CN102988293B - Oxaliplatin folic acid targeted lipidosome and application thereof - Google Patents
Oxaliplatin folic acid targeted lipidosome and application thereof Download PDFInfo
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- CN102988293B CN102988293B CN201210483348.1A CN201210483348A CN102988293B CN 102988293 B CN102988293 B CN 102988293B CN 201210483348 A CN201210483348 A CN 201210483348A CN 102988293 B CN102988293 B CN 102988293B
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- oxaliplatin
- phospholipid
- folate
- folic acid
- targeted liposome
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 title claims abstract description 100
- 229960001756 oxaliplatin Drugs 0.000 title claims abstract description 100
- 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 title abstract description 31
- 235000019152 folic acid Nutrition 0.000 title abstract description 18
- 239000011724 folic acid Substances 0.000 title abstract description 18
- 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 title abstract description 13
- 229960000304 folic acid Drugs 0.000 title abstract description 13
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 41
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 41
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims abstract description 40
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 34
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 27
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 17
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960000502 poloxamer Drugs 0.000 claims abstract description 14
- 229920001983 poloxamer Polymers 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 239000002502 liposome Substances 0.000 claims description 72
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- 206010028980 Neoplasm Diseases 0.000 claims description 30
- 238000000108 ultra-filtration Methods 0.000 claims description 30
- 239000007864 aqueous solution Substances 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 14
- 238000001704 evaporation Methods 0.000 claims description 10
- 230000008020 evaporation Effects 0.000 claims description 10
- 239000012530 fluid Substances 0.000 claims description 10
- 230000014759 maintenance of location Effects 0.000 claims description 10
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- 239000000243 solution Substances 0.000 claims description 7
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- 239000012467 final product Substances 0.000 claims description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 4
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 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 2
- 239000008347 soybean phospholipid Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 13
- 230000008685 targeting Effects 0.000 abstract description 12
- 208000002699 Digestive System Neoplasms Diseases 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- 230000000118 anti-neoplastic effect Effects 0.000 abstract 1
- 230000002708 enhancing effect Effects 0.000 abstract 1
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229940014144 folate Drugs 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 229940067606 lecithin Drugs 0.000 description 4
- 235000010445 lecithin Nutrition 0.000 description 4
- 239000000787 lecithin Substances 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
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- 238000012986 modification Methods 0.000 description 2
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000005909 tumor killing Effects 0.000 description 2
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
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- -1 dimethyl sulfoxine Chemical compound 0.000 description 1
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- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
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- 229960002949 fluorouracil Drugs 0.000 description 1
- 229940064302 folacin Drugs 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention discloses an oxaliplatin folic acid targeted lipidosome and an application thereof. The raw materials of the oxaliplatin folic acid targeted lipidosome comprise oxaliplatin, phospholipids, cholesterol acid, folic acid- polyethylene glycol monostearate and poloxamer F68. The structure of the folic acid- polyethylene glycol monostearate is demonstrated as follows, wherein n is equal to 45 to 136. The oxaliplatin folic acid targeted lipidosome which is prepared by the invention can be applied to preparing medicine for treating gastrointestinal tumors. Compared with the prior art, the obtained oxaliplatin folic acid targeted lipidosome has the advantages of small grain size, high entrapment efficiency, improving pharmacokinetic behavior, good targeting and enhancing antineoplastic efficacy. In addition, the cost of raw materials is low and the process is simple.
Description
(1) technical field
The present invention relates to medicinal liposome field, relate in particular to a kind of oxaliplatin folate-targeted liposome and application thereof.
(2) background technology
Oxaliplatin is third generation platinum-containing anticancer drug.Within 2004, FDA approval Oxaliplatin for Injection is combined the first-line treatment for progressive stage colon rectal cancer with 5-fluorouracil and folinic acid.The oxaliplatin formulations now having gone on the market has aqueous injection and freeze-dried powder.Oxaliplatin centering advanced colorectal cancer is evident in efficacy, also can treat other digestive tract tumor such as gastric cancer.But along with oxaliplatin extensive application clinically, its untoward reaction is also constantly found and is reported.Neurotoxicity, gastrointestinal reaction, bone marrow depression are its common untoward reaction.
