CN103520734A - Albumin-based nano particle and preparation method and application thereof - Google Patents
Albumin-based nano particle and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an albumin-based nano particle and a preparation method and an application thereof. The nano particle comprises albumin molecules and macromolecules with positive charges. According to the preparation method, albumin is pretreated with the macromolecules with the positive charges, the albumin nano particle is formed under electrostatic interaction, intermolecular cross-linking is further realized with a sulfydryl-containing compound, and the stable albumin-based nano particle is obtained. Organic solvents are not used in the preparation process of the albumin-based nano particle, the particle size of the prepared albumin-based nano particle is controllable, and the albumin-based nano particle is even in distribution and can be used for loading drugs.
Description
Technical field
The present invention relates to biological medicine new material technology field, relate in particular to a kind of based on albuminous nanoparticle, Preparation Method And The Use.
Background technology
Albumin is a class a large amount of albumen existing in blood plasma.In pharmaceutical carrier research, common albumin comprises human serum albumin, bovine serum albumin, oralbumin, can from human serum, Ox blood serum, Ovum Gallus domesticus album, obtain respectively.Human serum albumin is plasma protein the abundantest in human body, and human serum albumin has multiple effect in vivo, as: the dissolubility that 1) increases long-chain fatty acid; 2) conjugated bilirubin; 3) be combined with multi-medicament, as medicines such as penicillins, sulfonamides, indoles, Benzodiazepineses.
In albumin molecule, there is multi-medicament binding site, to the equal energy of different types of medicine payload; It has the features such as water solublity is high, good stability, degradable simultaneously, and its biocompatibility Gao，Yi Bei U.S. food Drug Administration (FDA) approval is for human body, so albumin is the ideal carrier of drug conveying.Based on albuminous nanoparticle, for drug conveying, can improve the dissolubility of hydrophobic drug, and improve the dynamic metabolism of medicine.By controlling the particle diameter of nanoparticle, can improve passive target effect, improve medicine in the picked-up of tumor site.Meanwhile, the amino existing on albumin, sulfydryl etc., can further modify active targeting group to improve targeting.
The prior art discloseder method of preparing albumin nano granular is divided into two parts conventionally, forms nanoparticle and stabilized nanoscale particle.The method that forms albumin nano granular mainly contains desolventizing method and emulsion process.Desolventizing method (International Journal of Pharmaceutics, 2003,257,169 – 180) be to add organic solvent in albumin aqueous solution, the dissolubility of albumin molecule is reduced, generation is separated and forms nanoparticle, adds the volume fraction of organic solvent need reach 40%.Emulsion process (International Journal of Pharmaceutics, 2007,340,163 – 172) is that use Oleum Gossypii semen or cyclohexane give are oil phase, has an effect with albuminous aqueous solution, produces nanoparticle.These processes that form albumin nano granular have been used organic solvent, have increased the difficulty of post processing, may can cause the adverse consequencess such as pharmaceutical properties is unstable, anaphylaxis by residual organic solvent simultaneously.The common method of stablizing albumin nano granular is cross-linking method.Glutaraldehydes (Journal of Microencapsulation, 2001,18,825 – 829) etc. can be by stable reaction albumin nano granular with amino containing the cross-linking agent of aldehyde radical.Owing to may producing toxic and side effects in vivo containing cross-link agent, such cross-linking agent is unsuitable for human body and uses.Having in report has used glutathion or cysteine to carry out pretreatment (Chinese patent application publication number CN102988996A) to albumin, by the effect of sulfhydryl and disulfide bond, stablize albumin nano granular, but it forms nanoparticle also by adding organic solvent to realize.
Summary of the invention
The object of the present invention is to provide a kind of based on albuminous nanoparticle, Preparation Method And The Use; Nanoparticle of the present invention has the advantages that particle size distribution is even, size is controlled, its preparation process is not with an organic solvent, reduced the difficulty of post processing, also organic solvent-free is residual for formed nanoparticle simultaneously, has avoided the adverse consequencess such as the caused pharmaceutical properties of organic solvent residual is unstable, anaphylaxis.
For reaching this object, the present invention by the following technical solutions:
First aspect, the invention provides a kind ofly based on albuminous nanoparticle, and this nanoparticle comprises albumin molecule and positively charged macromole;
Preferably, described albumin molecule is any one or the two or more mixture in human serum albumin, bovine serum albumin, recombination human serum albumin, oralbumin;
Preferably, described positively charged macromole is any one or the two or more mixture in poly-D-lysine, spermine, poly-spermine, Protamine sulfates..
