CN103989636A - Nitrogen mustard liposome and preparation method thereof - Google Patents
Nitrogen mustard liposome and preparation method thereof Download PDFInfo
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- CN103989636A CN103989636A CN201410261737.9A CN201410261737A CN103989636A CN 103989636 A CN103989636 A CN 103989636A CN 201410261737 A CN201410261737 A CN 201410261737A CN 103989636 A CN103989636 A CN 103989636A
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- chlormethine
- liposome
- phatidylcholine
- phosphoglyceride
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- 0 CCOCC(COC(CCCc(cc1)ccc1N(CC*)CCCl)=O)OP(O)(OCC[N+](C)(C)C)=O Chemical compound CCOCC(COC(CCCc(cc1)ccc1N(CC*)CCCl)=O)OP(O)(OCC[N+](C)(C)C)=O 0.000 description 1
- XGPKIOAEPQZUED-UHFFFAOYSA-N C[N](C)(C)CCOP(O)(OCC(CO)O)=O Chemical compound C[N](C)(C)CCOP(O)(OCC(CO)O)=O XGPKIOAEPQZUED-UHFFFAOYSA-N 0.000 description 1
- TXFLGZOGNOOEFZ-UHFFFAOYSA-N ClCCNCCCl Chemical compound ClCCNCCCl TXFLGZOGNOOEFZ-UHFFFAOYSA-N 0.000 description 1
- SBHMDAKEWJOPHS-UHFFFAOYSA-N OC(CCCC(C=C1)=CCC1N(CCCl)CCCl)=O Chemical compound OC(CCCC(C=C1)=CCC1N(CCCl)CCCl)=O SBHMDAKEWJOPHS-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to a nitrogen mustard liposome and a preparation method thereof. The nitrogen mustard liposome disclosed by the invention is self-assembled by a nitrogen mustard-glycerin phosphatidyl choline compound, or assembled by the nitrogen mustard-glycerin phosphatidyl choline compound and phosphatidylcholine in common, so as to obtain the nitrogen mustard liposome. By adopting the nitrogen mustard liposome disclosed by the invention, the nitrogen mustard drug loading capacity of the liposome is obviously improved, and the stability of the nitrogen mustard drug is improved.
Description
Technical field
The present invention relates to Liposomal formulation of a kind of antitumor drug chlormethine and preparation method thereof.
Background technology
Chlormethine is a class alkylating agent that is applied to the earliest clinical cancer therapy, and the kinds cancers such as chronic lymphocytic leukemia, lymphosarcoma, Hokdkin disease, ovarian cancer are had to therapeutic effect.Because chlormethine is the narrow spectrum antitumor group of a kind of non-structure, no matter dissociate or be connected with various carriers, all there is antitumor action.But, the low and facile hydrolysis of the dissolubility of chlormethine series pharmaceuticals in aqueous solution, the development of its curative effect and preparation is all restricted.Therefore, nitrogen mustards compound is carried out to structural modification, by improving, the form of medicine increases drug solubility and stability is chlormethine series pharmaceuticals study hotspot and emphasis to improve drug effect, to reduce Side effect.
Liposome is a kind of single or multiple lift vesicle of arranging orderly lipid bilayer composition, has similar biomembranous bilayer structure, and the main component of liposome is phospholipid, and liposome bilayer structure can become lipotropy and hydrophilic medicament carrier.Liposome for oncotherapy, has the feature such as targeting, lymph directionality as pharmaceutical carrier, because it can increase curative effect of medication, reduces toxic and side effects, and more and more concerned.But Liposomal formulation ubiquity is low to hydrophobic drug drug loading, and in the process such as metabolism, storage, be prone to the phenomenon of drug leakage, therefore make medicine effect performance be restricted, affected its further application at therapeutic field of tumor.
Chlormethine can be with liposomal encapsulated, and maximum problem is that chlormethine molecule is easy to spill, the performance of appreciable impact drug effect.Therefore, be necessary to develop the chlormethine liposome of good stability, for the treatment of various tumors.
Summary of the invention
The object of the invention is to propose a kind of chlormethine liposome and preparation method thereof.
Technical scheme:
The invention provides a kind of chlormethine liposome and preparation method thereof.
Described chlormethine liposome is the vesicle shape microsphere that the vesicle shape microsphere that is self-assembled into by two chlormethine-phosphoglyceride phatidylcholine compound or two chlormethine-phosphoglyceride phatidylcholine compound and adjuvant are self-assembled into.
