CN101829046A - Amphipathilic block polymer micelle nano medicament carrying system and preparation method - Google Patents
Amphipathilic block polymer micelle nano medicament carrying system and preparation method Download PDFInfo
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- 239000000693 micelle Substances 0.000 title claims abstract description 51
- 229920000642 polymer Polymers 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims description 10
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000004698 Polyethylene Substances 0.000 claims abstract description 11
- -1 polyethylene Polymers 0.000 claims abstract description 11
- 229920000573 polyethylene Polymers 0.000 claims abstract description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 6
- 229940079593 drug Drugs 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 150000005846 sugar alcohols Polymers 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 238000011068 loading method Methods 0.000 claims description 12
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 10
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 7
- 229960001156 mitoxantrone Drugs 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- 239000000385 dialysis solution Substances 0.000 claims description 4
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 238000000502 dialysis Methods 0.000 claims description 3
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- 238000002296 dynamic light scattering Methods 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 229920002505 N-(Carbonyl-Methoxypolyethylene Glycol 2000)-1,2-Distearoyl-Sn-Glycero-3-Phosphoethanolamine Polymers 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- SRLOHQKOADWDBV-NRONOFSHSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] 2-(2-methoxyethoxycarbonylamino)ethyl phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCCNC(=O)OCCOC)OC(=O)CCCCCCCCCCCCCCCCC SRLOHQKOADWDBV-NRONOFSHSA-M 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 description 2
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- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
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- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 101710160107 Outer membrane protein A Proteins 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
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- 210000004204 blood vessel Anatomy 0.000 description 1
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- 229960000304 folic acid Drugs 0.000 description 1
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- 239000011724 folic acid Substances 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
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- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
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Abstract
The invention relates to a method for increasing medicament carrying amount and entrapment rate of polymer micelles on an anti-tumor medicament by using hydrophobic molecules. The polymer micelles are prepared from amphipathilic polymer such as polyethylene glycol-phosphatidyl ethanolamine (PEG-DSPE) by a membrane hydration method, and the micelles can be used for wrapping insoluble or low water-soluble anti-tumor medicaments for chemotherapy of tumor. Compared with the polymer micelles prepared without adding hydrophobic molecules, the polymer micelles obtained by adding the hydrophobic molecules such as phospholipid molecules with longer aliphatic chains (10 to 20 carbon atoms) in a certain proportion during preparing the polymer micelles by using the membrane hydration method obviously increase the entrapment rate and the medicament carrying amount on the raw material medicaments of the anti-tumor medicaments. The entrapment rate increment of the polymer micelles on the raw material medicaments improves the utilization rate of the raw material medicaments, and the medicament carrying amount of the polymer micelles improves the efficiency of medicament transmission during treating the tumor so as to lay a foundation for further increasing the curative effect of the anti-tumor medicament.
Description
Technical field:
The invention belongs to biomedicine field, be particularly related to a kind of Amphipathilic block polymer micelle nano medicament carrying system and preparation method, specifically, add phospholipid such as PHOSPHATIDYL ETHANOLAMINE, phosphatidylcholine etc. in the process of polymer micelle utilizing the film water legal system to be equipped with, and then increase the method for micelle entrapment efficiency and drug loading, with the target of the efficiency of transmission that reaches the utilization rate that improves crude drug and pharmaceutical carrier.
Background technology:
Polymer micelle is a kind of amphipathic nature polyalcohol nanoparticle that self assembly forms in water that utilizes, its particle size range is usually between 10-100nm, the water-wet side of polymer is formed micellar shell, micellar kernel is formed in the hydrophobic side of polymer, constitute a hydrophobic microenvironment, thereby, it had significant solubilization for hydrophobic drug provides a spatial accommodation.Polymer micelle has very high stability, and is below its critical micelle concentration (CMC) Chang Keda mg/L order of magnitude, also very low even concentration is separated association rate when very low.In addition, the polymer micelle particle diameter is little and even, has the good permeability of organizing, and especially assembling in the tissue with seepage blood vessel such as tumor or areas of inflammation increases, and promptly so-calledly enhancedly penetrates and keeps effect, and this makes micelle have natural passive target effect.The hydrophilic long-chain on polymer micelle surface makes it can escape engulfing of human body reticuloendothelial system to a certain extent circulation time in vivo, has long circulation time, helps the gathering of micelle in tumor or areas of inflammation.In addition, also available targeting part of the hydrophilic molecule of micellar surface such as antibody or micromolecule part (as folic acid, biotin etc.) are modified, thereby the cell with corresponding cell surface antigen or receptor is had initiatively targeting, help medicine at target cell or tissue gathering higher concentration.In a word, because polymer micelle has in high stability, the solubilization to hydrophobic drug, targeting and the body characteristics such as long cyclicity, make increasing in recent years research worker with it as pharmaceutical carrier, study its application in fields such as the chemotherapy of disease especially tumor and gene therapies.
