CN102698285A - Oligo (ethylene glycol) modified chlorambucil nanomedicine and preparation method thereof - Google Patents
Oligo (ethylene glycol) modified chlorambucil nanomedicine and preparation method thereof Download PDFInfo
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- CN102698285A CN102698285A CN2012101874210A CN201210187421A CN102698285A CN 102698285 A CN102698285 A CN 102698285A CN 2012101874210 A CN2012101874210 A CN 2012101874210A CN 201210187421 A CN201210187421 A CN 201210187421A CN 102698285 A CN102698285 A CN 102698285A
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Abstract
The invention discloses an oligo (ethylene glycol) modified chlorambucil medicine. The structural formula of the short-chain polyethylene glycol modified chlorambucil medicine is shown as a formula I; and in the formula I, the number-average molar mass of oligo (ethylene glycol) (OEG) segments is 198-1,998. The medicine is an amphiphilic anti-cancer medicine, can be self-assembled to form nanoparticles in water or a buffer solution, has long blood circulation time, can target tumors through ultra permeability and enhanced permeation and retention (EPR) effect and can effectively target cancer tissues through the EPR effect of the tumors; and compared with other chlorambucil medicine systems, the chlorambucil medicine has the advantages of high medicine loading rate, high druggability and the like and is expected to be used for clinical treatment of various tumors.
Description
Technical field
The present invention relates to the cancer therapy drug transportation art, be specifically related to chlorambucil (CBL) Nano medication of a kind of short chain polyalkylene glycol (OEG) modification and preparation method thereof.
Background technology
Chlorambucil (CBL) has another name called tumor can be right, chlorine ammonia Bu Buxi, Amboclorin; Be nitrogen mustard derivatives, act on similarly that kinds of tumors is had inhibitory action with cyclophosphamide; Clinical chronic lymphocytic leukemia, lymphosarcoma, He Jinjieshi disease, ovarian cancer, breast carcinoma, chorioepithelium tumor, the multiple myeloma etc. of being used for; Be comparatively sophisticated cancer therapy drug, but because its poorly water-soluble, so be difficult to give full play to its drug effect.Through CBL is combined preparation can improve its water solublity with carrier; And high-permeability that can be through tumor and retention effect (being the EPR effect) are optionally in the cancerous tissue enrichment; Reach effective kill cancer cell and reduce the effect that injures normal structure, caused extensive studies interest.
Variety carrier is used to combine with CBL the preparation Nano medication.Prepare Nano medication like Song etc. through the nanoemulsions embedding; Solved solubility problem (the Song HL of former medicine; Nie SF; Yang XG, et al.Characterization and in vivo evaluation of novel lipid – chlorambucil nanospheres prepared using a mixture of emulsifiers for parenteral administration, International Journal of Nanomedicine 2010 (5): 933-942).Ganta etc. carry CBL through polyethyleneglycol modified long-acting nanoemulsions, have obtained better medicament dynamic performance (Ganta S, Sharma P; Panton JW; Et al, Pharmacokinetics and pharmacodynamics of chlorambucil delivered in long-circulating nanoemulsion, Journal of Drug Targeting; 2010,18 (2): 125-133).Bielawski etc. are through having prepared Nano medication with CBL and daiamid dendritic macromole bonding, and discovery is compared with former medicine has better anti-cancer properties (Bielawski, K; Bielawska, A, Muszyn ' ska A; Cytotoxic activity of G3 PAMAM-NH2 dendrimer-chlorambucil conjugate in human breast cancer cells; Environmental Toxicology and Pharmacology, 2011,32:364-372).Huang etc. have prepared degradable Nano medication through the phospholipid polyalcohol bonding with CBL and ultra cladodification; The growth of anticancer effectively (Liu J, Huang W, Pang Y; The in vitro biocompatibility of self-assembled hyperbranched copolyphosphate nanocarriers; Biomaterials, 2010,31 5643-5651).People such as Xu Haixing, Xu Peihu, Huang Zhijun disclose a kind of CBL drug delivery system that comprises magnetic fluid in one Chinese patent application CN102100915 A, this system is by PEG-HA-CHL component and Fe
3O
4The magnetic fluid component is by weight being 1: the mixed of 1-5 is formulated, and wherein, the constituent content of PEG-HA-CHL component is counted by weight: chlorambucil 20-100; PEG 500-1500, HA100-500, DCC 10-50; DMAP 1-10; Succinic anhydride 100-500, EDC 10-50, sodium sulfite 20-100; This system can utilize external magnetic field to realize the targeted of medicine.Above-mentioned these all systems have all been used a large amount of carriers, cause drug loading low, and the use of a large amount of baroque carriers causes biocompatibility issues easily simultaneously, become the property of medicine poor.
