CN103040756B - A kind of preparation method of mPEG epirubicin hydrochloride magnetic liposome - Google Patents
A kind of preparation method of mPEG epirubicin hydrochloride magnetic liposome Download PDFInfo
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- CN103040756B CN103040756B CN201310003932.7A CN201310003932A CN103040756B CN 103040756 B CN103040756 B CN 103040756B CN 201310003932 A CN201310003932 A CN 201310003932A CN 103040756 B CN103040756 B CN 103040756B
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Abstract
The present invention relates to liposome, specifically disclose a kind of method preparing mPEG epirubicin hydrochloride magnetic liposome.By simple precipitation legal system for nano ferriferrous oxide, alcohol injection prepares blank mPEGization magnetic liposome, and ammonium sulphate gradient bag carries Farmorubine Hydrochloride.Characterized by transmission electron microscope, the mPEGization Farmorubine Hydrochloride nano-magnetic Via Liposomes granule of preparation is subsphaeroidal, and mean diameter is about 50nm, and prepared liposome has good envelop rate, vitro stability and slow release effect.Preparation technology of the present invention is easy, with low cost, is easy to carry out scale preparation.
Description
Technical field
The present invention relates to liposome, refer in particular to a kind of method preparing mPEG epirubicin hydrochloride magnetic liposome with alcohol injection in conjunction with ammonium sulphate gradient, especially a kind of preparation technology is simple, with low cost, product has the preparation method of the nano-magnetic Evacet of good envelop rate and stability.
Technical background
Liposome refers to and adopts lipoids bilayer by drug encapsulation in the interior and spherical preparation of superminiature of similar microencapsulation that is that formed, since the 60's of last century, someone first using liposome as since pharmaceutical carrier, liposome has targeting highly due to it, can be wrapped medicine and the peculiar advantage such as realizing controlled-release, slow releasing pharmaceutical by available protecting, has become the focus of international the world of medicine research; Ferriferrous oxide nano microgranule is a kind of magnetic material with inverse spinel structure, because the magnetic tunable performance of its uniqueness is by the extensive investigation and application of people, in recent years, ferroso-ferric oxide is widely used in the systems such as nuclear magnetic resonance, drug-supplying system, biological medicine, biosensor; But, due to independent magnetic particle poor biocompatibility, the reasons such as easy reunion, the coated magnetic particle of the little material of side effect replaces independent magnetic particle just gradually and is applied in organism, therefore ferriferrous oxide nano microgranule is embedded in the good liposome of biocompatibility, as the magnetic material of magnetic targeting drug delivery system, there is good application prospect.
Farmorubine Hydrochloride (Doc) is a kind of anthracyclines of wide spectrum, anticancer spectrum is wide, evident in efficacy, can treat kinds of tumors, but the toxic and side effects that this medicine is serious, the side reactions such as especially serious heart damage, bone marrow depression limit its application clinically; By drug encapsulation in liposome, medicine can be wrapped, improve the therapeutic index of medicine, reduce the therapeutic dose of medicine, reduce the toxic and side effects of medicine, alleviate allergy and immunoreation and delay drug release by available protecting; Result of study shows, the toxicity of the toxicity ratio free drug of liposome amycin reduces by 50% ~ 70%, easily engulfed by reticuloendothelial system identification for avoiding liposome, extend the circulation time in vivo of Evacet, hydrophilic macromolecule chain can be adopted to modify surface of liposome, magnetic liposome is the novel targeted preparation of one that recent domestic is studied energetically, this preparation can make medicine have biological function, active magnetic target function and treatment function simultaneously, therefore has larger application prospect; But current magnetic liposome mostly also exists many inevitable shortcomings, such as circulation time in vivo is short, physics and chemistry stability is not enough, it is bad etc. that vesicle surface lacks dispersibility in target site and magnetic liposome aqueous solution, therefore, a kind of Farmorubine Hydrochloride magnetic long circulating magnetic liposome with premium properties is developed imperative.
Summary of the invention
The object of the invention is to provide a kind of method preparing mPEG epirubicin hydrochloride magnetic liposome with alcohol injection in conjunction with ammonium sulphate gradient.