The hydrophilic section molecule that is used for preparing micellar amphipathic nature polyalcohol usually is a Polyethylene Glycol, because Polyethylene Glycol has safety in excellent biological compatibility and the body; Hydrophobic section molecule common type is then more, as aliphatic chain is synthetic phospholipids such as the PHOSPHATIDYL ETHANOLAMINE of 10 to 20 carbon atoms and phosphatidylcholine, and for example polyesters (polylactic acid, polycaprolactone) also has oligomeric hydrophobic amino acid such as polyhistidyl and phenylalanine etc.Because polymer micelle holds the hydrophobic small molecules medicine by hydrophobic microenvironment, therefore be used as in the research of pharmaceutical carrier at polymer micelle, the normal discovery in the process of preparation carrier micelle, entrapment efficiency is on the low side and drug loading is less than normal, and this has influenced the utilization rate of material medicine and the efficient that polymer micelle transmits medicine in vivo largely.
Summary of the invention
The object of the invention provides a kind of Amphipathilic block polymer micelle nano medicament carrying system and preparation method.Utilizing the film water legal system to be equipped with in the process of polymer micelle, the hydrophobic molecule such as the PHOSPHATIDYL ETHANOLAMINE that have 10-20 fat of carbon atom chain by interpolation, increase envelop rate or the drug loading of polymer micelle, and then improve the utilization rate of material medicine or the efficiency of transmission of pharmaceutical carrier crude drug.
A kind of amphipathic nature polyalcohol micelle nano medicament carrying system provided by the invention, it comprise amphipathic nature polyalcohol as carrier material, add hydrophobic molecule and embedding hydrophobicity or the low antitumor drug of water solublity and make, mean diameter is in the 10nm-100nm scope.
Amphipathilic block polymer is Polyethylene Glycol-PHOSPHATIDYL ETHANOLAMINE, polyethylene glycol-lysine or polyethylene glycol-phenylalanine etc.
Hydrophobic molecule is biocompatibility and the good phospholipid of biological safety that contains 10-20 fat of carbon atom chain, comprises PHOSPHATIDYL ETHANOLAMINE, phosphatidylcholine etc., but is not limited to the hydrophobic molecule of listed fatty chain.
The mass ratio of Amphipathilic block polymer, hydrophobic molecule and medicine is 10: 0.5-2: 1-3, the molecular weight of amphipathic nature polyalcohol are 2,000 dalton to 15,000 dalton.
Described medicine is a mitoxantrone, can also be other the hydrophobicity or the antitumor drug of low aqueous solubility.
The preparation method of a kind of amphipathic nature polyalcohol micelle nano medicament carrying system provided by the invention comprises the steps:
1) under the room temperature in organic solvent with amphipathic nature polyalcohol solution, antitumor drug and hydrophobic molecule mix homogeneously, in 25-45 ℃ of scope water-bath, revolve to steam to volatilize and remove organic solvent, form polymer medicine film; Described organic solvent is chloroform, methanol or acetonitrile;
2) polymer medicine film vacuum drying is 6-8 hour;
3) under 30-55 ℃, polymer medicine film forms polymer micelle being to stir (800-1500rpm) 5-60min in its weight 1-10 water doubly;
4) polymer micelle of making is transferred to bag filter dialysis 6-8 hour, separates the free drug of unentrapped.The molecular cut off of bag filter is 1,000-20, and 000 dalton, dialysis solution is a water.
