CN108295046A - The preparation method and albumin nanoparticle obtained of a kind of albumin nanoparticle and application - Google Patents
The preparation method and albumin nanoparticle obtained of a kind of albumin nanoparticle and application Download PDFInfo
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- CN108295046A CN108295046A CN201611260061.7A CN201611260061A CN108295046A CN 108295046 A CN108295046 A CN 108295046A CN 201611260061 A CN201611260061 A CN 201611260061A CN 108295046 A CN108295046 A CN 108295046A
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- 102000009027 Albumins Human genes 0.000 title claims abstract description 88
- 108010088751 Albumins Proteins 0.000 title claims abstract description 88
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 239000003814 drug Substances 0.000 claims abstract description 77
- 229940079593 drug Drugs 0.000 claims abstract description 50
- 239000002904 solvent Substances 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 230000002209 hydrophobic effect Effects 0.000 claims description 21
- OYINILBBZAQBEV-UWJYYQICSA-N (17s,18s)-18-(2-carboxyethyl)-20-(carboxymethyl)-12-ethenyl-7-ethyl-3,8,13,17-tetramethyl-17,18,22,23-tetrahydroporphyrin-2-carboxylic acid Chemical compound N1C2=C(C)C(C=C)=C1C=C(N1)C(C)=C(CC)C1=CC(C(C)=C1C(O)=O)=NC1=C(CC(O)=O)C([C@@H](CCC(O)=O)[C@@H]1C)=NC1=C2 OYINILBBZAQBEV-UWJYYQICSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 10
- 102000008100 Human Serum Albumin Human genes 0.000 claims description 9
- 108091006905 Human Serum Albumin Proteins 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- -1 sulphur threoses Chemical class 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
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- 235000018417 cysteine Nutrition 0.000 claims description 6
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical group OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 6
- 238000005215 recombination Methods 0.000 claims description 6
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- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 claims description 4
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- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical group Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 claims description 2
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- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 claims description 2
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- SSKVDVBQSWQEGJ-UHFFFAOYSA-N pseudohypericin Natural products C12=C(O)C=C(O)C(C(C=3C(O)=CC(O)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 SSKVDVBQSWQEGJ-UHFFFAOYSA-N 0.000 claims description 2
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- SQNZJJAZBFDUTD-UHFFFAOYSA-N durene Chemical compound CC1=CC(C)=C(C)C=C1C SQNZJJAZBFDUTD-UHFFFAOYSA-N 0.000 claims 2
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- SURLGNKAQXKNSP-DBLYXWCISA-N chlorin Chemical compound C\1=C/2\N/C(=C\C3=N/C(=C\C=4NC(/C=C\5/C=CC/1=N/5)=CC=4)/C=C3)/CC\2 SURLGNKAQXKNSP-DBLYXWCISA-N 0.000 description 1
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- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 1
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
Abstract
The invention belongs to field of medicaments, preparation method and albumin nanoparticle obtained and the application of a kind of albumin nanoparticle are provided.The preparation method of albumin nanoparticle of the present invention is to mix reduced form albumin in a solvent with drug molecule, and homogeneous to obtain the final product.The preparation method is simple and easy to do, popularization easy to operation, is suitable for the extensive preparation of albumin nanoparticle.For albumin nanoparticle grain size made from preparation method of the present invention at 20 50 nanometers, albumen size is small, can penetrate tissue space and reach inside tumor.Albumin nanoparticle made from preparation method of the present invention has good biocompatibility and functional stabilization, it can be achieved that efficiently being contained to hydrophilic and dewatering medicament in vivo.In addition albumin nanoparticle structural stability obtained, can make freeze drying powder injection long term storage.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of nano-carrier for containing a variety of drugs, it is especially a kind of
The preparation method of albumin nanoparticle and albumin nanoparticle obtained and application.
Background technology
Medically, cancer refers to the malignant tumour originating from epithelial tissue, is most common one kind in malignant tumour.Relatively
It answers, the malignant tumour originating from mesenchymal tissue is referred to as sarcoma.There are a small number of malignant tumours not named by mentioned above principle, such as kidney mother
Cytoma, malignant teratoma etc.." cancer " described in general people traditionally refers to all malignant tumours.Tumour is body each
Under kind tumorigenesis factor effect, the cell of local organization loses at the genetic level leads to paraplasm to the normal regulation of growth
The neoformation formed with differentiation.Neoformation once being formed, does not stop growing, his growth is not by normal machine because the cause of disease is eliminated
Body Physiological effect, but destruction normal structure and organ, this point are especially apparent in malignant tumour.Compared with benign tumour, dislike
Property tumor growth rate it is fast, be in infiltrative growth, bleeding, necrosis, ulcer etc. easily occur, and often have DISTANT METASTASES IN, cause human body
Become thin, inability, anaemia, loss of appetite, fever and serious organ function are impaired etc., ultimately cause death.