The present invention is realized by following steps:
(1) preparation of nano ferriferrous oxide:
Under agitation; ferric sesquichloride and ferrous chloride are added in the distilled water of deoxygenation and obtain mixed solution 1; wherein the mass ratio of ferric sesquichloride and ferrous chloride is 2.90-2.95:1; dropwise instill ammonia until after solution to be mixed 1 becomes black; sodium hydroxide solution is adopted to regulate the pH of mixed solution 1 to be 10, under nitrogen protection 80 DEG C of backflow 2 h, after reaction terminates; use distilled water wash 2-3 time after filtering, obtain nano ferriferrous oxide.
In described mixed solution 1, ferric sesquichloride concentration is 0.01-0.02 mol/L.
The concentration of described ammonia is 2 mol/L.
Described distilled water adopts the method deoxygenation of heated and boiled.
The particle size range of described nano ferriferrous oxide is 10-30 nm.
Described sodium hydroxide solution concentration is 1mol/L.
(2) preparation of mPEGization Farmorubine Hydrochloride nano-magnetic liposome:
Take lecithin, cholesterol, mPEG and nano ferriferrous oxide, ultrasonic being dissolved in dehydrated alcohol obtains mixed solution 2, and the mass ratio of lecithin, cholesterol, mPEG and nano ferriferrous oxide is respectively 50:1,6.25:1-12.5:1,5:1-15:1; Mixed solution 2 is slowly injected 0.1 mol/L ammonium sulfate solution and obtain mixed solution 3, the volume ratio of dehydrated alcohol and ammonium sulfate is 3:5; By mixed solution 3 in 30 DEG C of water bath sonicator 30 min, 60 DEG C of decompression rotary evaporations, until can not smell ethanol taste, obtain blank liposome; Blank liposome is loaded in bag filter, to dialyse 24 h by PBS solution, Farmorubine Hydrochloride is added in blank liposome after dialysis, Farmorubine Hydrochloride and lecithin mass ratio are 1:165-1:200, are placed in 55 DEG C of water-baths and hatch 30 min, use two-layer 0.2 μm of filtering with microporous membrane liposome, control liposome size, and the granule that elimination is not sealed, obtain magnetic epirubicin hydrochloride liposome, 4 DEG C of stored refrigerated.
The aperture of described microporous filter membrane is 0.2 μm.
In described mixed solution 2, nano ferriferrous oxide concentration controls at 0.0005-0.001 mol/L.
Adopt pattern and the particle diameter of magnetic epirubicin hydrochloride liposome obtained by transmission electron microscope observing; By the effect of externally-applied magnetic field, investigate the external magnetic responsiveness of obtained magnetic epirubicin hydrochloride liposome.
Accompanying drawing explanation
The TEM photo of the nano ferriferrous oxide that Fig. 1 is prepared according to embodiment 1, prepared nano ferriferrous oxide particle size range is 10-30 nm, and dispersibility is better;
The transmission electron microscope photo of the nano-magnetic Evacet that Fig. 2 is prepared according to embodiment 1, Farmorubine Hydrochloride long circulating magnetic liposome granule rounding, mean diameter are about 50 nm;
The mPEGization Farmorubine Hydrochloride nano-magnetic liposome that Fig. 3 is prepared according to embodiment 1 is attracted photo by external magnetic field; Magnetic liposome (a) is gathered in Magnet side (b) rapidly in 3min, shows that prepared mPEGization Farmorubine Hydrochloride nano-magnetic liposome has good magnetic responsiveness.
Detailed description of the invention
embodiment 1
Under agitation; under agitation; 0.5 g ferric sesquichloride and 0.17 g ferrous chloride are added in the distilled water of 150 mL deoxygenations, slowly the ammonia of instillation 2 mol/L, after question response thing becomes black; 1mol/LNaOH solution is utilized to regulate pH to be 10; 80 DEG C of backflow 2 h under nitrogen protection, after reaction terminates, distilled water wash 2-3 time; use distilled water wash 2-3 time after filtering, obtain nano ferriferrous oxide.
