CN103432591A - 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, be specifically related to a kind of nano-micelle medicine that ethylene oxide polymer is carrier and preparation method thereof of take.
Background technology
Poly(ethylene oxide) is a kind of water-soluble polymer that can stable existence under physiological condition; because its space structure can stop the close of plasma protein; be widely used in the hydrophilic protective layer of polymer micelle; both can prevent particles agglomerate; can avoid again the reticuloendothelial system in body to identify, engulf; thereby the retention time of prolong drug in blood circulation, reach macrocyclic purpose.
Several high molecular nanometer micelle delivery systems that have application prospect at present clinical have two kinds of forms substantially to supporting of small-molecule drug: physically encapsulation and chemical bonding.Physically encapsulation macromolecule carrier used usually 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 that 1) significantly improves medicine; 2) medicine is had to protection and slow releasing function, can reduce toxic and side effects; 3) change the approach that enters cell, reduce medicine anti-; 4) due to certain granular size being arranged, cancerous issue has " infiltration of enhancing and retention effect " to them, i.e. and " EPR effect ", drug particles, in the relative enrichment of diseased region, is conducive to improve curative effect, reduces general toxicity.But both exist respectively again weak point: physically encapsulation exists the initial stage violent release, and the medicine loading is relatively low; Polymer bond drug due to medicine by covalent bond and macromolecule carrier bonding, significantly improved the stability of medicine in blood, not there will be initial stage violent release phenomenon, and drug loading is improved, but after bonding, most of pharmaceutically active is lost or reduces, in order to guarantee effectively to discharge active medicine under condition in vivo, the bonding mode of macromolecule carrier and medicine is had to higher requirement, increase synthetic difficulty and cost.The carrier macromolecule adopted at present is two blocks or many blocks often, wherein contain one or more hydrophobic blocks, and they are except providing hydrophobicity, not more effect, but occupy sizable mass ratio, be unfavorable for the raising of drug loading, also increased the burden of metabolism and excretion.
Summary of the invention
The objective of the invention is that existing physically encapsulation method drug loading is low in order to solve, burst drug release and polymer bond drug Chinese medicine dissociate, discharge be difficult to control, the problem of poor stability, and provide a kind of nano-micelle medicine that ethylene oxide polymer is carrier and preparation method thereof of take.
At first the present invention provides a kind of nano-micelle medicine that ethylene oxide polymer is carrier of take, described drug molecule is present in nano-micelle with physically encapsulation and chemical bonding two states, the medicine of physically encapsulation is the hydrophobicity anticarcinogen, the mass percent of the medicine of physically encapsulation in the nano-micelle medicine is 10-30%, the described carrier block copolymer that to be poly(ethylene oxide) section and chemical bonding be comprised of the poly(ethylene oxide) section of hydrophobicity anticarcinogen molecule, it is 10-20% that chemical bonding has the mass content of hydrophobicity anticarcinogen in block copolymer, the structural formula of described carrier is as shown in formula I:
In formula I, the span of x is 10～225; The span that the span of y is 4～30, d is 4～30, d≤y, and Drug1 is that bonding has hydrophobicity anticarcinogen molecule, it with the poly(ethylene oxide) strand between with ester bond, be connected.
Preferably, the described anticarcinogen of the hydrophobicity for chemical bonding molecule is selected from one or more of paclitaxel, Docetaxel, baccatin III, 10-deacetylation baccatin III, camptothecine, 10-hydroxycamptothecine or SN38.
Preferably, the described anticarcinogen of the hydrophobicity for physically encapsulation is selected from paclitaxel, Docetaxel, baccatin III, camptothecine, 10-hydroxycamptothecine, SN38 or amycin Anthraquinone and processes the hydrophobic product obtained through ammonification.
Preferably, described amycin Anthraquinone is amycin, pirarubicin, epirubicin or rubidomycin.
