CN1416812A - Liver-targeting mitomycin magnetic nano particle and its prepn and application in medicine - Google Patents
Liver-targeting mitomycin magnetic nano particle and its prepn and application in medicine Download PDFInfo
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- CN1416812A CN1416812A CN 01129882 CN01129882A CN1416812A CN 1416812 A CN1416812 A CN 1416812A CN 01129882 CN01129882 CN 01129882 CN 01129882 A CN01129882 A CN 01129882A CN 1416812 A CN1416812 A CN 1416812A
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- mitomycin
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Abstract
The liver-targeting Mitomycin magnetic nano particle has nano carrier of polyalkyl cyanoacrylate, embedded Mitomycin and embedded or adsorbed magnetic fluid. Its preparation includes preparation of saturated colloid solution of Mitomycin and containing nano level magnetic fluid and adding alkyl cyanoacrylate monomer for polymerization. The said nano particle can form the freeze dried powder injection of human keratin; and increase the hematic medicine concentration in liver cancer region to kill cancer cell while reducing the hematic medicine concentration in other organs to reduce systemic toxicity. It has outstanding curative effect especially on intractable primary liver cancer.
Description
Technical field
The present invention relates to field of medicaments, a kind of in more detail liver targeting mitomycin magnetic nano particle that is used for the treatment of hepatocarcinoma.The invention still further relates to the preparation method of this liver targeting mitomycin magnetic nano particle.The invention still further relates to this application of liver targeting mitomycin magnetic nano particle in pharmacy.
Background technology
Mitomycin (being called for short MMC, down together) is a broad-spectrum anti-cancer drug, and is outstanding to the digestive tract tumor effect, but because the mitomycin injection of using does not clinically have targeting at present, the whole body toxic and side effects is big, can't increase its therapeutic dose, causes treatment not reach original ideal effect.
Goal of the invention
The objective of the invention is to the defective at the prior art existence, a kind of liver targeting mitomycin magnetic nano particle is provided, it has liver target, therefore can increase its therapeutic dose, increases the lethal effect to hepatoma carcinoma cell.
The present invention also aims to provide the preparation method of this liver targeting mitomycin magnetic nano particle.
The present invention also aims to provide this application of liver targeting mitomycin magnetic nano particle in pharmacy.
Liver targeting mitomycin magnetic nano particle of the present invention is a carrier with paracyanogen base alkyl acrylate ester nanoparticles, interior embedding mitomycin, embedding or absorption nanoscale magnetic fluid.
Liver targeting mitomycin magnetic nano particle particle size range is at 20nm～250nm.
Described magnetic fluid is iron sesquioxide, ferrofluid or its mixture.
When liver targeting mitomycin magnetic nano particle of the present invention was used as curing cancer drug, wherein said nanoscale magnetic fluid content was 20-50% weight, and mitomycin content is 2-10% weight.
Liver targeting mitomycin magnetic nano particle of the present invention can be made intravenous lyophilized injectable powder, this injection is behind intravenously administrable, under no externally-applied magnetic field situation, has natural liver targeting function, the hepatic tissue distributive law reaches 54～70%, at externally-applied magnetic field, intensity is greater than under the 0.35T the action of a magnetic field, and medicine distributes at liver and obviously increases.Therefore, can strengthen the local blood drug level in hepatocarcinoma zone, thus control with kill and wound cancerous cell, and lower the blood drug level of other organ, thereby lower the general toxicity effect of medicine, the primary hepatocarcinoma to refractory more has outstanding curative effect especially.
The preparation method of liver targeting mitomycin magnetic nano particle of the present invention comprises: the colloid solution that will contain the nanoscale magnetic fluid with mitomycin is saturated, adds monomer alpha-cyanoacrylate alkane ester, carries out polyreaction.
Wherein the nanoscale magnetic fluid can be used prior art for preparing, also can commercially availablely obtain, and the inventor provides the preparation method of nanoscale magnetic fluid as follows: with FeCl through constantly exploring
3With FeCl
2Soluble in water, add the oleic acid dispersant, add sodium hydroxide solution, suspension is placed force the magnetic particle sedimentation on the Magnet, add dispersant, cross 1 tm screen and get the nanoscale magnetic fluid.
Nanoscale magnetic fluid preparation method more specifically is as follows: get 1.5mol FeCl
3With 0.8mol FeCl
2Be dissolved in respectively in the 1000ml distilled water, filter.Filtrate is mixed, and adds 0.5～1% oleic acid dispersant, puts in the 3000ml beaker, beaker is placed ultrasonic cleaner, mixing speed 1500r/min heats 40 ℃, uses 6mol/LNaOH solution, drips speed with 5ml/min and drips in the beaker, continue to stir following 40 ℃ of insulation 30min, suspension placed force the magnetic particle sedimentation on the Magnet, the supernatant that inclines adds above-mentioned dispersant 0.5%, handle 20min in the ultrasonic cleaner, cross 1 μ sieve.