Summary of the invention
The objective of the invention is to deficiency, a kind of chlorambucil medicine (OEG-CBL) of short chain polyalkylene glycol modification and the Nano medication that self assembly forms thereof are provided, and their method for preparing is provided to existing CBL conveying technology.
The chlorambucil medicine that a kind of short chain polyalkylene glycol is modified, structural formula is shown in the formula I:
In the formula I; The number-average molecular weight of
segment (being called for short the OEG segment) is 198 ~ 1998; Be preferably 198 ~ 999, further be preferably 299 ~ 599.
The method for preparing of the chlorambucil medicine that a kind of short chain polyalkylene glycol is modified comprises step:
With chlorambucil and end group is that the Polyethylene Glycol of methyl is a raw material; 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl) is a catalyst; Pyridine is a reaction dissolvent; Make the hydroxyl reaction in the Polyethylene Glycol (OEG) that carboxyl and end group in the chlorambucil be methyl, the chlorambucil medicine that the short chain polyalkylene glycol shown in the preparation formula I is modified.
Wherein, Described end group is that the structural formula of the Polyethylene Glycol of methyl is shown in the formula II:
its number-average molecular weight be 199 ~ 1999; Be preferably 199 ~ 1000; Further be preferably 300 ~ 600, can further improve drug loading.
N has identical implication in formula I and the formula II, and n is an average degree of polymerization.
The value of n among the present invention (being the molecular weight size of OEG) does not influence the preparation of OEG-CBL; Adopt described method for preparing all can obtain corresponding OEG-CBL; Just the molecular weight size of OEG has certain influence to drug loading, along with the molecular weight increase drug loading of OEG is on a declining curve.
Described reaction condition is in nitrogen or inert gas shielding, under 18 ℃ ~ 30 ℃ ambient temperature, to react at least 48 hours.Described noble gas is selected the conventional noble gas in this area for use, a kind of as in helium, the argon etc.
Consider that from the angle that economizes in raw materials chlorambucil and end group are that the mol ratio of the Polyethylene Glycol of methyl is preferably 1 ~ 2: 1; Catalyst and end group are that the mol ratio of the Polyethylene Glycol of methyl is preferably 1 ~ 2: 1.
After reaction finishes reactant liquor poured in the normal hexane and precipitate, isolate deposition, precipitate with reuse normal hexane after an amount of dissolved in chloroform; Repetitive operation; Collecting precipitation is crossed 100-200 order gross porosity column chromatography silica gel post and is purified, and obtains the chlorambucil medicine that short chain polyalkylene glycol is modified.
The condition that the described 100-200 of mistake order gross porosity column chromatography silica gel post is purified is: adopt 100-200 order gross porosity column chromatography silica gel post; Eluant is an ethyl acetate; And dichloromethane and methanol volume ratio are 1: 1 mixed solvent; Earlier by rinsed to there not being excessive CBL, changing by dichloromethane and methanol volume ratio is the chlorambucil medicine that 1: 1 mixed solvent flushing obtains the short chain polyalkylene glycol modification.
It is a kind of that to use chlorambucil medicine that described short chain polyalkylene glycol modifies be the Nano medication solution that self assembly forms in 6.5 ~ 7.5 the buffer solution at aqueous solution or pH.Described OEG-CBL is amphipathic medicine, therefore can be in the approaching buffer solution of water and pH and water self assembly formation nano-particle.Described buffer can be selected field, this area buffer commonly used for use, like phosphate (PBS) buffer solution etc.
The method for preparing of described Nano medication solution is fairly simple, comprises two kinds of methods, is specially:
Method one; Comprise step: the chlorambucil medicine of earlier described short chain polyalkylene glycol being modified is dissolved in processes solution in the oxolane, then drips of solution is added in the deionized water that stirs, behind stirring and sonic oscillation; Revolve to steam and remove oxolane, obtain Nano medication solution.
