CN103432591B - Nano-micelle medicine using ethylene epoxide polymer as a carrier and a preparation method thereof - Google Patents
Nano-micelle medicine using ethylene epoxide polymer as a carrier and a preparation method thereof Download PDFInfo
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Abstract
The invention provides a nano-micelle medicine using ethylene epoxide polymer as a carrier and a preparation method thereof, belongs to the field of biomedical materials, and solves the problems that the medicine loading capacity is low, dissociation and release of a medicine of medicine sudden release and macromolecule bonding are difficult to be controlled, and the stability is bad. According to the invention, a medicine molecule exists in a nano-micelle in two states of physical coating and chemical bonding; a medicine in the state of physical coating is a hydrophobic anticancer medicine, the medicine in the state of physical coating makes up 10-30% of the nano-micelle medicine in mass percent, and the coating efficiency can reach 90%-100%. The carrier macromolecule is segmented copolymer composed of a polyethylene oxide segment and a polyethylene oxide segment with chemical bonding hydrophobic anticancer medicine molecules, and the mass content of the chemical bonding hydrophobic anticancer medicine in the segmented copolymer is 10-20%.
Description
Technical field
The invention belongs to biomedical materials field, being specifically related to a kind of take ethylene oxide polymer as nano-micelle medicine of carrier and preparation method thereof.
Background technology
Poly(ethylene oxide) be a kind of in physiological conditions can the water-soluble polymer of stable existence; because its space structure can stop the close of plasma protein; be widely used in the hydrophilic protective layer of polymer micelle; both particles agglomerate can be prevented; the reticuloendothelial system identification in body can be avoided again, engulf; thus the retention time of prolong drug in blood circulation, reach macrocyclic object.
Several high molecular nanometer micelle delivery systems in clinical at present with application prospect have two kinds of forms substantially to supporting of small-molecule drug: physically encapsulation and chemical bonding.Physically encapsulation macromolecule carrier usually used is polyethylene glycol-ester or polyethylene glycol-amino acid block copolymer, and polyester or polyamino acid are as the core of micelle; Chemical bonding carrier used mainly contains polyamino acid and poly-N-(2-hydroxypropyl) Methacrylamide, and hydrophobic drug is bonded on the side chain of carrier.Both take full advantage of the advantage of nano-micelle: the water solublity 1) significantly improving medicine; 2) there are protection and slow releasing function to medicine, can toxic and side effects be reduced; 3) change the approach entering cell, reduce medicine and resist; 4) owing to there being certain granular size, cancerous issue has " infiltration of enhancing and retention effect " them, i.e. " EPR effect ", and drug particles, in the relative enrichment of diseased region, is conducive to improving curative effect, reducing general toxicity.But both also exist weak point again respectively: physically encapsulation also exists initial stage violent release, medicine loading is relatively low; Polymer bond drug is because medicine is by covalent bond and macromolecule carrier bonding, significantly improve medicine stability in blood, there will not be initial stage violent release phenomenon, and drug loading is improved, but most of pharmaceutically active is lost or reduces after bonding, in order to ensure effectively to discharge active medicine under condition in vivo, to the bonding pattern of macromolecule carrier and medicine, there is higher requirement, increasing difficulty and the cost of synthesis.The carrier macromolecule of current employing two blocks or many blocks often, wherein containing one or more hydrophobic block, they are except providing hydrophobicity, more do not act on, but occupy sizable mass ratio, be unfavorable for the raising of drug loading, also add the burden of metabolism and excretion.
Summary of the invention
The object of the invention is to solve that existing physically encapsulation method drug loading is low, burst drug release and polymer bond drug Chinese medicine dissociate, discharge be difficult to control, the problem of poor stability, and to provide a kind of take ethylene oxide polymer as nano-micelle medicine of carrier and preparation method thereof.
First the present invention provides a kind of take ethylene oxide polymer as the nano-micelle medicine of carrier, described drug molecule is present in nano-micelle with physically encapsulation and chemical bonding two states, the medicine of physically encapsulation is hydrophobic anticancer medicine, the mass percent of medicine in nano-micelle medicine of physically encapsulation is 10-30%, described carrier is the block copolymer that poly(ethylene oxide) section and chemical bonding are made up of the poly(ethylene oxide) section of hydrophobic anticancer medicine molecule, chemical bonding has the mass content of hydrophobic anticancer medicine in block copolymer to be 10-20%, the structural formula of described carrier is as shown in formula I:
In formula I, the span of x is 10 ~ 225; The span of y to be the span of 4 ~ 30, d be 4 ~ 30, d≤y, Drug1, for being bonded with hydrophobic anticancer medicine molecule, is connected with ester bond between it with polyethylene oxide molecules chain.
Preferably, the described hydrophobic anticancer medicine molecule for chemical bonding is selected from one or more in paclitaxel, Docetaxel, baccatin III, 10-deacetylation baccatin III, camptothecine, 10-hydroxycamptothecine or SN38.
