CN103055321A - Methoxy polyethylene glycol-polyphosphate diblock copolymer and adriamycin bonding medicine thereof - Google Patents
Methoxy polyethylene glycol-polyphosphate diblock copolymer and adriamycin bonding medicine thereof Download PDFInfo
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- CN103055321A CN103055321A CN2011103170087A CN201110317008A CN103055321A CN 103055321 A CN103055321 A CN 103055321A CN 2011103170087 A CN2011103170087 A CN 2011103170087A CN 201110317008 A CN201110317008 A CN 201110317008A CN 103055321 A CN103055321 A CN 103055321A
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Abstract
The invention discloses a macromolecular bonding medicine based on adriamycin. The active ingredient of the bonding medicine is nanoparticles formed by bonding of a polyphosphate polymer and adriamycin. Specifically, the polyphosphate polymer can be a methoxy polyethylene glycol-polyphosphate diblock copolymer with amino as the side group. The invention also provides a methoxy polyethylene glycol-polyphosphate copolymer with an amino side group and a method for synthesizing the copolymer. The polyphosphate adriamycin macromolecular bonding medicine provided in the invention can self-assemble to form nanoparticles with a particle size of about 30nm. Through the intrinsic scale effect of the nanoparticles and by combining a charge reversal technology, the nanoparticles can better concentrate in a tumor tissues and a cell, thus enhancing the targeting property of adriamycin on a tumor site. And the adriamycin bonded on a polyphosphate polymer chain can have responsiveness to a tumor tissue microenvironment, and can be rapidly released in the tumor tissue under a weakly acidic condition. And a good tumor cell-killing effect can be achieved.
Description
Technical field
The present invention relates to a kind of poly glycol monomethyl ether-poly phosphate di-block copolymer and poly phosphate amycin macromole bonding medicine prepared therefrom.Particularly, the general formula of described poly phosphate amycin macromole bonding medicine is mPEG
a-PAOOP
b-Cya-ADR-DMMA, a=45-113 wherein, b=25-150.More specifically, the synthetic mPEG that prepared of the present invention
45-PAOOP
25-Cya-ADR-DMMA or mPEG
45-PAOOP
75-Cya-ADR-DMMA or mPEG
113-PAOOP
150Three kinds of amycin macromole of-Cya-ADR-DMMA bonding medicine.Poly phosphate amycin macromole bonding medicine provided by the invention can self assembly in aqueous solution forms the nano-particle about particle diameter 30nm.
Background technology
Amycin belongs to the anthracyclines antibiotic, at first extracts discovery by gondola scientist from a kind of streptomycete the beginning of the sixties in eighties of last century.From find that so far, amycin is a kind of medicine very common in oncotherapy always, it belongs to broad spectrum activity tumor antibiotic, is cell cycle nonspecific agent (CCNSA), and the tumor cell of various growth cycles is had lethal effect.Amycin can produce widely biochemical effect to body, therefore is used on a large scale the treatment of various cancers, and especially for breast carcinoma, amycin is one of choice drug for the treatment of breast carcinoma clinically.The basic role principle of amycin at first is the major groove district that embeds the DNA in the nucleus, forms the strong interaction of DNA-medicine, and interference and inhibition DNA's is synthetic thus, copies and transcribes; Secondly, amycin can suppress the topoisomerase that DNA plays a crucial role in synthetic by combination; And the metabolism of amycin in cell and body can produce oxygen-derived free radicals, and oxygen-derived free radicals can destroy DNA, stops DNA synthetic; By the combined effect of several modes, amycin can cause the unusual of the physiological activity such as cellular replication, thereby reaches the purpose of cell killing.
Although the use of amycin is so wide, also really shown the preferably therapeutic effect for tumor, it still faces problems as antitumor drug.Because amycin itself is nonselective all to work to normal cell in the body and tumor cell, therefore, in the kill tumor cell, also can cause human normal cell's undesired death, thus serious side effect during the generation medication.Its main toxic reaction has, and leukocyte and thrombocytopenia can occur about 60%～80% patient; 100% patient has alopecia in various degree, can recover growth after the drug withdrawal; Amycin embodies very strong cardiac toxicity, shows as arrhythmia, the ST-T change can occur, and use early vitamin B6 and coenzyme Q10 and can lower it to the toxicity of heart in 1～6 month after drug withdrawal; Nauseating, loss of appetite; Medicine overflows outside the blood vessel can cause tissue ulcer and necrosis.Therefore, the drug administration carrier of research amycin and delivery system are the keys that improves amycin medicine curative effect.How amycin optionally can be transported in tumor tissues and the tumor cell with the toxic and side effects that reduces amycin is the prior development direction of amycin drug delivery system.
In recent years, become based on the medicine-carried system of high molecular nanometer granule that small-molecule drug and genomic medicine carry out carrying in the body and the important breakthrough mouth of medicament research and development.The transport system of high molecular nanometer granule has more advantage in actual applications; such as good biocompatibility, have the potential of targeted delivery, have better stability; can effectively protect bioactive molecule to the toleration of physiological environment, and strengthen cell to being passed the absorption of molecule.It is worthy of note that especially the nanoparticle of macromolecular self-assembly has infiltration and retention effect (the Enhanced permeability and retention effect of enhancing, the EPR effect), can promote medicine in the enrichment of tumor tissues, and can be effectively by the tumor locus Cell uptake, enter Cytoplasm and various organelle, so the high molecular nanometer granule is the candidate that has the antitumor drug transmission system of potential.Wherein, there has been relevant medicine-carried system to have made some progress, DOXIL such as Johnson Co.'s production, it uses the complex of the derivant of liposome and polyethylene glycol, wrap a year doxorubicin hydrochloride with this, avoid engulfing of Mononuclear phagocyte system, cause amycin blood circulation time in vivo obviously to increase, reduce doxorubicin cardiotoxicity, increase the effect that the tumor target tissue absorbs.DOXIL is used for clinical use by FDA (FDA) approval at present, mainly in the treatment of refractory ovarian.The U.S. FDA novel form Genexol-PM that ratified at present Korea S Samyang company research and development enters the I phase clinical research stage for another example, Genexol-PM uses Biodegradable material polyethylene glycol-polylactic acid nano-particle bag to carry the hydrophobic anticancer drug paclitaxel, with the enrichment of enhancing paclitaxel in tumor cell, and have the potentiality of carrying more heavy dose of medicine to tumor locus.
Find that in research Recent study personnel have also found the new polymer-poly phosphate with biocompatibility and biodegradability on the basis of the macromolecule medicine-carried systems such as Polyethylene Glycol and polylactic acid.With respect to traditional polymeric carbon chain, a distinguishing feature of poly phosphate is the phosphorus atoms that has a pentavalent on the main polymer chain, thereby so that the side group of polymer can come functionalized to realize concrete unique function by polymerization and the specific modification of different monomers.Utilize side group to be the phosphate ester monomer of amino such as Du Jinzhi etc., success synthesized a kind of amphipathic cationic micelle, since amino with positive charge by electrostatic interaction in conjunction with siRNA, so that this bi-block copolymer becomes a kind of new and effective siRNA medicine-carried system.