Method two comprises step: the chlorambucil medicine that described short chain polyalkylene glycol is modified is dispersed in water or pH and in 6.5 ~ 7.5 the buffer solution, through stirring and sonic oscillation, obtains Nano medication solution.
The Nano medication particle grain size is at 50nm ~ 200nm in the described Nano medication solution.
Chlorambucil medicine and Nano medication solution that described short chain polyalkylene glycol is modified have cytotoxicity to cancerous cell, can be used as the medicine of treatment cancer, also can be used for preparing the medicine of treating cancer.Described cancer comprises chronic lymphocytic leukemia, lymphosarcoma, He Jinjieshi disease, ovarian cancer, breast carcinoma, chorioepithelium tumor, multiple myeloma etc.
The invention has the beneficial effects as follows: OEG-CBL of the present invention is amphipathic cancer therapy drug; Can be that self assembly forms nano-particle in 6.5 ~ 7.5 the buffer solution at water or pH; Particle diameter has increased the dissolubility of CBL in water on the one hand greatly at 50 ~ 200nm, and owing to used short chain OEG as carrier; The drug loading of the OEG-CBL of feasible preparation has overcome the low shortcoming of existing drug delivery system drug loading up to 13% ~ 60% (percentage by weight); It is long that this Nano medication has blood circulation time on the other hand; Can be ultra penetrating and retention effect target tumor; Can effectively utilize the EPR effect target on cancer tissue of tumor more, and compare, have the carrying drug ratio height with other the drug system of chlorambucil; Become advantages such as the property of medicine is strong, be expected to be used for the clinical treatment of kinds of tumors.Cell experiment proves that OEG-CBL Nano medication of the present invention has the cytotoxicity higher than CBL, like Fig. 3.
Description of drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of OEG-CBL of the present invention;
Fig. 2 is OEG-CBL of the present invention forms nano-particle in water particle size distribution figure;
Fig. 3 is OEG-CBL of the present invention and the CBL toxic effect figure to breast cancer cell.
The specific embodiment
The present invention provides some specific embodiments, but the present invention does not receive the restriction of these specific embodiments.
The preparation of embodiment 1 OEG-CBL
(1.04g 3.42mmol) is dissolved in the exsiccant pyridine of 10mL CBL, adds EDCHCl (0.6563g then; 3.42mmol) and OEG (number-average molecular weight is 552 for 0.9437g, 1.71mmol) to pyridine solution; Under argon shield, 30 ℃ of room temperature reaction 48h.After reaction finishes reactant liquor poured in the 100mL normal hexane and precipitate, the centrifuging and taking deposition precipitates with reuse normal hexane after an amount of dissolved in chloroform; Repeat to precipitate 2 times, collecting precipitation is crossed 100-200 order gross porosity column chromatography silica gel post and is purified; Eluant is an ethyl acetate; And dichloromethane and methanol volume ratio be the mixed solvent of 1:1, earlier by rinsed to there not being excessive CBL, change mixed solvent by dichloromethane and methanol 1:1 and wash and obtain product OEG-CBL.
Fig. 1 is the nuclear-magnetism figure of OEG-CBL.Wherein the peak of 4.21ppm place appearance is that OEG is connected the ester bond-CH that produces with CBL
2The peak of-OCO-, its integration and the OEG of 3.33ppm place end group methoxyl group CH
3The ratio at-O peak is 2:3; Proof OEG terminal-OH and CBL-COOH reacts completely; Formed ester bond; All the other each peak integrations are consistent with each H ratio of OEG and CBL, formed the product OEG-CBLL of expection so can confirm OEG and CBL reaction, and the segmental number-average molecular weight of OEG is 551 among the OEG-CBL.Drug loading is 35.5%.