The present invention also provides a kind of preparation method of take the nano-micelle medicine that ethylene oxide polymer is carrier, comprising:
Step 1: by poly(ethylene oxide) and allyl glycidyl ether reaction, obtain bi-block copolymer A;
Step 2: the bi-block copolymer A that will obtain containing micromolecule carboxylic acid and the step 1 of sulfydryl carries out additive reaction, obtains bi-block copolymer B;
Step 3: the bi-block copolymer B that will obtain for hydrophobicity anticarcinogen Drug1 and the step 2 of chemical bonding carries out esterification, obtains the block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of hydrophobicity anticarcinogen molecule;
Step 4: the block copolymer that the poly(ethylene oxide) section that will obtain for hydrophobicity anticarcinogen and the step 3 of physically encapsulation and bonding are comprised of the poly(ethylene oxide) section of hydrophobicity anticarcinogen molecule is mixed with organic solution, prepares to take the nano-micelle medicine that ethylene oxide polymer is carrier.
Preferably, the reaction temperature of described step 1 is 20 ℃-50 ℃, and the response time is 12-24 hour.
Preferably, the mol ratio of described poly(ethylene oxide) and allyl glycidyl ether is (10～225): (4～30).
Preferably, the described micromolecule carboxylic acid containing sulfydryl is mercaptopropionic acid or TGA.
Preferably, the reaction condition of described step 2 is: the uviol lamp room temperature that is 254nm or 365nm with wavelength is irradiated 4-10 hour.
Preferably, the mass percent of the described anticarcinogen of the hydrophobicity for chemical bonding and bi-block copolymer B is (11～24): (76～89).
Beneficial effect of the present invention
(1) at first the present invention provides a kind of nano-micelle medicine that ethylene oxide polymer is carrier of take, described drug molecule is present in nano-micelle with physically encapsulation and chemical bonding two states, the medicine of physically encapsulation is the hydrophobicity anticarcinogen, this medicine combines physically encapsulation and two kinds of methods of chemical bonding simultaneously, take full advantage of the hydrophobic property of hydrophobic drug itself and the stronger affine ability of dissolving each other between hydrophobic drug, realize the nanometer assembling, reach higher medicament contg; The drug loading that has simultaneously solved traditional parcel dosage form is low, burst drug release and polymer bond drug Chinese medicine dissociate difficulty, discharges problems such as being difficult to control, and has stability preferably.
(2) the carrier of the present invention di-block copolymer that to be poly(ethylene oxide) section and bonding be comprised of the poly(ethylene oxide) section of hydrophobicity anticarcinogen molecule, wherein one section poly(ethylene oxide) is served as the shell that hydrophilic section forms micelle, on another section poly(ethylene oxide), bonding has hydrophobic drug of the same race or not of the same race, the core that serves as micelle, the hydrophobicity of carrier is provided by the drug molecule of bonding, special hydrophobic polyester or polyamino acid block have been exempted, add that the affine performance of dissolving each other between drug molecule is often higher than the affine performance of dissolving each other between drug molecule and common polymer segment, thereby 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 thering is very high drug loading, also have an advantage: packaging medicine discharges very fast comparatively speaking, the bonding drug release is slower, and both also deposit the advantage of bringing into play both, guarantees to reach very soon active drug concentration after dispenser, and the energy longer time of sustained release, thereby can reduce the dispenser frequency; When adopting different pharmaceutical, can realize easily the common conveying of two kinds of anticarcinogens, characteristics due to nano-micelle itself, in the time of can guaranteeing to enter tumor cell, the ratio of two kinds of medicines be determined, needs according to therapeutic alliance, can regulate ratio and the release dynamics of two kinds of medicines, in order to obtain best synergy.Significant to clinical drug combination.
(4) the present invention also provides a kind of preparation method of take the nano-micelle medicine that ethylene oxide polymer is carrier, described medicine be take polyethylene oxide block copolymer as carrier, good biocompatibility, the 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 synthetic difficulty and cost; Adopt light-catalysed mercapto-alkene additive reaction to realize the conversion of carrier polymer side group simultaneously, the reaction condition gentleness, efficiency is high, and side reaction is few, and the nano-micelle medicine prepared has higher medicine loading and supports efficiency.
The accompanying drawing explanation
The hydrogen nuclear magnetic resonance spectrogram of bi-block copolymer B in deuterochloroform that Fig. 1 is the embodiment of the present invention 1 preparation.