The traditional primary treatments of malignant tumour have operation, radiation, chemotherapy three major models.In recent years, it was
The disadvantage for overcoming monotherapy ineffective, combine a variety of drugs, with different mechanisms to tumour treated " cocktail is treated
Method " has become the effective means for the treatment of cancer, and the fast-developing of nanotechnology is also that treating cancer provides new material and newly
Thinking.Nano-carrier can not only improve the solubility of drug, enhance the stability of drug, and control different pharmaceutical is released on demand
It puts, but also the total drug for transmitting suitable dose can be targeted and reach lesion, and cancer cell is killed with different mechanism, to subtract
Few dosage, reduces poisonous side effect of medicine, improves drug bioavailability and therapeutic index.It goes through to be applied to clinic at present
The nano-carrier for containing a variety of drugs mainly have liposome, polymer nano granules, albumin nanoparticle etc..
Liposome is not generally high to the encapsulation rate of hydrophilic medicament, is easy leakage, and internal Targeting distribution is undesirable, stability
It is poor.And liposome also makes it that can not integrate multiple functions depending on unduly for PEG, to cannot achieve the optimization of system
Design.Polymer nano granules are inefficient to containing for dewatering medicament molecule, are easy aggregation in vivo, stability is poor, and right
The factors such as the influence and size of drug molecule, form and surface chemistry limit its in clinical application.Current is white
The drugloading rate of protein drug carrier is smaller, and size is mostly other in the micron-scale, it is difficult to be penetrated into inside tumor, the drug-rich of tumour
Effect is poor.
Invention content
In view of this, present invention aims at provide a kind of stable height containing a variety of drugs in view of the drawbacks of the prior art
The nano-carrier of effect can not be by a variety of drug molecules the shortcomings that overcome albumin nanoparticle size to be not easy to penetrate tissue greatly
It is delivered to inside tumor.
To achieve the purpose of the present invention, the present invention adopts the following technical scheme that：
A kind of preparation method of albumin nanoparticle mixes reduced form albumin with drug molecule, in a solvent
Matter.
Wherein, it is preferred that the reduced form albumin, which is mixed by albumin with reducing agent, to be dissolved in water and be made.Albumin with also
Former agent mixing, disorganized form is reduced under the action of reducing agent by the disulfide bond reduction of albumen, albumin.
In some embodiments, the albumin mixes specially albumin with reducing agent and is codissolved in water with reducing agent
In, it shakes 1 hour at room temperature, reaction solution is poured into bag filter, is dialysed in pure water.
Wherein, the molecular cut off of the bag filter is preferably 3kD.The dialysis time is preferably 12 hours or more.
Albumin described in preparation method of the present invention is preferably human serum albumin, more preferably recombinant human serum albumin egg
In vain.Recombination human serum albumin is to utilize the human serum albumins of technique for gene engineering production, recombination human serum albumin and blood
Source human serum albumin amino acid composition having the same and structure feature, action function are completely the same.Recombinant human serum albumin
It is identical with blood source human serum albumin in cell culture, pharmaceutic adjuvant and clinical application etc., since it is than blood source people's blood
Albumin purity is high, and stable quality is also advantageous over blood source human serum albumin in terms of safety.
It will be understood by those skilled in the art that in the preparation method of albumin nanoparticle of the present invention, the reduction
Agent includes but not limited to for glutathione, dithiothreitol (DTT), cysteine or homocysteine.
The homocysteine is also known as homocysteine or same cysteine, and abbreviation-blood is same, is the different of cysteine
Kind, include an additional methylene (- CH2-) before side chain part mercapto (- SH).
According to the present invention, the molar ratio of the albumin and reducing agent is 1:(1-100).In some embodiments, institute
The molar ratio for stating albumin and reducing agent is 1:50.
In the preparation method of albumin nanoparticle of the present invention, the albumin of reduced form is as carrier and drug molecule
Mixing contains drug in a solvent.The wherein described drug molecule is hydrophilic medicament and/or hydrophobic drug, and the solvent is water
Or organic solvent.
In some embodiments, the drug molecule is hydrophilic medicament, hydrophilic medicament molecule and the white egg of reduced form
White be codissolved in water mixes.