Liposome is a kind of drug-supplying system of good biocompatibility, as the delivery vehicles of antitumor drug, can improve the tumor-targeting of medicine, reduces drug toxicity, therefore receives people's concern.Oxaliplatin is made to liposome and be delivered in body, medicine better can be delivered to tumor locus, improve the antitumor action of medicine, reduce its toxic reaction.Oxaliplatin is water soluble drug, and after being prepared into liposome, envelop rate is not high and seepage easily occurs.Should keep the envelop rate that liposome is higher, can not therefore reduce the drug level in liposome again, this is a difficult point preparing oxaliplatin liposome.
After conventional liposome enters body circulation, very fast being identified by macrophage and engulf of meeting, to such an extent as to can not arrive tumor tissues.Being prepared into long circulating liposomes can make this situation make moderate progress.
And part target liposomes is connected to the initiatively targeting part of target tumor at surface of liposome chain, can increase the dissolubility of medicine, the half-life of prolong drug, improve the targeting of medicine, reduce toxic and side effects.Folic acid is conventional targeting part, is that a kind of vitamin of needed by human does not have toxicity, the folacin receptor of malignant cell surface overexpression is had to height affinity, so the present invention selects folic acid as targeting part.In Chinese patent 200310124776.6,200710025130.0 and WO/2007/099377, oxaliplatin long circulating liposomes is disclosed, but they otherwise the raw material adopting is expensive, or technological requirement is very high, or envelop rate is lower.
Therefore, this area is in the urgent need to a kind of inexpensive, method that technique is simply prepared oxaliplatin target liposomes is provided, and requires the liposome encapsulation that obtains high, and Targeting Effect is good.
(3) summary of the invention
The object of the invention is to provide the oxaliplatin folate-targeted liposome that a kind of envelop rate is high, Targeting Effect good, toxic and side effects is few, pharmacokinetics behavior obviously improves.
For achieving the above object, the present invention adopts following technical scheme:
An oxaliplatin folate-targeted liposome, its raw materials comprises oxaliplatin, phospholipid, the solid acid of gallbladder, folic acid-polyethylene glycol mono stearate and poloxamer F68, the structure of described folic acid-polyethylene glycol mono stearate is as follows:
Wherein, n=45～136.
In the present invention, folic acid-polyethylene glycol mono stearate is as targeting modification thing, and described oxaliplatin folate-targeted liposome can be prepared by the conventional method of this area, and concrete recommendation of the present invention is prepared by anti-phase evaporation-high pressure homogenization method.
In each raw material components of the present invention, the mass ratio of phospholipid and cholesterol is 3～8:1, is preferably 5 ~ 7:1, most preferably is 6:1; The mass ratio of oxaliplatin and phospholipid is 1:30～60, is preferably 1:45 ~ 55, most preferably is 1:50; The mass ratio of poloxamer F68 and phospholipid is 1:5～15, is preferably 1:9 ~ 11, most preferably is 1:10; The mol ratio of folic acid-polyethylene glycol mono stearate and phospholipid is 1～10:100, is preferably 2 ~ 5:100, most preferably is 2.5:100.
Concrete, the preparation of described oxaliplatin folate-targeted liposome comprises the steps:
Get phospholipid, cholesterol is dissolved in dichloromethane, then adds the aqueous solution of oxaliplatin, stir, ultrasonic, rotary evaporation is removed organic solvent, after gel subsides, add the aqueous solution containing folic acid-polyethylene glycol mono stearate and poloxamer F68, continue evaporation, high pressure homogenize, water standardize solution, with slipstream film bag, carry out ultrafiltration, water, as replacement fluid, repeats ultrafiltration, adjusts suspension volume and obtains oxaliplatin folate-targeted liposome.
Or the preparation of described oxaliplatin folate-targeted liposome comprises the steps:
Get phospholipid, cholesterol is dissolved in dichloromethane, then the aqueous solution that adds oxaliplatin, stir, ultrasonic, rotary evaporation is removed organic solvent, after gel subsides, adds the aqueous solution of poloxamer F68 by component, continue evaporation, high pressure homogenize, adds the aqueous solution of folic acid-polyethylene glycol mono stearate, is placed in constant temperature oscillation reactor, micro oscillation is hatched, water standardize solution, carries out ultrafiltration with slipstream film bag, and water is as replacement fluid, repeat ultrafiltration, adjust suspension volume and obtain oxaliplatin folate-targeted liposome.