Amphipathic nature polyalcohol is Polyethylene Glycol-PHOSPHATIDYL ETHANOLAMINE, the concentration 1-10mg/ml of this solution; The concentration 0.1-5mg/ml of material medicine (hydrophobicity or water solublity hang down medicine);
The volume ratio of Amphipathilic block polymer, hydrophobic molecule and material medicine: 1-2: 1-5: 1-10, v/v/v.
The invention provides a kind of amphipathic nature polyalcohol micelle nano medicament carrying system and preparation method.Utilizing the film water legal system to be equipped with in the process of polymer micelle, the hydrophobic molecule such as the PHOSPHATIDYL ETHANOLAMINE that have 10-20 fat of carbon atom chain by interpolation, increase envelop rate or the drug loading of polymer micelle, and then improve the utilization rate of material medicine or the efficiency of transmission of pharmaceutical carrier crude drug.With the micellar phase ratio that does not add hydrophobic molecule (as phospholipid) preparation, the method for the invention can improve 10-100% with polymer micelle medicine carrying amount or envelop rate.
Description of drawings
The mitoxantrone standard curve that Fig. 1 HPLC method is set up.
The molecular formula of Fig. 2 mPEG2000-DSPE.
The micelle particle size distribution figure that Fig. 3 dynamic light scattering method detects.
The micelle particle size distribution figure that Fig. 4 dynamic light scattering method detects.
The specific embodiment
Embodiment 1
Get Polyethylene Glycol-PHOSPHATIDYL ETHANOLAMINE (mPEG2000-DSPE of 5mg/ml, available from U.S. Avantipolar lipid company) chloroformic solution 1ml and mitoxantrone (available from Beijing Xin Ze Science and Technology Ltd.) the chloroformic solution 0.1ml of 0.5mg/ml join in the round-bottomed flask, PHOSPHATIDYL ETHANOLAMINE (the DSPE that adds 0.1mg/ml again, available from U.S. Avanti polar lipid company) chloroform suspension 0.5ml, in 30 ℃ of water-baths, revolve behind the mixing to steam and volatilize organic solvent, formation polymer medicine film; The medicine film that does not add PHOSPHATIDYL ETHANOLAMINE solution with batch parallel preparation in contrast.Then medicine film vacuum drying is spent the night (8 hours), the flask of pastille film is put 50 ℃ of water-baths again and added 5ml distilled water magnetic agitation 20min, carrier micelle promptly forms.Be that 1.4 ten thousand daltonian bag filter dialysed overnight (dialysis solution is a distilled water) are to separate the free drug of unentrapped at last with the polymer micelle molecular cut off of making.The particle size distribution of dynamic light scattering method analysis of control group and test group (the results are shown in Figure 3, A is a matched group, and B is a test group), mean diameter is about 10nm-11nm respectively.
Set up the standard curve (see figure 1) of mitoxantrone content analysis with high performance liquid chromatography, and detect the mitoxantrone drug level that dialysis post polymerization thing micelle bag carries.Calculate the envelop rate and the drug loading of polymer micelle.Test repeats 3 times, the results are shown in Table 1, illustrates by adding PHOSPHATIDYL ETHANOLAMINE, and make envelop rate increase by 23.6%, drug loading has increased by 23.2%.
Medicament contg/dosage * 100% that envelop rate=the micelle bag carries
The medicament contg that drug loading=the micelle bag carries/(quality+medicament contg of polymeric material) * 100%.
The envelop rate of table 1 polymer micelle and drug loading
Embodiment 2
Get Polyethylene Glycol-PHOSPHATIDYL ETHANOLAMINE (mPEG2000-DSPE of 5mg/ml, available from U.S. Avantipolar lipid company) methanol solution 1ml and mitoxantrone (available from Beijing Xin Ze Science and Technology Ltd.) the methanol solution 0.1ml of 0.5mg/ml join in the round-bottomed flask, PHOSPHATIDYL ETHANOLAMINE (the DSPE that adds 0.1mg/ml again, available from U.S. Avanti polar lipid company) methanol suspension 0.5ml, in 35 ℃ of water-baths, revolve behind the mixing to steam and volatilize organic solvent, formation polymer medicine film; Then medicine film vacuum drying is spent the night, the flask of pastille film is put 40 ℃ of water-baths again and added 5ml distilled water magnetic agitation 20min, carrier micelle promptly forms.Be that 14,000 daltonian bag filter dialysed overnight (dialysis solution is a distilled water) are to separate the free drug of unentrapped at last with the polymer micelle molecular cut off of making.Dynamic light scattering method is analyzed micellar particle size distribution, the results are shown in Figure 4, the about 11nm of its mean diameter.