Described two chlormethine-phosphoglyceride phatidylcholine compound be any one or two kinds in dibenzoic acid chlormethine-phosphoglyceride phatidylcholine compound or henyl butyric acid chlormethine-phosphoglyceride phatidylcholine compound arbitrarily than mixture.
Described adjuvant be in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, DSPC, DPPC or cholesterol any one or a few arbitrarily than mixture.The molar content of two chlormethine in liposome-phosphoglyceride phatidylcholine compound is 1%-100%.
The mean diameter of described liposome is 50-300nm.
The preparation method of chlormethine liposome of the present invention, by the mixture of two chlormethine-phosphoglyceride phatidylcholine compound or two chlormethine-phosphoglyceride phatidylcholine compound and adjuvant, be dissolved in organic solvent, revolve solvent evaporated, add aqueous solution aquation, obtain chlormethine liposome.
Described organic solvent be in chloroform, dichloromethane, methanol and ethanol one or more arbitrarily than mixture.
Described aqueous solution be in phosphate buffer, citrate buffer solution, sodium chloride solution and glucose solution one or more arbitrarily than mixture.
Hydration temperature is 20-70 DEG C.
Described adjuvant be in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, DSPC, DPPC or cholesterol any one or a few arbitrarily than mixture.
Two chlormethine-phosphoglyceride phatidylcholine compound that the present invention adopts is dibenzoic acid chlormethine-phosphoglyceride phatidylcholine compound (I) and henyl butyric acid chlormethine-phosphoglyceride phatidylcholine compound (II), and concrete structure formula is as follows:
Chlormethine liposome of the present invention can be for the treatment of the various tumors such as breast carcinoma.
Beneficial effect:
1. the drug loading of chlormethine liposome involved in the present invention is high, and drug loading scope is 1%-100% (molar content).
2. chlormethine liposome component involved in the present invention is simple, can not need the additives such as cholesterol.
3. chlormethine liposome involved in the present invention adopts the self assembly of two chlormethine-phosphoglyceride phatidylcholine compound, and stability is good especially.
4. chlormethine liposome involved in the present invention is high to cytotoxicity, has targeting.
5. chlormethine liposome preparation process involved in the present invention is simple, is convenient to suitability for industrialized production.
Brief description of the drawings:
The transmission electron microscope picture of Fig. 1 chlormethine liposome.
The particle diameter scintigram of Fig. 2 chlormethine liposome, vertical coordinate is intensity, abscissa is particle diameter (nanometer).
(abscissa is concentration to breast cancer cell survival rate under Fig. 3 chlormethine liposome exists, ug/ml), wherein, ■ is henyl butyric acid chlormethine-phosphoglyceride phatidylcholine compound liposome, ▼ is henyl butyric acid chlormethine-phosphoglyceride phatidylcholine compound and DSPC blend liposome (mol ratio 75:25), ● be henyl butyric acid chlormethine-phosphoglyceride phatidylcholine compound and DSPC blend liposome (mol ratio 50:50), ▲ be henyl butyric acid chlormethine-phosphoglyceride phatidylcholine compound and DSPC blend liposome (mol ratio 25:75).
Detailed description of the invention
Followingly further illustrate the present invention by embodiment, but the invention is not restricted to following examples.
Raw material dibenzoic acid chlormethine-phosphoglyceride phatidylcholine compound (I) or henyl butyric acid chlormethine-phosphoglyceride phatidylcholine compound (II) are synthesized by laboratory, and method is shown in reference example 1 and 2.
Reference example 1
Synthesizing of dibenzoic acid chlormethine-phosphoglyceride phatidylcholine compound (I)
In round-bottomed flask, add benzoic acid nitrogen mustard (1mol), N, N'-carbonyl dimidazoles (CDI) (0.5mol), dichloromethane is made solvent, room temperature reaction 0.5 hour, after TLC (thin layer chromatography) demonstration has been reacted, in system, add phosphoglyceride phatidylcholine (GPC) (0.2mol) He 1,8-diazabicylo 11 carbon-7-alkene (DBU) (0.8mol), react 1 hour, after TLC demonstration has been reacted, separate whitely with post or class yellow product by precipitation, yield 90%.Reference example 2
Henyl butyric acid chlormethine-phosphoglyceride phatidylcholine compound (II)
In round-bottomed flask, add chlorambucil (1mol), CDI (1.3mol), oxolane is made solvent, room temperature reaction 1 hour, after TLC demonstration has been reacted, in system, add GPC (0.2mol) and DBU (1.1mol), react 4 hours, after TLC demonstration has been reacted, separate whitely with post or class yellow product by precipitation, yield 80%.