In some embodiments, the drug molecule is hydrophobic drug, and reduced form albumin is dissolved in water, hydrophobicity medicine
Object molecule is dissolved in organic solvent, and reduced form albumin solution and hydrophobic drug solution are then thoroughly mixed to form lotion.
In some embodiments, the drug molecule had not only included hydrophilic medicament but also had included hydrophobic drug, therein
Hydrophilic medicament molecule is codissolved in water with reduced form albumin and mixes, addition after hydrophobic drug is dissolved in organic solvent
To in the mixed aqueous solution of above-mentioned hydrophilic medicament molecule and reduced form albumin, it is thoroughly mixed to form lotion.
Wherein, described be sufficiently mixed can be to be mixed under ul-trasonic irradiation.
It will be understood by those skilled in the art that the hydrophilic medicament include but not limited to doxorubicin hydrochloride, indocyanine green,
Mitoxantrone hydrochloride, IR-780, protoporphyrin or hypericin.The hydrophobic drug includes but not limited to chlorin-e6, four
Tolyl porphyrin and its metal complex, taxol or cis-platinum.
Further, after hydrophobic drug solution and reduced form albumin solution form lotion or hydrophobic drug is molten
Further include being passed through nitrogen or inertia after liquid forms lotion with the reduced form albumin mixed aqueous solution containing hydrophilic medicament molecule
The step of gas, to remove the organic solvent dissolved in lotion used in hydrophobic drug.The organic solvent has higher
Volatility, and it is immiscible with water, microemulsion can be formed.The organic solvent include but not limited to for chloroform, dichloromethane,
Ethyl acetate or ether.
According to the present invention, the molar ratio of the reduced form albumin and the drug molecule is 1:(0.025-0.25).
In some embodiments, the molar ratio of the reduced form albumin and the drug molecule is 1:0.25.
Preparation method of the present invention carries out homogeneous after reduced form albumin is mixed with drug molecule, so that albumin is molten
Liquid forms microemulsion.
In some embodiments, the homogeneous is that absolute ethyl alcohol is added.
Preferably, it is added with stirring absolute ethyl alcohol in strong.
Wherein, the addition of the absolute ethyl alcohol and the grain size of nano particle are proportionate.
In some embodiments, the addition speed of the absolute ethyl alcohol is 1mL/min-10mL/min.The anhydrous second
The addition of alcohol is 3mL.
It will be appreciated by those skilled in the art that the homogenizing method can also be ultrasonication and high-pressure homogeneous.
Further, the organic solvent of dissolving hydrophobic drug, albumin are removed after albumin solution forms microemulsion
Self assembly is cross-linked to form spherical albumin nanoparticle by intermolecular disulfide bond.
Wherein, the method for the removal organic solvent is preferably dried in vacuo.
The present invention also provides albumin nanoparticles made from above-mentioned preparation method.
Experiment shows albumin nanoparticle grain size made from preparation method of the present invention at 20-50 nanometers, albumen ruler
It is very little small, tissue space can be penetrated and reach inside tumor, and hydrophilic and hydrophobic drug can be contained simultaneously, realized to hydrophilic
With efficiently containing for dewatering medicament, it to be used for the synergistic treatment of tumour.Therefore the present invention also provides the albumin nanos
The application of grain in medicine preparation.
Preferably, the drug is antitumor drug.
As shown from the above technical solution, the present invention provides the preparation methods of a kind of albumin nanoparticle and obtained white
Protein nano particle and application.The preparation method of albumin nanoparticle of the present invention is by reduced form albumin and drug point
Son mixes in a solvent, and homogeneous to obtain the final product.The preparation method is simple and easy to do, popularization easy to operation, is suitable for albumin nanoparticle
Extensive preparation.Albumin nanoparticle grain size made from preparation method of the present invention is at 20-50 nanometers, albumen size
It is small, tissue space can be penetrated and reach inside tumor.Albumin nanoparticle has in vivo made from preparation method of the present invention
There are good biocompatibility and functional stabilization, it can be achieved that efficiently being contained to hydrophilic and dewatering medicament, and then utilizes white egg
Daytime, right targeting and passive target effect, high by a variety of hydrophilic and hydrophobic drug molecule of heterogeneity, different function
Effect is safely delivered to inside tumor, realizes the tumour chicken tail of the collaborations such as chemotherapy, optical dynamic therapy, sensitive radiotherapy, immunization therapy
Wine therapy.In addition albumin nanoparticle structural stability obtained, can make freeze drying powder injection long term storage.