Preferably, the described hydrophobic anticancer medicine for physically encapsulation is selected from the hydrophobic products that paclitaxel, Docetaxel, baccatin III, camptothecine, 10-hydroxycamptothecine, SN38 or amycin Anthraquinone obtain through ammoniated treatment.
Preferably, described amycin Anthraquinone is amycin, pirarubicin, epirubicin or rubidomycin.
It take ethylene oxide polymer as the preparation method of the nano-micelle medicine of carrier that the present invention also provides a kind of, comprising:
Step one: by poly(ethylene oxide) and allyl glycidyl ether reaction, obtain bi-block copolymer A;
Step 2: the bi-block copolymer A that small carboxylic acid molecules and the step one containing sulfydryl obtains is carried out additive reaction, obtains bi-block copolymer B;
Step 3: the bi-block copolymer B that the hydrophobic anticancer medicine Drug1 and step 2 that are used for chemical bonding obtain is carried out esterification, the block copolymer that the poly(ethylene oxide) section obtaining poly(ethylene oxide) section and be bonded with hydrophobic anticancer medicine molecule forms;
Step 4: the block copolymer of the poly(ethylene oxide) section hydrophobic anticancer medicine and step 3 that are used for physically encapsulation obtained and the poly(ethylene oxide) section composition that is bonded with hydrophobic anticancer medicine molecule is mixed with organic solution, and preparing with ethylene oxide polymer is the nano-micelle medicine of carrier.
Preferably, the reaction temperature of described step one is 20 DEG C-50 DEG C, and the response time is 12-24 hour.
Preferably, described poly(ethylene oxide) and the mol ratio of allyl glycidyl ether are (10 ~ 225): (4 ~ 30).
Preferably, the described small carboxylic acid molecules containing sulfydryl is mercaptopropionic acid or TGA.
Preferably, the reaction condition of described step 2 is: irradiate 4-10 hour by the uviol lamp room temperature that wavelength is 254nm or 365nm.
Preferably, described is (11 ~ 24) for the hydrophobic anticancer medicine of chemical bonding and the mass percent of bi-block copolymer B: (76 ~ 89).
Beneficial effect of the present invention
(1) first the present invention provides a kind of take ethylene oxide polymer as the nano-micelle medicine of carrier, described drug molecule is present in nano-micelle with physically encapsulation and chemical bonding two states, the medicine of physically encapsulation is hydrophobic anticancer medicine, physically encapsulation and chemical bonding two kinds of methods combining get up by this medicine simultaneously, make full use of the stronger affine ability of dissolving each other between the hydrophobic property of hydrophobic drug itself and hydrophobic drug, realize nanometer assembling, reach higher medicament contg; Solve low, the burst drug release of drug loading of tradition parcel dosage form and polymer bond drug Chinese medicine to dissociate difficulty, release is difficult to the problems such as control, and has good stability simultaneously.
(2) carrier of the present invention is the di-block copolymer of poly(ethylene oxide) section and the poly(ethylene oxide) section being bonded with hydrophobic anticancer medicine molecule composition, wherein one section of poly(ethylene oxide) serves as the shell that hydrophilic section forms micelle, another section of poly(ethylene oxide) is bonded with hydrophobic drug of the same race or not of the same race, serve as the core of micelle, the hydrophobicity of carrier is provided by the drug molecule of bonding, eliminate special hydrophobic polyester or polyamino acid block, to add between drug molecule affine dissolves each other performance often higher than the affine performance of dissolving each other between drug molecule and common polymer segment, thus medicine of the present invention has higher medicine loading and supports efficiency.Experimental result shows: in nano-micelle medicine of the present invention, the parcel amount of the medicine of physically encapsulation is 10-30%, and parcel efficiency can reach 90-100%.
(3) bonding medicine used in the present invention and packaging medicine, can be identical, also can be different, when adopting same medicine, except there is very high drug loading, also has an advantage: packaging medicine release is very fast comparatively speaking, bonding drug release is comparatively slow, and both also deposit the advantage both then playing, and reach active drug concentration very soon after ensureing dispenser, and the time that energy sustained release is longer, thus dispenser frequency can be reduced; When adopting different pharmaceutical, the common conveying of two kinds of anticarcinogens can be achieved easily, due to the feature of nano-micelle itself, when can ensure to enter tumor cell, the ratio of two kinds of medicines is determined, according to the needs of therapeutic alliance, ratio and the release dynamics of two kinds of medicines can be regulated, to obtain best synergy.Significant to clinical drug combination.