As preferably, the volume ratio of the aqueous solution of dichloromethane and oxaliplatin is 2～4:1, most preferably is 3:1.
As preferably, described high pressure homogenize condition is: pressure 200～800 bar, times 2～8 min; Preferred high pressure homogenize condition is: pressure 300～500 bar, times 4～6 min; Most preferred high pressure homogenize condition is: pressure 400 bar, times 5 min.
As preferably, the molecular retention amount of slipstream film bag is 3K～50K, and more preferably 5 ~ 10K, most preferably is 10K.
As preferably, slipstream film bag ultrafiltration number of times is 3 ~ 4 times.
As preferably, it is at 40～60 ℃, 100～500 rmin that described micro oscillation is hatched
-1condition under hatch 0.5～2 h; Most preferably at 45 ℃, 200 rmin
-1condition under hatch 1h.
The preferred described oxaliplatin folate-targeted liposome of the present invention is prepared in accordance with the following steps:
Proportioning raw materials is: the mass ratio of phospholipid and cholesterol is 6:1, and the mass ratio of oxaliplatin and phospholipid is 1:50, and the mass ratio of poloxamer F68 and phospholipid is 1:10, and the mol ratio of folic acid-polyethylene glycol mono stearate and phospholipid is 2.5:100, get phospholipid, cholesterol is dissolved in dichloromethane, then the aqueous solution that adds oxaliplatin, the volume ratio of the aqueous solution of dichloromethane and oxaliplatin is 3:1, stir, ultrasonic, rotary evaporation is removed organic solvent, after gel subsides, add the aqueous solution containing folic acid-polyethylene glycol mono stearate and poloxamer F68, continue evaporation, high pressure homogenize 5 min under 400bar condition, water standardize solution, the slipstream film bag that is 10K by molecular retention amount carries out ultrafiltration, water is as replacement fluid, repeat ultrafiltration 3 times, adjust suspension volume and obtain oxaliplatin folate-targeted liposome.
In raw material components of the present invention, described phospholipid is in natural phosphatidyl choline, soybean phospholipid, synthetic phospholipid, to choose any one kind of them or several mixing.
Folate-conjugated polyethylene glycol monostearate of the present invention is prepared by the following method:
By the carboxyl of folic acid and the free hydroxyl group coupled reaction of polyethylene glycol mono stearate, synthesize and obtain, it is characterized in that realizing by following steps: take folic acid, triethylamine, add dimethyl sulfoxine (DMSO) to dissolve, add dicyclohexylcarbodiimide (DCC), N-hydroxy-succinamide (NHS), lucifuge stirring at room, spends the night, and removes by filter by-product; Then add polyethylene glycol mono stearate, heating for dissolving, reaction is spent the night, and obtains crude product; Be placed in bag filter water dialysis, lyophilizing and get final product.Folic acid: dicyclohexylcarbodiimide (DCC): N-hydroxy-succinamide (NHS): the mass ratio of polyethylene glycol mono stearate is 2～8:2～8:1～4:20～80, is preferably 5:6:2.6:50.
The oxaliplatin folate-targeted liposome that the present invention makes can be applicable to preparation treatment digestive tract tumor medicine, and for example the form with ejection preparation is used for the treatment of digestive tract tumor.
Compared with prior art, the present invention obtains oxaliplatin folate-targeted liposome particle diameter is little, envelop rate is high; Pharmacokinetics behavior obviously improves; Targeting is good, antitumor curative effect strengthens; And raw material is inexpensive, technique is simpler.
(4) accompanying drawing explanation
Fig. 1 is the infrared spectrogram of polyethylene glycol mono stearate.
Fig. 2 is the infrared spectrogram of folic acid.
Fig. 3 is the infrared spectrogram of embodiment 1 gained folic acid-polyethylene glycol mono stearate.
Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of embodiment 1 gained folic acid-polyethylene glycol mono stearate.