Embodiment 1:
In round-bottomed flask, add dibenzoic acid chlormethine-phosphoglyceride phatidylcholine compound (1mmol) and DSPC (1mmol), chloroform dissolves, and revolves solvent evaporated, adds phosphate buffer, 60 DEG C of aquations, obtain chlormethine liposome mixture.Drug loading is 50% (mol ratio), adopts particle diameter scanner to measure, and mean diameter is 150nm.Embodiment 2:
In round-bottomed flask, add henyl butyric acid chlormethine-phosphoglyceride phatidylcholine compound (0.5mmol) and DPPC (1.5mol), chloroform dissolves, and revolves solvent evaporated, adds citrate buffer solution, 55 DEG C of aquations, obtain chlormethine liposome mixture.Drug loading is 25% (mol ratio), adopts particle diameter scanner to measure, and mean diameter is 200nm.
Embodiment 3:
In round-bottomed flask, add dibenzoic acid chlormethine-phosphoglyceride phatidylcholine compound (1.5mmol) and soybean lecithin (0.5mol), dichloromethane dissolves, and revolves solvent evaporated, adds glucose solution, 65 DEG C of aquations, obtain chlormethine liposome mixture.Drug loading is 75% (mol ratio), adopts particle diameter scanner to measure, and mean diameter is 100nm.Embodiment 4:
In round-bottomed flask, add dibenzoic acid chlormethine-phosphoglyceride phatidylcholine compound (0.01mmol) and Ovum Gallus domesticus Flavus lecithin (0.99mol), dissolve with methanol, revolves solvent evaporated, adds phosphate buffer, 50 DEG C of aquations, obtain chlormethine liposome mixture.Drug loading is 1% (mol ratio), adopts particle diameter scanner to measure, and mean diameter is 50nm.
Embodiment 5:
In round-bottomed flask, add henyl butyric acid chlormethine-phosphoglyceride phatidylcholine compound (1mmol), dissolve with ethanol, revolves solvent evaporated, adds glucose solution, and 45 DEG C of aquations obtain chlormethine liposome mixture.Drug loading is 100% (mol ratio), adopts particle diameter scanner to measure, and liposome mean diameter is 300nm.
Embodiment 6:
In round-bottomed flask, add dibenzoic acid chlormethine-phosphoglyceride phatidylcholine compound (1mmol), dissolve with ethanol, revolves solvent evaporated, adds glucose solution, and 35 DEG C of aquations obtain chlormethine liposome mixture.Drug loading is 100% (mol ratio), adopts particle diameter scanner to measure, and liposome mean diameter is 250nm.
Embodiment 7:
In round-bottomed flask, add dibenzoic acid chlormethine-phosphoglyceride phatidylcholine compound (0.4mmol) and add henyl butyric acid chlormethine-phosphoglyceride phatidylcholine compound (0.6mmol), dissolve with methanol, revolve solvent evaporated, add phosphate buffer, 50 DEG C of aquations, obtain chlormethine liposome mixture.Drug loading is 100% (mol ratio), adopts particle diameter scanner to measure, and mean diameter is 160nm.
Embodiment 8:
The morphology characterization of chlormethine liposome mixture
By transmission electron microscope, the shape characteristic of chlormethine liposome mixture is scanned.Embodiment 6 chlormethine liposome mixture are microspheroidal as shown in Figure 1 under aqueous systems.Can be obtained by result, chlormethine liposome mixture has the self assembly ability similar to liposome.
Embodiment 9:
The study on the stability of chlormethine liposome mixture
The stability of the chlormethine liposome mixture of by HPLC method being prepared by the embodiment of the present invention 1～6 under 37 DEG C of conditions of PBS (pH=7.4) is investigated, chlormethine liposome mixture declines 5% at 24 hours medicament contgs, and the former medicine of benzoic acid nitrogen mustard and chlorambucil all decomposed in 1 hour.Can be obtained by result, chlormethine liposome mixture has fabulous stability in aqueous solution.
