CN109966504A - A kind of albumin nanoparticle and the preparation method and application thereof that cell quickly absorbs - Google Patents
A kind of albumin nanoparticle and the preparation method and application thereof that cell quickly absorbs Download PDFInfo
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Abstract
The present invention relates to a kind of albumin nanoparticles that cell quickly absorbs, including the albumin through phenyl boric acid base group modification；The partial size of the albumin nanoparticle is 8-100nm.It has the advantages that can be quickly by cellular uptake, the cell incubation time needed for significantly reducing nano material.The present invention also provides the preparation method of the albumin nanoparticle, corresponding albumin nano preparation and preparation method thereof.Albumin nano preparation wraps up pharmacological active substance with albumin nanoparticle, be advantageously implemented contain drug in vivo it is quick, maximize intake, have a very important role and meaning for promoting therapeutic effect.
Description
Technical field
The present invention relates to biomedicine field, it is fast to relate more specifically to a kind of cell for especially a kind of albumin nanoparticle
The albumin nanoparticle and its preparation method and application of speed intake.
Background technique
With the fast development of materials chemistry and nanosecond medical science, biodegradable Nano medication delivery platform, including receive
Rice grain, micella and liposome etc., have been widely used for biomedical diagnostic and treatment.The delivery system of a large amount of functionalization is continuous
It is suggested, wherein based on the nano particle of protein since it is renewable with biodegradability, low cytotoxicity, resource
Property, high drug binding ability and to target cell it is significant intake and receive more and more attention.
Albumin (Albumin) is the most abundant haemocyanin in blood, the important transhipment egg as many biomolecule
It is white, it bears and transports the important function that slightly solubility endogenous compound recycles in vivo, such as fatty acid and bilirubin etc..White egg
It is white that there are unique physicochemical properties, such as solubility height, in physiological conditions good (the mean half-life 15-20 of stability
It).On the other hand, it also has the characteristics of safe and non-toxic, non-immunogenicity, good biocompatibility, specific targeting, is improving
It can be effectively reduced toxic side effect while curative effect of medication, therefore be a kind of ideal pharmaceutical carrier.
The hydrophobic pocket that albumin has can wrap up a large amount of hydrophobic drug, transport it into target organ and group
It knits.In entity tumor, the nano particle based on albumin, can be real by the infiltration and reservation (EPReffect) effect of enhancing
Accumulation in present solid tumor.In addition, in glycoprotein (gp60) receptor of tumor surface height expression, it also can be mutual with albumin
Effect, to further promote nano particle in the enrichment of tumor region.
Currently, researches show that it to apply although albumin has many advantages in anti-tumor aspect as nano-carrier
There are still important problems.When albumin nanoparticle is absorbed by tumour cell by endocytosis, generally require longer
Time.Experiment in vitro is shown, when using albumin nanoparticle incubated cell, at least needs just have enough nanometers within 24 hours
Grain is by cellular uptake.When nano particle transport drug molecule recycles in vivo, due to metabolic presence, how limited
Circulation time in vivo and effective blood concentration under, realize maximized cellular uptake amount for therapeutic effect have it is very heavy
The function and significance wanted.
Though albumin, which has had been reported that, is used to prepare nanoparticle with patent, as patent document CN1925874A,
CN1237901A, CN1638736A, CN1448128A, CN1911446A and CN1324613A.But the product being directed to and
Technology is to be prepared that partial size is suitable, nanometer formulation of stable dispersion, for feature and function, and wants in present patent application
Solve the problems, such as the difference of essence.So far, there is not yet being to prepare the albumin nanoparticle that cell quickly absorbs
The document report of purpose.
Summary of the invention
The purpose of the present invention is to provide a kind of albumin nanoparticle, especially a kind of albumin that cell quickly absorbs
Nano particle and its preparation method and application.Albumin nanoparticle provided by the invention can significantly subtract quickly by cellular uptake
The cell incubation time needed for having lacked nano material is advantageously implemented and contains the maximization intake of drug in vivo.
For this purpose, in a first aspect, the present invention provides a kind of albumin nanoparticle, including modified albumin, the warp
The albumin of modification is the albumin through phenyl boric acid base group modification.
Further, the partial size of the albumin nanoparticle is 8-100nm, preferably 10-60nm, further preferably 10-
40nm is still more preferably 10-20nm.