Fig. 5, Fig. 6 is the particle size distribution figure of embodiment 2 gained oxaliplatin folate-targeted liposomees.
Fig. 7 is the release in vitro curve of embodiment 2 gained oxaliplatin folate-targeted liposomees.
Fig. 8 embodiment 2 impacts of gained oxaliplatin folate-targeted liposome on the relative tumor proliferation rate of tumor bearing nude mice (T/C).
The tumor tissues drug level curve chart of Fig. 9 embodiment 2 gained oxaliplatin folate-targeted liposomees.
Figure 10 is the plasma drug level curve chart of embodiment 2 gained oxaliplatin folate-targeted liposomees.
(5) specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percent, ratio, ratio or umber by weight.Unless otherwise defined, the same meaning that all specialties of using in literary composition and scientific words and one skilled in the art are familiar.
Embodiment 1: folate-conjugated polyethylene glycol monostearate synthetic
Precision takes folic acid 0.5 g, 0.5 mL triethylamine, and 15 mL DMSO dissolve, and add 0.6 g dicyclohexylcarbodiimide (DCC), 0.26 g N-hydroxy-succinamide (NHS), and lucifuge stirring at room, spends the night, and removes by filter by-product.Then add 5g Polyethylene Glycol (molecular weight 4000) monostearate, be heated to 35 ℃ of dissolvings, 35 ℃ of reactions are spent the night, and obtain crude product.Be poured into molecular retention amount and be in 3500 bag filter, put in the 500 mL beakers of filling water, stir, dialyse two days, lyophilizing and get final product.
Synthetic route chart is as follows:
After synthetic, the infrared spectrum of investigation folate-conjugated polyethylene glycol monostearate and proton nmr spectra are to study its structure.Fig. 1 is the outer collection of illustrative plates of the red absorption of polyethylene glycol mono stearate, 3433 cm
-1place is the stretching vibration peak of the hydroxyl of polyethylene glycol mono stearate, 2882 cm
-1place is a plurality of CH of polyethylene glycol mono stearate
2the strong characteristic absorption that stretching vibration produces.Fig. 2 is the infrared absorption pattern of folic acid, 3323,3418,3546 cm
-1place is N-H stretching vibration peak, 1695 cm
-1place is ν C=O absorption, 1606,1570, the 1405 skeleton stretching vibrations that are phenyl ring.Fig. 3 compared to Figure 1,3433 cm
-1strong and the wide stretching vibration absworption peak that the hydroxyl of place's polyethylene glycol mono stearate produces disappears, at 3328 cm
-1place produces N-H stretching vibration peak; Fig. 3 compares with Fig. 2, at 2890 cm
-1place occurs that ν C-H absorbs by force, because the polyethylene glycol mono stearate of link has a plurality of CH
2group.Therefore from Fig. 3, can tentatively determine that folic acid-polyethylene glycol mono stearate is synthetic.Folate-conjugated polyethylene glycol monostearate is dissolved in and is raised in deuterated dimethyl sulfoxide (DMSO-d6), detect its hydrogen spectrum, 1HNMR nmr frequency is 400.00MHz, sees Fig. 4.1HNMR spectrum data ownership: δ 0.91～0.94 (m, CH3), δ 2.06～2.63 (m, CH2), δ 2.90～3.47 (m, OCH2), δ 4.42 (m, OH), δ 6.56 (m, NH2), δ 6.58～7.73 (m, Ar-H), δ 6.83 (m, NH), δ 8.56 (s, Ar-H), δ 9.85 (s, COO-H).In conjunction with infrared spectrum and proton nmr spectra result, can substantially determine that folic acid-polyethylene glycol mono stearate is synthetic.