The hydrogen nuclear magnetic resonance spectrogram of block copolymer (B) in deuterochloroform that the poly(ethylene oxide) section that Fig. 2 is 2 preparations of micromolecule paclitaxel (A) and the embodiment of the present invention and bonding are comprised of the poly(ethylene oxide) section of paclitaxel.
Fig. 3 be the embodiment of the present invention 3 preparation take the electromicroscopic photograph (A) of the nano-micelle medicine that ethylene oxide polymer is carrier and the micelle grain-size graph (B) of Dynamic Light Scattering Determination.
The graph of relation that Fig. 4 is different ratios of raw materials and parcel amount and parcel efficiency in the embodiment of the present invention 13.
The specific embodiment
At first the present invention provides a kind of nano-micelle medicine that ethylene oxide polymer is carrier of take, described drug molecule is present in nano-micelle with physically encapsulation and chemical bonding two states, the medicine of physically encapsulation is the hydrophobicity anticarcinogen, the mass percent of the medicine of physically encapsulation in the nano-micelle medicine is 10%-30%, the diameter of described nano-micelle medicine is 20-200nm, the described carrier block copolymer that to be poly(ethylene oxide) section and bonding be comprised of the poly(ethylene oxide) section of hydrophobicity anticarcinogen molecule, it is 10-20% that chemical bonding has the mass content of hydrophobicity anticarcinogen in block copolymer, structural formula is as shown in formula I:
In formula I, the span of x is 10～225; The span that the span of y is 4～30, d is 4～30, d≤y, and Drug1 is that bonding has hydrophobicity anticarcinogen molecule, between hydrophobicity anticarcinogen molecule and poly(ethylene oxide) strand, with ester bond, is connected.
Hydrophobicity for chemical bonding anticarcinogen molecule of the present invention is preferably selected from one or more of paclitaxel, Docetaxel, baccatin III, 10-deacetylation baccatin III, camptothecine, 10-hydroxycamptothecine or SN38.A hydroxyl that can react is arranged in the said medicine molecule, they with the poly(ethylene oxide) strand between with ester bond, be connected.
Hydrophobicity for physically encapsulation anticarcinogen of the present invention is preferably selected from paclitaxel, Docetaxel, baccatin III, camptothecine, 10-hydroxycamptothecine, SN38 or amycin Anthraquinone and processes the hydrophobic product obtained through ammonification.Described amycin Anthraquinone is preferably amycin, pirarubicin, epirubicin or rubidomycin.Described ammonification processing procedure is for adding equimolar triethylamine in said medicine, add again after hydrochlorate and to obtain, described amycin Anthraquinone is usually with the hydrochloride form administration, can increase its dissolubility in water, so these medicines must first be converted into hydrophobic form, then wrap up, in order to reach higher parcel amount and parcel efficiency.
The present invention also provides a kind of preparation method of take the nano-micelle medicine that ethylene oxide polymer is carrier, comprising:
Step 1: by poly(ethylene oxide) and allyl glycidyl ether reaction, obtain bi-block copolymer A;
Step 2: the bi-block copolymer A that will obtain containing micromolecule carboxylic acid and the step 1 of sulfydryl carries out additive reaction, obtains bi-block copolymer B;
Step 3: the bi-block copolymer B that will obtain for hydrophobicity anticarcinogen and the step 2 of chemical bonding carries out esterification, obtains the block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of hydrophobicity anticarcinogen molecule;
Step 4: the block copolymer that the poly(ethylene oxide) section that will obtain for hydrophobicity anticarcinogen and the step 3 of physically encapsulation and bonding are comprised of the poly(ethylene oxide) section of hydrophobicity anticarcinogen molecule is mixed with organic solution, prepares to take the nano-micelle medicine that ethylene oxide polymer is carrier.