Second aspect, the invention provides the preparation method of nanoparticle described in first aspect, and described preparation method comprises the steps:
(1) albumin molecule is mixed in aqueous solution with positively charged macromole, the pH value of regulator solution is 7.2-10.5;
(2) step (1) gained mixed liquor is reacted at 5-70 ℃, preferably 10-60 ℃, further preferred 20-40 ℃ to 1-60 minute, preferred 5-30 minute;
(3) to step (2) gained mixed liquor, add the compound containing sulfydryl, at 5-70 ℃, preferably 10-60 ℃, further preferred 20-40 ℃, react more than 30 minutes, form stable albumin nano granular.
As preferably, in step (1), the concentration of described albumin molecule in aqueous solution is 1-200mg/ml, be preferably 10-100mg/ml, and the concentration of described positively charged macromole in aqueous solution is 1-200mg/ml, be preferably 10-100mg/ml;
Preferably, by add the pH value of alkaline matter regulator solution in aqueous solution; Further preferably, described alkaline matter is any one or the two or more mixture in sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
As preferably, described in step (3), containing the compound of sulfydryl, be any one or the two or more mixture in glutathion, cysteine, dithiothreitol, DTT, mercaptoethanol;
Preferably, the final concentration of the described compound containing sulfydryl in mixed liquor is 0.001-100mM, 0.1-10mM more preferably.
As preferably, above-mentioned preparation method also comprise by step (3) gained containing the mixed liquor of stablizing albumin nano granular dialyse, the step of processed;
Preferably, the temperature of described dialysis is 0～30 ℃, further preferably 4～28 ℃;
Preferably, described processed is high speed centrifugation, lyophilization, spraying is dry or distilling under reduced pressure.
The third aspect, the invention provides a kind ofly based on albuminous nanoparticle, by preparation method described in second aspect present invention, is made.
Fourth aspect, the invention provides described in first aspect present invention or the third aspect nanoparticle as the application of pharmaceutical carrier.
Preferably, described medicine is cancer therapy drug and/or optical dynamic therapy medicine;
Further preferably, described cancer therapy drug is any one or the two or more mixture in paclitaxel, Docetaxel, amycin, curcumin, cisplatin and analog thereof;
Further preferably, described optical dynamic therapy medicine is any one or the two or more mixture in temoporfin (Temoporfin), 5-ALA (5-Aminolevulinic acid), protoporphyrin IX (Protoporphyrin IX), protoporphyrin IX disodium salt (Protoporphyrin IX disodium), Verteporfin (Verteporfin), single Radix Asparagi amine acyl group chlorin (NPe6), tetraphenylporphyrin.
The 5th aspect, the invention provides a kind of preparation method of albumin nano granular of drug loading, comprises the steps:
(1) albumin molecule is mixed in aqueous solution with positively charged macromole, then add drug solution, the pH value of regulator solution is 7.2-10.5, forms the suspension of albumin nano granular of drug loading;
Preferably, the concentration of described albumin molecule in aqueous solution is 1-200mg/ml, be preferably 10-100mg/ml, and the concentration of described positively charged macromole in aqueous solution is 1-200mg/ml, be preferably 10-100mg/ml;
Preferably, described medicine is cancer therapy drug and/or optical dynamic therapy medicine; Further preferably, described cancer therapy drug is any one or the two or more mixture in paclitaxel, Docetaxel, amycin, curcumin, cisplatin and analog thereof; Further preferably, described optical dynamic therapy medicine is any one or the two or more mixture in temoporfin, 5-ALA, protoporphyrin IX, protoporphyrin IX disodium salt, Verteporfin, single Radix Asparagi amine acyl group chlorin, tetraphenylporphyrin;
Preferably, the solvent of described drug solution is any one or the two or more mixture in water, ethanol, acetone, dimethyl sulfoxide, oxolane;
(2) step (1) gained suspension reacts 1-60 minute, preferred 5-30 minute at 5-70 ℃, preferably 10-60 ℃, further preferred 20-40 ℃;
(3) to step (2) gained suspension, add the compound containing sulfydryl, at 5-70 ℃, preferably 10-60 ℃, further preferred 20-40 ℃, react more than 30 minutes, obtain the sub-suspension of albumin nano granular of stable drug loading;
Preferably, the described compound containing sulfydryl is any one or the two or more mixture in glutathion, cysteine, dithiothreitol, DTT, mercaptoethanol;
Preferably, the final concentration of the described compound containing sulfydryl in reactant liquor is 0.001-100mM, 0.1-10mM more preferably;
(4) the stable sub-suspension of albumin nano granular of step (3) gained is dialysed, processed, obtain albumin nano granular of drug loading;
Preferably, the temperature of described dialysis is 0～30 ℃, more preferably 4～28 ℃;
Preferably, described processed is high speed centrifugation, lyophilization, spraying is dry or distilling under reduced pressure.