Embodiment 10:
The antitumor action experiment of chlormethine liposome mixture
MCF-7 breast cancer cell is seeded in 96 orifice plates, with calf serum (PAA) culture fluid containing 10%, is placed in 5%CO
2in incubator, 37 DEG C are cultured to cell attachment, discard culture fluid, add the culture fluid 200mL of chlormethine liposome, establish 5 Concentraton gradient, and each concentration is established the multiple hole of 5 concentration, and each concentration joins respectively corresponding aerial, 5%CO
2, in 37 DEG C of incubators, cultivate 24 hours, add the MTT of the 5mg/mL of 20mL.Hatched 4 as a child for 37 DEG C, and inhaled and abandon supernatant, and added 100mLDMSO to dissolve, selected 450nm, and used enzyme-linked immunosorbent assay instrument device to measure each hole absorption value, through calculating the half growth inhibitory concentration IC of chlormethine liposome
50value is 100 μ g/mL left and right.Can be obtained by the above results, chlormethine liposome is all inhibited to breast cancer cell.
Claims (10)
1. a chlormethine liposome, is characterized in that, chlormethine liposome is the vesicle shape microsphere that the vesicle shape microsphere that is self-assembled into by two chlormethine-phosphoglyceride phatidylcholine compound or two chlormethine-phosphoglyceride phatidylcholine compound and adjuvant are self-assembled into.
2. chlormethine liposome according to claim 1, it is characterized in that, described two chlormethine-phosphoglyceride phatidylcholine compound be any one or two kinds in dibenzoic acid chlormethine-phosphoglyceride phatidylcholine compound or henyl butyric acid chlormethine-phosphoglyceride phatidylcholine compound arbitrarily than mixture.
3. chlormethine liposome according to claim 1, is characterized in that, described adjuvant be in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, DSPC, DPPC or cholesterol any one or a few arbitrarily than mixture.
4. chlormethine liposome according to claim 1, is characterized in that, the molar content of two chlormethine in described liposome-phosphoglyceride phatidylcholine compound is 1%-100%.
5. chlormethine liposome according to claim 1, is characterized in that, the mean diameter of described liposome is 50-300nm.
6. prepare the method for the arbitrary described chlormethine liposome of claim 1-5 for one kind, it is characterized in that, by the mixture of two chlormethine-phosphoglyceride phatidylcholine compound or two chlormethine-phosphoglyceride phatidylcholine compound and adjuvant, be dissolved in organic solvent, revolve solvent evaporated, add aqueous solution aquation, obtain chlormethine liposome.
7. the method for preparing according to claim 6 chlormethine liposome, is characterized in that, described organic solvent be in chloroform, dichloromethane, methanol or ethanol any one or a few arbitrarily than mixture.
8. the method for preparing according to claim 6 chlormethine liposome, is characterized in that, described aqueous solution be in phosphate buffer, citrate buffer solution, sodium chloride solution or glucose solution any one or a few arbitrarily than mixture.
9. the method for preparing according to claim 6 chlormethine liposome, is characterized in that, temperature when aquation is 20-70 DEG C.
10. the application of the arbitrary described chlormethine liposome of claim 1-5 in preparation treatment breast cancer tumour medicine.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104225615A (en) * | 2014-09-24 | 2014-12-24 | 东南大学 | Taxol phospholipids compound, medicine composition and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198100A (en) * | 2011-05-19 | 2011-09-28 | 马淑贤 | Carmustine powder injection and preparation technology thereof |
| CN102698285A (en) * | 2012-06-04 | 2012-10-03 | 浙江大学 | Oligo (ethylene glycol) modified chlorambucil nanomedicine and preparation method thereof |
| CN103193820A (en) * | 2013-04-27 | 2013-07-10 | 东南大学 | Nitrogen mustard phospholipid compound and preparation method thereof |
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- 2014-06-12 CN CN201410261737.9A patent/CN103989636A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198100A (en) * | 2011-05-19 | 2011-09-28 | 马淑贤 | Carmustine powder injection and preparation technology thereof |
| CN102698285A (en) * | 2012-06-04 | 2012-10-03 | 浙江大学 | Oligo (ethylene glycol) modified chlorambucil nanomedicine and preparation method thereof |
| CN103193820A (en) * | 2013-04-27 | 2013-07-10 | 东南大学 | Nitrogen mustard phospholipid compound and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104225615A (en) * | 2014-09-24 | 2014-12-24 | 东南大学 | Taxol phospholipids compound, medicine composition and application thereof |
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Application publication date: 20140820 |
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