But the polyreaction of phosphate ester also faces some limitations; if directly synthesize poly phosphate with the functionalized phosphate ester monomer of side group by polymerization; the selection of its side group is limited; thereby functionalized group very easily disturbs polyreaction to cause occuring side reaction; therefore need to protect relevant group in the monomer; cause the synthetic difficulty of monomer, increased the complexity of synthetic route.In order to overcome this problem, we design synthetic side group and are the poly phosphate of two keys, monomer whose 2-allyloxy-2-oxygen-1,3,2-dioxaphospholane synthesizing and purifying is relatively easy, after polyreaction, " click chemistry " occurs for the two keys by polymer pendant groups and thiol molecule thereby reaction is carried out functionalized modification to polymer pendant groups, the synthetic bottleneck of functional poly phosphate ester before having overcome." click chemistry " reaction condition is gentle, and the speed of reaction is fast, and reaction-ure conversion-age is high, and on this basis, the inventor has finished the present invention.
Utilizing chemical reaction is a kind of same effective drug delivery system except using high molecular nanometer granule bag medicine carrying thing at the macromole bonding medicine that high molecular polymer chain end or side group bonding antitumor drug form.With use granule bag medicine carrying phase ratio, macromole bonding medical instrument has its unique advantage, can medicine be introduced polymer chain by chemical bonding, very firmly be combined with macromolecular chain formation, thereby so that medicine is more stable, avoid enzyme and immune attack in the physiological environment in the human body, reach slow release and long-acting purpose; And usually can the control key composite medicine and the ratio of polymer, overcome bag and carried the shortcoming that pharmaceutical methods spreads in vivo easily medicine and can't accurately control drug loading; And the chemical bond that bonding uses has sensitivity usually, and medicine can optionally be discharged in linked groups and cell, in conjunction with the EPR effect, can also reduce the toxic and side effects of medicine when strengthening drug bioavailability.
In order to improve the therapeutic effect of high molecular nanometer granule medicine-carried system, except the known passive targetings such as EPR effect, research worker is also studying how further strengthen its accumulation ability in tumor cell always.At this on the one hand, modifying some targeting groups at nano grain surface is a kind of method relatively more commonly used with the specific albumen of positioning tumor cell surface or receptor.Studies show that, the surface potential of nano-particle can affect the picked-up of cell, the ability that electronegative granule enters cell a little less than, electropositive granule then is easy to by cellular uptake, therefore, utilize potential the becoming of charge reversal technology to improve tumor cell to a kind of strategy of granule picked-up, the method mainly is by the pH sensitive group electromotive force of particle surface to be controlled, when material is in circulation time in the blood of pH neutrality, its surface potential is partially negative, embody the stealthy effect in the body, avoided material removing in vivo; And after material enters tumor tissues since in the tumor tissues environment (pH ≈ 6.8) of slant acidity and so that the particle surface electromotive force transfer on the occasion of, can be better and cell surface be the protein binding of negative electricity, thereby enter cell; The method comprehensively improves the ability that nano-particle enters cell by the interaction that reduces removing and enhancing and cell.
Summary of the invention
The invention discloses a kind of macromole bonding medicine based on amycin, its active component is the nano-particle that poly phosphate polymer-bound amycin forms, and this poly phosphate polymer specifically can be side group and is amino poly glycol monomethyl ether-poly phosphate di-block copolymer.The present invention also provides the method for a kind of side group for amino poly glycol monomethyl ether-polyphosphate ester copolymer and synthetic this copolymer.Poly phosphate amycin macromole bonding medicine provided by the invention can self assembly in aqueous solution forms the nano-particle about particle diameter 30nm.By the scale effect of nano-particle itself and in conjunction with the charge reversal technology, better enrichment in tumor tissues and cell of nano-particle has improved the targeting of amycin to tumor locus.And can there be response in the amycin of bonding to the tumor tissues microenvironment on the poly phosphate polymer chain, discharges under the solutions of weak acidity in the tumor tissues rapidly, and tumor cell is had preferably fragmentation effect.Therefore, the biodegradable macromole bonding of this class medicine has a good application prospect in amycin conveying and treatment of cancer.
An object of the present invention is to provide a kind of poly phosphate amycin macromole bonding medicine, its active component is the nano-particle that poly phosphate polymer-bound amycin forms, and wherein said poly phosphate polymer can be poly glycol monomethyl ether-poly phosphate di-block copolymer.
Described amycin poly phosphate bonding medicine can be adriamycin bonded and 2, the 3-dimethyl maleic anhydride of above-mentioned polymer pendant groups.
Described nano-particle also can carry out chemical modification or ligand modified.
In above-mentioned poly glycol monomethyl ether-poly phosphate di-block copolymer, described poly phosphate by structural formula suc as formula the five-membered cyclic phosphate ester monomer polymerization of (I) after further functionalized forming:
In above-mentioned poly glycol monomethyl ether-poly phosphate di-block copolymer, initial block is poly glycol monomethyl ether, and another block is described poly phosphate; The degree of polymerization of described poly glycol monomethyl ether block is 45-113, and corresponding number-average molecular weight is 2,000-5,000g/mol; The degree of polymerization of described poly phosphate block is 25-150, and corresponding number-average molecular weight is 6,925-27,700g/mol.
The general formula of above-mentioned poly phosphate amycin macromole bonding medicine can be mPEG
a-PAOOP
b-Cya-ADR-DMMA, a=45-113 wherein, b=25-150 (value of a and b should be respectively any number in the described scope), wherein mPEG is the abbreviation of poly glycol monomethyl ether, subscript a is that this polymer poly is right; PAOOP is the abbreviation of poly-(2-allyloxy-2-oxygen-1,3,2-dioxaphospholane), and subscript b is that this polymer poly is right; Cya is the abbreviation of mercaptoethylmaine hydrochlorate, and ADR is the abbreviation of amycin, and DMMA is the abbreviation of 2,3-dimethyl maleic anhydride.
In specific embodiment of the present invention, the inventor has synthesized mPEG
45-PAOOP
25-Cya-ADR-DMMA or mPEG
45-PAOOP
75-Cya-ADR-DMMA or mPEG
113-PAOOP
150-Cya-ADR-DMMA, and relevant detection data are provided.
The present invention also provides a kind of method of synthetic poly phosphate amycin macromole bonding medicine.
