CN103040756A - Preparation method of mPEG epirubicin hydrochloride magnetic liposome - Google Patents
Preparation method of mPEG epirubicin hydrochloride magnetic liposome Download PDFInfo
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- CN103040756A CN103040756A CN2013100039327A CN201310003932A CN103040756A CN 103040756 A CN103040756 A CN 103040756A CN 2013100039327 A CN2013100039327 A CN 2013100039327A CN 201310003932 A CN201310003932 A CN 201310003932A CN 103040756 A CN103040756 A CN 103040756A
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Abstract
The invention relates to a liposome, and particularly discloses a method for preparing an mPEG (ethyl glycolate) epirubicin hydrochloride magnetic liposome. Nano ferroferric oxide is prepared by a simple precipitation method; a blank mPEG magnetic liposome is prepared by an ethanol injection method; and epirubicin hydrochloride is entrapped by an ammonium sulfate gradient method. A transmission electron microscope characterizes that particles of the prepared mPEG epirubicin hydrochloride nano magnetic liposome are nearly spherical; the mean particle size is approximately 50nm; and the prepared liposome has better entrapment rate, in-vitro stability and slow release effect. The method is simple and convenient in preparation technology, and low in cost, and facilitates scale preparation.
Description
Technical field
The present invention relates to liposome, refer in particular to a kind of method for preparing mPEGization Farmorubine 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 refer to adopt the lipoids bilayer with drug encapsulation in the interior and spherical preparation of the superminiature similar microencapsulation that forms, since the 60's of last century, someone at first with liposome as pharmaceutical carrier since, liposome since its have height targeting, can effectively protect peculiar advantages such as being wrapped medicine and capable of realizing controlled-release, slow releasing pharmaceutical, become the focus of international the world of medicine research; The ferriferrous oxide nano microgranule is a kind of magnetic material with inverse spinel structure, because of its unique magnetic tunable performance by people's broad research and application, in recent years, ferroso-ferric oxide is widely used in the systems such as nuclear magnetic resonance, drug-supplying system, biological medicine, biosensor; But, because independent magnetic particle biocompatibility is poor, the reasons such as easy reunion, the magnetic particle that the little material of side effect coats replaces just gradually independent magnetic particle and is applied in the organism, therefore the ferriferrous oxide nano microgranule is embedded in the good liposome of biocompatibility, as the magnetic material of magnetic targeting drug delivery system, has good application prospect.
Farmorubine Hydrochloride (Doc) is a kind of anthracyclines of wide spectrum, anticancer spectrum is wide, and is 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 have limited its application clinically; With drug encapsulation in liposome, the therapeutic index that can effectively protect and be wrapped medicine, improves medicine, reduce medicine therapeutic dose, reduce medicine toxic and side effects, alleviate allergy and immunoreation and delay drug release; Result of study shows, the toxicity of the toxicity specific ionization medicine of liposome amycin reduces by 50%～70%, engulfed for avoiding liposome easily to be identified by reticuloendothelial system, prolong the body-internal-circulation time of Evacet, can adopt the hydrophilic macromolecule chain that surface of liposome is modified, magnetic liposome is a kind of novel targeted preparation that recent domestic is studied energetically, this preparation can make medicine have simultaneously biological function, active magnetic target function and treatment function, therefore has larger application prospect; But present magnetic liposome mostly exists many inevitable shortcomings, for example the body-internal-circulation time is short, physics and chemistry stability is not enough, it is bad etc. that the vesicle surface lacks in target site and the magnetic liposome aqueous solution dispersibility, therefore, the long circulation magnetic liposome of a kind of Farmorubine Hydrochloride magnetic with premium properties of exploitation is imperative.
Summary of the invention
The object of the invention provides a kind of method for preparing mPEGization Farmorubine Hydrochloride magnetic liposome with alcohol injection in conjunction with ammonium sulphate gradient.
The present invention realizes by following steps:
(1) preparation of nano ferriferrous oxide:
Under stirring condition; obtain mixed solution 1 in the distilled water with ferric sesquichloride and ferrous chloride adding deoxygenation; wherein the mass ratio of ferric sesquichloride and ferrous chloride is 2.90-2.95:1; dropwise splash into ammonia until after solution to be mixed 1 becomes black; the pH that adopts sodium hydroxide solution to regulate mixed solution 1 is 10, and 80 ℃ of 2 h that reflux under nitrogen protection are after reaction finishes; use distilled water wash 2-3 time after filtering, obtain nano ferriferrous oxide.
Ferric sesquichloride concentration is 0.01-0.02 mol/L in the described mixed solution 1.
