CN102973525B - Antharcycline antitumor antibiotics loaded nano-micelle preparation and preparation method thereof - Google Patents
Antharcycline antitumor antibiotics loaded nano-micelle preparation and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an antharcycline antitumor antibiotics loaded nano-micelle preparation, which comprises antharcycline antitumor antibiotics, A-B-C type triblock polymer and assisting agents, wherein the antharcycline antitumor antibiotics is one or more of adriamycin, daunorubicin, pharmorubicin, perarubicin or lacinomycin; and the A-B-C type triblock polymer is polyethylene glycol-polyethylene glycol containing carboxyl on side chain-polyester. According to the preparation, drugs are coated in the nano-micelle by virtue of the coaction of self-assembly of segmented copolymer and electrostatic adsorption, the nano-micelle has uniform and stable grain diameter, the encapsulation efficiency reaches 99 percent, and the prepared nano-micelle preparation is of a spherical structure with grain diameter between 20 and 300nm; and the shell of the micelle is made from polyethylene glycol molecules, so that drugs are prevented from being contacted with enzyme and other protein molecules in blood or identified and swallowed by a reticuloendothelial system in the body, so that the circulating period of micelle in the body can be prolonged.
Description
Technical field
The invention belongs to biomedical materials field, be specifically related to a kind of nano-micelle preparations and preparation method that supports anthracene nucleus antineoplastic antibiotic.
Background technology
Anthracene nucleus antineoplastic antibiotic is the effective broad-spectrum anti-cancer drug of a class, is widely used in clinically the various cancers for the treatment of, as leukemia, lymphoma, breast carcinoma, pulmonary carcinoma, hepatocarcinoma and multiple other entity tumors.This series antineoplastic medicament mainly comprises: amycin (Doxorubicin, ADM), daunorubicin (Daunorubicin, DNR), epirubicin (Epirubicin, EPI), Perarubicin (Pirarubicin, THP-ADM), aklavine (Aclacinomycin, ACM).Clinical administration mostly is intravenous drip at present, but dutriomycin can not see through blood brain barrier, and rapid distribution whole body after intravenous injection, and bone marrow and heart are had to comparatively serious toxic and side effects.Bolos intravenous administration dosage is large simultaneously, low at lesions position functioning efficiency.
In order to change the tissue distribution of anthracene nucleus antineoplastic antibiotic and to improve its selectivity to tumor tissues, recent domestic has been developed a series of nanometer antitumor drug dosage forms, as liposome, microsphere, Emulsion, inorganic and metal nano medicine carrying body etc.Chinese patent CN 101234204 B disclose a kind of high molecule bonding adriamycin medicine, its Nano capsule and preparation method thereof.Chinese patent CN 100361985C and CN 1850276 B disclose two kinds of taxol polymer bond drugs.These two kinds of bonding medicines are all to adopt the method for " chemistry supports " that medicine is bonded on macromolecule carrier, and this method can effectively be improved the dissolubility of medicine, have reduced the toxic and side effects of medicine when improving former medication effect.But support and compare with chemistry, physics supports has advantages of that medicine supports that process is simple, mechanisms for drug release is clear and definite.As Chinese patent CN-1256091C discloses a kind of Doxorubicin Or Doxorubicin Hydrochloride Liposome Injection And Its Preparation Process; Chinese patent CN-1927183 B discloses Antineoplasma medicine pidorubicin slow release microsphere preparation and preparation method; Chinese patent CN 101322681 B disclose the nano-micelle preparations of the anthracene nucleus antineoplastic antibiotic that polyglycol derivatization phospholipid bag carries.At present, the existing multiple mode of utilizing polymer support physics to support cancer therapy drug enters clinical research, and minority is gone on the market, as utilizes liposome to support the Doxil of amycin and utilize albumin to wrap up the Abraxane of paclitaxel.But the problem that lipidosome injection, microsphere and Emulsion all exist, and drug loading is low, burst drug release and polymer bond drug Chinese medicine dissociate.
Recently, utilizing the self assembly preparation of amphiphilic macromolecular to have slow release, targeting, macrocyclic micellar preparation receives very big concern, and becomes the study hotspot of drug-supplying system.Polyethylene Glycol 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, reaches macrocyclic object.In order further to improve the stability of micelle, Chinese patent CN 102604065 A disclose the polyethylene glycol-ester that biodegradable triblock copolymer Polyethylene Glycol-side chain contains functional group, utilize the functional group in this triblock copolymer mid-block to prepare crosslinked polymer micelle or vesicle.