The method of described synthetic poly phosphate amycin macromole bonding medicine be take side group as amino poly glycol monomethyl ether-poly phosphate di-block copolymer under different pH value conditions (for example, pH value is in the 6.5-8.5 scope, preferred pH=6.5,6.7 and 8.0, see following embodiment) successively with the 2-imino group sulfane hydrochlorate of different proportion, Mal-ADR, 2, the 3-dimethyl maleic anhydride (for example, the mol ratio of three and used poly glycol monomethyl ether-poly phosphate di-block copolymer side group amino can be at least respectively 1/10,1/20 and 3/1 (seeing following embodiment) reaction, thereby it is adriamycin bonded and 2 finally to obtain in poly glycol monomethyl ether-poly phosphate di-block copolymer poly phosphate block side group, the amycin macromole bonding medicine of 3-dimethyl maleic anhydride, choosing above-mentioned rate of charge scope is in the structure of assurance side group for amino polyethylene glycol-phosphate ester block polymer, the amino of side group is replaced by 2-imino group sulfane hydrochlorate and Mal-ADR fully, and 2-imino group sulfane hydrochlorate can be with 2 after being bonded to polymer pendant groups, 3-dimethyl maleic anhydride complete reaction, finally obtaining side group is the poly phosphate amycin macromole bonding medicine of Mal-ADR and 2,3-dimethyl maleic anhydride.Wherein, described Mal-ADR can obtain by maleic anhydride and 6-aminocaprolc acid and tert-butyl carbazate and amycin reaction.Mal is the abbreviation of maleimide base group.
The present invention also provides the poly glycol monomethyl ether of a kind of side group for two keys-poly phosphate di-block copolymer.
Above-mentioned poly phosphate is polymerized by the five-membered cyclic phosphate ester monomer of structural formula suc as formula (I).
Above-mentioned side group is that initial block is poly glycol monomethyl ether in the poly glycol monomethyl ether-poly phosphate di-block copolymer of two keys, and another block is described poly phosphate; The degree of polymerization of described poly glycol monomethyl ether block is 45-113, and corresponding number-average molecular weight is 2,000-5,000g/mol; The degree of polymerization of described poly phosphate block is 25-150, and corresponding number-average molecular weight is 4,100-24,600g/mol.
Above-mentioned side group for two keys poly glycol monomethyl ether-the poly phosphate di-block copolymer is mPEG
45-PAOOP
25Or mPEG
45-PAOOP
75Or mPEG
113-PAOOP
150
The present invention also provides the method for the poly glycol monomethyl ether of a kind of synthetic side group for two keys-poly phosphate di-block copolymer.
Described synthetic side group is as macromole evocating agent take the terminal hydroxy group poly glycol monomethyl ether for the method for the poly glycol monomethyl ether of two keys-polyphosphoric acid di-block copolymer, with 1,5,7-three nitrine dicyclos (4.4.0) last of the ten Heavenly stems-5-alkene is catalyst, obtains di-block copolymer by structural formula suc as formula the ring-opening polymerization of the annular phosphate monomer of (I).
Above-mentioned annular phosphate monomer can pass through 2-chloro-2-oxygen-1,3, and 2-dioxaphospholane and propenyl reaction obtain.Reaction condition is, in anhydrous tetrahydro furan, take triethylamine as acid binding agent, makes 2-chloro-2-oxygen-1,3, after the propenyl reaction of 2-dioxaphospholane and equimolar amounts, obtains above-mentioned phosphate ester monomer by distillation purifying.
Above-mentioned 2-chloro-2-oxygen-1,3, the 2-dioxaphospholane can obtain by ethylene glycol and Phosphorous chloride. reaction.Reaction condition is, under 25 ℃, in anhydrous methylene chloride, behind the glycol reaction of Phosphorous chloride. and times mole such as grade, by distillation purifying 2-chloro-1,3, the 2-dioxaphospholane passes into dioxygen oxidation again in anhydrous benzene, obtain above-mentioned 2-chloro-2-oxygen-1 behind the distillation purifying, 3,2-dioxaphospholane.
The present invention also provides a kind of side group to be amino poly glycol monomethyl ether-poly phosphate di-block copolymer.Wherein said poly phosphate by structural formula suc as formula the five-membered cyclic phosphate ester monomer polymerization of (I) after further functionalized forming.
Above-mentioned side group is that initial block is poly glycol monomethyl ether in amino poly glycol monomethyl ether-poly phosphate di-block copolymer, and another block is described poly phosphate; The degree of polymerization of described poly glycol monomethyl ether block is 45-113, and corresponding number-average molecular weight is 2,000-5,000g/mol; The degree of polymerization of described poly phosphate block is 25-150, and corresponding number-average molecular weight is 6,925-27,700g/mol.
Above-mentioned side group can be mPEG for amino poly glycol monomethyl ether-poly phosphate di-block copolymer
45-PAOOP
25-Cya or mPEG
45-PAOOP
75-Cya or mPEG
113-PAOOP
150-Cya.
The present invention also provides the method for a kind of synthetic side group for amino poly glycol monomethyl ether-poly phosphate di-block copolymer.
Described synthetic side group is for the poly glycol monomethyl ether of two keys-polyphosphoric acid di-block copolymer use benzoin dimethylether catalysis take side group for the method for amino poly glycol monomethyl ether-polyphosphoric acid di-block copolymer, under the 365nm irradiation under ultraviolet ray, utilize the sulfydryl of mercaptoethylmaine hydrochlorate to carry out the click chemistry reaction of sulfydryl with two keys, thereby finally synthesize the poly glycol monomethyl ether that side group is amino-poly phosphate di-block copolymer.
Advantage of the present invention and good effect
The present invention has obtained having the poly glycol monomethyl ether of good biocompatibility and biodegradability-poly phosphate di-block copolymer, and its physics, chemical property can be regulated by the composition of telomerized polymer.The invention provides poly glycol monomethyl ether-poly phosphate two block macromole adriamycin bonding medicines of biocompatibility; in aqueous solution, can self assembly form nano-particle; and has good stability; preparation method is simple; repeatable high; can protect amycin not to be free on the toxic and side effects that blood causes amycin as carrier, scale effect that again can combining nano granule itself and character so that amycin better be enriched in tumor tissues and the tumor cell.
Poly glycol monomethyl ether-poly phosphate two block macromole bonding medicines provided by the invention can form the nano-particle with negative charge, the particle diameter of this nano-particle is about 30nm, surface charge has avoided nano-particle to be removed rapidly in vivo and ineffective about-20mV.Under the slant acidity environment, owing to being degraded, the amido link of polymer lateral chain exposes amino, surface charge can be gradually from negative value change on the occasion of, can change into about 10mV behind the 2h, detect by flow cytometer and can find because surface charge changes on the occasion of, the amounts of particles showed increased that enters cell.