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 by weighing lecithin, cholesterol, mPEG and nano ferriferrous oxide, ultrasonic being dissolved in obtains mixed solution 2 in the dehydrated alcohol, 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 obtain mixed solution 3, the volume ratio of dehydrated alcohol and ammonium sulfate is 3:5; In 30 ℃ of ultrasonic 30 min of water-bath, 60 ℃ of decompression rotary evaporations make blank liposome until can not smell ethanol flavor with mixed solution 3; Blank liposome is packed in the bag filter, with PBS solution 24 h that dialyse, add Farmorubine Hydrochloride in the blank liposome after the dialysis, Farmorubine Hydrochloride and lecithin mass ratio are 1:165-1:200, place 55 ℃ of water-baths to hatch 30 min, use two-layer 0.2 μ m filtering with microporous membrane liposome, the control liposome size, and the granule do not sealed of elimination, namely get the magnetic epirubicin hydrochloride liposome, 4 ℃ of stored refrigerated.
The aperture of described microporous filter membrane is 0.2 μ m.
Nano ferriferrous oxide concentration is controlled at 0.0005-0.001 mol/L in the described mixed solution 2.
Adopt pattern and the particle diameter of the obtained magnetic epirubicin hydrochloride liposome of transmission electron microscope observing; By the effect of externally-applied magnetic field, investigate the external magnetic responsiveness of obtained magnetic epirubicin hydrochloride liposome.
Description of drawings
Fig. 1 is according to the TEM photo of the nano ferriferrous oxide of embodiment 1 preparation, and prepared nano ferriferrous oxide particle size range is 10-30 nm, and dispersibility is better;
Fig. 2 is according to the transmission electron microscope photo of the nano-magnetic Evacet of embodiment 1 preparation, and the long circulation magnetic liposome of Farmorubine Hydrochloride granule rounding, mean diameter are about 50 nm;
Fig. 3 is attracted photo according to the mPEGization Farmorubine Hydrochloride nano-magnetic liposome of embodiment 1 preparation by external magnetic field; Magnetic liposome (a) is gathered in rapidly Magnet one side (b) in 3min, show that prepared mPEGization Farmorubine Hydrochloride nano-magnetic liposome has good magnetic responsiveness.
The specific embodiment
Embodiment 1
Under stirring condition; under stirring condition; 0.5 g ferric sesquichloride and 0.17 g ferrous chloride are added in the distilled water of 150 mL deoxygenations, slowly splash into the ammonia of 2 mol/L, after the question response thing becomes black; utilizing 1mol/LNaOH solution to regulate pH is 10; 80 ℃ of 2 h that reflux under nitrogen protection, after reaction finishes, distilled water wash 2-3 time; use distilled water wash 2-3 time after filtering, obtain nano ferriferrous oxide.
Take by weighing 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 obtain mixed solution 3, with mixed solution 3 in 30 ℃ of ultrasonic 30 min of water-bath, 60 ℃ of decompression rotary evaporations make blank liposome until can not smell ethanol flavor; Blank liposome is packed in the bag filter, with PBS solution 24 h that dialyse, add 0.55 mg Farmorubine Hydrochloride in the blank liposome after the dialysis, place 55 ℃ of water-baths to hatch 30 min, use two-layer 0.2 μ m filtering with microporous membrane liposome, control liposome size, and the granule do not sealed of elimination, namely get the magnetic epirubicin hydrochloride liposome, 4 ℃ of stored refrigerated.
Adopt pattern and the particle diameter of the obtained magnetic epirubicin hydrochloride liposome of 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 stirring condition; under stirring condition; 1.08g ferric sesquichloride and 0.37 g ferrous chloride are added in the distilled water of 200 mL deoxygenations, slowly splash into the ammonia of 2 mol/L, after the question response thing becomes black; utilizing 1mol/LNaOH solution to regulate pH is 10; 80 ℃ of 2 h that reflux under nitrogen protection, after reaction finishes, distilled water wash 2-3 time; use distilled water wash 2-3 time after filtering, obtain nano ferriferrous oxide.
Take by weighing 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 obtain mixed solution 3, with mixed solution 3 in 30 ℃ of ultrasonic 30 min of water-bath, 60 ℃ of decompression rotary evaporations make blank liposome until can not smell ethanol flavor; Blank liposome is packed in the bag filter, with PBS solution 24 h that dialyse, add 0.60 mg Farmorubine Hydrochloride in the blank liposome after the dialysis, place 55 ℃ of water-baths to hatch 30 min, use two-layer 0.2 μ m filtering with microporous membrane liposome, control liposome size, and the granule do not sealed of elimination, namely get the magnetic epirubicin hydrochloride liposome, 4 ℃ of stored refrigerated.