Further, the albumin includes human serum albumins (HSA), bovine serum albumin(BSA) (BSA), recombinant human serum albumin
One of albumen, ovalbumin, ovalbumin, seralbumin, lactoalbumin, myoalbumin, leucosin, legumelin
Or it is several.
Second aspect, the present invention provide the preparation method of albumin nanoparticle, include the following steps:
(1) albumin aqueous solution is prepared；
(2) 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne is added in the albumin aqueous solution being prepared to step (1)
Diimmonium salt hydrochlorate (EDC) and n-hydroxysuccinimide (NHS), carry out reaction activation；
(3) phenyl boric acid donor is added into the solution after step (2) reaction activation, is reacted；
(4) solution after step (3) reaction is successively dialysed, dehydration, obtains albumin nanoparticle.
Further, step (1) includes: and weighs a certain amount of albumin to be dissolved in phosphate buffer, and preparation concentration is 10-
The albumin aqueous solution of 200mg/ml, preferred concentration 10-100mg/ml, further preferred concentration are 20-80mg/ml.
Further, the pH of the phosphate buffer is 4.0-6.5, preferably 5.0-6.0.
Further, in step (2), the mole ratio of EDC and albumin is 10-70:1, preferably 40:1；NHS's and EDC
Mole ratio is 1-2:1；Reaction activation 20-80min, preferably 30min.
Further, step (3) the phenyl boric acid donor includes the one or more of following compound:
Further, preferably 3- amino-phenyl boric acid.
Further, the condition of step (3) described reaction is normal-temperature reaction 8-24h, preferably 12h.
Further, the temperature of dialysis described in step (4) is 0-20 DEG C, and the dehydration includes being freeze-dried, being spraying
One or more of dry or vacuum distillation.
Further, the partial size for the albumin nanoparticle that step (4) is prepared be 8-100nm, preferably 10-60nm, into
One step is preferably 10-40nm, is still more preferably 10-20nm.
The third aspect, the present invention provide a kind of albumin nano preparation, including (1) described albumin nanoparticle；(2)
A effective amount of pharmacological active substance.
Term " effective quantity ", which refers to, to be realized in subject and treats, prevents, mitigates and/or alleviate corresponding disease or illness
Dosage.
Further, the pharmacological active substance accounts for the 0.1%-60% of albumin nano preparation gross mass, preferably 5%-
40%, further preferably 10%-20%.
Further, the pharmacological active substance include analgesic antipyretic medicine, arcotic, antiasthmatic, antibiotic, antidepressants,
Antidiabetic, antifungal, antihypertensive, anti-inflammatory agent, antineoplastic, anxiolytic, immunosuppressor, anti-migraines
Medicine, sedative hypnotics, antianginal drug, antipsychotic drug, antimanic drug, antiarrhymic, anti-arthritic, antigout
Medicine, anticoagulation, Thrombolytic Drugs, anti-fibrinolytic medicine, hemorheology reagent, antiplatelet drug, anticonvulsive drug, anti-Parkinson's drug, anti-group
Amine antipruritic, calcium adjust medicine, antimicrobial, antiviral agent, antimicrobial, anti-infectious agent, bronchodilators, hormone, hypoglycemic
Medicine, lipid-lowering medicine, protein, nucleic acid, promoting erythrocyte generate medicine, antiulcer, anti-reflux medicine, antiemetic, liposoluble vitamin, meter Tuo
Smooth, ganciclovir valine ester, nitroso ureas salt, anthracycline antibiotic or ellipticine.
Fourth aspect, the present invention provide the preparation method of the nanometer formulation, comprising:
S1: the albumin nanoparticle being mixed with glutathione solution, is reacted, and obtains space structure expansion
Albumin homogeneous solution；
S2: pharmacological active substance is added into the albumin homogeneous solution that step S1 is obtained, is sufficiently stirred, obtains albumin
The thick solution of nanometer formulation；
S3: the thick solution for the albumin nano preparation that step S2 is obtained is dialysed, and obtains package pharmacological active substance
Albumin nano preparation.
Further, glutathione solution described in step S1 is the phosphate buffer of glutathione, pH value 5.0-
9.0, preferably 6.5-7.5, further preferably 7.0-7.4；The concentration of glutathione is 0.01-60mM, preferably 0.01-
40mM。
Further, the temperature of reaction described in step S1 is 10-60 DEG C, and the time of reaction is 10-300min.
Further, albumin is final concentration of in the albumin homogeneous solution that space structure described in step S1 is unfolded
0.01-100mg/ml, preferably 1-100mg/ml, further preferably 5-80mg/ml.