Summary of the invention
The problem of the object of the invention is that the drug loading of existing micellar preparation parcel is low in order to solve, burst drug release and polymer bond drug Chinese medicine dissociating, and a kind of nano-micelle preparations and preparation method that supports anthracene nucleus antineoplastic antibiotic is provided.
First, the invention provides a kind of nano-micelle preparations that supports anthracene nucleus antineoplastic antibiotic, this nano-micelle preparations comprises anthracene nucleus antineoplastic antibiotic, A-B-C type triblock polymer and adjuvant, described anthracene nucleus antineoplastic antibiotic is selected from one or more in amycin, daunorubicin, epirubicin, Perarubicin or aklavine, described A-B-C type triblock polymer is the polyethylene glycol-ester that Polyethylene Glycol-side chain contains carboxyl, wherein, A block molecular weight polyethylene glycol is 200-10000; The molecular weight of the Polyethylene Glycol that B block side chain contains carboxyl is 100-2000; The molecular weight of C block polyester is 200-10000, and the mass percent of described anthracene nucleus antineoplastic antibiotic in nano-micelle preparations is 1%～50%.
Preferably, described polyester is the polymer of levorotatory lactide, dextrorotation lactide, racemization lactide, Acetic acid, hydroxy-, bimol. cyclic ester or 6-caprolactone, or one or both random copolymer of above-mentioned monomer.
Preferably, described adjuvant is pharmaceutically acceptable antioxidant, osmotic pressure regulator, pH value regulator and/or solubilizing agent.
The present invention also provides a kind of preparation method that supports the nano-micelle preparations of anthracene nucleus antineoplastic antibiotic, the method is that anthracene nucleus antineoplastic antibiotic is wrapped in the nano-micelle of A-B-C type triblock polymer formation, makes the nano-micelle preparations that supports anthracene nucleus antineoplastic antibiotic.
Preferably, described a kind of preparation method that supports the nano-micelle preparations of anthracene nucleus antineoplastic antibiotic, comprises the following steps:
(1) anthracene nucleus antineoplastic antibiotic and A-B-C type triblock polymer are dissolved in organic solvent, make the polymeric film of anthracycline-containing antitumor antibiotics, described anthracene nucleus antineoplastic antibiotic is selected from one or more in amycin, daunorubicin, epirubicin, Perarubicin or aklavine;
(2) polymeric film step (1) being obtained is transferred in water or in medicinal buffer solution, 25
oc ~ 70
oaquation 1 ~ 60 min under C, after lyophilization, obtains supporting the nano-micelle preparations of anthracene nucleus antineoplastic antibiotic.
Preferably, described a kind of preparation method that supports the nano-micelle preparations of anthracene nucleus antineoplastic antibiotic, comprises the following steps:
(1) A-B-C type triblock polymer is dissolved in organic solvent, obtains A-B-C triblock polymer film;
(2) anthracene nucleus antineoplastic antibiotic is dissolved in water or medicinal buffer salt solution, obtain solution; The A-B-C triblock polymer film that step (1) is obtained is transferred in this solution, 25
oc ~ 70
oaquation 1 ~ 60 min under C, after lyophilization, obtain supporting the nano-micelle preparations of anthracene nucleus antineoplastic antibiotic, described anthracene nucleus antineoplastic antibiotic is selected from one or more in amycin, daunorubicin, epirubicin, Perarubicin or aklavine.
Preferably, the concentration of described A-B-C type triblock polymer is 1 ~ 20 mg/mL.
Preferably, the concentration of described anthracene nucleus antineoplastic antibiotic is 0.1 ~ 1 mg/mL.
Preferably, described organic solvent is selected from one or more in acetone, chloroform, dichloromethane, oxolane or acetonitrile.
Preferably, described medicinal buffer salt solution is sodium chloride injection, glucose injection or phosphate buffer solution.