(4) the present invention also provides a kind of take ethylene oxide polymer as the preparation method of the nano-micelle medicine of carrier, described medicine take polyethylene oxide block copolymer as carrier, good biocompatibility, second block adopts allyl glycidyl ether to do polymerization single polymerization monomer, raw material is cheap and easy to get, do not change mechanism of polymerization and catalyst system and catalyzing, significantly reduce synthesis difficulty and cost; Adopt light-catalysed mercapto-alkene additive reaction to realize the conversion of carrier polymer side base, reaction condition is gentle, and efficiency is high, and side reaction is few simultaneously, and the nano-micelle medicine prepared has higher medicine loading and supports efficiency.
Accompanying drawing explanation
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of bi-block copolymer B in deuterochloroform prepared by the embodiment of the present invention 1.
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of block copolymer (B) in deuterochloroform that the poly(ethylene oxide) section of micromolecule paclitaxel (A) and the embodiment of the present invention 2 preparation forms with the poly(ethylene oxide) section being bonded with paclitaxel.
Fig. 3 be the embodiment of the present invention 3 prepare take ethylene oxide polymer as the electromicroscopic photograph (A) of the nano-micelle medicine of carrier and the micelle grain-size graph (B) of Dynamic Light Scattering Determination.
Fig. 4 is different ratios of raw materials and parcel amount and wrap up the graph of relation of efficiency in the embodiment of the present invention 13.
Detailed description of the invention
First the present invention provides a kind of take ethylene oxide polymer as the nano-micelle medicine of carrier, described drug molecule is present in nano-micelle with physically encapsulation and chemical bonding two states, the medicine of physically encapsulation is hydrophobic anticancer medicine, the mass percent of medicine in nano-micelle medicine of physically encapsulation is 10%-30%, the diameter of described nano-micelle medicine is 20-200nm, described carrier is the block copolymer of poly(ethylene oxide) section and the poly(ethylene oxide) section being bonded with hydrophobic anticancer medicine molecule composition, chemical bonding has the mass content of hydrophobic anticancer medicine in block copolymer to be 10-20%, structural formula is as shown in formula I:
In formula I, the span of x is 10 ~ 225; The span of y to be the span of 4 ~ 30, d be 4 ~ 30, d≤y, Drug1 is for being bonded with hydrophobic anticancer medicine molecule, and hydrophobic anticancer medicine molecule is connected with ester bond with between polyethylene oxide molecules chain.
Hydrophobic anticancer medicine molecule for chemical bonding of the present invention is preferably selected from one or more in paclitaxel, Docetaxel, baccatin III, 10-deacetylation baccatin III, camptothecine, 10-hydroxycamptothecine or SN38.There is a hydroxyl that can react in said medicine molecule, be connected with ester bond between they with polyethylene oxide molecules chain.
Hydrophobic anticancer medicine for physically encapsulation of the present invention is preferably selected from the hydrophobic products that paclitaxel, Docetaxel, baccatin III, camptothecine, 10-hydroxycamptothecine, SN38 or amycin Anthraquinone obtain through ammoniated treatment.Described amycin Anthraquinone is preferably amycin, pirarubicin, epirubicin or rubidomycin.Described ammoniated treatment process is for will add equimolar triethylamine in said medicine, obtain after adding hydrochlorate again, described amycin Anthraquinone is usually with hydrochloride form administration, its dissolubility in water can be increased, so these medicines first must be converted into hydrophobic form, then wrap up, to reach higher parcel amount and parcel efficiency.
It take ethylene oxide polymer as the preparation method of the nano-micelle medicine of carrier that the present invention also provides a kind of, comprising:
Step one: by poly(ethylene oxide) and allyl glycidyl ether reaction, obtain bi-block copolymer A;
Step 2: the bi-block copolymer A that small carboxylic acid molecules and the step one containing sulfydryl obtains is carried out additive reaction, obtains bi-block copolymer B;
Step 3: the bi-block copolymer B that the hydrophobic anticancer medicine and step 2 that are used for chemical bonding obtain is carried out esterification, the block copolymer that the poly(ethylene oxide) section obtaining poly(ethylene oxide) section and be bonded with hydrophobic anticancer medicine molecule forms;
Step 4: the block copolymer of the poly(ethylene oxide) section hydrophobic anticancer medicine and step 3 that are used for physically encapsulation obtained and the poly(ethylene oxide) section composition that is bonded with hydrophobic anticancer medicine molecule is mixed with organic solution, and preparing with ethylene oxide polymer is the nano-micelle medicine of carrier.
Poly(ethylene oxide) and allyl glycidyl ether are reacted described in step one of the present invention, be specially under nitrogen protection, the poly(ethylene oxide) of different molecular weight is put in reaction vessel, add solvent toluene and carry out azeotropic water removing, after 2-5 hour, Cesium hydrate. is added in reaction vessel, 40 DEG C-70 DEG C stirring reaction 2-4 hour, except desolventizing, continue to add allyl glycidyl ether, 20 DEG C-50 DEG C reaction 12-24 hour, be preferably 40 DEG C of reactions 24 hours, be cooled to room temperature, use ether sedimentation, filter, pressed powder bi-block copolymer A is obtained after vacuum drying, described poly(ethylene oxide) and the mol ratio of Cesium hydrate. are 1:1, described poly(ethylene oxide) and the mol ratio of allyl glycidyl ether are (10 ~ 225): (4 ~ 30).