Step 1 of the present invention is described by poly(ethylene oxide) and allyl glycidyl ether reaction, be specially under nitrogen protection, put into the poly(ethylene oxide) of different molecular weight in reaction vessel, add solvent toluene to carry out azeotropic water removing, after 2-5 hour, add Cesium hydrate. in reaction vessel, 40 ℃ of-70 ℃ of stirring reaction 2-4 hour, except desolventizing, continue to add allyl glycidyl ether, 20 ℃-50 ℃ reaction 12-24 hour, be preferably 40 ℃ of reactions 24 hours, be cooled to room temperature, use the ether sedimentation, filter, obtain pressed powder bi-block copolymer A after vacuum drying, the mol ratio of described poly(ethylene oxide) and Cesium hydrate. is 1:1, the mol ratio of described poly(ethylene oxide) and allyl glycidyl ether is (10～225): (4～30).
The described esterification of step 3 of the present invention is specially: first bi-block copolymer B is dissolved in dichloromethane solvent, then add successively activator 1,3-dicyclohexylcarbodiimide (DCC), catalyst DMAP (DMAP) and for the hydrophobicity anticarcinogen of chemical bonding, 25 ℃ of reactions 48 hours, use the ether sedimentation, filter, obtain the block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of hydrophobicity anticarcinogen molecule after vacuum drying.The described anticarcinogen of the hydrophobicity for chemical bonding, 1,3-dicyclohexylcarbodiimide (DCC) and DMAP (DMAP) mol ratio are 1:1:1; For the hydrophobicity anticarcinogen of chemical bonding and the mass percent of bi-block copolymer B, be (11～24): (76～89).
The described block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of hydrophobicity anticarcinogen molecule of step 4 of the present invention is dissolved in oxolane, add again for the hydrophobicity anticarcinogen of physically encapsulation and make polymer solution, utilize Rotary Evaporators, dry organic solvent volatilizees, form thin and uniform polymeric film in the bottom of flask, intermediate water is joined in flask, 25 ℃～70 ℃ lower aquation 1～60min, be preferably 25 ℃ of lower aquation 10min, filtering with microporous membrane with 0.45 μ m, make and take the nano-micelle drug solution that ethylene oxide polymer is carrier.By the nano micellar solution lyophilization, the nano-micelle medicament freeze-drying powder that to obtain take ethylene oxide polymer be carrier.
Below in conjunction with specific embodiment, the present invention is done to further detailed description.
Embodiment 1
Under nitrogen protection, get 5g poly(ethylene oxide) (degree of polymerization is 11), add 20ml toluene to carry out azeotropic water removing, after 2 hours, add the 1.5g Cesium hydrate. in reaction vessel, 40 ℃ of stirring reactions 2 hours, then except desolventizing, add 4.75mL allyl glycidyl ether (degree of polymerization is 4), 40 ℃ are reacted 24 hours, are cooled to room temperature, with the sedimentation of 200mL ether, filter, obtain pressed powder bi-block copolymer A after vacuum drying;
Above-mentioned 4g bi-block copolymer A is dissolved in the oxolane (THF) of 20mL, logical nitrogen 30min, then add the 8.5g mercaptopropionic acid, the uviol lamp room temperature that is 254nm with wavelength is irradiated 8 hours, with the sedimentation of 200mL ether, filters, 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 to (10mg/mL) in dry dichloromethane, add the 0.11g camptothecine successively in solvent, 0.059g1,3-dicyclohexylcarbodiimide (DCC), 0.035g4-dimethylamino naphthyridine (DMAP) and camptothecine, 25 ℃ are reacted 48 hours, use the ether sedimentation, filter, obtain the block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of camptothecine after vacuum drying, productive rate is 90%, and wherein the content of camptothecine is measured with ultraviolet spectra, and content is 10%;
The block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of camptothecine is dissolved in oxolane, add again camptothecine, utilize Rotary Evaporators, dry organic solvent volatilizees, in the bottom of flask, form thin and uniform polymeric film joins intermediate water in flask, 25 ℃ of lower aquation 10min, with the filtering with microporous membrane of 0.45 μ m, make and take the nano-micelle medicine that ethylene oxide polymer is carrier.The mass percent of the block copolymer that camptothecine and poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of camptothecine is 20:80, and the parcel amount for the camptothecine of physically encapsulation in resulting nano-micelle medicine is 15%, and parcel efficiency reaches 75%.