The 6th aspect, the albumin nano granular that the invention provides a kind of drug loading is sub, by preparation method described in fifth aspect present invention, is made.
Preparation method based on albuminous nanoparticle of the present invention utilizes positively charged macromole to carry out pretreatment to albumin, by electrostatic interaction, form albumin nano granular, and further utilize containing the compound of sulfydryl and realize intermolecular cross-linking, obtain stable albumin nano granular; Above-mentioned preparation method not with an organic solvent, has reduced the difficulty of post processing, and also organic solvent-free is residual for formed nanoparticle simultaneously, has avoided the adverse consequencess such as the caused pharmaceutical properties of organic solvent residual is unstable, anaphylaxis.Above-mentioned preparation method gained albumin nano granular seed footpath is evenly distributed, size is controlled, and mean diameter can regulate in 10～5000nm.
Accompanying drawing explanation
Fig. 1 is the scanning electron microscope diagram sheet of embodiment 1 gained albumin nano granular.
Fig. 2 is the scanning electron microscope diagram sheet of embodiment 2 gained albumin nano granular.
Fig. 3 is the particle size distribution figure that embodiment 3 gained are loaded with albumin nano granular of cisplatin.
Fig. 4 is the laser co-focusing picture that embodiment 4 gained are loaded with albumin nano granular of amycin.
Fig. 5 is that embodiment 6 gained are loaded with albumin nano granular of paclitaxel and particle diameter and the potential image of blank nanoparticle; A is the particle diameter of blank nanosphere, and B is the particle diameter of the nanoparticle of year paclitaxel, the current potential that C is blank nanoparticle, and D is for carrying the particle diameter of the nanoparticle of paclitaxel.
Fig. 6 is the sub-uv-visible absorption spectra of albumin nano granular that embodiment 9 gained are loaded with protoporphyrin IX disodium salt.
The specific embodiment
Describe the present invention by the following examples, but the present invention is not limited in following embodiment.
Configuration is containing the 1ml aqueous solution of 1mg human serum albumin and 0.6mg poly-D-lysine, after mixing, add sodium hydroxide, regulate pH value to 8.5, add the 0.1M dithiothreitol, DTT solution of 10 μ L after standing 5 minutes, room temperature is placed albumin nano granular that spends the night stablely.
The scanning electron microscope diagram sheet of gained nanoparticle is as accompanying drawing 1.
Embodiment 2
Configuration is containing the 1ml aqueous solution of 1mg human serum albumin and 1mg poly-D-lysine, after mixing, add sodium hydroxide, regulate pH value to 9.5, add the 0.1M dithiothreitol, DTT solution of 10 μ L after standing 60 minutes, room temperature is placed albumin nano granular that 8 hours must be stable.
The scanning electron microscope diagram sheet of gained nanoparticle is as accompanying drawing 2.
Embodiment 3
Getting 10mg bovine serum albumin is dissolved in 1ml water, and add 10mg poly-D-lysine, the 1mg/ml aqueous solution that adds 100 μ L cisplatin after mixing, add potassium hydroxide, regulate pH value to 8.2, the suspension obtaining reacts 30 minutes under room temperature, then adds wherein the 1M cysteine of 10 μ L and under room temperature standing 30 minutes, by suspension high speed centrifugation, obtain the sub-powder of albumin nano granular.
Gained containing the particle size distribution figure of the nanoparticle of cisplatin as accompanying drawing 3.
Embodiment 4
Getting 100mg oralbumin is dissolved in 1ml water, and add 50mg to gather spermine, the 1mg/ml aqueous solution that adds 200 μ L amycin after mixing, add sodium carbonate, regulate pH value to 10.5, the suspension obtaining reacts 30 minutes at 60 ℃, then adds wherein the 1M cysteine of 100 μ L and at 60 ℃, react 2 hours, suspension, at 4 ℃ and water dialysis postlyophilization, is obtained being loaded with the sub-powder of albumin nano granular of amycin.