Embodiment 2 oxaliplatin folate-targeted liposomees 1
Adopt direct preparation method: get lecithin 4 g, cholesterol 667 mg are dissolved in dichloromethane 60 mL, add 20 mL containing the aqueous solution of 80 mg oxaliplatins, stir 30 min, ultrasonic 20 min, 40 ℃ of rotary evaporations are removed organic solvent, after gel subsides, by component, add containing folic acid-polyethylene glycol mono stearate 580 mg, the aqueous solution 50mL of F68 400mg, continue evaporation 30 min, high pressure homogenize 400 bar, 5 min, water is settled to 100 mL, then adopt cross-flow ultrafiltration method separated free oxaliplatin, the slipstream film bag that is 10K by molecular retention amount carries out ultrafiltration, water is as replacement fluid, repeat ultrafiltration 3 times, finally be concentrated into 1/4 of about original volume, by ultra-filtration centrifuge tube method, survey its envelop rate and the last drug level of high effective liquid chromatography for measuring, envelop rate is 92.15%, particle diameter is 102 nm, oxaliplatin concentration is 615.38 μ gmL
-1, add water and adjust liposome turbid liquor Chinese medicine concentration to 500 μ gmL
-1obtain.
Embodiment 3: oxaliplatin folate-targeted liposome 2
Adopt direct preparation method: get lecithin 4 g, cholesterol 667 mg are dissolved in dichloromethane 60 mL, add 20 mL containing the aqueous solution of 80 mg oxaliplatins, stir 30 min, ultrasonic 20 min, 40 ℃ of rotary evaporations are removed organic solvent, after gel subsides, by component, add folic acid-polyethylene glycol mono stearate 580 mg, the aqueous solution 50mL of F68 400mg, continue evaporation 30 min, high pressure homogenize 400 bar, 5 min, water is settled to 100 mL, then adopt cross-flow ultrafiltration method separated free oxaliplatin, the slipstream film bag that is 5K by molecular retention amount carries out ultrafiltration, water is as replacement fluid, repeat ultrafiltration 3 times, finally be concentrated into 1/4 of about original volume, by ultra-filtration centrifuge tube method, survey its envelop rate and the last drug level of high effective liquid chromatography for measuring, its envelop rate is 72.86%, drug level is 598.70 μ gmL
-1, add water and adjust liposome turbid liquor Chinese medicine concentration to 500 μ gmL
-1obtain.
Embodiment 4: oxaliplatin folate-targeted liposome 3
Adopt direct preparation method: get lecithin 4 g, cholesterol 667 mg are dissolved in dichloromethane 60 mL, add 20 mL containing the aqueous solution of 40 mg oxaliplatins, stir 30 min, ultrasonic 20 min, 40 ℃ of rotary evaporations are removed organic solvent, after gel subsides, by component, add folic acid-polyethylene glycol mono stearate 580 mg, the aqueous solution 50mL of F68 400mg, continue evaporation 30 min, high pressure homogenize 400 bar, 5 min, water is settled to 100 mL, then adopt cross-flow ultrafiltration method separated free oxaliplatin, the slipstream film bag that is 10K by molecular retention amount carries out ultrafiltration, water is as replacement fluid, repeat ultrafiltration 4 times, finally be concentrated into 1/4 of about original volume, by ultra-filtration centrifuge tube method, survey its envelop rate and the last drug level of high effective liquid chromatography for measuring, its envelop rate is 92.83%, drug level is 568.25 μ gmL
-1, add water and adjust liposome turbid liquor Chinese medicine concentration to 500 μ gmL
-1obtain.
Embodiment 5: oxaliplatin folate-targeted liposome 4
Insertion after adopting: get lecithin 4 g, cholesterol 667 mg are dissolved in dichloromethane 60 mL, add 20 mL containing the aqueous solution of 80 mg oxaliplatins, stir 30 min, ultrasonic 20 min, 40 ℃ of rotary evaporations are removed organic solvent, after gel subsides, by component, add aqueous solution 50 mL containing F68 400 mg, continue evaporation 30 min, high pressure homogenize 400 bar, 5 min, add folic acid-polyethylene glycol mono stearate 580 mg aqueous solution 10 mL to mix, be placed in 45 ℃ of constant temperature oscillation reactors, 200 rmin
-1micro oscillation is hatched 1h, water is settled to 100 mL, then adopt cross-flow ultrafiltration method separated free oxaliplatin, the slipstream film bag that is 10K by molecular retention amount carries out ultrafiltration, and water, as replacement fluid, repeats ultrafiltration 3 times, finally be concentrated into 1/4 of about original volume, by ultra-filtration centrifuge tube method, survey its envelop rate and the last drug level of high effective liquid chromatography for measuring, 86.26%, drug level is 525.74 μ gmL
-1, add water and adjust liposome turbid liquor Chinese medicine concentration to 500 μ gmL
-1obtain.