Under nitrogen protection, get 5g poly(ethylene oxide) (degree of polymerization is 45), add 20ml toluene to carry out azeotropic water removing, after 2 hours, add the 0.37g Cesium hydrate. in reaction vessel, 40 ℃ of stirring reactions 2 hours, then except desolventizing, add 2.37mL allyl glycidyl ether (degree of polymerization is 8), 40 ℃ are reacted 24 hours, are cooled to room temperature, with the sedimentation of 200mL ether, filter, obtain pressed powder bi-block copolymer A after vacuum drying;
Above-mentioned 4g bi-block copolymer A is dissolved in the oxolane (THF) of 20mL, logical nitrogen 30min, then add the 5.65g mercaptopropionic acid, the uviol lamp room temperature that is 254nm with wavelength is irradiated 8 hours, 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 to (10mg/mL) in dry dichloromethane, add the 0.24g paclitaxel successively in solvent, 0.058g1,3-dicyclohexylcarbodiimide (DCC), 0.034g4-dimethylamino naphthyridine (DMAP), 25 ℃ are reacted 48 hours, use the ether sedimentation, filter, obtain the block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of paclitaxel after vacuum drying, productive rate is 89%, and wherein the content of paclitaxel is measured with ultraviolet spectra, and content is 20%; The hydrogen nuclear magnetic resonance spectrogram of block copolymer (B) in deuterochloroform that the poly(ethylene oxide) section that Fig. 2 is 2 preparations of micromolecule paclitaxel (A) and the embodiment of the present invention and bonding are comprised of the poly(ethylene oxide) section of paclitaxel, as can be seen from the figure, success of the present invention has synthesized the block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of paclitaxel;
The block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of paclitaxel is dissolved in oxolane, add again paclitaxel, utilize Rotary Evaporators, dry organic solvent volatilizees, in the bottom of flask, form thin and uniform polymeric film joins intermediate water in flask, 25 ℃ of lower aquation 10min, with the filtering with microporous membrane of 0.45 μ m, make and take the nano-micelle medicine that ethylene oxide polymer is carrier.The mass percent of the block copolymer that paclitaxel and poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of paclitaxel is 11:89, and the parcel amount for the paclitaxel of physically encapsulation in resulting nano-micelle medicine is 10%, and parcel efficiency reaches 100%.
Embodiment 3
Under nitrogen protection, get 5g poly(ethylene oxide) (degree of polymerization is 113), add 20ml toluene to carry out azeotropic water removing, after 2 hours, add the 0.15g Cesium hydrate. in reaction vessel, 40 ℃ of stirring reactions 2 hours, then except desolventizing, add 0.95mL allyl glycidyl ether (degree of polymerization is 8), 40 ℃ are reacted 24 hours, are cooled to room temperature, with the sedimentation of 200mL ether, filter, obtain pressed powder bi-block copolymer A after vacuum drying;
Above-mentioned 4g bi-block copolymer A is dissolved in the oxolane (THF) of 20mL, logical nitrogen 30min, then add the 2.83g mercaptopropionic acid, the uviol lamp room temperature that is 254nm with wavelength is irradiated 8 hours, 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 to (10mg/mL) in dry dichloromethane, add the 0.15g paclitaxel successively in solvent, 0.036g1,3-dicyclohexylcarbodiimide (DCC), 0.021g4-dimethylamino naphthyridine (DMAP), 25 ℃ are reacted 48 hours, use the ether sedimentation, filter, obtain the block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of paclitaxel after vacuum drying, productive rate is 92%, and wherein the content of paclitaxel is measured with ultraviolet spectra, and content is 15%;
The block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of paclitaxel is dissolved in oxolane, add again paclitaxel, utilize Rotary Evaporators, dry organic solvent volatilizees, in the bottom of flask, form thin and uniform polymeric film joins intermediate water in flask, 25 ℃ of lower aquation 10min, with the filtering with microporous membrane of 0.45 μ m, make and take the nano-micelle medicine that ethylene oxide polymer is carrier.The mass percent of the block copolymer that paclitaxel and poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of paclitaxel is 17:83, parcel amount for the paclitaxel of physically encapsulation in resulting nano-micelle medicine is 16.2%, and parcel efficiency reaches 95%.Fig. 3 be the embodiment of the present invention 3 preparation take the electromicroscopic photograph (A) of the nano-micelle medicine that ethylene oxide polymer is 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 to carry out azeotropic water removing, after 2 hours, add the 0.075g Cesium hydrate. in reaction vessel, 40 ℃ of stirring reactions 2 hours, then except desolventizing, add 1.19mL allyl glycidyl ether (degree of polymerization is 20), 40 ℃ are reacted 24 hours, are cooled to room temperature, with the sedimentation of 200mL ether, filter, obtain pressed powder bi-block copolymer A after vacuum drying;