Beneficial effect of the present invention
(1) the present invention adopts the polyethylene glycol-ester parcel anthracene nucleus antineoplastic antibiotic that triblock copolymer Polyethylene Glycol-side chain contains carboxyl, utilize carboxyl in triblock copolymer mid-block and the combined effect of the electrostatic interaction of anthracene nucleus antineoplastic antibiotic and the self assembly of carrier, pharmaceutical pack is wrapped in nano-micelle, improved the drug loading of micellar preparation, also improved the stability of micelle simultaneously, the problem of having avoided the medicine of polymer bond drug to dissociate from polymer support, resulting nano-micelle particle diameter is homogeneous, stable very.Experimental result shows: encapsulation efficiency can reach 99%, resulting micellar preparation structure spherical in shape, and particle diameter is 20 to 300nm, may be dissolved in water-based vehicle direct injection or intravenous drip;
(2) triblock copolymer of the present invention is amphipathic, can be self-assembled into nano-micelle, formed polymer micelle and bi-block copolymer likeness in form, and polymer micelle can support fat-soluble medicine and have the water soluble drug of affinity with carboxyl;
(3) in triblock copolymer of the present invention, on B block, there is carboxyl function group, after being combined with anthracene nucleus antineoplastic antibiotic, there is hydrophobicity, be assembled into after micelle and C section polyester segments forms the core of micelle jointly, Polyethylene Glycol forms the shell of micelle, medicine is played to insulation blocking, the introducing of interlude B has not only improved the loading of medicine, also help the stability that improves micelle, in vivo in lower pH value environment, it is protonated that carboxyl is tending towards, weaken with the effect of drug molecule, medicine is easy to discharge from micelle;
(4) the complete bio-compatible of triblock copolymer of the present invention and biodegradation, resulting nano-micelle pharmaceutical preparation is expected by " infiltration of enhancing and retention effect ", (EPR) at tumor locus, to accumulate in blood circulation, realize the targeting of amycin to tumor locus, be convenient to medical application.
Accompanying drawing explanation
Fig. 1 is mPEG in the embodiment of the present invention 1
2K-PEG (COOH)
2k-PLA
2khydrogen nuclear magnetic resonance spectrogram in deuterochloroform;
Fig. 2 is mPEG in the embodiment of the present invention 1
0.2k-PEG (COOH)
1k-PCL
0.2khydrogen nuclear magnetic resonance spectrogram in deuterochloroform;
Fig. 3 is the transmission electron microscope picture of the epirubicin nano-micelle of the embodiment of the present invention 3 preparations;
Fig. 4 is drug loading and the envelop rate changing trend diagram of the epirubicin nano-micelle of the embodiment of the present invention 3 preparations;
Fig. 5 is that the epirubicin nano-micelle of the embodiment of the present invention 3 preparations is at the release profiles of pH5.0 and 7.4 phosphate buffered solution;
Fig. 6 is the embodiment of the present invention 3 epirubicin nano-micelles and the suppression ratio comparison diagram of micromolecule epirubicin to Hela cell.
The specific embodiment
The invention provides a kind of nano-micelle preparations that supports anthracene nucleus antineoplastic antibiotic, this nano-micelle preparations comprises anthracene nucleus antineoplastic antibiotic, A-B-C type triblock polymer and adjuvant, described anthracene nucleus antineoplastic antibiotic is selected from amycin (ADM), daunorubicin (DNR), epirubicin (EPI), one or more in Perarubicin (THP-ADM) or aklavine (ACM), described A-B-C type triblock polymer is the polyethylene glycol-ester that Polyethylene Glycol-side chain contains carboxyl, wherein, A block molecular weight polyethylene glycol (number all) is 200-10000, the molecular weight of the Polyethylene Glycol that B block side chain contains carboxyl (number all) is 100-2000, the molecular weight of C block polyester (number all) is 200-10000, and the mass percent of described anthracene nucleus antineoplastic antibiotic in nano-micelle preparations is 1%～50%.
The micellar preparation structure spherical in shape of gained, particle diameter is 20 to 300nm, may be dissolved in water-based vehicle direct injection or intravenous drip.
Polyester of the present invention is preferably the polymer of levorotatory lactide, dextrorotation lactide, racemization lactide, Acetic acid, hydroxy-, bimol. cyclic ester or 6-caprolactone, or one or both random copolymer of above-mentioned monomer, more preferably racemization lactide or 6-caprolactone.