Further, described in step S3 dialysis include: the thick solution of the albumin nano preparation is put into bag filter, and
Extra glutathione, pharmacological active substance are removed with dialysis in PBS solution at 0-20 DEG C；Wherein, the bag filter retention
Molecular weight is not less than 1000.
5th aspect, the present invention provide the albumin nanoparticle or the nanometer formulation answering in drug delivery
With.
When nano particle transport drug molecule recycles in vivo, due to metabolic presence, such as net in liver and spleen tissue
The scavenging effect of shape endothelial system (RES) and macrophage system (MPS) to the foreign particle in blood, limited internal
Under circulation time and effective blood concentration, realize maximized intake have a very important role for therapeutic effect and
Meaning.Although albumin, which has had been reported that, is used to prepare nano particle, the technical solution being directed to is to be prepared
Partial size is suitable, stable dispersion nanometer formulation, for feature and function, and essence has been solved the problems, such as in present patent application
Difference.So far, there is not yet document report for the purpose of preparing the albumin nanoparticle that cell quickly absorbs.
In order to realize nano material can quickly by cellular uptake, the present invention to the chemical and physical features of nano material,
Such as size, charge and surface nature, have made intensive studies.Albumin nanoparticle grain obtained in technical solution of the present invention
Diameter range is 8-100nm, and preferably 10-40nm, zeta potential value is -4.0mV-1.5mV；Albumin nano provided by the invention
The surface-functionalized modification phenyl boric acid group of grain, since phenyl boric acid can be with the highly expressed sialic acid residues phase interaction of cell surface
With, and then nano particle is mediated quickly to be swallowed intake by cell.
Compared with prior art, the invention has the following advantages that
(1) the present invention provides a kind of albumin nanoparticles, using with complete bio-compatible, good solubility and length
The albumin of half-life period is carrier, is surface modified by chemical reaction, realizes nano-carrier quickly by cellular uptake, shows
The cell incubation time needed for work reduces nano material.
(2) the present invention provides the preparation methods of the albumin nanoparticle, and preparation method is simple for this, can be in
Property environment under form preferable nano particle in aqueous solution, it is long and have good to be stored at room temperature the time for size uniformity, good dispersion
Good stability.
(3) the present invention provides a kind of albumin nano preparations, wrap up pharmacological active substance with albumin nanoparticle, have
Conducive to realize contain drug in vivo it is quick, maximize intake, for promoted therapeutic effect have a very important role and
Meaning.
(4) the present invention provides the preparation methods of albumin nano preparation, destroy white egg by using glutathione solution
Disulfide bond in white nano particle is unfolded its space structure to obtain homogeneous solution, in order to wrap up pharmacological active substance, improves
Drug encapsulation efficiency；The organic solution of pharmacological active substance is added in albumin homogeneous solution, hydrophobe phase interaction is passed through
The package of pharmacological active substance is realized with, charge interaction etc..The preparation method is simple, contains high-efficient, is prepared
Albumin nano preparation is saved with uniform discrete form in the aqueous solution at 0-10 DEG C and is up to 12 months, at 10-40 DEG C
It is saved and is up to 4 months with uniform discrete form in aqueous solution.
Detailed description of the invention
By reading the following detailed description of the preferred embodiment, various other advantages and benefits are common for this field
Technical staff will become clear.The drawings are only for the purpose of illustrating a preferred embodiment, and is not considered as to the present invention
Limitation.And throughout the drawings, the same reference numbers will be used to refer to the same parts.In the accompanying drawings:
Fig. 1 is that the albumin nanoparticle that cell quickly absorbs in the present invention synthesizes schematic diagram.
Fig. 2 is that the HAS-PBA albumin nanoparticle that cell prepared by embodiment 1 quickly absorbs and unmodified HSA are white
Infrared spectroscopy (IR) figure of albumen.
Fig. 3 is that the HAS-PBA albumin nanoparticle that cell prepared by embodiment 1 quickly absorbs and unmodified HSA are white
UV-Vis spectra (UV-Vis) figure of albumen.
Fig. 4 is the HAS-PBA albumin nanoparticle grain size distribution that cell prepared by embodiment 1 quickly absorbs.
Fig. 5 is the HAS-PBA albumin nanoparticle Zeta potential figure that cell prepared by embodiment 1 quickly absorbs.