Amycin has fluorescence, and other compounds in preparation process all do not have fluorescence, and the fluorescent characteristic of nanoparticle can determine that amycin is enclosed in nanoparticle, gained containing the Laser Scanning Confocal Microscope picture of the nanoparticle of amycin as accompanying drawing 4.
Embodiment 5
Getting 10mg recombination human serum albumin is dissolved in 1ml water, and add 10mg to gather spermine, the 1mg/ml aqueous solution that adds 100 μ L curcumins after mixing, add potassium carbonate, regulate pH value to 9.0, the suspension obtaining reacts 30 minutes at 20 ℃, then adds wherein the 1M mercaptoethanol of 10 μ L and at 20 ℃, react 8 hours, after suspension is dialysed with water at 30 ℃, carry out spray dried dry, obtain the sub-powder of albumin nano granular.
Embodiment 6
Getting 1mg bovine serum albumin is dissolved in 1ml water, and add 0.6mg poly-D-lysine, the 10mg/ml alcoholic solution that adds 10 μ L paclitaxels after mixing, adds potassium hydroxide after mixing, and regulates pH value to 9.0, the suspension obtaining at 20 ℃ standing 5 minutes, the 0.1M dithiothreitol, DTT that adds wherein again 10 μ L, at 20 ℃ standing 8 hours, will suspension and water dialysis after carry out high speed centrifugation, collecting precipitation, dry, obtains being surrounded by the sub-powder of albumin nano granular of paclitaxel.
Gained is compared containing the nanoparticle of paclitaxel and the blank nanoparticle that do not contain paclitaxel, and both particle diameters and current potential all do not have significant difference, illustrate that the process of drug loading does not affect the character of nanoparticle.Containing the particle diameter of paclitaxel and blank nanoparticle and potential image as accompanying drawing 5, the particle diameter that wherein A is blank nanosphere, B is for carrying the particle diameter of the nanoparticle of paclitaxel, the current potential that C is blank nanoparticle, D is for carrying the particle diameter of the nanoparticle of paclitaxel.
Embodiment 7
Getting 200mg bovine serum albumin is dissolved in 1ml water, and add 200mg to gather spermine, the 1mg/ml alcoholic solution that adds 100 μ L temoporfins after mixing, add potassium hydroxide, regulate pH value to 9.0, the suspension obtaining reacts 30 minutes at 20 ℃, then adds wherein the 1M dithiothreitol, DTT of 100 μ L and at 20 ℃ standing 8 hours, by suspension high speed centrifugation, obtain the sub-powder of albumin nano granular.
Embodiment 8
Getting 10mg bovine serum albumin is dissolved in 1ml water, and add 10mg poly-D-lysine, the 10mg/ml aqueous solution that adds the 5-ALA of 200 μ L after mixing, add potassium hydroxide, regulate pH value to 9.0, the suspension obtaining reacts 30 minutes at 20 ℃, then adds wherein the 1M dithiothreitol, DTT of 10 μ L and at 20 ℃, react 2 hours, by suspension high speed centrifugation, obtain the sub-powder of albumin nano granular.
Embodiment 9
Getting 10mg bovine serum albumin is dissolved in 1ml water, and add 10mg poly-D-lysine, the 0.5mg/ml aqueous solution that adds 200 μ L protoporphyrin IX disodium salts after mixing, add potassium hydroxide, regulate pH value to 9.5, the suspension obtaining reacts 30 minutes at 20 ℃, then adds wherein the 1M dithiothreitol, DTT of 10 μ L and at 20 ℃, react 2 hours, by suspension high speed centrifugation, obtain the sub-powder of albumin nano granular.
Albumin nano granular obtaining is soluble in water, test ultraviolet-visible absorption spectroscopy, the characteristic absorption peak that occurs protoporphyrin IX disodium salt at 390nm place, illustrates that protoporphyrin IX disodium salt is loaded in nanoparticle, and the UV, visible light absorption spectra after normalization is shown in accompanying drawing 6.
Getting 10mg bovine serum albumin is dissolved in 1ml water, and add 10mg Protamine sulfates., the 5mg/ml tetrahydrofuran solution that adds 100 μ L Verteporfins after mixing, add potassium hydroxide, regulate pH value to 9.5, the suspension obtaining reacts 30 minutes at 20 ℃, then adds wherein the 1M dithiothreitol, DTT of 10 μ L and at 20 ℃, react 2 hours, suspension, at 4 ℃ and water dialysis postlyophilization, is obtained to the sub-powder of albumin nano granular.
