CN102989005A - Methotrexate-loaded magnetosome drug carrier and preparation method thereof - Google Patents
Methotrexate-loaded magnetosome drug carrier and preparation method thereof Download PDFInfo
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- CN102989005A CN102989005A CN2012105193088A CN201210519308A CN102989005A CN 102989005 A CN102989005 A CN 102989005A CN 2012105193088 A CN2012105193088 A CN 2012105193088A CN 201210519308 A CN201210519308 A CN 201210519308A CN 102989005 A CN102989005 A CN 102989005A
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- methotrexate
- magnetic corpusculum
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- pharmaceutical carrier
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Abstract
The invention provides a methotrexate-loaded magnetosome drug carrier and a preparation method thereof. Methotrexate is crosslinked on a biological film of a magnetosome through genipin and the magnetosome is extracted from magnetotactic bacteria. The preparation method comprises the following steps of: 10, dispersing magnetosome particles after being subjected to purifying and freeze drying in a solvent and adding a methotrexate solution; 20, ultrasonically dispersing and fully mixing the mixed liquor obtained in the step 10; 30, adding a genipin solution and continuing the ultrasonic dispersion to be uniform; and 40, putting the mixed liquor obtained in the step 30 in a shaker to carry out crosslinking and obtaining the methotrexate-loaded magnetosome drug carrier after crosslinking saturation. According to the invention, a natural magnetic targeting antitumor drug delivering system can be constructed; and meanwhile, the utilization ratio of methotrexate can be increased and the toxic and side effects of methotrexate to normal cells and tissues can be reduced. The preparation method is simple in process and convenient for operation.
Description
[technical field]
The present invention relates to bio-medical pharmaceutical carrier technical field, particularly magnetic corpusculum pharmaceutical carrier of a kind of load methotrexate and preparation method thereof.
[background technology]
The research of pharmaceutical carrier is one of focus of field of medicaments always, and wherein the development and use of new material occupies critical role in pharmaceutical carrier research.
The magnetic corpusculum is by natural magnetism nano-particle synthetic in the magnetotactic bacteria body.As the core texture of magnetotactic bacteria, the magnetic corpusculum is by lipid bilayer and the inner mineral nitrogen crystal (Fe of outside
3O
4Perhaps Fe
3S
4) form, in cell, become catenation.Wherein, the bimolecular lipid membrane thickness of the little surface of magnetic is 2-3nm, and abundant PHOSPHATIDYL ETHANOLAMINE is arranged on the Magnetosome membrane, makes its surface be electronegativity.Film has a large amount of protein and aminoacid on the magnetic corpusculum, and these albumen and aminoacid (such as primary amino radical etc.) can be used to link bioactive molecule under the effect of some two-way cross-linking agent (glutaraldehyde, Biformyl, two butanimide fatty acid esters etc.).And genipin is a kind of Biological cross-linker that obtains that extracts from cape jasmine fruit, can react with primary amino radical, and the mild condition of cross-linking reaction occurs, and particularly its acute toxicity is well below chemical cross-linking agents such as glutaraldehydes.Compare with the magnetic nanoparticle of synthetic, in the bacterial body synthetic magnetic corpusculum have that form homogeneous, particle size distribution are narrower, the characteristics such as biomembrane parcel and good biocompatibility, thereby have broad application prospects in fields such as biomedicine, pharmacy, biomaterials.
Methotrexate is a kind of clinical in antimetabolic and antifolic broad-spectrum anti-cancer drug, and acute leukemia, malignant lymphoma cutaneous T cell lymphoma, multiple myeloma, incidence cancer, lung bronchogenic carcinoma, various soft tissue sarcoma, breast carcinoma, ovarian cancer, cervical cancer, carcinoma of testis, malignant mole, chorionic epithelioma etc. all are suitable for.But its water solublity is relatively poor, and gastrointestinal tract, liver, genitourinary system, respiratory system, blood system, cental system etc. are had in various degree toxic and side effects.Adopt genipin that methotrexate is loaded on the magnetic corpusculum, can construct a kind of natural magnetic anti-tumor drugs targeting delivery system, can improve the utilization rate of methotrexate simultaneously and reduce its toxic and side effects to normal cell and tissue.
[summary of the invention]
One of the technical problem to be solved in the present invention, be to provide the magnetic corpusculum pharmaceutical carrier of a kind of load methotrexate, can construct a kind of natural magnetic anti-tumor drugs targeting delivery system, can improve the utilization rate of methotrexate simultaneously and reduce its toxic and side effects to normal cell and tissue.
The present invention realizes one of technical problem like this:
The magnetic corpusculum pharmaceutical carrier of a kind of load methotrexate, described methotrexate is to be linked on the biomembrane of magnetic corpusculum by genipin.