Before the small carboxylic acid molecules just containing sulfydryl described in step 2 of the present invention and bi-block copolymer A carry out additive reaction, first described bi-block copolymer A is dissolved in oxolane, logical nitrogen 15-30min, then the small carboxylic acid molecules containing sulfydryl is added, the uviol lamp room temperature be preferably with wavelength is 254nm or 365nm irradiates 4-10 hour, is more preferably 8 hours, uses ether sedimentation, filter, after vacuum drying, obtain bi-block copolymer B.On described bi-block copolymer A, double bond is 1:5 with the mol ratio of the small carboxylic acid molecules containing sulfydryl.The described small carboxylic acid molecules containing sulfydryl is mercaptopropionic acid or TGA.
Esterification described in step 3 of the present invention is specially: be first dissolved in dichloromethane solvent by bi-block copolymer B, then activator 1 is added successively, 3-dicyclohexylcarbodiimide (DCC), catalyst DMAP (DMAP) and the hydrophobic anticancer medicine for chemical bonding, 25 DEG C of reactions 48 hours, use ether sedimentation, filter, the block copolymer that the poly(ethylene oxide) section obtaining poly(ethylene oxide) section after vacuum drying and be bonded with hydrophobic anticancer medicine molecule forms.The described hydrophobic anticancer medicine for chemical bonding, 1,3-dicyclohexylcarbodiimide (DCC) and DMAP (DMAP) mol ratio are 1:1:1; Be (11 ~ 24) for the hydrophobic anticancer medicine of chemical bonding and the mass percent of bi-block copolymer B: (76 ~ 89).
Described in step 4 of the present invention by poly(ethylene oxide) section and be bonded with hydrophobic anticancer medicine molecule poly(ethylene oxide) section composition block copolymer be dissolved in oxolane, polymer solution made by the hydrophobic anticancer medicine added again for physically encapsulation, utilize Rotary Evaporators, volatilize dry organic solvent, thin and uniform polymeric film is formed in the bottom of flask, intermediate water is joined in flask, aquation 1 ~ 60min at 25 DEG C ~ 70 DEG C, aquation 10min at being preferably 25 DEG C, with the filtering with microporous membrane of 0.45 μm, obtained take ethylene oxide polymer as the nano-micelle drug solution of carrier.By nano micellar solution lyophilization, namely obtaining take ethylene oxide polymer as the nano-micelle medicament freeze-drying powder of carrier.
Below in conjunction with specific embodiment, further detailed description is done to the present invention.
Embodiment 1
Under nitrogen protection, get 5g poly(ethylene oxide) (degree of polymerization is 11), add 20ml toluene and carry out azeotropic water removing, after 2 hours, 1.5g Cesium hydrate. is added, 40 DEG C of stirring reactions 2 hours, then except desolventizing in reaction vessel, add 4.75mL allyl glycidyl ether (degree of polymerization is 4), 40 DEG C are reacted 24 hours, are cooled to room temperature, with the sedimentation of 200mL ether, filter, after vacuum drying, obtain pressed powder bi-block copolymer A;
Be dissolved in the oxolane (THF) of 20mL by above-mentioned 4g bi-block copolymer A, logical nitrogen 30min, then adds 8.5g mercaptopropionic acid, irradiate 8 hours by the uviol lamp room temperature that wavelength is 254nm, with the sedimentation of 200mL ether, filter, obtain bi-block copolymer B after vacuum drying, productive rate is 87%; The hydrogen nuclear magnetic resonance spectrogram of the bi-block copolymer B prepared in deuterochloroform as shown in Figure 1;
Above-mentioned bi-block copolymer B 0.89g is dissolved in dry dichloromethane (10mg/mL), 0.11g camptothecine is added successively in solvent, 0.059g1,3-dicyclohexylcarbodiimide (DCC), 0.035g4-dimethylamino naphthyridine (DMAP) and camptothecine, 25 DEG C are reacted 48 hours, use ether sedimentation, filter, the block copolymer that the poly(ethylene oxide) section obtaining poly(ethylene oxide) section after vacuum drying and be bonded with camptothecine forms, productive rate is 90%, and wherein the content ultraviolet spectra of camptothecine is measured, and content is 10%;
Poly(ethylene oxide) section and the block copolymer of the poly(ethylene oxide) section composition being bonded with camptothecine are dissolved in oxolane, add camptothecine again, utilize Rotary Evaporators, volatilize dry organic solvent, form thin and uniform polymeric film in the bottom of flask, intermediate water is joined in flask, aquation 10min at 25 DEG C, with the filtering with microporous membrane of 0.45 μm, obtained take ethylene oxide polymer as the nano-micelle medicine of carrier.The mass percent of the block copolymer that camptothecine and poly(ethylene oxide) section and the poly(ethylene oxide) section being bonded with camptothecine forms is 20:80, is 15%, wraps up efficiency and reach 75% in the nano-micelle medicine obtained for the parcel amount of the camptothecine of physically encapsulation.