Liver targeting mitomycin magnetic nano particle of the present invention preparation method more specifically comprises: it is saturated with mitomycin to contain nano-scale magnetic particle,colloid solution earlier, and adding emulsifying agent, with citric acid regulator solution pH to 5.5～7.5, under electromagnetic agitation, progressively splash into monomer alpha-cyanoacrylate alkane ester reaction 3 hours then, filter with 1～10 μ sintered glass funnel, filtrate is through repeatedly normal saline washing, evaporation, lyophilization, the packing gland
60The Co sterilization, radiation dose 10
4Gy, low-temperature dark is preserved.
Described emulsifying agent is poloxamer, Brij, Polysorbate, span, glucosan, concentration range 0.1～3% weight.
The liver targeting mitomycin magnetic nano particle of the inventive method preparation reaches following standard through following detection:
1. be brown fine powder by perusal, no-sundries, not conglomeration;
2. the sample particle footpath is analyzed through the MALVERN laser particle analyzer, and mean diameter is 100 ± 25nm, and particle size distribution is between 20nm～250nm;
3. sample is under transmission electron microscope, and form is garden shape substantially, no adhesion;
4. normal saline impregnation liquid pH=5.5～7.5 of injectable powder;
5. use high performance liquid chromatography, measuring MMC content should be greater than 5%;
6. magnetic fluid content should be greater than 28% (g/g) in the injectable powder;
7. animal body test, liver tumor suppression ratio 〉=99%;
8. stability test, sample be 4～8 ℃ of airtight keeping in Dark Place 1 year, medicine MMC content constant substantially (excursion ± 0.1%).
The present invention compared with prior art has following obvious advantage:
1, generally speaking, antitumor drug (Western medicine), owing to be insoluble in water and oil phase, the nanoparticle drug loading all is lower than 2%, liver targeting mitomycin magnetic nano particle drug loading of the present invention can be up to 5%;
2, liver targeting mitomycin magnetic nano particle of the present invention not only itself has liver passive target performance, and the externally-applied magnetic field guiding makes liver targeting rate be able to further raising.
3, liver targeting mitomycin magnetic nano particle of the present invention can increase its therapeutic dose, increases the lethal effect to hepatoma carcinoma cell.
The specific embodiment
Embodiment 1
With 2ml monomer Tisuacryl, in the presence of emulsifying agent 0.5%Pluronic F68, be injected into 100ml and contain in the 70mg magnetic fluid colloidal solution.This colloid solution gives earlier saturated by MMC medicine institute, and to regulate aqueous solution pH be 5.5, at magnetic agitation 500r/min, behind the reaction 3h, filter with the G3 sintered glass funnel, filtrate through the evaporation of vacuum room temperature, lyophilization, screening, packing gland,
60Co sterilization, low temperature, keep in Dark Place.Product is under transmission electron microscope, and form is rounded, no adhesion.Mean diameter is 108 ± 2nm, and particle size distribution SPAN is 1.1, and magnetic fluid content is 28.5% (g/g), drug loading 5.8%.Mouse tail vein injection test: behind the injection 15min, medicine MMC 71.5% concentrates in liver, guide with externally-applied magnetic field, can use medicine to distribute and increase to 84.9% at liver, injected dose is 0.1mg (MMC)/kg. time, injecting 10 times (30d), is 99.2% to liver-cancer solid tumor (HepS) suppression ratio.
Embodiment 2
Repeat example 1 operation, different is that magnetic fluid weight is increased to 140mg.Regulate aqueous solution pH=7, sample is figure substantially under transmission electron microscope, adhesion is arranged on a small quantity, and after filtration, it is 125 ± 2nm that laser particle analyzer is analyzed mean diameter, particle size distribution 1.3, magnetic fluid content 38.1%, drug loading 5.1%.Mouse test: behind the injection 15min, no magnetic field and introduction by magnetic field is arranged, medicine is respectively 54.8% and 89.5% at liver, when injected dose is 0.1mg (MMC)/kg. time, injects altogether 10 times (30d).To liver-cancer solid tumor (HepS) suppression ratio is 99.5%.