Further, described magnetic corpusculum is to extract to obtain in the magnetotactic bacteria body.
Two of the technical problem to be solved in the present invention, be to provide the preparation method of the magnetic corpusculum pharmaceutical carrier of a kind of load methotrexate, the method technique is simple, easy to operate, preparation process does not adopt poisonous organic solvent, environmental protection is a kind of environmentally friendly pharmaceutical carrier, thereby practical and have broad application prospects.
The present invention realizes two of technical problem like this:
The preparation method of the magnetic corpusculum pharmaceutical carrier of a kind of load methotrexate comprises the steps:
Magnetic corpusculum granule after step 10, the also lyophilization of will purifying disperses then to add methotrexate solution in the solvent;
Step 20, with the mixed liquor ultra-sonic dispersion of step 10, fully mix;
Step 30, adding genipin solution, it is even to continue ultra-sonic dispersion;
Step 40, that the mixed liquor of step 30 is put into shaking table is crosslinked, the crosslinked magnetic corpusculum pharmaceutical carrier that namely obtains the load methotrexate after saturated.
Further, described magnetic corpusculum is to extract to obtain in the magnetotactic bacteria body.
Further, the solvent in the step 10 is PBS buffer or normal saline.
Further, the ultra-sonic dispersion of step 30 is the ultra-sonic dispersion at intermittence.
Further, described step 40 is specially: it is that 4 ℃-40 ℃, rotating speed are that shaking table below the 500rpm is crosslinked that the mixed liquor of step 30 is put into temperature, the crosslinked magnetic corpusculum pharmaceutical carrier that namely obtains the load methotrexate after saturated.
The present invention has following advantage:
The magnetic corpusculum has natural external lipid bilayer and inner mineral nitrogen crystal (Fe
3O
4Perhaps Fe
3S
4) structure, be a kind of natural targeting vector; Genipin is the cross-linking agent of natural extract, toxicity is far below glutaraldehyde and many other cross-linking agent commonly used, simultaneously digestive system, the cardiovascular system central nervous system disease of unifying is had significant curative effect and also has certain antiinflammatory and treatment soft tissue injury effect, product has certain interventional therapeutic effect.In addition, owing to do not adopt poisonous organic solvent, environmental protection meets the requirement of current environmentally friendly shaped material in the preparation process of carrier.
The magnetic corpusculum pharmaceutical carrier of load methotrexate of preparation is without burst effect, and drug loading and envelop rate are high, and deenergized period is long, can be in two months the medicine of sustained release nearly 80%; And can construct a kind of natural magnetic anti-tumor drugs targeting delivery system, can improve the utilization rate of methotrexate simultaneously and reduce its toxic and side effects to normal cell and tissue.The characteristics such as this pharmaceutical carrier biomembrane parcel and good biocompatibility, this preparation method technique is simple simultaneously, and is easy to operate, thereby practical and have broad application prospects.
[specific embodiment]
The present invention relates to the magnetic corpusculum pharmaceutical carrier of a kind of load methotrexate, described methotrexate is to be linked on the biomembrane of magnetic corpusculum by genipin; Described magnetic corpusculum is to extract to obtain in the magnetotactic bacteria body.
The invention still further relates to the preparation method of the magnetic corpusculum pharmaceutical carrier of a kind of load methotrexate, comprise the steps:
Magnetic corpusculum granule after step 10, the also lyophilization of will purifying disperses then to add methotrexate solution in the solvent;
Step 20, with the mixed liquor ultra-sonic dispersion of step 10, fully mix;
Step 30, adding genipin solution, it is even to continue ultra-sonic dispersion;
Step 40, that the mixed liquor of step 30 is put into shaking table is crosslinked, the crosslinked magnetic corpusculum pharmaceutical carrier that namely obtains the load methotrexate after saturated.
Described magnetic corpusculum is to extract to obtain in the magnetotactic bacteria body.
More excellent, the solvent in the step 10 is PBS buffer or normal saline.
More excellent, the ultra-sonic dispersion of step 30 is the ultra-sonic dispersion at intermittence.
More excellent, described step 40 is specially: it is that 4 ℃-40 ℃, rotating speed are that shaking table below the 500rpm is crosslinked that the mixed liquor of step 30 is put into temperature, the crosslinked magnetic corpusculum pharmaceutical carrier that namely obtains the load methotrexate after saturated.
The present invention is further illustrated below in conjunction with embodiment.