The preparation method of A-B-C type triblock polymer of the present invention is known technology, and concrete preparation process is as follows:
The first step: under nitrogen protection, in reaction vessel, put into the PEG of different molecular weight, add solvent toluene to carry out azeotropic water removing, after 2-5 hour, in reaction vessel, add cerium hydroxide, 40 ℃ of-70 ℃ of stirring reaction 2-4 hour, except desolventizing, continue to add allyl glycidyl ether, 20 ℃-50 ℃ reaction 12-24 hour, are cooled to room temperature, with the sedimentation of 200-500mL ether, filter, obtain pressed powder PEG-PAGE after vacuum drying, the mol ratio of described PEG, cerium hydroxide and allyl glycidyl ether is 1:1:4-20;
Second step: get in the THF that above-mentioned PEG-PAGE is dissolved in 10-50 mL, after stirring and dissolving, add catalyst Z n[N (SiMe
3)
2]
2and polyester monocase, stirring at room reaction, after 2-10 hour, with the sedimentation of 200-500mL ether, is filtered, and obtains polymer polyethylene glycol-(side pi-allyl replaces ethylene glycol)-polyester after vacuum drying; Described PEG-PAGE and the mol ratio of polyester monocase are 1:50-400; The addition of catalyst is 1/1000 ~ 5/100 of PEG-PAGE, and described polyester is the polymer of levorotatory lactide, dextrorotation lactide, racemization lactide, Acetic acid, hydroxy-, bimol. cyclic ester or 6-caprolactone, or one or both random copolymer of above-mentioned monomer;
The 3rd step: triblock polymer polyethylene glycol-(side pi-allyl replaces the ethylene glycol)-polyester of getting in step 2 joins in the THF of 10-50 mL, logical nitrogen 15-30 min, then add TGA, by the uviol lamp room temperature that wavelength is 254 nm, irradiate 4-10 hour, with the sedimentation of 200-500mL ether, filter, after vacuum drying, obtain A-B-C type triblock polymer.The mol ratio of described polyethylene glycol-(side pi-allyl replaces ethylene glycol)-polyester upside pi-allyl and TGA is 1:1.
A kind of nano-micelle preparations that supports anthracene nucleus antineoplastic antibiotic of the present invention, also can add adjuvant as required, and described adjuvant is pharmaceutically acceptable adjuvant, is preferably antioxidant, osmotic pressure regulator, pH value regulator and/or solubilizing agent.Described antioxidant is preferably bad hematic acid, EDTA, and osmotic pressure regulator is preferably sodium chloride, glucose and mannitol, and pH value regulator is preferably phosphate buffer solution, and solubilizing agent is preferably tween.
The invention provides a kind of preparation method that supports the nano-micelle preparations of anthracene nucleus antineoplastic antibiotic, the method is that anthracene nucleus antineoplastic antibiotic is wrapped in the nano-micelle of A-B-C type triblock polymer formation, makes the nano-micelle preparations that supports anthracene nucleus antineoplastic antibiotic.
Preferably, described a kind of preparation method that supports the nano-micelle preparations of anthracene nucleus antineoplastic antibiotic, comprises the following steps:
(1) anthracene nucleus antineoplastic antibiotic and A-B-C type triblock polymer are dissolved in organic solvent, under decompression or vacuum condition, remove organic solvent again, make the polymeric film of anthracycline-containing antitumor antibiotics, described anthracene nucleus antineoplastic antibiotic is selected from one or more in amycin, daunorubicin, epirubicin, Perarubicin or aklavine;
(2) polymeric film of anthracycline-containing antitumor antibiotics step (1) being obtained is transferred in water or in medicinal buffer solution, 25
oc ~ 70
oaquation 1 ~ 60 min under C, after lyophilization, obtains supporting the nano-micelle preparations of anthracene nucleus antineoplastic antibiotic.