Embodiment 6: the particle diameter of experimental example 2 gained oxaliplatin folate-targeted liposomees, pH value are investigated
This research adopts laser particle analyzer to measure particle diameter and the distribution thereof of the oxaliplatin folate-targeted liposome of embodiment 2, and sample is directly measured, and it the results are shown in Figure 5; After 100 times of dilute with waters, laser granulometry working sample particle diameter, the results are shown in Figure 6.After diluted sample, variability is little, particle size range still narrower, be Unimodal Distribution.The pH value that records oxaliplatin folate-targeted liposome solutions with pH meter is 6.53 ± 0.05(n=5).
Embodiment 7: the vitro release experiment of embodiment 2 gained oxaliplatin folate-targeted liposomees
Specific experiment is as follows: precision measures oxaliplatin folate-targeted liposome turbid liquor 1 mL of embodiment 2, put in bag filter, two ends clamp with dialysis clamp, join in the beaker that 100 mL aqueous solutions are housed, under (37 ± 0.5) ℃ constant temperature, with cuvette method, measure release in vitro (100 rmin
-1stir, interval 1h draws dialysis solution 3 mL, then adds 3 mL aqueous solutions).HPLC analyzes, and measures oxaliplatin concentration, and after concentration correction, converts and obtain the release of liposome.Get 1 mL oxaliplatin folate-targeted liposome turbid liquor, methanol breakdown of emulsion, tries to achieve oxaliplatin total amount.Release in vitro curve is shown in Fig. 7.Release in vitro curve meets first-order release model, and release regression equation is ln (1-Q)=-0.1653t-0.4628(R
2=0.9768).
Embodiment 8: the pharmacodynamic experiment of embodiment 2 gained oxaliplatin folate-targeted liposomees
First carry out recovery and the cultivation of the strain of HCT-116 human colon cancer cell, set up HCT-116 human colon carcinoma model of nude mice bearing tumor, inoculation nude mice self-sow, vernier caliper measurement tumor volume, waits tumor growth to 50-75 mm
3after by animal by minutes 3 groups at random of tumor volumes, every group 6: model control group (injecting 5% glucose injection next day of tail vein), oxaliplatin folate-targeted liposome group (gives oxaliplatin folate-targeted liposome, eight days 2.5 mg/kg of first day to the every other day once, the 9th day to the 15 day 5 mg/kg once a day), oxaliplatin injection group (gives oxaliplatin injection, every other day once, the 9th day to the 15 day 5 mg/kg once a day for eight days 2.5 mg/kg of first day to the).Meanwhile, each is organized nude mice and starts to use automatic reading vernier caliper measurement tumor footpath after administration, surveys once every other day, dynamically observes the Graft Versus Tumor of given the test agent.According to the gross tumor volume result of measuring, calculate relative tumour volume (RTV).The evaluation index of anti-tumor activity adopts relative tumor proliferation rate T/C(%).Found that, in transplantation tumor, in rapid growth during the phase, after administration, two groups of T/C all decline.Starting press to the 8th day 2.5mg/kg every other day single administration in the situation that, the 3rd day, the 7th day and the 9th day, the T/C of target liposomes group and injection group did not more all have significant difference; At the 5th day, the T/C of target liposomes and injection group relatively had significant difference.At the tenth daystart, to finishing, the T/C of target liposomes and injection group more all have significant difference, see Fig. 8.Illustrate that oxaliplatin folate-targeted liposome group and injection group are improving dosage and increasing after administration number of times, tumor killing effect all strengthens, and target liposomes group reinforced effects is more obvious than injection group, statistically have significant difference, prompting oxaliplatin folate-targeted liposome tumor killing effect is better than oxaliplatin injection.