Description of the drawings
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technology description to be briefly described.
Fig. 1 shows that embodiment 1 contains hydrophilic medicament (adriamycin) and the white egg of hydrophobic drug (chlorin-e6) small size
The photo of white nanoparticle solution；
Fig. 2 is that embodiment 1 contains hydrophilic medicament (adriamycin) and the white egg of hydrophobic drug (chlorin-e6) small size
The absorption spectrum testing result figure of white nano particle；
Fig. 3 is that embodiment 1 contains hydrophilic medicament (adriamycin) and the white egg of hydrophobic drug (chlorin-e6) small size
White nano particle dynamic scattering analysis figure；
Fig. 4 is that embodiment 1 contains hydrophilic medicament (adriamycin) and the white egg of hydrophobic drug (chlorin-e6) small size
Cell survival rate statistical chart after white nano particle is incubated altogether with MCF-7 tumour cells；
Fig. 5 contains hydrophobic drug (tetramethylphenyl porphyrin) small size albumin nanoparticle dynamic optical for embodiment 3 and dissipates
Penetrate analysis chart.
Specific implementation mode
The invention discloses a kind of preparation method of albumin nanoparticle and obtained albumin nanoparticle and its applications.
Those skilled in the art can use for reference present disclosure, be suitably modified technological parameter realization.In particular, it should be pointed out that all similar
Replacement and change it is apparent to those skilled in the art, they are considered as being included in the present invention.The present invention
Method and product be described by preferred embodiment, related personnel can obviously not depart from the content of present invention, essence
Method described herein is modified or is suitably changed and is combined in god and range, to realize and apply the technology of the present invention.
For a further understanding of the present invention, with reference to specific embodiment, present invention is described.Unless otherwise specified,
Involved reagent is commercial product in the embodiment of the present invention, can be bought and be obtained by commercial channel.
Embodiment 1：Contain the small size albumin of hydrophilic medicament (adriamycin) and hydrophobic drug (chlorin-e6)
The preparation of nano particle
300mg recombination human serum albumins, 75mg glutathione are codissolved in 5mL pure water, are shaken 1 hour at room temperature.
Reaction solution is poured into bag filter (3kD), is dialysed 12 hours in pure water.Reaction solution is settled to 6mL with pure water, is obtained
To the reduced form albumin solution of a concentration of 50mg/mL.20mg reduced forms albumin solution and 2mg doxorubicin hydrochlorides are codissolved in
In 2mL pure water, the 100 μ L of chloroformic solution (10mg/mL) of chlorin-e6 are then added.While solution is sufficiently mixed
It is passed through nitrogen, removes chloroform.Under vigorous stirring, with the speed of 1mL/min to be added dropwise absolute ethyl alcohol 3mL.Pass through vacuum drying
Ethyl alcohol is removed, obtains containing adriamycin and the albumin nanoparticle solution of chlorin-e6.It visually observes to obtain and contains Ah mould
The albumin nanoparticle solution of element and chlorin-e6, the results are shown in Figure 1.Solution clear, illustrate without precipitation and it is miscellaneous
Matter.And absorption spectrum testing result shows the characteristic absorption peak for adriamycin and chlorin e 6 occurred, it was demonstrated that the nano particle
Two kinds of drugs (Fig. 2) of adriamycin and chlorin-e6 are contained simultaneously.
What dynamic scattering analysis was shown contain adriamycin and the albumin nanoparticle grain size of chlorin-e6 is
20-50nm (Fig. 3).
The albumin nanoparticle solution obtained for containing adriamycin and chlorin-e6 is transferred to 3kD super filter tubes, is led to
Cross ultrafiltration and collect and be not packed in free adriamycin/chlorin-e6 of nano particle, and do quantitative detection, be then calculated by
The drug accounting of encapsulating.As a result the albumin nanoparticle solution of adriamycin and chlorin-e6 are contained to Ah made from display
The encapsulation rate of mycin is 95.21 ± 1.77%, and the encapsulation rate to chlorin-e6 is 98.02 ± 0.84%.
The albumin nanoparticle solution obtained for containing adriamycin and chlorin-e6 (is contained into 2 μ g/ml adriamycins
With 1 μ g/ml chlorins-e6) it is incubated altogether 2 hours with MCF-7 tumour cells, then use 660 nanometer lasers (power 0.2W/
cm2) irradiate 1 minute.Tumour cell after treatment is continued into culture 24 hours, cell survival rate is detected using CCK-8, as a result such as
Fig. 4.