Above-mentioned 4g bi-block copolymer A is dissolved in the oxolane (THF) of 20mL, logical nitrogen 30min, then add the 3.53g mercaptopropionic acid, the uviol lamp room temperature that is 254nm with wavelength is irradiated 8 hours, 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 to (10mg/mL) in dry dichloromethane, add the 0.11g camptothecine successively in solvent, 0.059g 1, 3-dicyclohexylcarbodiimide (DCC), 0.035g4-dimethylamino naphthyridine (DMAP) and camptothecine, 25 ℃ are reacted 48 hours, use the ether sedimentation, filter, obtain the block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of camptothecine after vacuum drying, productive rate is 93%, the mass percent of camptothecine and bi-block copolymer B is 11:89, wherein the content of camptothecine is measured with ultraviolet spectra, content is 10%,
The block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of camptothecine is dissolved in oxolane, add again camptothecine, utilize Rotary Evaporators, dry organic solvent volatilizees, in the bottom of flask, form thin and uniform polymeric film joins intermediate water in flask, 25 ℃ of lower aquation 10min, with the filtering with microporous membrane of 0.45 μ m, make and take the nano-micelle medicine that ethylene oxide polymer is carrier.The mass percent of the block copolymer that camptothecine and poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of camptothecine is 20:80, and the parcel amount for the camptothecine of physically encapsulation in resulting nano-micelle medicine is 15%, and parcel efficiency reaches 75%.
Embodiment 5
Under nitrogen protection, get 5g poly(ethylene oxide) (degree of polymerization is 225), add 20ml toluene to carry out azeotropic water removing, after 2 hours, add the 0.075g Cesium hydrate. in reaction vessel, 40 ℃ of stirring reactions 2 hours, then except desolventizing, add 1.78mL allyl glycidyl ether (degree of polymerization is 30), 40 ℃ are reacted 24 hours, are cooled to room temperature, with the sedimentation of 200mL ether, filter, obtain pressed powder bi-block copolymer A after vacuum drying;
Above-mentioned 4g bi-block copolymer A is dissolved in the oxolane (THF) of 20mL, logical nitrogen 30min, then add the 4.75g mercaptopropionic acid, the uviol lamp room temperature that is 254nm with wavelength is irradiated 8 hours, 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 to (10mg/mL) in dry dichloromethane, add the 0.11g10-hydroxy camptothecin successively in solvent, 0.062g1, 3-dicyclohexylcarbodiimide (DCC), 0.037g4-dimethylamino naphthyridine (DMAP) and 10-hydroxycamptothecine, 25 ℃ are reacted 48 hours, use the ether sedimentation, filter, obtain the block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of 10-hydroxycamptothecine after vacuum drying, productive rate is 90%, the mass percent of 10-hydroxycamptothecine and bi-block copolymer B is 11:89, wherein the content of 10-hydroxycamptothecine is measured with ultraviolet spectra, content is 10%,
The block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of 10-hydroxycamptothecine is dissolved in oxolane, add again 10-hydroxycamptothecine, utilize Rotary Evaporators, dry organic solvent volatilizees, in the bottom of flask, form thin and uniform polymeric film joins intermediate water in flask, 25 ℃ of lower aquation 10min, with the filtering with microporous membrane of 0.45 μ m, make and take the nano-micelle medicine that ethylene oxide polymer is carrier.The mass percent of the block copolymer that 10-hydroxycamptothecine and poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of 10-hydroxycamptothecine is 20:80, parcel amount for the 10-hydroxycamptothecine of physically encapsulation in resulting nano-micelle medicine is 16%, and parcel efficiency reaches 80%.