Embodiment one:
With purify and lyophilization after magnetic corpusculum granule to be scattered in pH be that obtaining concentration is the little liquid solution of magnetic of 0.1mg/mL in 7.4 the PBS solution; Then the methotrexate solution that adds equivalent, ultra-sonic dispersion (50W, 5min).Fully behind the mixing, add the 10mg/mL genipin solution, make that genipin concentration is 1mg/mL in the mixed liquor, continue intermittently ultra-sonic dispersion (50W, each 1min, interval 5min), repeat 10 times, again mixed liquor is put into 37 ℃, the crosslinked 24h of shaking table of 60rpm.
At last, the drug loading that obtains the magnetic corpusculum pharmaceutical carrier of load methotrexate is 48.6%, and envelop rate is that 94.4%, 0.5 hour burst size is 4.8%, does not have burst effect, and preparation is 82.4% in the time of two months.
Embodiment two:
Present embodiment and embodiment one are basic identical, and difference is that genipin concentration is 0.5mg/mL in the mixed liquor.
At last, the drug loading that obtains the magnetic corpusculum pharmaceutical carrier of load methotrexate is 48.0%, and envelop rate is that 86.6%, 0.5 hour burst size is 5.4%, does not have burst effect, and preparation is 82.1% in the time of two months.
Embodiment three:
Present embodiment and embodiment one are basic identical, and difference is that genipin concentration is 5mg/mL in the mixed liquor.
At last, the drug loading that obtains the magnetic corpusculum pharmaceutical carrier of load methotrexate is 49.0%, and envelop rate is that 90.4%, 0.5 hour burst size is 5.3%, does not have burst effect, and preparation is 85.1% in the time of two months.
Embodiment four:
Present embodiment and embodiment one are basic identical, and difference is that cross-linking reaction time is 12h.
At last, the drug loading that obtains the magnetic corpusculum pharmaceutical carrier of load methotrexate is 46.3%, and envelop rate is that 86.1%, 0.5 hour burst size is 5.5%, does not have burst effect, and preparation is 78.0% in the time of two months.
Embodiment five:
Present embodiment and embodiment one are basic identical, and difference is that cross-linking reaction time is 48h.
At last, the drug loading that obtains the magnetic corpusculum pharmaceutical carrier of load methotrexate is 46.5%, and envelop rate is that 87.3%, 0.5 hour burst size is 4.0%, does not have burst effect, and preparation is 66.1% in the time of two months.
The magnetic corpusculum pharmaceutical carrier of the load methotrexate of the present invention preparation is without burst effect, and drug loading and envelop rate are high, and deenergized period is long, can be in two months the medicine of sustained release nearly 80%; And can construct a kind of natural magnetic anti-tumor drugs targeting delivery system, can improve the utilization rate of methotrexate simultaneously and reduce its toxic and side effects to normal cell and tissue.The characteristics such as this pharmaceutical carrier biomembrane parcel and good biocompatibility, this preparation method technique is simple simultaneously, and is easy to operate, thereby have practical and wide application prospect.
The magnetic corpusculum that the present invention uses has natural external lipid bilayer and inner mineral nitrogen crystal (Fe
3O
4Perhaps Fe
3S
4) structure, be a kind of natural targeting vector; Genipin is the cross-linking agent of natural extract, toxicity is far below glutaraldehyde and many other cross-linking agent commonly used, simultaneously digestive system, the cardiovascular system central nervous system disease of unifying is had significant curative effect and also has certain antiinflammatory and treatment soft tissue injury effect, product has certain interventional therapeutic effect.In addition, owing to do not adopt poisonous organic solvent, environmental protection meets the requirement of current environmentally friendly shaped material in the preparation process of carrier.
Although more than described the specific embodiment of the present invention; but being familiar with those skilled in the art is to be understood that; our described specific embodiment is illustrative; rather than for the restriction to scope of the present invention; those of ordinary skill in the art are in modification and the variation of the equivalence of doing according to spirit of the present invention, all should be encompassed in the scope that claim of the present invention protects.
Claims (7)
1. the magnetic corpusculum pharmaceutical carrier of a load methotrexate, it is characterized in that: described methotrexate is to be linked on the biomembrane of magnetic corpusculum by genipin.
2. the magnetic corpusculum pharmaceutical carrier of a kind of load methotrexate according to claim 1 is characterized in that: described magnetic corpusculum is to extract to obtain in the magnetotactic bacteria body.
3. the preparation method of the magnetic corpusculum pharmaceutical carrier of a load methotrexate is characterized in that: comprise the steps:
Magnetic corpusculum granule after step 10, the also lyophilization of will purifying disperses then to add methotrexate solution in the solvent;
Step 20, with the mixed liquor ultra-sonic dispersion of step 10, fully mix;
Step 30, adding genipin solution, it is even to continue ultra-sonic dispersion;
Step 40, that the mixed liquor of step 30 is put into shaking table is crosslinked, the crosslinked magnetic corpusculum pharmaceutical carrier that namely obtains the load methotrexate after saturated.