Embodiment 11
Getting 10mg bovine serum albumin is dissolved in 1ml water; and add 10mg to gather spermine; the 5mg/ml aqueous solution that adds the mono-Radix Asparagi amine of 100 μ L acyl group chlorin after mixing; add potassium hydroxide; regulate pH value to 9.0, the suspension obtaining reacts 30 minutes at 20 ℃, then adds wherein the 1M dithiothreitol, DTT of 10 μ L and at 20 ℃, react 2 hours; by suspension high speed centrifugation, obtain the sub-powder of albumin nano granular.
Embodiment 12
Getting 10mg bovine serum albumin is dissolved in 1ml water, and add 10mg to gather spermine, the DMSO solution that adds the 5mg/ml of 10 μ L tetraphenylporphyrins after mixing, add potassium hydroxide, regulate pH value to 9.0, the suspension obtaining reacts 30 minutes at 20 ℃, then adds wherein the 1M glutathion of 10 μ L and at 20 ℃, react 2 hours, by suspension high speed centrifugation, obtain the sub-powder of albumin nano granular.
Embodiment 13
Getting 1mg bovine serum albumin is dissolved in 1ml water, and add 1mg to gather spermine, the acetone soln that adds the 1mg/ml of 10 μ L protoporphyrin IXs after mixing, add potassium hydroxide, regulate pH value to 9.0, the suspension obtaining reacts 30 minutes at 20 ℃, then adds wherein the 0.1M glutathion of 10 μ L and at 20 ℃ standing 8 hours, by suspension high speed centrifugation, after being dried, obtain the sub-powder of albumin nano granular that contains protoporphyrin IX.
Applicant's statement, the present invention illustrates product of the present invention and detailed preparation method by above-described embodiment, but the present invention is not limited to the said goods and detailed preparation method, do not mean that the present invention must rely on the said goods and detailed preparation method could be implemented.Person of ordinary skill in the field should understand, any improvement in the present invention, to the selection of the interpolation of the equivalence replacement of each raw material of product of the present invention and auxiliary element, concrete mode etc., within all dropping on protection scope of the present invention and open scope.
Claims (10)
1. based on an albuminous nanoparticle, it is characterized in that, comprise albumin molecule and positively charged macromole;
Preferably, described albumin molecule is any one or the two or more mixture in human serum albumin, bovine serum albumin, recombination human serum albumin, oralbumin;
Preferably, described positively charged macromole is any one or the two or more mixture in poly-D-lysine, spermine, poly-spermine, Protamine sulfates..
2. the preparation method based on albuminous nanoparticle described in claim 1, is characterized in that, comprises the steps:
(1) albumin molecule is mixed in aqueous solution with positively charged macromole, the pH value of regulator solution is 7.2-10.5;
(2) step (1) gained mixed liquor is reacted at 5-70 ℃, preferably 10-60 ℃, further preferred 20-40 ℃ to 1-60 minute, preferred 5-30 minute;
(3) to step (2) gained mixed liquor, add the compound containing sulfydryl, at 5-70 ℃, preferably 10-60 ℃, further preferred 20-40 ℃, react more than 30 minutes, form stable albumin nano granular.
3. preparation method according to claim 2, it is characterized in that, in step (1), the concentration of described albumin molecule in aqueous solution is 1-200mg/ml, be preferably 10-100mg/ml, and the concentration of described positively charged macromole in aqueous solution is 1-200mg/ml, be preferably 10-100mg/ml;
Preferably, by add the pH value of alkaline matter regulator solution in aqueous solution; Further preferably, described alkaline matter is any one or the two or more mixture in sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
4. according to the preparation method described in claim 2 or 3, it is characterized in that, in step (3), the described compound containing sulfydryl is any one or the two or more mixture in glutathion, cysteine, dithiothreitol, DTT, mercaptoethanol;
Preferably, the final concentration of the described compound containing sulfydryl in mixed liquor is 0.001-100mM, 0.1-10mM more preferably.
5. according to the preparation method described in claim 2-4 any one, it is characterized in that, also comprise by step (3) gained containing the mixed liquor of stablizing albumin nano granular dialyse, the step of processed;
Preferably, the temperature of described dialysis is 0～30 ℃, preferably 4～28 ℃;
Preferably, described processed is high speed centrifugation, lyophilization, spraying is dry or distilling under reduced pressure.
6. based on an albuminous nanoparticle, by preparation method described in claim 2-5 any one, made.
Described in claim 1 or 6 nanoparticle as the application of pharmaceutical carrier.