Embodiment 6
Identical with embodiment 2 steps, difference is, for valence bond and the hydrophobicity anticarcinogen be Docetaxel, hydrophobicity anticarcinogen for physically encapsulation is Docetaxel, the mass percent of Docetaxel and bi-block copolymer B is 20:80, wherein for valence bond and the content of Docetaxel by the NMR method, measure, content is 17%; The mass percent of the block copolymer that Docetaxel and poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of Docetaxel is 14:86, parcel amount for the Docetaxel of physically encapsulation in resulting nano-micelle medicine is 12%, and parcel efficiency reaches 86%.
Identical with embodiment 3 steps, difference is, for valence bond and the hydrophobicity anticarcinogen be SN38, hydrophobicity anticarcinogen for physically encapsulation is SN38, the mass percent of SN38 and bi-block copolymer B is 11:89, wherein for valence bond and the content of SN38 by the NMR method, measure, content is 10%; The mass percent of the block copolymer that SN38 and poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of SN38 is 30:70, in resulting nano-micelle medicine, the parcel amount of SN38 is 21%, and parcel efficiency reaches 70%.
Embodiment 8
Identical with embodiment 4 steps, difference is, for valence bond and the hydrophobicity anticarcinogen be baccatin III, hydrophobicity anticarcinogen 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 the content of baccatin III by the NMR method, measure, content is 15%; The mass percent of the block copolymer that baccatin III and poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of baccatin III is 20:80, and in resulting nano-micelle medicine, the parcel amount of baccatin III is 16%, and parcel efficiency reaches 80%.
Embodiment 9
Identical with embodiment 3 steps, difference is, hydrophobicity anticarcinogen for physically encapsulation is amycin, the mass percent of the block copolymer that amycin and poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of paclitaxel is 20:80, in resulting nano-micelle medicine, the parcel amount of amycin is 19%, and parcel efficiency reaches 95%.
Identical with embodiment 3 steps, difference is, hydrophobicity anticarcinogen for physically encapsulation is pirarubicin, the mass percent of the block copolymer that pirarubicin and poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of paclitaxel is 30:70, in resulting nano-micelle medicine, the parcel amount of pirarubicin is 29%, and parcel efficiency reaches 97%.
Embodiment 11
Identical with embodiment 3 steps, difference is, hydrophobicity anticarcinogen for physically encapsulation is epirubicin, the mass percent of the block copolymer that epirubicin and poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of paclitaxel is 30:70, in resulting nano-micelle medicine, the parcel amount of epirubicin is 28%, and parcel efficiency reaches 93%.
Embodiment 12
Identical with embodiment 3 steps, difference is, hydrophobicity anticarcinogen for physically encapsulation is rubidomycin, the mass percent of the block copolymer that rubidomycin and poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of paclitaxel is 33:67, in resulting nano-micelle medicine, the parcel amount of rubidomycin is 30%, and parcel efficiency reaches 91%.
Embodiment 13
The block copolymer that the poly(ethylene oxide) section that embodiment 3 is obtained and bonding are comprised of the poly(ethylene oxide) section of paclitaxel is dissolved in (10mg/mL) in the flask that is loaded with oxolane, press 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 respectively paclitaxel and amycin, join in polymer solution, utilize Rotary Evaporators, dry organic solvent volatilizees, form thin and uniform polymeric film in the bottom of flask, intermediate water is joined in flask, 25 ℃ of lower aquation 10min, filtering with microporous membrane with 0.45 μ m, make and take the nano-micelle medicine that ethylene oxide polymer is carrier.Measure again content of taxol and amycin content in nano-micelle, calculate parcel amount and parcel efficiency.Experimental result as shown in Figure 4, wherein figure (A) is paclitaxel and the parcel amount that adds different material and the relation of wrapping up efficiency, figure (B) is amycin and the parcel amount that adds different material and the relation of wrapping up efficiency, as can be seen from the figure suitably adjust proportioning raw materials, medicament contg can be in the range regulation of 5-30%, and parcel efficiency, can be up to 100% generally more than 80%, by contrast, amycin has higher parcel amount and parcel efficiency than paclitaxel.