Embodiment 9: the targeting characteristic test of embodiment 2 gained oxaliplatin folate-targeted liposomees
First carry out recovery and the cultivation of the strain of HCT-116 human colon cancer cell, set up HCT-116 human colon carcinoma model of nude mice bearing tumor, inoculation nude mice self-sow, vernier caliper measurement tumor volume, waits tumor growth to 50-75 mm
3after by animal by minutes 3 groups at random of tumor volumes: blank group 5% glucose injection, from tail intravenously administrable, take out tumor tissues once and do blank, 6; 10 mg/kg oxaliplatin injections for oxaliplatin injection group, are administered once, 36; Oxaliplatin folate-targeted liposome is administered once with 10 mg/kg, 36.Oxaliplatin injection group and oxaliplatin folate-targeted liposome, from tail intravenously administrable, are pressed different time points 0.05,0.5,1,1.5 after administration, 2,2.5,3,3.5,4,6,8,48 h put to death, and nude mice tumor mass is put to-20 ℃ of Refrigerator stores, and then HPLC method detects tumor tissues drug level.Found that, the AUC (0-48h) of oxaliplatin folate-targeted liposome is 62.79 μ g/g*h, and Cmax is 8.458 μ g/g.The AUC of oxaliplatin injection (0-48h) is 28.099 μ g/g*h, and Cmax is 2.016 μ g/g.Two groups of comparisons, the relative uptake ratio (Re) of oxaliplatin folate-targeted liposome is 2.23, peak concentration is 4.20 than (Ce), sees Fig. 9.Illustrate that oxaliplatin folate-targeted liposome obviously strengthens compared with the targeting of oxaliplatin injection, peak concentration significantly improves.
Embodiment 10: the pharmacokinetics experiment of embodiment 2 gained oxaliplatin (OHP) folate-targeted liposomees
Take folic acid-polyethylene glycol mono stearate as targeting modification thing, prepare oxaliplatin folate-targeted liposome.Carry out again recovery and the cultivation of the strain of HCT-116 human colon cancer cell, set up HCT-116 human colon carcinoma model of nude mice bearing tumor, inoculation nude mice self-sow, vernier caliper measurement tumor volume, waits tumor growth to 50-75 mm
3after by animal by minutes 3 groups at random of tumor volumes: blank group, use 5% glucose injection, from tail intravenously administrable, take out tumor tissues once and do blank, 6; Oxaliplatin injection group, with 10 mg/kg oxaliplatin injections, is administered once, 36; Oxaliplatin folate-targeted liposome, with 10 mg/kg oxaliplatin folate-targeted liposomees, is administered once, 36.Oxaliplatin injection group and oxaliplatin folate-targeted liposome are from tail intravenously administrable, and after administration, by different time points 0.05,0.5,1,1.5,2,2.5,3,3.5,4,6,8,48 h pluck eyeball blood sampling 0.5～2 mL, with anticoagulant tube, collect.Centrifugal 4000 r/min, 10 min, get blood plasma, then HPLC method detection of drugs concentration.Plasma drug level curve is shown in Figure 10.Found that, the AUC (0-48h) of OHP folate-targeted liposome is 130.278 mg/L*h, and CLz is 0.077 L/h/kg, and Cmax is 26.56 mg/L.The AUC of OHP injection (0-48h) is 22.271 mg/L*h, and CLz is 0.448 L/h/kg, and Cmax is 14.297 mg/L.With respect to OHP injection, the peak serum concentration of OHP folate-targeted liposome has improved 86%, AUC (0-48h) and has improved 485%, and elimination factor reduces, and pharmacokinetics behavior obviously improves.
Claims (9)
1. an oxaliplatin folate-targeted liposome, the raw materials that it is characterized in that described oxaliplatin folate-targeted liposome comprises oxaliplatin, phospholipid, cholesterol, folic acid-polyethylene glycol mono stearate and poloxamer F68, the mass ratio of phospholipid and cholesterol is 3～8:1, the mass ratio of oxaliplatin and phospholipid is 1:30～60, the mass ratio of poloxamer F68 and phospholipid is 1:5～15, and the mol ratio of folic acid-polyethylene glycol mono stearate and phospholipid is 1～10:100; The structure of described folic acid-polyethylene glycol mono stearate is as follows:
Wherein, n=45～136.