The preparation of embodiment 2 OEG-CBL
(1.018g 3.35mmol) is dissolved in the exsiccant pyridine of 10mL CBL, adds EDCHCl (0.6428g then; 3.35mmol) and OEG (number-average molecular weight is 300 for 0.6235g, 2.07mmol) to pyridine solution; Under argon shield, 20 ℃ of room temperature reaction 48h.After reaction finishes reactant liquor poured in the 100mL normal hexane and precipitate, the centrifuging and taking deposition precipitates with reuse normal hexane after an amount of dissolved in chloroform; Repeat to precipitate 2 times, collecting precipitation is crossed 100-200 order gross porosity column chromatography silica gel post and is purified; Eluant is an ethyl acetate; And dichloromethane and methanol volume ratio be the mixed solvent of 1:1, earlier by rinsed to there not being excessive CBL, change mixed solvent by dichloromethane and methanol 1:1 and wash and obtain product; Resulting product is OEG-CBL, and the segmental number-average molecular weight of OEG is 299 among the OEG-CBL.Drug loading is 49.7%.。
The preparation of embodiment 3 OEG-CBL
(0.4665g 1.534mmol) is dissolved in the exsiccant pyridine of 10mL CBL, adds EDCHCl (0.2929g then; 1.534mmol) and OEG (number-average molecular weight is 1000 for 1.023g, 1.023mmol) to pyridine solution; Under argon shield, 18 ℃ of room temperature reaction 48h.After reaction finishes reactant liquor poured in the 100mL normal hexane and precipitate, the centrifuging and taking deposition precipitates with reuse normal hexane after an amount of dissolved in chloroform; Repeat to precipitate 3 times, collecting precipitation is crossed 100-200 order gross porosity column chromatography silica gel post and is purified; Eluant is an ethyl acetate; And dichloromethane and methanol volume ratio be the mixed solvent of 1:1, earlier by rinsed to there not being excessive CBL, change mixed solvent by dichloromethane and methanol 1:1 and wash and obtain product; Resulting product is OEG-CBL, and the segmental number-average molecular weight of OEG is 999 among the OEG-CBL.Drug loading is 23.3%.
The preparation of embodiment 4 OEG-CBL Nano medications
OEG (the 551)-CBL 10mg of embodiment 1 preparation is dissolved in the 500 μ l oxolanes; Be added dropwise in the deionized water of 10ml high-speed stirred (6000 rev/mins) with 15 seconds every speed; Stir 30min; Sonic oscillation 30min, 20 ℃ of outstanding steamings of room temperature eliminate oxolane, obtain Nano medication solution.
With the particle size distribution of this Nano medication solution with nano-particle in the dynamic light scattering detection Nano medication solution, particle size distribution figure such as Fig. 2.The mean diameter that records nano-particle in the Nano medication solution is 150.2nm, and particle size distribution is 0.170.
The take the logarithm human breast cancer cell MCF-7 cell of trophophase, with the PBS buffer solution washing of pH=7.4 2 times, 0.25% trypsinization, the RPMI-1640 culture fluid that contains 10% calf serum, 100U/mL penicillin and streptomycin is diluted to 4.5 * 10
7The single cell suspension of individual/L concentration is inoculated in 96 orifice plates with it, and every hole 100 μ L, establish 3 multiple holes for every group by totally 9 groups.Change culture fluid after cultivating 24h.Experimental group adds each concentration OEG-CBL Nano medication culture fluid, and positive controls adds each concentration C BL crude drug, and the blank group does not add any medicine.Behind 48h, add the RPMI-1640 culture fluid 100 μ L that contain the MTT dye liquor after the dosing, continue to cultivate 2-4h, produce the bluish violet crystal.Exhaust supernatant, every hole adds dimethyl sulfoxide (DMSO) 100 μ L, and vibration dissolving 10min measures with enzyme linked immunosorbent assay, is 562nm when measuring wavelength, the light absorption value in every hole (A) during reference wavelength 620nm.Calculate IR by following formula:
IR (%)=(1-experimental group A value or positive controls A value/blank group A value) * 100%.
OEG-CBL and CBL are to toxic effect figure such as Fig. 3 of breast cancer cell; Show: OEG-CBL is the same with CBL to have cytotoxicity to breast cancer cell; And the OEG-CBL Nano medication has the cytotoxicity higher than CBL, and this result shows that the OEG-CBL medicine can be used for as cancer therapy drug.
The preparation of embodiment 5 OEG (551)-CBL Nano medication
OEG (the 551)-CBL 10mg of embodiment 1 preparation is dispersed in the PBS buffer solution of 10ml 0.1M (mol/L) pH=7.5, stirs 30min, and sonic oscillation 30min directly obtains Nano medication solution.