Embodiment 2
Under nitrogen protection, get 5g poly(ethylene oxide) (degree of polymerization is 45), add 20ml toluene and carry out azeotropic water removing, after 2 hours, 0.37g Cesium hydrate. is added, 40 DEG C of stirring reactions 2 hours, then except desolventizing in reaction vessel, add 2.37mL allyl glycidyl ether (degree of polymerization is 8), 40 DEG C are reacted 24 hours, are cooled to room temperature, with the sedimentation of 200mL ether, filter, after vacuum drying, obtain pressed powder bi-block copolymer A;
Above-mentioned 4g bi-block copolymer A is dissolved in the oxolane (THF) of 20mL, logical nitrogen 30min, then 5.65g mercaptopropionic acid is added, 8 hours are irradiated by the uviol lamp room temperature that wavelength is 254nm, with the sedimentation of 200mL ether, filter, obtain bi-block copolymer B after vacuum drying, productive rate is 90%;
Above-mentioned bi-block copolymer B0.76g is dissolved in dry dichloromethane (10mg/mL), 0.24g paclitaxel is added successively in solvent, 0.058g1,3-dicyclohexylcarbodiimide (DCC), 0.034g4-dimethylamino naphthyridine (DMAP), 25 DEG C are reacted 48 hours, use ether sedimentation, filter, the block copolymer that the poly(ethylene oxide) section obtaining poly(ethylene oxide) section after vacuum drying and be bonded with paclitaxel forms, productive rate is 89%, and wherein the content ultraviolet spectra of paclitaxel is measured, and content is 20%; Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of block copolymer (B) in deuterochloroform that the poly(ethylene oxide) section of micromolecule paclitaxel (A) and the embodiment of the present invention 2 preparation forms with the poly(ethylene oxide) section being bonded with paclitaxel, as can be seen from the figure, the block copolymer that the poly(ethylene oxide) section that the present invention has successfully synthesized poly(ethylene oxide) section and has been bonded with paclitaxel forms;
Poly(ethylene oxide) section and the block copolymer of the poly(ethylene oxide) section composition being bonded with paclitaxel are dissolved in oxolane, add paclitaxel again, utilize Rotary Evaporators, volatilize dry organic solvent, form thin and uniform polymeric film in the bottom of flask, intermediate water is joined in flask, aquation 10min at 25 DEG C, with the filtering with microporous membrane of 0.45 μm, obtained take ethylene oxide polymer as the nano-micelle medicine of carrier.The mass percent of the block copolymer that paclitaxel and poly(ethylene oxide) section and the poly(ethylene oxide) section being bonded with paclitaxel forms is 11:89, is 10%, wraps up efficiency and reach 100% in the nano-micelle medicine obtained for the parcel amount of the paclitaxel of physically encapsulation.
Embodiment 3
Under nitrogen protection, get 5g poly(ethylene oxide) (degree of polymerization is 113), add 20ml toluene and carry out azeotropic water removing, after 2 hours, 0.15g Cesium hydrate. is added, 40 DEG C of stirring reactions 2 hours, then except desolventizing in reaction vessel, add 0.95mL allyl glycidyl ether (degree of polymerization is 8), 40 DEG C are reacted 24 hours, are cooled to room temperature, with the sedimentation of 200mL ether, filter, after vacuum drying, obtain pressed powder bi-block copolymer A;
Above-mentioned 4g bi-block copolymer A is dissolved in the oxolane (THF) of 20mL, logical nitrogen 30min, then 2.83g mercaptopropionic acid is added, 8 hours are irradiated by the uviol lamp room temperature that wavelength is 254nm, with the sedimentation of 200mL ether, filter, obtain bi-block copolymer B after vacuum drying, productive rate is 90%;
Above-mentioned bi-block copolymer B0.85g is dissolved in dry dichloromethane (10mg/mL), 0.15g paclitaxel is added successively in solvent, 0.036g1,3-dicyclohexylcarbodiimide (DCC), 0.021g4-dimethylamino naphthyridine (DMAP), 25 DEG C are reacted 48 hours, use ether sedimentation, filter, the block copolymer that the poly(ethylene oxide) section obtaining poly(ethylene oxide) section after vacuum drying and be bonded with paclitaxel forms, productive rate is 92%, and wherein the content ultraviolet spectra of paclitaxel is measured, and content is 15%;
Poly(ethylene oxide) section and the block copolymer of the poly(ethylene oxide) section composition being bonded with paclitaxel are dissolved in oxolane, add paclitaxel again, utilize Rotary Evaporators, volatilize dry organic solvent, form thin and uniform polymeric film in the bottom of flask, intermediate water is joined in flask, aquation 10min at 25 DEG C, with the filtering with microporous membrane of 0.45 μm, obtained take ethylene oxide polymer as the nano-micelle medicine of carrier.The mass percent of the block copolymer that paclitaxel and poly(ethylene oxide) section form with the poly(ethylene oxide) section being bonded with paclitaxel is 17:83, be 16.2% for the parcel amount of the paclitaxel of physically encapsulation in the nano-micelle medicine obtained, parcel efficiency reaches 95%.Fig. 3 be the embodiment of the present invention 3 prepare take ethylene oxide polymer as the electromicroscopic photograph (A) of the nano-micelle medicine of carrier and the micelle grain-size graph (B) of Dynamic Light Scattering Determination, as can be seen from the figure, the diameter of nano-micelle medicine of the present invention is 20-200nm.