Embodiment 3
Under stirring condition; under stirring condition; 0.5 g ferric sesquichloride and 0.17 g ferrous chloride are added in the distilled water of 150 mL deoxygenations, slowly splash into the ammonia of 2 mol/L, after the question response thing becomes black; utilizing 1mol/LNaOH solution to regulate pH is 10; 80 ℃ of 2 h that reflux under nitrogen protection, after reaction finishes, distilled water wash 2-3 time; use distilled water wash 2-3 time after filtering, obtain nano ferriferrous oxide.
Take by weighing 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 obtain mixed solution 3, with mixed solution 3 in 30 ℃ of ultrasonic 30 min of water-bath, 60 ℃ of decompression rotary evaporations make blank liposome until can not smell ethanol flavor; Blank liposome is packed in the bag filter, with PBS solution 24 h that dialyse, add 0.75 mg Farmorubine Hydrochloride in the blank liposome after the dialysis, place 55 ℃ of water-baths to hatch 30 min, use two-layer 0.2 μ m filtering with microporous membrane liposome, control liposome size, and the granule do not sealed of elimination, namely get the magnetic epirubicin hydrochloride liposome, 4 ℃ of stored refrigerated.
Claims (9)
1. the preparation method of a mPEGization Farmorubine Hydrochloride magnetic liposome, take ferroso-ferric oxide as magnetic material, 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 by weighing lecithin, cholesterol, mPEG and nano ferriferrous oxide, ultrasonic being dissolved in obtains mixed solution 2 in the dehydrated alcohol, 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 obtain mixed solution 3, the volume ratio of dehydrated alcohol and ammonium sulfate is 3:5; In 30 ℃ of ultrasonic 30 min of water-bath, 60 ℃ of decompression rotary evaporations make blank liposome until can not smell ethanol flavor with mixed solution 3; Blank liposome is packed in the bag filter, with PBS solution 24 h that dialyse, add Farmorubine Hydrochloride in the blank liposome after the dialysis, Farmorubine Hydrochloride and lecithin mass ratio are 1:165-1:200, place 55 ℃ of water-baths to hatch 30 min, use two-layer 0.2 μ m filtering with microporous membrane liposome, the control liposome size, and the granule do not sealed of elimination, namely get the magnetic epirubicin hydrochloride liposome, 4 ℃ of stored refrigerated.
2. the preparation method of a kind of mPEGization Farmorubine Hydrochloride magnetic liposome as claimed in claim 1, it is characterized in that: the aperture of described microporous filter membrane is 0.2 μ m.
3. the preparation method of a kind of mPEGization Farmorubine Hydrochloride magnetic liposome as claimed in claim 1, it is characterized in that: nano ferriferrous oxide concentration is controlled at 0.0005-0.001 mol/L in the described mixed solution 2.
4. the preparation method of a kind of mPEGization Farmorubine Hydrochloride magnetic liposome as claimed in claim 1; it is characterized in that: the preparation method of described nano ferriferrous oxide is: under stirring condition; obtain mixed solution 1 in the distilled water with ferric sesquichloride and ferrous chloride adding deoxygenation; wherein the mass ratio of ferric sesquichloride and ferrous chloride is 2.90-2.95:1; dropwise splash into ammonia until after solution to be mixed 1 becomes black; the pH that adopts sodium hydroxide solution to regulate mixed solution 1 is 10; 80 ℃ of 2 h that reflux under nitrogen protection; after reaction finishes; use distilled water wash 2-3 time after filtering, obtain nano ferriferrous oxide.
5. the preparation method of a kind of mPEGization Farmorubine Hydrochloride magnetic liposome as claimed in claim 4, it is characterized in that: ferric sesquichloride concentration is 0.01-0.02 mol/L in the described mixed solution 1.
6. the preparation method of a kind of mPEGization Farmorubine Hydrochloride magnetic liposome as claimed in claim 4, it is characterized in that: the concentration of described ammonia is 2 mol/L.
7. the preparation method of a kind of mPEGization Farmorubine Hydrochloride magnetic liposome as claimed in claim 4 is characterized in that: the method deoxygenation of described distilled water employing heated and boiled.
8. the preparation method of a kind of mPEGization Farmorubine Hydrochloride magnetic liposome as claimed in claim 4, it is characterized in that: the particle size range of described nano ferriferrous oxide is 10-30 nm.
9. the preparation method of a kind of mPEGization Farmorubine Hydrochloride magnetic liposome as claimed in claim 4, it is characterized in that: described sodium hydroxide solution concentration is 1mol/L.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN106692993A (en) * | 2017-01-04 | 2017-05-24 | 中国科学院自动化研究所 | Specific targeted magnetic resonance-optical dual-mode imaging probe and preparation method thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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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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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN106692993A (en) * | 2017-01-04 | 2017-05-24 | 中国科学院自动化研究所 | Specific targeted magnetic resonance-optical dual-mode imaging probe and preparation method 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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