The described organic solvent of above-mentioned steps (1) is preferably one or more in acetone, chloroform, dichloromethane, oxolane or acetonitrile; The concentration of described A-B-C type triblock polymer is preferably 1 ~ 20 mg/mL, 5 ~ 10mg/mL more preferably, and the concentration of anthracene nucleus antineoplastic antibiotic is preferably 0.1 ~ 1 mg/mL, and more preferably 0.5 ~ 1;
The polymeric film of anthracycline-containing antitumor antibiotics obtained above is transferred in water or in medicinal buffer solution, 25
oc ~ 70
oaquation 1 ~ 60 min under C, after filtration sterilization, obtains the nano micellar solution of anthracene nucleus antineoplastic antibiotic, by nano micellar solution lyophilization, obtains supporting the nano-micelle lyophilized powder of anthracene nucleus antineoplastic antibiotic.Described buffer solution is preferably sodium chloride injection, glucose injection or phosphate buffer solution, and described hydration temperature is preferably 50
oc ~ 60
oc, hydration time is preferably 1 ~ 5 min.
A kind of preparation method that supports the nano-micelle preparations of anthracene nucleus antineoplastic antibiotic of the present invention, can also adopt following steps:
(1) A-B-C type triblock polymer is dissolved in organic solvent, then removes organic solvent under decompression or vacuum condition, obtain A-B-C triblock polymer film;
(2) anthracene nucleus antineoplastic antibiotic is dissolved in water or medicinal buffer salt solution, obtain solution; The A-B-C triblock polymer film that step (1) is obtained is transferred in this solution, 25
oc ~ 70
oaquation 1 ~ 60 min under C, after lyophilization, obtain supporting the nano-micelle preparations of anthracene nucleus antineoplastic antibiotic, described anthracene nucleus antineoplastic antibiotic is selected from one or more in amycin, daunorubicin, epirubicin, Perarubicin or aklavine.
The described organic solvent of above-mentioned steps (1) is preferably one or more in acetone, chloroform, dichloromethane, oxolane or acetonitrile; The concentration of described A-B-C type triblock polymer is preferably 1 ~ 20 mg/mL, more preferably 5 ~ 10mg/mL.
The concentration of the anthracene nucleus antineoplastic antibiotic that above-mentioned steps (2) is described is preferably 0.1 ~ 1 mg/mL, more preferably 0.5 ~ 1 mg/mL; Described buffer solution is preferably sodium chloride injection, glucose injection or phosphate buffer solution, and described hydration temperature is preferably 50
oc ~ 60
oc, hydration time is preferably 1 ~ 5 min.
In order to further illustrate the present invention, below in conjunction with embodiment, describe the present invention.
Embodiment 1: the nano-micelle that wraps up amycin with the A-B-C type triblock polymer preparation of different molecular weight
Table 1
According to the formula of table 1, taking respectively 100mg A-B-C type triblock polymer is dissolved in acetonitrile, be placed in round-bottomed flask, the concentration of described A-B-C type triblock polymer is 1 mg/mL, utilizes Rotary Evaporators, and dry organic solvent volatilizees, on the surface of round-bottomed flask, form thin and uniform polymeric film, 10 mg amycin (ADM) are soluble in water, obtain the aqueous solution of amycin, the concentration of ADM is 0.1 mg/mL, the aqueous solution of amycin is joined in round-bottomed flask to 60
oaquation 1 min under C, the filtering with microporous membrane degerming with 0.22 um, makes nano micellar solution, obtains supporting the nano-micelle lyophilized powder of anthracene nucleus antineoplastic antibiotic through lyophilization.The sample P 1-P6 structure spherical in shape of gained, particle diameter is 20 to 300nm.A-B-C type triblock polymer mPEG in sample P 1
2K-PEG (COOH)
2k-PLA
2khydrogen nuclear magnetic resonance spectrogram in deuterochloroform as shown in Figure 1, A-B-C type triblock polymer mPEG in sample P 2
0.2k-PEG (COOH)
1k-PCL
0.2khydrogen nuclear magnetic resonance spectrogram in deuterochloroform as shown in Figure 2.
Embodiment 2: the nano-micelle that wraps up daunorubicin with the A-B-C type triblock polymer preparation of different molecular weight
Table 2
According to the formula of table 2, taking respectively 100mg A-B-C type triblock polymer is dissolved in acetone, be placed in round-bottomed flask, the concentration of described A-B-C type triblock polymer is 10 mg/mL, utilize Rotary Evaporators, dry organic solvent volatilizees, on the surface of round-bottomed flask, form thin and uniform polymeric film, 5 mg daunorubicins (DNR) are dissolved in sodium chloride injection, obtain the aqueous solution of daunorubicin, the concentration of described ADM is 0.5 mg/mL, the aqueous solution of daunorubicin is joined in round-bottomed flask to 70
oaquation 5 min under C, the filtering with microporous membrane degerming with 0.22 um, makes nano micellar solution, obtains supporting the nano-micelle lyophilized powder of anthracene nucleus antineoplastic antibiotic through lyophilization.The sample P 7-P11 structure spherical in shape of gained, particle diameter is 20 to 300nm.