The mean diameter that adopts dynamic light scattering to record nano-particle in this Nano medication solution is 150.2nm, and particle size distribution is 0.170.
Claims (10)
1. the chlorambucil medicine modified of a short chain polyalkylene glycol is characterized in that structural formula is shown in the formula I:
In the formula I,
segmental number-average molecular weight is 198 ~ 1998.
2. the method for preparing of the chlorambucil medicine modified of a short chain polyalkylene glycol comprises step:
With chlorambucil and end group is that the Polyethylene Glycol of methyl is a raw material; 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride is a catalyst; Pyridine is a reaction dissolvent; Make the hydroxyl reaction in the Polyethylene Glycol that carboxyl and end group in the chlorambucil be methyl, the chlorambucil medicine that the preparation short chain polyalkylene glycol is modified;
Wherein, described end group is that the structural formula of the Polyethylene Glycol of methyl is shown in the formula II:
its number-average molecular weight be 199 ~ 1999;
The structural formula of the chlorambucil medicine that described short chain polyalkylene glycol is modified is shown in the formula I:
In the formula I,
segmental number-average molecular weight is 198 ~ 1998;
N has identical implication in formula I and the formula II.
3. method for preparing according to claim 2 is characterized in that, described reaction condition is in nitrogen or inert gas shielding, under 18 ℃ ~ 30 ℃ ambient temperature, to react at least 48 hours.
4. method for preparing according to claim 2 is characterized in that, chlorambucil and end group are that the mol ratio of the Polyethylene Glycol of methyl is 1 ~ 2:1.
5. method for preparing according to claim 2 is characterized in that, catalyst and end group are that the mol ratio of the Polyethylene Glycol of methyl is 1 ~ 2:1.
6. method for preparing according to claim 2 is characterized in that, after reaction finishes reactant liquor is poured in the normal hexane and precipitates; Isolate deposition; With reuse normal hexane deposition after an amount of dissolved in chloroform, repetitive operation, collecting precipitation; Cross 100-200 order gross porosity column chromatography silica gel post and purify, obtain the chlorambucil medicine that short chain polyalkylene glycol is modified.
7. method for preparing according to claim 6; It is characterized in that; The condition that the described 100-200 of mistake order gross porosity column chromatography silica gel post is purified is: eluant is an ethyl acetate; And dichloromethane and methanol volume ratio be the mixed solvent of 1:1, earlier by rinsed to there not being excessive CBL, changing by dichloromethane and methanol volume ratio is the chlorambucil medicine that the mixed solvent flushing of 1:1 obtains the short chain polyalkylene glycol modification.
8. a chlorambucil medicine of modifying with the described short chain polyalkylene glycol of claim 1 is the Nano medication solution that assembling forms in 6.5 ~ 7.5 the buffer solution at aqueous solution or pH.
9. the method for preparing of Nano medication solution according to claim 8; Comprise step: the chlorambucil medicine of earlier the described short chain polyalkylene glycol of claim 1 being modified is dissolved in processes solution in the oxolane; Then drips of solution is added in the deionized water that stirs; Behind stirring and sonic oscillation, revolve to steam and remove oxolane, obtain Nano medication solution;
Perhaps, comprise step: the chlorambucil medicine that the described short chain polyalkylene glycol of claim 1 is modified is dispersed in water or pH and in 6.5 ~ 7.5 the buffer solution, through stirring and sonic oscillation, obtains Nano medication solution.
10. the application in the medicine of preparation treatment cancer of chlorambucil medicine that short chain polyalkylene glycol according to claim 1 is modified or the described Nano medication solution of claim 8.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103989636A (en) * | 2014-06-12 | 2014-08-20 | 东南大学 | Nitrogen mustard liposome and preparation method thereof |
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| CN101628919A (en) * | 2009-08-20 | 2010-01-20 | 浙江大学 | Camptothecin, self-emulsifying medicine precursor of derivative thereof and application thereof |
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| CN101628919A (en) * | 2009-08-20 | 2010-01-20 | 浙江大学 | Camptothecin, self-emulsifying medicine precursor of derivative thereof and application thereof |
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| CN103989636A (en) * | 2014-06-12 | 2014-08-20 | 东南大学 | Nitrogen mustard liposome and preparation method thereof |
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Application publication date: 20121003 |