The present invention can be used as macromole bonding medicine after utilizing the adriamycin bonded assembling of poly glycol monomethyl ether-poly phosphate bi-block copolymer to form nano-particle.By EPR effect and charge reversal effect, can improve the enrichment of nano-particle in tumor locus and cell, and the amycin by hydrazone key bonding can discharge rapidly under the slant acidity pH value, has proved that nano-particle can effectively discharge amycin and bring into play the effect of killer cell in tumor tissues.The present invention uses cytotoxicity experiment to verify the ability of nano-particle killer cell, the kill capability of granule when the kill capability of granule all is better than pH=7.4 under low pH value, and along with the increase of doxorubicin concentration, the survival rate of cell reduces gradually.
The present invention proves that by cytotoxicity experiment this macromole bonding medical instrument has good biocompatibility, simultaneously macromolecular material possesses under low pH condition charge reversal and discharges rapidly the characteristics of amycin, so that this biodegradable macromole bonding medicine has a good application prospect in treatment of cancer.
Description of drawings
When by reference to the accompanying drawings, can more easily understand above-mentioned aspect of the present invention and many advantages of following by reading following detailed description, wherein:
Fig. 1 is mPEG
a-PAOOP
bThe synthetic route chart of-Cya-ADR-DMMA.
Fig. 2 is AOOP's (2-allyloxy-2-oxygen-1,3,2-dioxaphospholane)
1H NMR spectrum.
Fig. 3 is mPEG
a-PAOOP
bGPC spectrum.The corresponding mPEG of Fig. 3 (A) wherein
45-PAOOP
25, the corresponding mPEG of Fig. 3 (B)
45-PAOOP
75, the corresponding mPEG of Fig. 3 (C)
113-PAOOP
150
Fig. 4 is mPEG
a-PAOOP
b 1H NMR spectrum.The corresponding mPEG of Fig. 4 (A) wherein
45-PAOOP
25, the corresponding mPEG of Fig. 4 (B)
45-PAOOP
75, the corresponding mPEG of Fig. 4 (C)
113-PAOOP
150
Fig. 5 is mPEG
a-PAOOP
b-Cya's
1H NMR spectrum.The corresponding mPEG of Fig. 5 (A) wherein
45-PAOOP
25-Cya, the corresponding mPEG of Fig. 5 (B)
45-PAOOP
75-Cya, the corresponding mPEG of Fig. 5 (C)
113-PAOOP
150-Cya.
Fig. 6 is the ESI-MS spectrum of Mal-ADR.
Fig. 7 is mPEG
a-PAOOP
b-Cya-ADR-DMMA's
1H NMR spectrum.The corresponding mPEG of Fig. 7 (A) wherein
45-PAOOP
25-Cya-ADR-DMMA, the corresponding mPEG of Fig. 7 (B)
45-PAOOP
75-Cya-ADR-DMMA, the corresponding mPEG of Fig. 7 (C)
113-PAOOP
150-Cya-ADR-DMMA.
Fig. 8 is mPEG
a-PAOOP
bThe cytotoxicity of-Cya-DMMA.The corresponding mPEG of Fig. 8 (A) wherein
45-PAOOP
25-Cya-DMMA, the corresponding mPEG of Fig. 8 (B)
45-PAEOOP
75-Cya-DMMA, the corresponding mPEG of Fig. 8 (C)
113-PAOOP
150-Cya-DMMA.
Fig. 9 is mPEG
a-PAOOP
bThe cytotoxicity of-Cya-ADR-DMMA nano-particle.The corresponding mPEG of Fig. 9 (A) wherein
45-PAOOP
25-Cya-ADR-DMMA, the corresponding mPEG of Fig. 9 (B)
45-PAOOP
75-Cya-ADR-DMMA, the corresponding mPEG of Fig. 9 (C)
113-PAOOP
150-Cya-ADR-DMMA.
The specific embodiment
Following embodiment is convenient to understand better the present invention, but does not limit the present invention.
Of the present inventionly provide a kind of poly phosphate amycin macromole bonding medicine, its active component is the nano-particle that poly phosphate polymer-bound amycin forms.
Wherein said poly phosphate polymer is poly glycol monomethyl ether-poly phosphate di-block copolymer, and the adriamycin bonded general formula of described poly phosphate is: mPEG
a-PAOOP
b-Cya-ADR-DMMA,
A=45-113 wherein, b=25-150, a and b are respectively any number in the described scope;
Wherein mPEG is the abbreviation of poly glycol monomethyl ether, and subscript a is that this polymer poly is right; PAOOP is the abbreviation of poly-(2-allyloxy-2-oxygen-1,3,2-dioxaphospholane), and subscript b is that this polymer poly is right; Cya is the abbreviation of mercaptoethylmaine hydrochlorate, and ADR is the abbreviation of amycin, and DMMA is the abbreviation of 2,3-dimethyl maleic anhydride.
Wherein said poly phosphate polymer is AB type poly glycol monomethyl ether-poly phosphate di-block copolymer, comprise poly glycol monomethyl ether (A block) and poly phosphate (B block), described B block is formed by the monomer polymerization of structural formula suc as formula (I), and this polyethylene glycol monomethyl ether-polycaprolactone-polyphosphate copolymer is expressed as mPEG-PAOOP.
Use poly glycol monomethyl ether as the initial block structure of di-block copolymer of the present invention, have following advantage and effect: 1. good hydrophilic, thereby can protect nano-particle avoid with blood in protein binding prolong the circulation time of nano-particle in blood; 2. biodegradable; 3. bio-compatible; 4. it is comparatively convenient to utilize its terminal hydroxyl to carry out ring-opening polymerisation; 5. raw material is comparatively cheap, saves cost.
Use the hydrophilic poly phosphate as another block of di-block copolymer of the present invention, mainly utilize poly phosphate easily functionalized advantage obtain side group with the copolymer of amido functional group, lay the foundation for adriamycin bonded.
Following embodiment provides by 1,5,7-, three nitrine dicyclos (4.4.0) last of the ten Heavenly stems-5-alkene catalysis, the synthetic di-block copolymer that the macromole Polyethylene Glycol causes and adriamycin bonded synthetic method.The method is: take the terminal hydroxy group poly glycol monomethyl ether as macromole evocating agent, 1,5,7-, three nitrine dicyclos (4.4.0) last of the ten Heavenly stems-5-alkene is catalyst, and the ring-opening polymerization by the annular phosphate monomer obtains di-block copolymer.Utilize two keys of poly phosphate side group to carry out the click chemistry reaction of sulfydryl, obtain side chain and be amino poly glycol monomethyl ether-poly phosphate block copolymer; React with amycin and 2,3-dimethyl maleic anhydride respectively by amino again, obtain the macromole bonding medicine based on amycin.
Raw materials used source and processing method are as follows among the following embodiment:
Poly glycol monomethyl ether (Mn=2000g/mol, mPEG
45Mn=5000g/mol, mPEG
113), being purchased from Aldrich company, purity 〉=99.5% dewaters with the methylbenzene azeotropic distillation before using.