Embodiment 3
Repeat 1 operation, different is to change emulsifying agent into 0.5% glucosan, and mixing speed is 2000r/min.Sample under transmission electron microscope, the part ovalize, the laser particle size analysis mean diameter is 110 ± 2nm, particle size distribution 1.2, magnetic fluid content 30.1%, drug loading 5.4%, mouse test, behind the injection 15min, no magnetic field with introduction by magnetic field is arranged, medicine is respectively 68.4% and 88.5% in liver, when injected dose is 0.1mg (MMC)/kg time, inject 10 times (30d), the liver-cancer solid tumor suppression ratio is 99.3%.
Claims (10)
1, a kind of liver targeting mitomycin magnetic nano particle is characterized in that with paracyanogen base alkyl acrylate ester nanoparticles be carrier, interior embedding mitomycin, embedding or absorption nanoscale magnetic fluid.
2, liver targeting mitomycin magnetic nano particle according to claim 1 is characterized in that particle size range is at 20nm～250nm.
3, liver targeting mitomycin magnetic nano particle according to claim 1 and 2 is characterized in that described magnetic fluid is iron sesquioxide, ferrofluid or its mixture.
4, liver targeting mitomycin magnetic nano particle according to claim 1 and 2 is characterized in that wherein said nanoscale magnetic fluid content is 20-50% weight, and mitomycin content is 2-10% weight.
5, liver targeting mitomycin magnetic nano particle according to claim 1 and 2 is characterized in that making intravenous lyophilized injectable powder.
6, the preparation method of the described liver targeting of claim 1 mitomycin magnetic nano particle, it is characterized in that comprising: the colloid solution that will contain the nanoscale magnetic fluid with mitomycin is saturated, adds monomer alpha-cyanoacrylate alkane ester, carries out polyreaction.
7, the preparation method of liver targeting mitomycin magnetic nano particle according to claim 6 is characterized in that the preparation method of described nanoscale magnetic fluid is as follows: with FeCl
3With FeCl
2Soluble in water, add the oleic acid dispersant, add sodium hydroxide solution, suspension is placed force the magnetic particle sedimentation on the Magnet, add dispersant, cross 1 tm screen and get the nanoscale magnetic fluid.
8, the preparation method of liver targeting mitomycin magnetic nano particle according to claim 6, it is characterized in that comprising: it is saturated with mitomycin to contain nano-scale magnetic particle,colloid solution earlier, and adds emulsifying agent, with citric acid regulator solution pH to 5.5～7.5, then under electromagnetic agitation, progressively splash into monomer alpha-cyanoacrylate alkane ester reaction 3 hours, filter with 1～10 μ sintered glass funnel, filtrate is through repeatedly normal saline washing, evaporation, lyophilization, the packing gland
60The Co sterilization, radiation dose 10
4Gy, low-temperature dark is preserved.
9, the preparation method of liver targeting mitomycin magnetic nano particle according to claim 8 is characterized in that described emulsifying agent is poloxamer, Brij, Polysorbate, span, glucosan, and concentration is 0.1～3% weight.
10, the application of the described liver targeting of claim 1 mitomycin magnetic nano particle in preparation treatment liver cancer diseases medicine.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01129882 CN1265787C (en) | 2001-11-07 | 2001-11-07 | Liver-targeting mitomycin magnetic nano particle and its prepn and application in medicine |
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|---|---|---|---|
| CN 01129882 CN1265787C (en) | 2001-11-07 | 2001-11-07 | Liver-targeting mitomycin magnetic nano particle and its prepn and application in medicine |
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| CN1416812A true CN1416812A (en) | 2003-05-14 |
| CN1265787C CN1265787C (en) | 2006-07-26 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100384415C (en) * | 2005-01-14 | 2008-04-30 | 上海医药工业研究院 | Preparation method of magnetic nanometer granule containing mitocin-C |
| CN100460018C (en) * | 2006-07-26 | 2009-02-11 | 郑州大学 | Polybutylcyanoacrylate nano-granule with resolubity, its application and use thereof |
| CN101108333B (en) * | 2007-07-05 | 2012-02-22 | 复旦大学 | Amino- magnetic nano particle with metallic copper ion fixed on surface and method of preparing the same and application thereof |
-
2001
- 2001-11-07 CN CN 01129882 patent/CN1265787C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100384415C (en) * | 2005-01-14 | 2008-04-30 | 上海医药工业研究院 | Preparation method of magnetic nanometer granule containing mitocin-C |
| CN100460018C (en) * | 2006-07-26 | 2009-02-11 | 郑州大学 | Polybutylcyanoacrylate nano-granule with resolubity, its application and use thereof |
| CN101108333B (en) * | 2007-07-05 | 2012-02-22 | 复旦大学 | Amino- magnetic nano particle with metallic copper ion fixed on surface and method of preparing the same and application thereof |
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| Publication number | Publication date |
|---|---|
| CN1265787C (en) | 2006-07-26 |
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