Take 0.1 g lecithin, 0.025 g cholesterol, 0.02 g mPEG, 2mg Fe
3o
4nano-particle, the ultrasonic 15mL of being dissolved in dehydrated alcohol obtains mixed solution 2, mixed solution 2 is slowly injected 25mL 0.1 mol/L ammonium sulfate solution and obtain mixed solution 3, by mixed solution 3 in 30 DEG C of water bath sonicator 30 min, 60 DEG C of decompression rotary evaporations, until can not smell ethanol taste, obtain blank liposome; Blank liposome is loaded in bag filter, to dialyse 24 h by PBS solution, 0.55 mg Farmorubine Hydrochloride is added in blank liposome after dialysis, be placed in 55 DEG C of water-baths and hatch 30 min, use two-layer 0.2 μm of filtering with microporous membrane liposome, control liposome size, and the granule that elimination is not sealed, obtain magnetic epirubicin hydrochloride liposome, 4 DEG C of stored refrigerated.
Adopt pattern and the particle diameter of magnetic epirubicin hydrochloride liposome obtained by transmission electron microscope observing; By the effect of externally-applied magnetic field, investigate the external magnetic responsiveness of obtained magnetic epirubicin hydrochloride liposome.
embodiment 2
Under agitation; under agitation; 1.08g ferric sesquichloride and 0.37 g ferrous chloride are added in the distilled water of 200 mL deoxygenations, slowly the ammonia of instillation 2 mol/L, after question response thing becomes black; 1mol/LNaOH solution is utilized to regulate pH to be 10; 80 DEG C of backflow 2 h under nitrogen protection, after reaction terminates, distilled water wash 2-3 time; use distilled water wash 2-3 time after filtering, obtain nano ferriferrous oxide.
Take 0.1 g lecithin, 0.0125 g cholesterol, 0.01 g mPEG, 2mg Fe
3o
4nano-particle, the ultrasonic 15mL of being dissolved in dehydrated alcohol obtains mixed solution 2, mixed solution 2 is slowly injected 25mL 0.1 mol/L ammonium sulfate solution and obtain mixed solution 3, by mixed solution 3 in 30 DEG C of water bath sonicator 30 min, 60 DEG C of decompression rotary evaporations, until can not smell ethanol taste, obtain blank liposome; Blank liposome is loaded in bag filter, to dialyse 24 h by PBS solution, 0.60 mg Farmorubine Hydrochloride is added in blank liposome after dialysis, be placed in 55 DEG C of water-baths and hatch 30 min, use two-layer 0.2 μm of filtering with microporous membrane liposome, control liposome size, and the granule that elimination is not sealed, obtain magnetic epirubicin hydrochloride liposome, 4 DEG C of stored refrigerated.
embodiment 3
Under agitation; under agitation; 0.5 g ferric sesquichloride and 0.17 g ferrous chloride are added in the distilled water of 150 mL deoxygenations, slowly the ammonia of instillation 2 mol/L, after question response thing becomes black; 1mol/LNaOH solution is utilized to regulate pH to be 10; 80 DEG C of backflow 2 h under nitrogen protection, after reaction terminates, distilled water wash 2-3 time; use distilled water wash 2-3 time after filtering, obtain nano ferriferrous oxide.
Take 0.15 g lecithin, 0.03 g cholesterol, 0.045 g mPEG, 3 mg Fe
3o
4nano-particle, the ultrasonic 15mL of being dissolved in dehydrated alcohol obtains mixed solution 2, mixed solution 2 is slowly injected 25mL 0.1 mol/L ammonium sulfate solution and obtain mixed solution 3, by mixed solution 3 in 30 DEG C of water bath sonicator 30 min, 60 DEG C of decompression rotary evaporations, until can not smell ethanol taste, obtain blank liposome; Blank liposome is loaded in bag filter, to dialyse 24 h by PBS solution, 0.75 mg Farmorubine Hydrochloride is added in blank liposome after dialysis, be placed in 55 DEG C of water-baths and hatch 30 min, use two-layer 0.2 μm of filtering with microporous membrane liposome, control liposome size, and the granule that elimination is not sealed, obtain magnetic epirubicin hydrochloride liposome, 4 DEG C of stored refrigerated.