1,5,7-, three nitrine dicyclos (4.4.0) last of the ten Heavenly stems-5-alkene (TBD) is available from Sigma-Aldrich company.
Phosphorous chloride., ethylene glycol heavily steam before the use.
Dichloromethane with the phosphorus pentoxide 24h that refluxes, steams before the use.
Triethylamine is successively used phthalic anhydride, NaOH and CaH
2The 24h that refluxes respectively steams before the use.
Benzene, steams before the use in 90 ℃ of lower backflow 24h with phosphorus pentoxide.
Oxolane (THF) refluxes with Na-K alloy, steams before the use.
Ether, toluene reflux dry with sodium sand, all steam before use.
Directly use without other reagent that specifies.It should be appreciated by those skilled in the art that except as otherwise noted, the used reagent of the present invention is can be from commercially available other reagent of analytical pure level of conventional chemical reagent company.
Experimental technique among the following embodiment if no special instructions, is conventional method.
One, 2-allyloxy-2-oxygen-1,3, the synthetic and sign of 2-dioxaphospholane (AOOP) annular phosphate monomer
(1) 2-chloro-2-oxygen-1,3,2-dioxaphospholane (COP) synthetic
The COP synthetic route is shown in Fig. 1 (A).The concrete steps of synthetic COP are: under 25 ℃, the dichloromethane solution of 301mL 3.25mol/L ethylene glycol is slowly added in the dichloromethane solution of 300mL 3.26mol/L Phosphorous chloride..After dropwising, continue reaction 0.5 hour, 45 ℃ of air-distillation desolventizings.After double distilling under reduced pressure (20Pa) obtains product again, product is dissolved in the 500mL benzene logical 3 days O
2Until react completely, again distilling under reduced pressure (20Pa) is collected 70 ℃ of fractions and is obtained COP.
(2) 2-allyloxy-2-oxygen-1,3, the synthetic and sign of 2-dioxaphospholane (AOOP)
Synthetic route is shown in Fig. 1 (B).The concrete steps of synthetic AOOP are: under-5 ℃ low-temp reactions are bathed, with the COP (14.25g that makes, 0.1mol) oxolane (30mL) solution be added drop-wise to propenyl (5.80g, 0.1mol) and triethylamine (10.12g, 0.1mol) oxolane (120mL) solution in, reaction is spent the night.Then at N
2Protection is lower, filters above solution, and oxolane decompression (20Pa) is removed in 40 ℃, and 72 ℃ fraction is collected in remaining liq distilling under reduced pressure (20Pa), obtains AOOP.
To AOOP carry out proton nmr spectra (
1H NMR) analyze, Fig. 2 is AOOP's
1The HNMR spectrogram is analyzed as follows:
1H NMR (CDCl
3, ppm): 4.45 (m ,-PO
CH 2CH
2-), 4.68 (m ,-OCH
2CHCH
2), 5.28 (dd ,-OCH
2CHCH
2-), 5.95 (m ,-OCH
2CHCH
2-).
Two, poly glycol monomethyl ether-poly phosphate di-block copolymer (mPEG
a-PAOOP
b) synthetic and characterize
Various molecular weight polyisoprene glycol monoethyl ethers-poly phosphate block polymer is take poly glycol monomethyl ether as initiator, causes the poly phosphate monomer polymerization and form under solution condition.Molecular weight by regulating poly glycol monomethyl ether and the rate of charge of poly phosphate and poly glycol monomethyl ether can obtain the poly glycol monomethyl ether of different molecular weight-poly phosphate block polymer.1,5,7-, three nitrine dicyclos (4.4.0) last of the ten Heavenly stems-5-alkene (TBD) belongs to the organic heterocyclic non-metallic catalyst, and its catalytic efficiency is higher, has been proved to be the ring-opening polymerisation that is applicable to lactone and lactide cyclic monomer.
Synthetic route is shown in Fig. 1 (C), with mPEG
45And mPEG
113Be initiator, 1,5,7-, three nitrine dicyclos (4.4.0) last of the ten Heavenly stems-5-alkene (TBD) is for catalyst prepares polymer, polyreaction glove box (available from: carry out (O Braun inert gas system (Shanghai) Co., Ltd.)
2With H
2The concentration of O is all less than 0.1ppm), with mPEG
45Be example as initiator, mPEG
a-PAOOP
bSynthetic concrete experimental procedure is as follows:
After the processing of the round-bottomed flask that 1) will react and inflated with nitrogen dry through repeatedly evacuation flame, put into glove box (available from: Braun inert gas system (Shanghai) Co., Ltd.).
2) proportioning by table 1 feeds intake: add mPEG in flask
45Or mPEG
113, AOOP monomer, THF and TBD, under 25 ℃ of stirrings, react.
3) reaction was shifted out glove box with product after 0.5 hour, used Rotary Evaporators that system is concentrated, precipitate twice with 0 ℃ ether methanol mixed solvent (ether: methanol=9: 1, v/v, 100mL), the collecting precipitation thing is drained till the constant weight with oil pump, namely gets product.
Different rate of charges can obtain different products, have so obtained a series of mPEG
a-PAOOP
bCopolymer sees Table 1.
The different rate of charges of table 1 (mol ratio) synthesize mPEG
a-PAOOP
b
1*The digitized representation polymer basis in the polymer lower right corner
1The degree of polymerization that H NMR obtains
To above-mentioned mPEG-PAOOP copolymer carry out proton nmr spectra (
1H NMR) analyzes, measure its degree of polymerization and number-average molecular weight.With number-average molecular weight and the molecular weight distribution PDI (Breadth parameter of molecular weight distribution) of gel permeation chromatography (GPC) method take polystyrene as standard analysis mPEG-PAOOP copolymer.The degree of polymerization, number-average molecular weight and molecular weight distribution PDI see Table 2.The GPC spectrum is seen Fig. 2.
1H NMR spectrum is seen Fig. 3.
Table 2mPEG
a-PAOOP
bThe sign of polymer
2aGPC measures;
2b1H NMR measures.
Fig. 3 is the GPC spectrogram of polymer, the corresponding mPEG of Fig. 3 (A)
45-PAOOP
25The corresponding mPEG of Fig. 3 (B)
45-PAOOP
75The corresponding mPEG of Fig. 3 (C)
113-PAOOP
150Three kinds of polymer present as we can see from the figure all is regular unimodal, and along with the corresponding shortening of its delivery time of increase of polymer molecular weight, and has the molecular weight distribution of relative narrower.