Claims (10)
1. take the nano-micelle medicine that ethylene oxide polymer is carrier for one kind, 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 the hydrophobicity anticarcinogen, the mass percent of the medicine of physically encapsulation in the nano-micelle medicine is 10-30%, the described carrier block copolymer that to be poly(ethylene oxide) section and chemical bonding be comprised of the poly(ethylene oxide) section of hydrophobicity anticarcinogen molecule, it is 10-20% that chemical bonding has the mass content of hydrophobicity anticarcinogen in block copolymer, the structural formula of described carrier is as shown in formula I:
In formula I, the span of x is 10～225; The span that the span of y is 4～30, d is 4～30, d≤y, and Drug1 is that bonding has hydrophobicity anticarcinogen molecule, it with the poly(ethylene oxide) strand between with ester bond, be connected.
2. a kind of nano-micelle medicine that ethylene oxide polymer is carrier of take according to claim 1; it is characterized in that, the described anticarcinogen of the hydrophobicity for chemical bonding molecule is selected from one or more of paclitaxel, Docetaxel, baccatin III, 10-deacetylation baccatin III, camptothecine, 10-hydroxycamptothecine or SN38.
3. a kind of nano-micelle medicine that ethylene oxide polymer is carrier of take according to claim 1, it is characterized in that, the described anticarcinogen of the hydrophobicity for physically encapsulation is selected from paclitaxel, Docetaxel, baccatin III, camptothecine, 10-hydroxycamptothecine, SN38 or amycin Anthraquinone and processes the hydrophobic product obtained through ammonification.
4. a kind of nano-micelle medicine that ethylene oxide polymer is carrier of take according to claim 3, is characterized in that, described amycin Anthraquinone is amycin, pirarubicin, epirubicin or rubidomycin.
5. any one described a kind of preparation method of take the nano-micelle medicine that ethylene oxide polymer is carrier of claim 1-4, is characterized in that, comprising:
Step 1: by poly(ethylene oxide) and allyl glycidyl ether reaction, obtain bi-block copolymer A;
Step 2: the bi-block copolymer A that will obtain containing micromolecule carboxylic acid and the step 1 of sulfydryl carries out additive reaction, obtains bi-block copolymer B;
Step 3: the bi-block copolymer B that will obtain for hydrophobicity anticarcinogen Drug1 and the step 2 of chemical bonding carries out esterification, obtains the block copolymer that poly(ethylene oxide) section and bonding are comprised of the poly(ethylene oxide) section of hydrophobicity anticarcinogen molecule;
Step 4: the block copolymer that the poly(ethylene oxide) section that will obtain for hydrophobicity anticarcinogen and the step 3 of physically encapsulation and bonding are comprised of the poly(ethylene oxide) section of hydrophobicity anticarcinogen molecule is mixed with organic solution, prepares to take the nano-micelle medicine that ethylene oxide polymer is carrier.
6. a kind of preparation method of take the nano-micelle medicine that ethylene oxide polymer is carrier according to claim 5, is characterized in that, the reaction temperature of described step 1 is 20 ℃-50 ℃, and the response time is 12-24 hour.
7. a kind of preparation method of take the nano-micelle medicine that ethylene oxide polymer is carrier according to claim 5, is characterized in that, the mol ratio of described poly(ethylene oxide) and allyl glycidyl ether is (10～225): (4～30).
8. a kind of preparation method of take the nano-micelle medicine that ethylene oxide polymer is carrier according to claim 5, is characterized in that, the described micromolecule carboxylic acid containing sulfydryl is mercaptopropionic acid or TGA.
9. a kind of preparation method of take the nano-micelle medicine that ethylene oxide polymer is carrier according to claim 5, is characterized in that, the reaction condition of described step 2 is: the uviol lamp room temperature that is 254nm or 365nm with wavelength is irradiated 4-10 hour.
10. a kind of preparation method of take the nano-micelle medicine that ethylene oxide polymer is carrier according to claim 5, it is characterized in that, the mass percent of the described anticarcinogen of the hydrophobicity for chemical bonding and bi-block copolymer B is (11～24): (76～89).
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