Claims (5)
1. a preparation method for mPEG epirubicin hydrochloride magnetic liposome take ferroso-ferric oxide as magnetic material, and Farmorubine Hydrochloride is interior bag medicine, and poly glycol monomethyl ether (mPEG) is dressing agent, and liposome is carrier, it is characterized in that comprising the steps:
(1) preparation of nano ferriferrous oxide;
(2) preparation of mPEGization Farmorubine Hydrochloride nano-magnetic liposome:
Take lecithin, cholesterol, mPEG and nano ferriferrous oxide, ultrasonic being dissolved in dehydrated alcohol obtains mixed solution 2, and the mass ratio of lecithin, cholesterol, mPEG and nano ferriferrous oxide is respectively 50:1,6.25:1-12.5:1,5:1-15:1; Mixed solution 2 is slowly injected 0.1 mol/L ammonium sulfate solution and obtain mixed solution 3, the volume ratio of dehydrated alcohol and ammonium sulfate is 3:5; By mixed solution 3 in 30 DEG C of water bath sonicator 30 min, 60 DEG C of decompression rotary evaporations, until can not smell ethanol taste, obtain blank liposome; Blank liposome is loaded in bag filter, to dialyse 24 h by PBS solution, Farmorubine Hydrochloride is added in blank liposome after dialysis, Farmorubine Hydrochloride and lecithin mass ratio are 1:165-1:200, are placed in 55 DEG C of water-baths and hatch 30 min, use two-layer 0.2 μm of filtering with microporous membrane liposome, control liposome size, and the granule that elimination is not sealed, obtain magnetic epirubicin hydrochloride liposome, 4 DEG C of stored refrigerated;
In described mixed solution 2, nano ferriferrous oxide concentration controls at 0.0005-0.001 mol/L;
The particle size range of described nano ferriferrous oxide is 10-30 nm;
The preparation method of described nano ferriferrous oxide is: under agitation; ferric sesquichloride and ferrous chloride are added in the distilled water of deoxygenation and obtain mixed solution 1; wherein the mass ratio of ferric sesquichloride and ferrous chloride is 2.90-2.95:1; dropwise instill ammonia until after solution to be mixed 1 becomes black; sodium hydroxide solution is adopted to regulate the pH of mixed solution 1 to be 10, under nitrogen protection 80 DEG C of backflow 2 h, after reaction terminates; use distilled water wash 2-3 time after filtering, obtain nano ferriferrous oxide.
2. the preparation method of a kind of mPEG epirubicin hydrochloride magnetic liposome as claimed in claim 1, is characterized in that: in described mixed solution 1, ferric sesquichloride concentration is 0.01-0.02 mol/L.
3. the preparation method of a kind of mPEG epirubicin hydrochloride magnetic liposome as claimed in claim 1, is characterized in that: the concentration of described ammonia is 2 mol/L.
4. the preparation method of a kind of mPEG epirubicin hydrochloride magnetic liposome as claimed in claim 1, is characterized in that: described distilled water adopts the method deoxygenation of heated and boiled.
5. the preparation method of a kind of mPEG epirubicin hydrochloride magnetic liposome as claimed in claim 1, is characterized in that: described sodium hydroxide solution concentration is 1mol/L.
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| RU2697802C1 (en) * | 2018-08-23 | 2019-08-20 | Федеральное Государственное Бюджетное Учреждение Науки Институт Биохимической Физики Им. Н.М. Эмануэля Российской Академии Наук (Ибхф Ран) | Method of producing magnetic liposomes |
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| CN105663043A (en) * | 2016-01-13 | 2016-06-15 | 无锡市妇幼保健院 | 131I-labelled c(RGDyk)-targeting doxorubicin thermosensitive nanoliposome and preparation and application thereof |
| CN106692993B (en) * | 2017-01-04 | 2019-12-31 | 中国科学院自动化研究所 | Specific targeted magnetic resonance-optical dual-mode imaging probe and preparation method thereof |
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Cited By (1)
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| RU2697802C1 (en) * | 2018-08-23 | 2019-08-20 | Федеральное Государственное Бюджетное Учреждение Науки Институт Биохимической Физики Им. Н.М. Эмануэля Российской Академии Наук (Ибхф Ран) | Method of producing magnetic liposomes |
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