Embodiment 4
Under nitrogen protection, get 5g poly(ethylene oxide) (degree of polymerization is 225), add 20ml toluene and carry out azeotropic water removing, after 2 hours, 0.075g Cesium hydrate. is added, 40 DEG C of stirring reactions 2 hours, then except desolventizing in reaction vessel, add 1.19mL allyl glycidyl ether (degree of polymerization is 20), 40 DEG C are reacted 24 hours, are cooled to room temperature, with the sedimentation of 200mL ether, filter, after vacuum drying, obtain pressed powder bi-block copolymer A;
Above-mentioned 4g bi-block copolymer A is dissolved in the oxolane (THF) of 20mL, logical nitrogen 30min, then 3.53g mercaptopropionic acid is added, 8 hours are irradiated by the uviol lamp room temperature that wavelength is 254nm, with the sedimentation of 200mL ether, filter, obtain bi-block copolymer B after vacuum drying, productive rate is 92%;
Above-mentioned bi-block copolymer B0.89g is dissolved in dry dichloromethane (10mg/mL), 0.11g camptothecine is added successively in solvent, 0.059g 1, 3-dicyclohexylcarbodiimide (DCC), 0.035g4-dimethylamino naphthyridine (DMAP) and camptothecine, 25 DEG C are reacted 48 hours, use ether sedimentation, filter, the block copolymer that the poly(ethylene oxide) section obtaining poly(ethylene oxide) section after vacuum drying and be bonded with camptothecine forms, productive rate is 93%, the mass percent of camptothecine and bi-block copolymer B is 11:89, wherein the content ultraviolet spectra of camptothecine is measured, content is 10%,
Poly(ethylene oxide) section and the block copolymer of the poly(ethylene oxide) section composition being bonded with camptothecine are dissolved in oxolane, add camptothecine again, utilize Rotary Evaporators, volatilize dry organic solvent, form thin and uniform polymeric film in the bottom of flask, intermediate water is joined in flask, aquation 10min at 25 DEG C, with the filtering with microporous membrane of 0.45 μm, obtained take ethylene oxide polymer as the nano-micelle medicine of carrier.The mass percent of the block copolymer that camptothecine and poly(ethylene oxide) section and the poly(ethylene oxide) section being bonded with camptothecine forms is 20:80, is 15%, wraps up efficiency and reach 75% in the nano-micelle medicine obtained for the parcel amount of the camptothecine of physically encapsulation.
Embodiment 5
Under nitrogen protection, get 5g poly(ethylene oxide) (degree of polymerization is 225), add 20ml toluene and carry out azeotropic water removing, after 2 hours, 0.075g Cesium hydrate. is added, 40 DEG C of stirring reactions 2 hours, then except desolventizing in reaction vessel, add 1.78mL allyl glycidyl ether (degree of polymerization is 30), 40 DEG C are reacted 24 hours, are cooled to room temperature, with the sedimentation of 200mL ether, filter, after vacuum drying, obtain pressed powder bi-block copolymer A;
Above-mentioned 4g bi-block copolymer A is dissolved in the oxolane (THF) of 20mL, logical nitrogen 30min, then 4.75g mercaptopropionic acid is added, 8 hours are irradiated by the uviol lamp room temperature that wavelength is 254nm, with the sedimentation of 200mL ether, filter, obtain bi-block copolymer B after vacuum drying, productive rate is 95%;
Above-mentioned bi-block copolymer B0.89g is dissolved in dry dichloromethane (10mg/mL), 0.11g10-hydroxy camptothecin is added successively in solvent, 0.062g1, 3-dicyclohexylcarbodiimide (DCC), 0.037g4-dimethylamino naphthyridine (DMAP) and 10-hydroxycamptothecine, 25 DEG C are reacted 48 hours, use ether sedimentation, filter, the block copolymer that the poly(ethylene oxide) section obtaining poly(ethylene oxide) section after vacuum drying and be bonded with 10-hydroxycamptothecine forms, productive rate is 90%, the mass percent of 10-hydroxycamptothecine and bi-block copolymer B is 11:89, wherein the content ultraviolet spectra of 10-hydroxycamptothecine is measured, content is 10%,
Poly(ethylene oxide) section and the block copolymer of the poly(ethylene oxide) section composition being bonded with 10-hydroxycamptothecine are dissolved in oxolane, add 10-hydroxycamptothecine again, utilize Rotary Evaporators, volatilize dry organic solvent, form thin and uniform polymeric film in the bottom of flask, intermediate water is joined in flask, aquation 10min at 25 DEG C, with the filtering with microporous membrane of 0.45 μm, obtained take ethylene oxide polymer as the nano-micelle medicine of carrier.The mass percent of the block copolymer that 10-hydroxycamptothecine and poly(ethylene oxide) section form with the poly(ethylene oxide) section being bonded with 10-hydroxycamptothecine is 20:80, be 16% for the parcel amount of the 10-hydroxycamptothecine of physically encapsulation in the nano-micelle medicine obtained, parcel efficiency reaches 80%.