Fig. 4 is mPEG-PAOOP's
1H NMR spectrogram, the mPEG-PAOOP of three kinds of different molecular weights that synthesized has similar spectrum, is analyzed as follows:
1H NMR (CDCl
3, ppm): 3.63 (s ,-CH
2CH
2O-), 4.25 (t ,-POCH
2CH
2-), 4.57 (t ,-POCH
2CH=CH
2), 5.30 (dd ,-POCH
2CH=CH
2), 5.93 (m ,-POCH
2CH=CH
2).The degree of polymerization of poly phosphate calculates by the triplet of 4.25ppm and the unimodal integral area ratio of 3.63ppm, and related data is added up in table 2.
By as seen from Table 2, according to
1H NMR result of calculation, mPEG
45-PAOOP
25Number-average molecular weight be 6100g/mol, corresponding block PAOOP
25Number-average molecular weight be 4100g/mol; MPEG
45-PAOOP
75Number-average molecular weight be 14300g/mol, corresponding block PAOOP
75Number-average molecular weight be 12300g/mol; MPEG
113-PAOOP
150Number-average molecular weight be 29600g/mol, corresponding block PAOOP
150Number-average molecular weight be 24600g/mol.
One, side group is amino poly glycol monomethyl ether-poly phosphate di-block copolymer (mPEG
a-PAOOP
b-Cya) synthetic and characterizing
Synthetic route is shown in Fig. 1 (D), with mPEG4
5-b-PAOOP
75Be example, under 25 ℃, get mPEG
45-b-PAOOP
75(200mg, 0.014mmol), the mercaptoethylmaine hydrochlorate (0.375g, 3.15mmol, two key moles 300%) and benzoin dimethylether (DMPA, 13.4mg, 0.05mmol, two key moles 5%) be dissolved in the 1.5mL dry DMF.After blasting nitrogen 20min, shine 30min under the 365nm ultraviolet light, product namely obtains side group and is amino poly glycol monomethyl ether-poly phosphate polymer (mPEG at 4 ℃ of lower use distill water dialysis 48h (molecular cut off is 2000) after the lyophilizing
45-PAOOP
75-Cya, PPC).To PPC carry out proton nmr spectra (
1H NMR) analyze, Fig. 5 is mPEG
a-PAOOP
b-Cya's
1H NMR spectrogram, the polymer of three kinds of different molecular weights all has similar spectrum as seen from Figure 5, according to
1H NMR analyzes,
1HNMR (D
2O, ppm): 1.92 (m ,-POCH
2CH
2CH
2-), 2.60 (t ,-CH
2CH
2CHS-), 2.75 (t ,-SCH
2CH
2NH
3 +Cl
-), 3.11 (t ,-SCH
2CH
2NH
3 +Cl
-), 3.57 (s ,-CH
2CH
2O-), 4.16 (m ,-POCH
2CH
2CH
2-), 4.26 (t ,-POCH
2CH
2-).By the triplet at 2.75ppm place and the triplet at 4.26ppm place, but the side group of all poly phosphate construction units of calculative determination is all modified by amination.
Two, amine-functionalized synthesizing of amycin derivant (Mal-ADR) of maleimide reaches sign
Synthetic route is shown in Fig. 1 (E), maleic anhydride (29.4g, 0.3mol) and 6-aminocaprolc acid (39.35g, 0.3mol) stirring 16h in glacial acetic acid (900mL), acetic acid is removed in 70 ℃ of lower decompressions (20Pa), obtains yellow syrupy shape solid, and (eluant is methylene chloride/methanol/acetic acid by silica gel column chromatography with it, 100: 5: 1, v/v) purification.Get the solid 6-Malaysia aminocaproic acid (2.11g behind the purification, 10mmol) with N-methylmorpholine (1.01g, 10mmol) be dissolved among the anhydrous THF (200mL), 4 ℃ to THF (10mL) solution that wherein dropwise is added dropwise to isobutyl chlorocarbonate (1.36g, 10mmol), stir 5min after, again to wherein dropwise dripping tert-butyl carbazate (1.32g, THF 10mmol) (10mL) solution, 4 ℃ of lower reaction 30min are again at 25 ℃ of lower reaction 1h.After distilling under reduced pressure (20Pa) desolventizing, with ethyl acetate and moisture mutually, organic facies is used anhydrous sodium sulfate drying again with 0.1N dilute hydrochloric acid solution, water, the washing of 5wt% sodium bicarbonate aqueous solution.After the desolventizing, solid is with silica gel column chromatography (eluant is methylene chloride/methanol, 100: 1-2, V/V) purification.With chromatography product (545mg, 2.4mmol) with trifluoroacetic acid (10mL) dissolving, in 0 ℃, stirring 8min, excessive trifluoroacetic acid is removed in 25 ℃ of lower decompressions (20Pa), the residue crude product grinds with ether, namely obtains 6-maleimide caproic acid hydrazides trifluoroacetate.Get 6-dimaleoyl imino caproic acid hydrazides trifluoroacetate (92mg, 27.1mmol) and be dissolved in (17.5mL) in the methanol with doxorubicin hydrochloride (52mg, 89.6mmol), add the trifluoroacetic acid of 50 μ L, lucifuge stirring reaction 24h under the room temperature.System is concentrated into 2.5mL, adds the 12.5mL acetonitrile, 4 ℃ leave standstill 48h and obtain crystallized product, centrifugal rear with methanol-(10: 1, v/v), vacuum drying namely got product to the washing of acetonitrile mixed solution, productive rate 70%.Mal-ADR is carried out the ESI mass spectral analysis, and as shown in Figure 5, this matter theory molecular weight is 750.3, and the m/z=751.04 that detects is [M+H]
+Signal peak, and product is without other impurity, prove that product structure and expection coincide, and purity is very high.
Three, the adriamycin bonded synthetic and sign (mPEG of poly glycol monomethyl ether-acid-sensitive sense of poly phosphate di-block copolymer
a-PAOOP
b-Cya-ADR-DMMA)
MPEG
a-PAOOP
b-Cya-ADR-DMMA is shown in Fig. 1 (G), with mPEG
45-PAOOP
75-Cya is example, with mPEG
45-PAOOP
75-Cya (PPC, 62.4mg, 0.003mmol) is dissolved in deionized water (pH=6.5,5mL), 25 ℃ of lower 2-imino group sulfane hydrochlorates (2.88mg, 0.021mmol) that add, stirring reaction 2h under the room temperature, ultrafiltration is to remove unreacted 2-imino group sulfane hydrochlorate.Add Mal-ADR (9.60mg, 0.012mmol) again in mixed solution, regulate pH to 6.7 with NaOH solution (0.1N), stir 3h, unreacted Mal-ADR is removed in ultrafiltration.Add 2,3-dimethyl maleic anhydride (DMMA, 77.6mg, 0.62mmol), regulate pH to 8.0-8.5 with NaOH solution (0.2N), unreacted DMMA is removed in ultrafiltration again, namely gets product after the lyophilizing.MPEG
45-PAOOP
25-Cya and mPEG
113-PAOOP
150-Cya bonding 2, building-up process and mPEG that 3-dimethyl maleic anhydride and acid-sensitive sense are adriamycin bonded
45-PAOOP
75-Cya is similar, only needs to change molar ratio and gets final product, and for example, concrete molar ratio is as follows: for mPEG
45-PAOOP
25-Cya, itself and 2-imino group sulfane hydrochlorate, Mal-ADR, 2, the mol ratio of 3-dimethyl maleic anhydride was respectively 1: 2,1: 1 and 1: 75; For mPEG
45-PAOOP
150-Cya, itself and 2-imino group sulfane hydrochlorate, Mal-ADR, 2, the mol ratio of 3-dimethyl maleic anhydride was respectively 1: 15,1: 7.5 and 1: 450.