8. application according to claim 7, is characterized in that, described medicine is cancer therapy drug and/or optical dynamic therapy medicine;
Preferably, described cancer therapy drug is any one or the two or more mixture in paclitaxel, Docetaxel, amycin, curcumin, cisplatin and analog thereof;
Preferably, described optical dynamic therapy medicine is any one or the two or more mixture in temoporfin, 5-ALA, protoporphyrin IX, protoporphyrin IX disodium salt, Verteporfin, single Radix Asparagi amine acyl group chlorin, tetraphenylporphyrin.
9. a preparation method for albumin nano granular of drug loading, is characterized in that, comprises the steps:
(1) albumin molecule is mixed in aqueous solution with positively charged macromole, then add drug solution, the pH value of regulator solution is 7.2-10.5, forms the suspension of albumin nano granular of drug loading;
Preferably, the concentration of described albumin molecule in aqueous solution is 1-200mg/ml, be preferably 10-100mg/ml, and the concentration of described positively charged macromole in aqueous solution is 1-200mg/ml, be preferably 10-100mg/ml;
Preferably, described medicine is cancer therapy drug and/or optical dynamic therapy medicine; Further preferably, described cancer therapy drug is any one or the two or more mixture in paclitaxel, Docetaxel, amycin, curcumin, cisplatin and analog thereof; Further preferably, described optical dynamic therapy medicine is any one or the two or more mixture in temoporfin, 5-ALA, protoporphyrin IX, protoporphyrin IX disodium salt, Verteporfin, single Radix Asparagi amine acyl group chlorin, tetraphenylporphyrin;
Preferably, the solvent of described drug solution is any one or the two or more mixture in water, ethanol, acetone, dimethyl sulfoxide, oxolane;
(2) step (1) gained suspension reacts 1-60 minute, preferred 5-30 minute at 5-70 ℃, preferably 10-60 ℃, further preferred 20-40 ℃;
(3) to step (2) gained suspension, add the compound containing sulfydryl, at 5-70 ℃, preferably 10-60 ℃, further preferred 20-40 ℃, react more than 30 minutes, obtain the sub-suspension of albumin nano granular of stable drug loading;
Preferably, the described compound containing sulfydryl is any one or the two or more mixture in glutathion, cysteine, dithiothreitol, DTT, mercaptoethanol;
Preferably, the final concentration of the described compound containing sulfydryl in reactant liquor is 0.001-100mM, 0.1-10mM more preferably;
(4) the stable sub-suspension of albumin nano granular of step (3) gained is dialysed, processed, obtain albumin nano granular of drug loading;
Preferably, the temperature of described dialysis is 0～30 ℃, more preferably 4～28 ℃;
Preferably, described processed is high speed centrifugation, lyophilization, spraying is dry or distilling under reduced pressure.
10. the albumin nano granular of drug loading, is made by preparation method described in claim 9.
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| CN106606783A (en) * | 2015-10-24 | 2017-05-03 | 复旦大学 | Drug delivery system for targeting co-delivery of photosensitizer and chemotherapeutic drug |
| CN107126566A (en) * | 2017-05-04 | 2017-09-05 | 中国药科大学 | Functional protein carrier and preparation method thereof |
| CN109395080A (en) * | 2018-10-31 | 2019-03-01 | 上海理工大学 | A kind of multi-functional albumen gel and preparation method thereof |
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| CN111407740A (en) * | 2020-03-17 | 2020-07-14 | 大连理工大学 | Albumin nanoparticles capable of activating and releasing drugs by ultrasound, and preparation method and application thereof |
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| CN106606783A (en) * | 2015-10-24 | 2017-05-03 | 复旦大学 | Drug delivery system for targeting co-delivery of photosensitizer and chemotherapeutic drug |
| CN106606783B (en) * | 2015-10-24 | 2019-08-09 | 复旦大学 | A kind of targeting is passed altogether to be released the drug of photosensitizer and chemotherapeutics and passs release system |
| CN107126566A (en) * | 2017-05-04 | 2017-09-05 | 中国药科大学 | Functional protein carrier and preparation method thereof |
| CN109395080A (en) * | 2018-10-31 | 2019-03-01 | 上海理工大学 | A kind of multi-functional albumen gel and preparation method thereof |
| CN110251672B (en) * | 2019-06-18 | 2022-04-01 | 深圳大学 | Nano diagnosis and treatment agent and preparation method and application thereof |
| CN110251672A (en) * | 2019-06-18 | 2019-09-20 | 深圳大学 | A kind of nanometer of diagnosis and treatment agent and the preparation method and application thereof |
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