Embodiment 3: with the PEG of different proportion
2K-PEG (COOH)
1k-PCL
3.5kthe nano-micelle of preparing with epirubicin
Table 3
According to the formula of table 3, take respectively the mPEG in embodiment 1
2K-PEG (COOH)
1k-PCL
3.5kbe dissolved in oxolane with epirubicin, be placed in round-bottomed flask, described mPEG
2K-PEG (COOH)
1k-PCL
3.5kconcentration be 20 mg/mL, utilize Rotary Evaporators, the dry organic solvent that volatilizees, forms thin on the surface of round-bottomed flask and uniform polymeric film joins glucose injection in round-bottomed flask, 40
oaquation 10 min under C, the filtering with microporous membrane degerming with 0.22 um, makes nano micellar solution, obtains supporting the nano-micelle lyophilized powder of anthracene nucleus antineoplastic antibiotic through lyophilization.
The sample P 12-P17 structure spherical in shape of gained, particle diameter is 20 to 300nm.The transmission electron microscope picture of sample P 15 as shown in Figure 3; Fig. 4 is drug loading and the envelop rate changing trend diagram of the epirubicin nano-micelle P15 of the embodiment of the present invention 3 preparations, and as can be seen from the figure, with respect to existing carrier, used carrier of the present invention has higher drug loading and envelop rate to Anthraquinones anticarcinogen; Fig. 5 is that the epirubicin nano-micelle P15 of the embodiment of the present invention 3 preparations is at the release profiles of pH5.0 and 7.4 phosphate buffered solution, as can be seen from the figure, the release of medicine has pH value sensitivity, under pH benzothiophene acid condition, medicine more easily discharges, and is conducive to medicine in intracellular release.
Embodiment 4: with the nano-micelle of A-B-C type triblock polymer preparation parcel different pharmaceutical
Table 4
Take the mPEG in embodiment 1
5K-PEG (COOH)
0.5k-PLGA
3kbe dissolved in dichloromethane, be placed in round-bottomed flask, described mPEG
5K-PEG (COOH)
0.5k-PLGA
3kconcentration be 5 mg/mL, on the surface of round-bottomed flask, form thin and uniform polymeric film, anthracene nucleus antineoplastic antibiotic ADM, DNR, EPI, THP-ADM and ACM in table 4 are dissolved in respectively in phosphate buffer, obtain respectively the aqueous solution of ADM aqueous solution, DNR aqueous solution, EPI aqueous solution, THP-ADM aqueous solution and ACM, the concentration of described ADM, DNR, EPI, THP-ADM and ACM is respectively 0.1 mg/mL, respectively the aqueous solution of ADM aqueous solution, DNR aqueous solution, EPI aqueous solution, THP-ADM aqueous solution and ACM is joined in round-bottomed flask to 25
oaquation 60 min under C, the filtering with microporous membrane degerming with 0.22 um, makes nano micellar solution, obtains supporting the nano-micelle lyophilized powder of anthracene nucleus antineoplastic antibiotic through lyophilization.The sample P 18-P22 structure spherical in shape of gained, particle diameter is 20 to 300nm.
Embodiment 5: the external tumor suppression experiment of epirubicin nano-micelle
Hela cell is by 6.0 * 10
4the density in individual/hole is inoculated in 96 orifice plates, overnight incubation in DMEM culture medium, sucking-off culture medium, every hole adds respectively the micromolecule epirubicin of variable concentrations and epirubicin micelle sample P that embodiment 3 obtains 15 each 100 μ L, 4 multiple holes of each sample, every hole adds culture medium 100 μ L, in 37
oc, 5%CO
2incubator in continue to cultivate 48 h and 72 h, every hole adds MTT 20 μ L (5mg/mL), then cultivates after 4 h, outwell culture medium, every hole adds 150 μ L DMSO to dissolve, and is placed in microplate reader, at 590 nm places, detect its absorption maximum, draw the cell inhibitory rate of each concentration group.Fig. 6 is obtained epirubicin nano-micelle and the suppression ratio of micromolecule epirubicin to Hela cell.As can be seen from Figure 6, the nano-micelle of epirubicin and micromolecule have suitable cytotoxicity, illustrate that encapsulation process does not affect the drug effect of medicine, and medicine can discharge from micelle effectively.