Embodiment 6
Identical with embodiment 2 step, difference is, for valence bond and hydrophobic anticancer medicine be Docetaxel, hydrophobic anticancer medicine for physically encapsulation is Docetaxel, the mass percent of Docetaxel and bi-block copolymer B is 20:80, wherein for valence bond and Docetaxel content with NMR method measure, content is 17%; The mass percent of the block copolymer that Docetaxel and poly(ethylene oxide) section form with the poly(ethylene oxide) section being bonded with Docetaxel is 14:86, be 12% for the parcel amount of the Docetaxel of physically encapsulation in the nano-micelle medicine obtained, parcel efficiency reaches 86%.
Embodiment 7
Identical with embodiment 3 step, difference is, for valence bond and hydrophobic anticancer medicine be SN38, hydrophobic anticancer medicine for physically encapsulation is SN38, the mass percent of SN38 and bi-block copolymer B is 11:89, wherein for valence bond and SN38 content with NMR method measure, content is 10%; The mass percent of the block copolymer that SN38 and poly(ethylene oxide) section form with the poly(ethylene oxide) section being bonded with SN38 is 30:70, in the nano-micelle medicine obtained, the parcel amount of SN38 is 21%, and parcel efficiency reaches 70%.
Embodiment 8
Identical with embodiment 4 step, difference is, for valence bond and hydrophobic anticancer medicine be baccatin III, hydrophobic anticancer medicine for physically encapsulation is baccatin III, the mass percent of baccatin III and bi-block copolymer B is 16:84, wherein for valence bond and baccatin III content with NMR method measure, content is 15%; The mass percent of the block copolymer that baccatin III and poly(ethylene oxide) section form with the poly(ethylene oxide) section being bonded with baccatin III is 20:80, and in the nano-micelle medicine obtained, the parcel amount of baccatin III is 16%, and parcel efficiency reaches 80%.
Embodiment 9
Identical with embodiment 3 step, difference is, hydrophobic anticancer medicine for physically encapsulation is amycin, the mass percent of the block copolymer that amycin and poly(ethylene oxide) section form with the poly(ethylene oxide) section being bonded with paclitaxel is 20:80, in the nano-micelle medicine obtained, the parcel amount of amycin is 19%, and parcel efficiency reaches 95%.
Embodiment 10
Identical with embodiment 3 step, difference is, hydrophobic anticancer medicine for physically encapsulation is pirarubicin, the mass percent of the block copolymer that pirarubicin and poly(ethylene oxide) section form with the poly(ethylene oxide) section being bonded with paclitaxel is 30:70, in the nano-micelle medicine obtained, the parcel amount of pirarubicin is 29%, and parcel efficiency reaches 97%.
Embodiment 11
Identical with embodiment 3 step, difference is, hydrophobic anticancer medicine for physically encapsulation is epirubicin, the mass percent of the block copolymer that epirubicin and poly(ethylene oxide) section form with the poly(ethylene oxide) section being bonded with paclitaxel is 30:70, in the nano-micelle medicine obtained, the parcel amount of epirubicin is 28%, and parcel efficiency reaches 93%.
Embodiment 12
Identical with embodiment 3 step, difference is, hydrophobic anticancer medicine for physically encapsulation is rubidomycin, the mass percent of the block copolymer that rubidomycin and poly(ethylene oxide) section form with the poly(ethylene oxide) section being bonded with paclitaxel is 33:67, in the nano-micelle medicine obtained, the parcel amount of rubidomycin is 30%, and parcel efficiency reaches 91%.