Fig. 6 is the transmission electron microscope (TEM) for the HAS-PBA albumin nanoparticle that cell prepared by embodiment 1 quickly absorbs
Figure.
Fig. 7 is the HAS-PBA albumin nanoparticle quickly absorbed of cell for preparing of embodiment 1 to LO2 cytotoxicity
It influences.
Fig. 8 is the HAS-PBA albumin nanoparticle quickly absorbed of cell for preparing of embodiment 1 to SH-SY5Y cell toxicant
The influence of property.
Fig. 9 is the HAS-PBA albumin nanoparticle quickly absorbed of cell for preparing of embodiment 1 to HT22 cytotoxicity
It influences.
Figure 10 is that the HAS-PBA albumin nanoparticle that cell prepared by embodiment 1 quickly absorbs and unmodified HSA are white
The cellular uptake image of albumen.
Specific embodiment
The illustrative embodiments of the disclosure are more fully described below with reference to accompanying drawings.Although showing this public affairs in attached drawing
The illustrative embodiments opened, it being understood, however, that may be realized in various forms the disclosure without the reality that should be illustrated here
The mode of applying is limited.It is to be able to thoroughly understand the disclosure on the contrary, providing these embodiments, and can be by this public affairs
The range opened is fully disclosed to those skilled in the art.The materials, reagents and the like used in the following examples, such as without special theory
It is bright, it is commercially available.
Embodiment 1 prepares the albumin nanoparticle that cell quickly absorbs
The albumin nanoparticle that cell quickly absorbs is prepared according to schematic diagram as shown in Figure 1, the specific steps are as follows:
It weighs 200mg human serum albumins (HSA), is dissolved in (0.1M, PH=in 10ml PBS buffer solution under condition of ice bath
5.8) 19.2mg EDC and 17.3mg NHS, is then added, after reaction activates 30min, 34.3mg 3- amino-phenyl boric acid is added
(PBA), normal-temperature reaction 12h.Acquired solution obtains HSA-PBA albumin nano with being lyophilized after 1000D bag filter dialysis 2d
Grain.
It is as shown in Figure 2-5 respectively infrared spectroscopy (IR) figure, the purple of the HSA-PBA albumin nanoparticle being prepared
Outside-visible light (UV-Vis) figure, grain size distribution and Zeta potential figure.
It is illustrated in figure 6 the transmission electron microscope picture for the HSA-PBA albumin nanoparticle being prepared, HSA-PBA albumin
The partial size of nano particle is 12-20nm, average grain diameter 15.2nm.
Embodiment 2 prepares the albumin nano preparation that cell quickly absorbs
The HSA-PBA albumin nanoparticle for taking 50mg embodiment 1 to be prepared is dissolved in 5ml deionized water, and GSH is added extremely
Final concentration of 5mM.Solution is stirred into 1h at 550rpm, 37 DEG C.Then, with the rate of 1.0ml/min be added dropwise 500 μ L Ah
Mycin (Dox) solution (3mg/ml, ethyl alcohol is as solvent), stirring at normal temperature is overnight, and at 4 DEG C, obtained particle suspension liquid is existed
It is centrifuged 15min under the conditions of 20000rpm, and cleans sediment 3 times to remove GSH and free Dox with deionized water.Finally use
10ml deionized water resuspended particle, is placed in freeze overnight in -80 DEG C of refrigerators, places into freeze drier and be lyophilized.Obtain
Dox-HSA-PBA albumin nano preparation.
The cytotoxicity of embodiment 3HSA-PBA detects
With the cytotoxicity of HSA-PBA albumin nanoparticle prepared by mtt assay measurement embodiment 1, the detection original of mtt assay
Reason is: tetramethyl azo azoles salt (3- (4,5-Dimethyl-2-thiazolyl) -2,5-diphenyl-2H- of yellow
Tetrazolium bromide, MTT) bluish violet formazan can be converted to by the succinate dehydrogenase in living cells mitochondria
Grain, DMSO can dissolve the formazan particle, detect its absorbance value at 490nm, the size and work of absorbance value with microplate reader
Cell quantity is positively correlated.And dead cell is without this function, therefore the vigor of the method indirect reaction cell can be used.