2. oxaliplatin folate-targeted liposome as claimed in claim 1, is characterized in that the preparation of described oxaliplatin folate-targeted liposome comprises the steps:
Get phospholipid, cholesterol is dissolved in dichloromethane, then adds the aqueous solution of oxaliplatin, stir, ultrasonic, rotary evaporation is removed organic solvent, after gel subsides, add the aqueous solution containing folic acid-polyethylene glycol mono stearate and poloxamer F68, continue evaporation, high pressure homogenize, water standardize solution, with slipstream film bag, carry out ultrafiltration, water, as replacement fluid, repeats ultrafiltration, adjusts suspension volume and get final product.
3. oxaliplatin folate-targeted liposome as claimed in claim 1, is characterized in that the preparation of described oxaliplatin folate-targeted liposome comprises the steps:
Get phospholipid, cholesterol is dissolved in dichloromethane, then adds the aqueous solution of oxaliplatin, stir, ultrasonic, rotary evaporation is removed organic solvent, after gel subsides, the aqueous solution that adds poloxamer F68 by component, continues evaporation, high pressure homogenize, add folic acid-polyethylene glycol mono stearate aqueous solution, be placed in constant temperature oscillation reactor, micro oscillation is hatched, water standardize solution, carries out ultrafiltration with slipstream film bag, and water is as replacement fluid, repeat ultrafiltration, adjust suspension volume and get final product.
4. the oxaliplatin folate-targeted liposome as described in one of claim 1～3, is characterized in that: described phospholipid is in natural phosphatidyl choline, soybean phospholipid, synthetic phospholipid, to choose any one kind of them or several mixing.
5. oxaliplatin folate-targeted liposome as claimed in claim 1, it is characterized in that: the mass ratio of phospholipid and cholesterol is 5～7:1, the mass ratio of oxaliplatin and phospholipid is 1:45～55, the mass ratio of poloxamer F68 and phospholipid is 1:9～11, and the mol ratio of folic acid-polyethylene glycol mono stearate and phospholipid is 2～5:100.
6. oxaliplatin folate-targeted liposome as claimed in claim 2 or claim 3, is characterized in that: the volume ratio of the aqueous solution of dichloromethane and oxaliplatin is 2～4:1; Described high pressure homogenize condition is: pressure 200～800bar, time 2～8min; The molecular retention amount of slipstream film bag is 3K～50K, and ultrafiltration number of times is 3～4 times; It is at 40～60 ℃, 100～500rmin that described micro oscillation is hatched
-1condition under hatch 0.5～2h.
7. oxaliplatin folate-targeted liposome as claimed in claim 6, is characterized in that: described high pressure homogenize condition is: pressure 300～500bar, time 4～6min; The molecular retention amount of slipstream film bag is 5K～10K.
8. oxaliplatin folate-targeted liposome as claimed in claim 7, it is characterized in that proportioning raw materials is: the mass ratio of phospholipid and cholesterol is 6:1, the mass ratio of oxaliplatin and phospholipid is 1:50, the mass ratio of poloxamer F68 and phospholipid is 1:10, and the mol ratio of folic acid-polyethylene glycol mono stearate and phospholipid is 2.5:100; Described oxaliplatin folate-targeted liposome is prepared in accordance with the following steps:
Get phospholipid, cholesterol is dissolved in dichloromethane, then the aqueous solution that adds oxaliplatin, the volume ratio of the aqueous solution of dichloromethane and oxaliplatin is 3:1, stir, ultrasonic, rotary evaporation is removed organic solvent, after gel subsides, add the aqueous solution containing folic acid-polyethylene glycol mono stearate and poloxamer F68, continue evaporation, high pressure homogenize 5min under 400bar condition, water standardize solution, the slipstream film bag that is 10K by molecular retention amount carries out ultrafiltration, water is as replacement fluid, repeat ultrafiltration 3 times, adjust suspension volume and obtain oxaliplatin folate-targeted liposome.
9. the application of oxaliplatin folate-targeted liposome as claimed in claim 1 in preparation treatment digestive tract tumor medicine.
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| CN102643280A (en) * | 2012-05-18 | 2012-08-22 | 福州大学 | Folic-acid-modified phthalocyanino-silicon, and preparation method and application thereof |
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| CN1868455A (en) * | 2006-05-20 | 2006-11-29 | 沈阳药科大学 | Intravenous nanometer suspension injection contg. oxaliplatin platinum phospholipid compound |
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