Claims (8)
1. amphipathic nature polyalcohol micelle nano medicament carrying system, it is characterized in that it comprise amphipathic nature polyalcohol as carrier material, add hydrophobic molecule and embedding hydrophobicity or the low antitumor drug of water solublity and make, mean diameter is in the 10nm-100nm scope.
2. drug-loading system according to claim 1 is characterized in that described Amphipathilic block polymer is Polyethylene Glycol-PHOSPHATIDYL ETHANOLAMINE, polyethylene glycol-lysine or polyethylene glycol-phenylalanine.
3. drug-loading system according to claim 1, it is characterized in that described hydrophobic molecule is biocompatibility and the good phospholipid of biological safety that contains 10-20 fat of carbon atom chain: PHOSPHATIDYL ETHANOLAMINE, phosphatidylcholine, but be not limited to the hydrophobic molecule of listed fatty chain.
4. drug-loading system according to claim 1, the mass ratio that it is characterized in that described Amphipathilic block polymer, hydrophobic molecule and medicine is 10: 0.5-2: 1-3; The molecular weight of amphipathic nature polyalcohol is 2,000 dalton to 15,000 dalton.
5. drug-loading system according to claim 1 is characterized in that described medicine is the antitumor drug of mitoxantrone or other hydrophobicity or low aqueous solubility.
6. the preparation method of an amphipathic nature polyalcohol micelle nano medicament carrying system is characterized in that comprising the steps:
1) under the room temperature in organic solvent with amphipathic nature polyalcohol solution, antitumor drug and hydrophobic molecule mix homogeneously, in 25-45 ℃ of scope water-bath, revolve to steam to volatilize and remove organic solvent, form polymer medicine film;
2) polymer medicine film vacuum drying is 6-8 hour;
3) under 30-55 ℃, polymer medicine film stirs 5-60min in for its weight 1-10 water doubly, and 800-1500rpm forms polymer micelle;
4) polymer micelle of making is transferred to bag filter dialysis 6-8 hour, separates the free drug of unentrapped.The molecular cut off of bag filter is 1,000-20, and 000 dalton, dialysis solution is a water.
7. method according to claim 6 is characterized in that described amphipathic nature polyalcohol is Polyethylene Glycol-PHOSPHATIDYL ETHANOLAMINE, the concentration 1-10mg/ml of this solution; The concentration 0.1-5mg/ml of material medicine; The volume ratio of Amphipathilic block polymer, hydrophobic molecule and material medicine: 1-2: 1-5: 1-10, v/v/v.
8. method according to claim 6 is characterized in that described organic solvent is chloroform, methanol or acetonitrile.
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| CN105853357A (en) * | 2016-04-26 | 2016-08-17 | 中国药科大学 | Multifunctional cooperative mixed micelle drug delivery system and preparation method thereof |
| CN109260029A (en) * | 2018-11-30 | 2019-01-25 | 黄冈师范学院 | A kind of water-soluble nano essential oil micellar solution and preparation method thereof |
| CN109663550A (en) * | 2013-03-01 | 2019-04-23 | 国立研究开发法人科学技术振兴机构 | Substance encapsulation micro-capsule and preparation method thereof |
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| CN103980434B (en) * | 2014-05-19 | 2016-08-24 | 苏州大学 | A kind of amphipathic nature polyalcohol, its preparation method, composite Nano pharmaceutical carrier and preparation method thereof |
| CN103980434A (en) * | 2014-05-19 | 2014-08-13 | 苏州大学 | Amphiphilic polymer, preparation method, composite nano drug carrier and preparation method thereof |
| CN105853357A (en) * | 2016-04-26 | 2016-08-17 | 中国药科大学 | Multifunctional cooperative mixed micelle drug delivery system and preparation method thereof |
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