To mPEG
a-PAOOP
b-Cya-ADR-DMMA carry out proton nmr spectra (
1H NMR) analyze, as seen from Figure 7, according to
1H NMR analyzes, for mPEG
a-PAOOP
b-Cya-ADR-DMMA, alphabetical a-l and p, q and s labelling whole mPEG
a-PAOOP
bThe proton signal of-Cya-ADR-DMMA.
Here need to prove, for the mPEG of different polymerization degree (that is, different a and b value)
a-PAOOP
b-Cya-ADR-DMMA's is synthetic, reaction condition and process except molar ratio without any variation.For example, the pH value of reaction is in the 6.5-8.5 scope, preferred pH=6.5,6.7 and 8.0, and 2-imino group sulfane hydrochlorate, Mal-ADR, 2, the molar ratio of 3-dimethyl maleic anhydride and used poly glycol monomethyl ether-poly phosphate di-block copolymer side group amino is at least respectively 1/10,1/20 and 3/1.
1, mPEG
a-PAOOP
bThe biocompatibility of-Cya-DMMA nano-particle
In this experiment, because namely there is the kill capability to cell in ADR itself, so in order to get rid of ADR to the interference of Biocompatibility, selected is not at the adriamycin bonded mPEG of side group
a-PAOOP
b-Cya-DMMA.The nanoparticles solution redilution that above-mentioned material is formulated as 1mg/mL is 10.6-340 μ g/mL.Measure variable concentrations mPEG by the MTT method
a-PAOOP
bThe cytotoxicity of-Cya-DMMA copolymer nano granule.Concrete test is: with the mPEG of variable concentrations
a-PAOOP
b-Cya-DMMA nanoparticles solution after 48 hours, is surveyed respectively cell survival rate with the MDA-MB-231 co-culture of cells respectively under pH=7.4 and pH=6.8 condition.The survival rate of cell is seen Fig. 8 (A) under the different disposal.
As seen from Figure 9, when polymer concentration increases to 340 μ g/mL from 10.6 μ g/mL, the nano-particle of the polymer formation of three kinds of different molecular weights does not all have significantly impact to cell viability under two kinds of pH conditions, cell viability maintains about 100% always, shows that above-mentioned nano-particle has good biocompatibility.
2, mPEG
a-PAOOP
b-Cya-ADR-DMMA nano-particle is to the sign of the kill capability of cell
With mPEG
a-PAOOP
bThe concentration that the nanoparticles solution and being diluted that-Cya-ADR-DMMA is formulated as 1mg/mL is adjusted amycin is 0.28-35 μ g/mL.Measure variable concentrations mPEG by the MTT method
a-PAOOP
bThe cytotoxicity of-Cya-ADR-DMMA copolymer nano granule.Concrete test is: with the mPEG of variable concentrations
a-PAOOP
b-Cya-ADR-DMMA nanoparticles solution after 48 hours, is surveyed respectively cell survival rate with the MDA-MB-231 co-culture of cells respectively under pH=7.4 and pH=6.8 condition.The survival rate of cell is seen Fig. 9 under the different disposal.
Because mPEG
a-PAOOP
b-Cya-ADR-DMMA is originally as macromole bonding medicine, and verified this material can better discharge amycin under the environment of pH slant acidity in release experiment, response with Inclusion environment in the cell, therefore with this material effects in the MDA-MB-231 cell.As seen from the figure, no matter under the polymer nano granules condition of which kind of pH environment and which kind of molecular weight, along with mPEG
a-PAOOP
bThe increase of its concentration of-Cya-ADR-DMMA, the survival rate of cell presents comparatively significantly downward trend, than the good biocompatibility of not adriamycin bonded material, the cytotoxicity that can judge material is that the amycin release that bonding is introduced causes, and works as mPEG
a-PAOOP
bWhen the concentration of-Cya-ADR-DMMA was 17.5 μ g/mL, the nano-particle of three kinds of molecular weight all can cause the MDA-MB-231 cell survival rate to be lower than 75% under two kinds of pH conditions, and mPEG has been described
a-PAOOP
b-Cya-ADR-DMMA has preferably cell killing ability.Simultaneously, under two kinds of pH conditions, can clearly find, no matter the concentration of material, all relatively low than the cell survival rate under the low ph environment, take the middle concentrations of nanoparticles of Fig. 9 (A) as 17.5 μ g/mL as example, the cell survival rate of pH=7.4 is about 75%, cell survival rate in the simulation tumor under the low pH environment is less than 60% then, and comparatively significantly difference is arranged.According to the Changing Pattern of material zeta current potential before as can be known, the surface charge of material can be gradually under this pH from negative value transfer on the occasion of, its zeta current potential can remain on+7.5mV behind 2h, and because can there be the more electronegative protein of taking in cell surface, so the material of surface charge polarization can better enter cell, therefore, the difference in the cell killing ability under the different pH value should ascribe the difference that material enters cell ability under condition of different pH to.When pH is 6.8, material surface can carry positive charge gradually, thereby more enrichment in cell, compare during with pH=7.4, material all can be relatively high in the amount of intracellular concentration and the amycin that discharges in cell, thereby better killer cell, and three kinds of polymer nano granules are basically identical to the kill capability of cell.This experimental results show that under tumor tissues meta-acid environment material can killing tumor cell, thereby reaches the purpose for the treatment of tumor.
Should be appreciated that, although with reference to its exemplary embodiment, the present invention is shown particularly and describe, but will be understood by those skilled in the art that, under the condition that does not deviate from by the defined the spirit and scope of the present invention of accompanying claim, the variation of various forms and details can be carried out therein, the combination in any of various embodiments can be carried out.
Claims (10)
1. poly phosphate amycin macromole bonding medicine, its active component is the nano-particle that poly phosphate polymer-bound amycin forms, wherein said poly phosphate polymer is poly glycol monomethyl ether-poly phosphate di-block copolymer, and the adriamycin bonded general formula of described poly phosphate is: mPEG
a-PAOOP
b-Cya-ADR-DMMA,
A=45-113 wherein, b=25-150, a and b are respectively any number in the described scope;
Wherein mPEG is the abbreviation of poly glycol monomethyl ether, and subscript a is that this polymer poly is right; PAOOP is the abbreviation of poly-(2-allyloxy-2-oxygen-1,3,2-dioxaphospholane), and subscript b is that this polymer poly is right; Cya is the abbreviation of mercaptoethylmaine hydrochlorate, and ADR is the abbreviation of amycin, and DMMA is the abbreviation of 2,3-dimethyl maleic anhydride.
