described in（IV）The copolymer of structure and there is formula（V）The small molecule reaction of structure, obtains with formula（VI）
The intermediate of structure；Finally, there is formula（VI）The intermediate of structure is obtained with formula by dialysis（Ⅰ）The polymer of structure.
5. a kind of preparation method of polymer lyophilized powder, it is characterised in that include the following steps：
（1）With formula（II）Or formula（III）The compound of structure is reacted in organic solvent with shielded amino acid monomer, is obtained
To the polymer with protection group；The amino acid monomer is carboxylic acid anhydrides in γ-benzyl-L-aspartate ester-N-；
（2）The polymer with protection group and monoethanolamine are reacted, obtained with formula（IV）The copolymer of structure；
（3）There is formula by described in（IV）The copolymer of structure and there is formula（V）The small molecule reaction of structure, obtains with formula（VI）
The intermediate of structure；Finally, there is formula（VI）The intermediate of structure obtains polymer lyophilized powder by dialysis, freeze-drying.
6. a kind of preparation method of intermediate, it is characterised in that include the following steps：
（1）With formula（II）Or formula（III）The compound of structure is reacted in organic solvent with shielded amino acid monomer, is obtained
To the polymer with protection group；The amino acid monomer is carboxylic acid anhydrides in γ-benzyl-L-aspartate ester-N-；
（2）The polymer with protection group and monoethanolamine are reacted, obtained with formula（IV）The copolymer of structure；
（3）There is formula by described in（IV）The copolymer of structure and there is formula（V）The small molecule reaction of structure, obtains with formula（VI）
The intermediate of structure.
7. according to the preparation method of claim 4,5 or 6, it is characterised in that step（1）In, the organic solvent is N,
Dinethylformamide or N,N-dimethylformamide and dichloromethane mixture；It is described reaction preferably in anhydrous conditions into
OK；Step（3）In, there is formula（IV）The copolymer of structure and there is formula（V）The small molecule reaction of structure carries out in a solvent, institute
State reaction preferably to carry out in anhydrous conditions, the reaction carries out in the presence of an organic base；
The compound structure being related to is as follows：
R6For hydrogen or following group：
R6 `For hydrogen or following group：
。
8. one kind carries medicine complexes micelle, polymer described in claim 1 and active medicine are included.
9. a kind of preparation method for carrying medicine complexes micelle, it is characterised in that comprise the following steps, active medicine is with having formula
（I）The polymer dissolving of structure in organic solvent, then instills aqueous medium, and then dialysis removing is organic in aqueous
Solvent obtains carrying medicine complexes micelle.
10. application of the polymer described in claim 1 in antitumor drug is prepared, or answering as active drug carrier
With；Application of the medicine complexes micelle in antitumor drug is prepared is carried described in claim 8；Intermediate described in claim 6
The application of intermediate prepared by preparation method in antitumor drug is prepared, or the application in active drug carrier is prepared.
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| CN113234215B (en) * | 2021-04-09 | 2022-02-15 | 华南理工大学 | Cationic cholic acid polyester antibacterial peptide and preparation method and application thereof |
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| CN114712520A (en) * | 2022-04-15 | 2022-07-08 | 中国药科大学 | Nanocrystalline drug stabilizing system, preparation method, pharmaceutical composition and application |
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