Fig. 4 is contained the results show that compared with chemotherapy caused by free adriamycin and chlorin-e6/light power collaboration
The albumin nanoparticle of adriamycin and chlorin-e6 can obviously generate higher tumour Synergistic killing effect.
Embodiment 2：Contain the preparation of the small size albumin nanoparticle of hydrophilic medicament (adriamycin)
300mg recombination human serum albumins, 50mg cysteines are codissolved in 5mL pure water, are shaken 1 hour at room temperature.
Reaction solution is poured into bag filter (3kD), is dialysed 12 hours in pure water.Reaction solution is settled to 6mL with pure water, is obtained
The reduced form albumin solution of a concentration of 50mg/mL.It is pure that 20mg reduced forms albumin with 4mg doxorubicin hydrochlorides is codissolved in 2mL
In water purification, it is 8.5 to adjust pH value.Under vigorous stirring, absolute ethyl alcohol 3mL is added dropwise into reaction solution with the speed of 1mL/min.It is logical
It crosses vacuum drying and removes ethyl alcohol, obtain the albumin nanoparticle solution for containing adriamycin.Wherein adriamycin encapsulation rate is 97.12
± 1.53%, it is 50nm that grain size measures average grain diameter by Particle Size Analyzer.
Embodiment 3：Contain the preparation of the small size albumin nanoparticle of hydrophobic drug (tetramethylphenyl porphyrin)
300mg recombination human serum albumins, 50mg cysteines are codissolved in 5mL pure water, are shaken 1 hour at room temperature.
Reaction solution is poured into bag filter (3kD), is dialysed 12 hours in pure water.Reaction solution is settled to 6mL with pure water, is obtained
The reduced form albumin solution of a concentration of 50mg/mL.20mg reduced form albumin is dissolved in 2mL pure water, is then added four
The 100 μ L of chloroformic solution (10mg/mL) of tolyl porphyrin.Solution forms to the lotion of chloroform-water under ultrasonication, while
Lotion surface nitrogen blowing removes chloroform.Under vigorous stirring, absolute ethyl alcohol is added dropwise into reaction solution with the speed of 1mL/min
3mL.Ethyl alcohol is removed by vacuum drying.Obtain containing the albumin nanoparticle solution of tetramethylphenyl porphyrin.Dynamic light scattering
Analysis shows that nano particle diameter average out to 37nm, is distributed as 20-60nm (Fig. 4), the zeta current potentials and stability of nano particle
Correlation, zeta current potentials are 27 ± 2.43mV, show that nano particle obtained is highly stable in water.It is to tetramethylphenyl porphyrin
Encapsulation rate be 82.23% ± 2.09%.
Claims (11)
1. a kind of preparation method of albumin nanoparticle, which is characterized in that by reduced form albumin and drug molecule in solvent
Middle mixing, homogeneous.
2. preparation method according to claim 1, which is characterized in that the reduced form albumin is by albumin and reducing agent
Mixing is dissolved in water and is made.
3. preparation method according to claim 2, which is characterized in that the albumin is recombination human serum albumin.
4. preparation method according to claim 2 or 3, which is characterized in that the reducing agent is glutathione, two sulphur threoses
Alcohol, cysteine or homocysteine.
5. according to the preparation method described in claim 2-4 any one, which is characterized in that the albumin and reducing agent rub
You are than being 1:(1-100).
6. according to the preparation method described in claim 1-5 any one, which is characterized in that the drug molecule is hydrophily medicine
Object and/or hydrophobic drug, the solvent are water or organic solvent.
7. preparation method according to claim 6, which is characterized in that the hydrophilic medicament is doxorubicin hydrochloride, indoles
Cyanines are green, mitoxantrone hydrochloride, IR-780, protoporphyrin or hypericin；The hydrophobic drug is chlorin-e6, durene
Base porphyrin and its metal complex, taxol or cis-platinum；The organic solvent is chloroform, dichloromethane, ethyl acetate or ether.
8. according to the preparation method described in claim 1-7 any one, which is characterized in that reduced form albumin and the drug
The molar ratio of molecule is 1:(0.025-0.25).
9. according to the preparation method described in claim 1-7 any one, which is characterized in that the homogeneous is that anhydrous second is added
Alcohol.
10. albumin nanoparticle made from preparation method described in claim 1-9 any one.
11. the application of albumin nanoparticle according to any one of claims 10 in medicine preparation.
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Application publication date: 20180720 |