4. the preparation method of the magnetic corpusculum pharmaceutical carrier of a kind of load methotrexate according to claim 3 is characterized in that: described magnetic corpusculum is to extract to obtain in the magnetotactic bacteria body.
5. according to claim 3 or the preparation method of the magnetic corpusculum pharmaceutical carrier of 4 described a kind of load methotrexates, it is characterized in that: the solvent in the step 10 is PBS buffer or normal saline.
6. it is characterized in that according to claim 3 or the preparation method of the magnetic corpusculum pharmaceutical carrier of described a kind of load methotrexate: the ultra-sonic dispersion of step 30 is ultra-sonic dispersion intermittently.
7. according to claim 3 or the preparation method of the magnetic corpusculum pharmaceutical carrier of 4 described a kind of load methotrexates, it is characterized in that: described step 40 is specially: it is that 4 ℃-40 ℃, rotating speed are that shaking table below the 500rpm is crosslinked that the mixed liquor of step 30 is put into temperature, the crosslinked magnetic corpusculum pharmaceutical carrier that namely obtains the load methotrexate after saturated.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012105193088A CN102989005A (en) | 2012-12-05 | 2012-12-05 | Methotrexate-loaded magnetosome drug carrier and preparation method thereof |
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| CN2012105193088A CN102989005A (en) | 2012-12-05 | 2012-12-05 | Methotrexate-loaded magnetosome drug carrier and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104524589A (en) * | 2014-12-09 | 2015-04-22 | 华侨大学 | Double cross-linking agent AMB-1 magnetosome drug carrier, and preparation method and application thereof |
| CN115254069A (en) * | 2022-06-18 | 2022-11-01 | 太古宙基因科技(深圳)有限公司 | Preparation and application of high-magnetism nano magnetic beads |
| WO2023160562A1 (en) * | 2022-02-28 | 2023-08-31 | 中国科学院上海药物研究所 | Methotrexate, and use of pharmaceutical composition thereof in tumor immunotherapy |
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| CN1927400A (en) * | 2006-09-25 | 2007-03-14 | 唐喜庆 | Biomagnetism nano target anti-cancer drug and its preparation |
| WO2007133801A2 (en) * | 2006-05-15 | 2007-11-22 | Dmitri B Kirpotin | Magnetic microparticles comprising organic substances |
| CN101077418A (en) * | 2007-02-08 | 2007-11-28 | 中国农业大学 | Bacteria nano magnetosome loaded with primary amino medicine and preparation method thereof |
| CN102240268A (en) * | 2011-05-06 | 2011-11-16 | 河北科技大学 | Sustained/controlled release microsphere of biological extract Genipin cross-linked chitosan coated stilbene compound and preparation method thereof |
-
2012
- 2012-12-05 CN CN2012105193088A patent/CN102989005A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007133801A2 (en) * | 2006-05-15 | 2007-11-22 | Dmitri B Kirpotin | Magnetic microparticles comprising organic substances |
| CN1927400A (en) * | 2006-09-25 | 2007-03-14 | 唐喜庆 | Biomagnetism nano target anti-cancer drug and its preparation |
| CN101077418A (en) * | 2007-02-08 | 2007-11-28 | 中国农业大学 | Bacteria nano magnetosome loaded with primary amino medicine and preparation method thereof |
| CN102240268A (en) * | 2011-05-06 | 2011-11-16 | 河北科技大学 | Sustained/controlled release microsphere of biological extract Genipin cross-linked chitosan coated stilbene compound and preparation method thereof |
Non-Patent Citations (1)
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| TING-YU LIU ET AL.: "Preparation and characterization of smart magnetic hydrogels and its use for drug release", 《JOURNAL OF MAGNETISM AND MAGNETIC MATERIALS》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104524589A (en) * | 2014-12-09 | 2015-04-22 | 华侨大学 | Double cross-linking agent AMB-1 magnetosome drug carrier, and preparation method and application thereof |
| CN104524589B (en) * | 2014-12-09 | 2017-07-21 | 华侨大学 | The magnetic corpusculum pharmaceutical carriers of double crosslinker AMB 1, its preparation method and application |
| WO2023160562A1 (en) * | 2022-02-28 | 2023-08-31 | 中国科学院上海药物研究所 | Methotrexate, and use of pharmaceutical composition thereof in tumor immunotherapy |
| CN115254069A (en) * | 2022-06-18 | 2022-11-01 | 太古宙基因科技(深圳)有限公司 | Preparation and application of high-magnetism nano magnetic beads |
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Application publication date: 20130327 |