Embodiment 13
The block copolymer that poly(ethylene oxide) section embodiment 3 obtained and the poly(ethylene oxide) section being bonded with paclitaxel form is dissolved in and is loaded with (10mg/mL) in the flask of oxolane, by block copolymer: paclitaxel=1:19, 1:9, 1:5, 3:10 and press block copolymer: amycin=1:19, 2:8, 3:7, the ratio of 4:6 takes paclitaxel and amycin respectively, join in polymer solution, utilize Rotary Evaporators, volatilize dry organic solvent, thin and uniform polymeric film is formed in the bottom of flask, intermediate water is joined in flask, aquation 10min at 25 DEG C, with the filtering with microporous membrane of 0.45 μm, obtained take ethylene oxide polymer as the nano-micelle medicine of carrier.Measure the content of taxol in nano-micelle and doxorubicin content again, calculate parcel amount and parcel efficiency.Experimental result as shown in Figure 4, wherein scheme (A) for adding the paclitaxel of different material and parcel amount and wrapping up the relation of efficiency, figure (B) is for adding the amycin of different material and parcel amount and wrapping up the relation of efficiency, as can be seen from the figure suitably proportioning raw materials is adjusted, medicament contg can in the range regulation of 5-30%, and parcel efficiency, can up to 100% generally more than 80%, by contrast, amycin has higher parcel amount and parcel efficiency than paclitaxel.
Claims (6)
1. one kind take ethylene oxide polymer as the nano-micelle medicine of carrier, it is characterized in that, described drug molecule is present in nano-micelle with physically encapsulation and chemical bonding two states, the medicine of physically encapsulation is hydrophobic anticancer medicine, the mass percent of medicine in nano-micelle medicine of physically encapsulation is 10-30%, described carrier is the block copolymer that poly(ethylene oxide) section and chemical bonding are made up of the poly(ethylene oxide) section of hydrophobic anticancer medicine molecule, chemical bonding has the mass content of hydrophobic anticancer medicine in block copolymer to be 10-20%, the structural formula of described carrier is as shown in formula I:
In formula I, the span of x is 10 ~ 225; The span of y to be the span of 4 ~ 30, d be 4 ~ 30, d≤y, Drug1, for being bonded with hydrophobic anticancer medicine molecule, is connected with ester bond between it with polyethylene oxide molecules chain.
2. according to claim 1 a kind of take ethylene oxide polymer as the nano-micelle medicine of carrier; it is characterized in that, the described hydrophobic anticancer medicine molecule for chemical bonding is selected from one or more in paclitaxel, Docetaxel, baccatin III, 10-deacetylation baccatin III, camptothecine, 10-hydroxycamptothecine or SN38.
3. according to claim 1 a kind of take ethylene oxide polymer as the nano-micelle medicine of carrier, it is characterized in that, the described hydrophobic anticancer medicine for physically encapsulation is selected from the hydrophobic products that paclitaxel, Docetaxel, baccatin III, camptothecine, 10-hydroxycamptothecine, SN38 or amycin Anthraquinone obtain through ammoniated treatment.
4. according to claim 3 a kind of take ethylene oxide polymer as the nano-micelle medicine of carrier, it is characterized in that, described amycin Anthraquinone is amycin, pirarubicin, epirubicin or rubidomycin.
5. a kind of described in any one of claim 1-4 take ethylene oxide polymer as the preparation method of the nano-micelle medicine of carrier, it is characterized in that, comprising:
Step one: by poly(ethylene oxide) and allyl glycidyl ether reaction, obtain bi-block copolymer A; The reaction temperature of described step one is 20 DEG C-50 DEG C, and the response time is 12-24 hour; Described poly(ethylene oxide) and the mol ratio of allyl glycidyl ether are (10 ~ 225): (4 ~ 30);
Step 2: the bi-block copolymer A that small carboxylic acid molecules and the step one containing sulfydryl obtains is carried out additive reaction, obtains bi-block copolymer B; The reaction condition of described step 2 is: irradiate 4-10 hour by the uviol lamp room temperature that wavelength is 254nm or 365nm;
Step 3: the bi-block copolymer B that the hydrophobic anticancer medicine Drug1 and step 2 that are used for chemical bonding obtain is carried out esterification, the block copolymer that the poly(ethylene oxide) section obtaining poly(ethylene oxide) section and be bonded with hydrophobic anticancer medicine molecule forms; Described is (11 ~ 24) for the hydrophobic anticancer medicine of chemical bonding and the mass percent of bi-block copolymer B: (76 ~ 89).
Step 4: the block copolymer of the poly(ethylene oxide) section hydrophobic anticancer medicine and step 3 that are used for physically encapsulation obtained and the poly(ethylene oxide) section composition that is bonded with hydrophobic anticancer medicine molecule is mixed with organic solution, and preparing with ethylene oxide polymer is the nano-micelle medicine of carrier.
6. according to claim 5 a kind of take ethylene oxide polymer as the preparation method of the nano-micelle medicine of carrier, it is characterized in that, the described small carboxylic acid molecules containing sulfydryl is mercaptopropionic acid.
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