Claims (4)
1. a nano-micelle preparations that supports anthracene nucleus antineoplastic antibiotic, it is characterized in that, this nano-micelle preparations comprises anthracene nucleus antineoplastic antibiotic, A-B-C type triblock polymer and adjuvant, described anthracene nucleus antineoplastic antibiotic is selected from one or more in amycin, daunorubicin, epirubicin, Perarubicin or aklavine, described A-B-C type triblock polymer is the polyethylene glycol-ester that Polyethylene Glycol-side chain contains carboxyl, wherein, A block molecular weight polyethylene glycol is 200-10000; The molecular weight of the Polyethylene Glycol that B block side chain contains carboxyl is 100-2000; The molecular weight of C block polyester is 200-10000, and the mass percent of described anthracene nucleus antineoplastic antibiotic in nano-micelle preparations is 1%～50%;
Described polyester is the polymer of levorotatory lactide, dextrorotation lactide, racemization lactide, Acetic acid, hydroxy-, bimol. cyclic ester or 6-caprolactone, or one or both random copolymer of above-mentioned monomer;
Described a kind of preparation method that supports the nano-micelle preparations of anthracene nucleus antineoplastic antibiotic, that anthracene nucleus antineoplastic antibiotic is wrapped in the nano-micelle of A-B-C type triblock polymer formation, make the nano-micelle preparations that supports anthracene nucleus antineoplastic antibiotic, specifically comprise the steps:
(1) anthracene nucleus antineoplastic antibiotic and A-B-C type triblock polymer are dissolved in organic solvent, make the polymeric film of anthracycline-containing antitumor antibiotics, described anthracene nucleus antineoplastic antibiotic is selected from one or more in amycin, daunorubicin, epirubicin, Perarubicin or aklavine; The concentration of described A-B-C type triblock polymer is 1～20mg/mL, and the concentration of anthracene nucleus antineoplastic antibiotic is 0.1～1mg/mL;
(2) the resulting polymeric film of step (1) is transferred in water or in medicinal buffer solution, aquation 1～60min at 25 ℃～70 ℃, after lyophilization, obtains supporting the nano-micelle preparations of anthracene nucleus antineoplastic antibiotic;
Or comprise the steps:
(1) A-B-C type triblock polymer is dissolved in organic solvent, obtains A-B-C triblock polymer film;
(2) anthracene nucleus antineoplastic antibiotic is dissolved in water or medicinal buffer salt solution, obtain solution, the A-B-C triblock polymer film that step (1) is obtained is transferred in this solution, aquation 1～60min at 25 ℃～70 ℃, after lyophilization, obtain supporting the nano-micelle preparations of anthracene nucleus antineoplastic antibiotic, described anthracene nucleus antineoplastic antibiotic is selected from one or more in amycin, daunorubicin, epirubicin, Perarubicin or aklavine.
2. a kind of nano-micelle preparations that supports anthracene nucleus antineoplastic antibiotic according to claim 1, is characterized in that, described adjuvant is pharmaceutically acceptable antioxidant, osmotic pressure regulator, pH value regulator and/or solubilizing agent.
3. a kind of nano-micelle preparations that supports anthracene nucleus antineoplastic antibiotic according to claim 1, is characterized in that, described organic solvent is selected from one or more in acetone, chloroform, dichloromethane, oxolane or acetonitrile.
4. a kind of nano-micelle preparations that supports anthracene nucleus antineoplastic antibiotic according to claim 1, is characterized in that, described medicinal buffer salt solution is sodium chloride injection, glucose injection or phosphate buffer solution.
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| CN102604065A (en) * | 2012-03-27 | 2012-07-25 | 中国科学院长春应用化学研究所 | Cross-linked biologically degradable carrier polymer, micelle and vesicle, and preparation method and application of the cross-linked biologically degradable carrier polymer, micelle and vesicle |
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| CN102973525A (en) | 2013-03-20 |
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