2. according to claim 1 poly phosphate amycin macromole bonding medicine, its active component is mPEG
45-PAOOP
25-Cya-ADR-DMMA, mPEG
45-PAOOP
75-Cya-ADR-DMMA or mPEG
113-POOP
150-Cya-ADR-DMMA.
3. according to claim 1 poly phosphate amycin macromole bonding medicine, initial block is poly glycol monomethyl ether in wherein said poly glycol monomethyl ether-poly phosphate di-block copolymer, another block is described poly phosphate; The degree of polymerization of described poly glycol monomethyl ether block is 45-113, and corresponding number-average molecular weight is 2,000-5,000g/mol; The degree of polymerization of described poly phosphate block is 25-150, and corresponding number-average molecular weight is 6,925-27,700g/mol.
4. according to claim 1 poly phosphate amycin macromole bonding medicine, the poly phosphate in wherein said poly glycol monomethyl ether-poly phosphate di-block copolymer by structural formula suc as formula the five-membered cyclic phosphate ester monomer polymerization of (I) after further functionalized forming:
5. according to claim 1 poly phosphate amycin macromole bonding medicine, adriamycin bonded and 2,3-dimethyl maleic anhydride forms by described poly glycol monomethyl ether-poly phosphate di-block copolymer side group for it.
6. according to claim 1 poly phosphate amycin macromole bonding medicine, it further carries out chemical modification or ligand modified.
7. the method for preparing the poly phosphate amycin macromole bonding medicine of claim 1, its take side group as amino poly glycol monomethyl ether-poly phosphate di-block copolymer under the proper pH value condition successively with the 2-imino group sulfane hydrochlorate of proper proportion, Mal-ADR, 2, the reaction of 3-dimethyl maleic anhydride, thereby it is adriamycin bonded and 2 finally to obtain in poly glycol monomethyl ether-poly phosphate di-block copolymer poly phosphate block side group, the amycin macromole bonding medicine of 3-dimethyl maleic anhydride, wherein, described Mal-ADR can obtain by maleic anhydride and 6-aminocaprolc acid and tert-butyl carbazate and amycin reaction, and Mal is the abbreviation of maleimide base group.
8. according to claim 7 method, wherein said pH value is in the 6.5-8.5 scope, 2-imino group sulfane hydrochlorate, Mal-ADR, 2, the molar ratio of 3-dimethyl maleic anhydride and used poly glycol monomethyl ether-poly phosphate di-block copolymer side group amino is at least respectively 1/10,1/20 and 3/1.
9. side group is the poly glycol monomethyl ether-polyphosphoric acid di-block copolymer of two keys, and wherein initial block is poly glycol monomethyl ether, and another block is described poly phosphate; The degree of polymerization of described poly glycol monomethyl ether block is 45-113, and corresponding number-average molecular weight is 2,000-5,000g/mol; The degree of polymerization of described poly phosphate block is 25-150, corresponding number-average molecular weight is 4,100-24,600g/mol, described copolymer is by following synthetic: take the terminal hydroxy group poly glycol monomethyl ether as macromole evocating agent, with 1,5,7-three nitrine dicyclos (4.4.0) last of the ten Heavenly stems-5-alkene is catalyst, obtains side group by structural formula suc as formula the ring-opening polymerization of the annular phosphate monomer of (I) and is the poly glycol monomethyl ether of two keys-polyphosphoric acid di-block copolymer.
10. side group is amino poly glycol monomethyl ether-polyphosphoric acid di-block copolymer, and wherein initial block is poly glycol monomethyl ether, and another block is described poly phosphate; The degree of polymerization of described poly glycol monomethyl ether block is 45-113, and corresponding number-average molecular weight is 2,000-5,000g/mol; The degree of polymerization of described poly phosphate block is 25-150, corresponding number-average molecular weight is 6,925-27,700g/mol, described copolymer is by following synthetic: be the poly glycol monomethyl ether-polyphosphoric acid di-block copolymer use benzoin dimethylether catalysis of two keys with the side group of claim 9, under the 365nm irradiation under ultraviolet ray, utilize the sulfydryl of mercaptoethylmaine hydrochlorate to carry out the click chemistry reaction of sulfydryl with two keys, thereby finally synthesize the poly glycol monomethyl ether that side group is amino-poly phosphate di-block copolymer.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103705931A (en) * | 2013-12-12 | 2014-04-09 | 深圳先进技术研究院 | Shell-droppable polymer nano carrier as well as preparation method and application thereof |
| CN104387591A (en) * | 2014-11-20 | 2015-03-04 | 合肥工业大学 | Hydrophilic polyethylene glycol-hydrophobic polyphosphate segmented copolymer as well as preparation methods and application of segmented copolymer |
| CN109223729A (en) * | 2018-09-21 | 2019-01-18 | 华南理工大学 | A kind of adriamycin bonded material and the preparation method and application thereof with polyphosphate of Contracting thioketones key |
| WO2022063206A1 (en) * | 2020-09-25 | 2022-03-31 | 亭创生物科技(上海)有限公司 | Functionalized diblock copolymer, preparation method therefor and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103705931A (en) * | 2013-12-12 | 2014-04-09 | 深圳先进技术研究院 | Shell-droppable polymer nano carrier as well as preparation method and application thereof |
| CN103705931B (en) * | 2013-12-12 | 2015-11-11 | 深圳先进技术研究院 | A kind of shell-droppable polymer nano carrier, its preparation method and application thereof |
| CN104387591A (en) * | 2014-11-20 | 2015-03-04 | 合肥工业大学 | Hydrophilic polyethylene glycol-hydrophobic polyphosphate segmented copolymer as well as preparation methods and application of segmented copolymer |
| CN104387591B (en) * | 2014-11-20 | 2017-04-05 | 合肥工业大学 | A kind of hydrophilic polyglycol hydrophobicity poly phosphate block copolymer and its production and use |
| CN109223729A (en) * | 2018-09-21 | 2019-01-18 | 华南理工大学 | A kind of adriamycin bonded material and the preparation method and application thereof with polyphosphate of Contracting thioketones key |
| CN109223729B (en) * | 2018-09-21 | 2021-05-14 | 华南理工大学 | Material with thioketal bond bonding adriamycin and polyphosphate ester and preparation method and application thereof |
| WO2022063206A1 (en) * | 2020-09-25 | 2022-03-31 | 亭创生物科技(上海)有限公司 | Functionalized diblock copolymer, preparation method therefor and use thereof |
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