It is respectively 1.0 × 10 by density5LO2 cell, SH-SY5Y cell and the HT22 cell suspension inoculation of/ml is in 96 holes
Culture plate, every 100 μ l of hole；Adhere-wall culture for 24 hours after, discard old culture solution, the every hole of experimental group be added 100ul contain it is certain density
100ul DMEM minimal medium is added in the DMEM minimal medium of HSA-PBA, the every hole of control group；After being incubated for 12h, every hole is added
100 μ l contain the DMEM minimal medium of 0.5mg/ml MTT；After acting on 4h, cell culture fluid is discarded, 150 μ l are added in every hole
DMSO Rong Xie formazan particle；After vibrating 10min on shaking table, absorption value of each hole at 490nm is measured with microplate reader.With control
The cell OD of group490Value is 100% cell viability, the cell viability value of experiment with computing group.HSA-PBA albumin nanoparticle pair
Fig. 7 is shown in the influence of LO2 cytotoxicity, and Fig. 8 is shown in the influence to SH-SY5Y cytotoxicity, and figure is shown in the influence to HT22 cytotoxicity
9。
4 cellular uptake imaging experiment of embodiment
The HSA-PBA albumin nanoparticle and HSA albumin of FITC fluorescent marker are prepared first: taking 15mg embodiment 1
The HSA-PBA albumin nanoparticle being prepared is dissolved in 10ml PBS buffer solution (0.1M, PH=5.8), and 30 μ L are added
FITC solution (1mg/mL, dimethyl sulfoxide is as solvent), is stirred at room temperature 3h, with 1000D bag filter dialyse 2d after be lyophilized.It will be upper
HSA-PBA powder after stating fluorescent marker is configured to solution (1mg/ml) with PBS.It is 1.0 × 10 by density5The LO2 cell of/ml
After suspension is inoculated in confocal ware wall for 24 hours, old culture solution is discarded, every hole is added 100ul and contains certain density FITC fluorescence
The minimal medium of the HSA-PBA of label；It is incubated for the different time respectively: 15min, 30min, 1h, 2h, 3h, 6h, 12h, for 24 hours
Deng being observed under OLYMPUS FV1000-IX81 laser confocal microscope after incubation, imaging results are as shown in Figure 10.
As shown in Figure 10, compared with HSA albumin, HSA-PBA albumin nanoparticle can quickly be absorbed by cell.It is added
Just start to be absorbed after HSA-PBA albumin nanoparticle 15min, and cellular uptake speed is fast, 2-3h realizes maximum
Change intake.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
In the technical scope disclosed by the present invention, any changes or substitutions that can be easily thought of by anyone skilled in the art,
It should be covered by the protection scope of the present invention.Therefore, protection scope of the present invention should be with the protection model of the claim
Subject to enclosing.
Claims (10)
1. a kind of albumin nanoparticle, which is characterized in that including modified albumin, the modified albumin is warp
The albumin of phenyl boric acid base group modification.
2. albumin nanoparticle as described in claim 1, which is characterized in that the partial size of the albumin nanoparticle is 8-
100nm。
3. albumin nanoparticle as claimed in claim 1 or 2, which is characterized in that the albumin includes human seralbumin egg
The white egg of white, bovine serum albumin(BSA), recombination human serum albumin, ovalbumin, ovalbumin, seralbumin, lactoalbumin, flesh
One or more of white, leucosin, legumelin.
4. the preparation method of any one of the claim 1-3 albumin nanoparticle, which comprises the steps of:
(1) albumin aqueous solution is prepared；
(2) it is sub- that 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne two is added in the albumin aqueous solution being prepared to step (1)
Amine hydrochlorate and n-hydroxysuccinimide carry out reaction activation；
(3) phenyl boric acid donor is added into the solution after step (2) reaction activation, is reacted；
(4) solution after step (3) reaction is successively dialysed, dehydration, obtains albumin nanoparticle.
5. preparation method as claimed in claim 4, which is characterized in that step (1) includes: to weigh a certain amount of albumin to be dissolved in
In phosphate buffer, the albumin aqueous solution that concentration is 10-200mg/ml is prepared.
6. preparation method as claimed in claim 4, which is characterized in that in step (2), 1- ethyl-(3- dimethylamino third
Base) mole ratio of phosphinylidyne diimmonium salt hydrochlorate and albumin is 10-70:1；N-hydroxysuccinimide and 1- ethyl-(3- bis-
Dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate mole ratio be 1-2:1；Reaction activation time is 20-80min.
7. a kind of albumin nano preparation, including the described in any item albumin nanoparticles of (1) claim 1-3；(2) have
The pharmacological active substance of effect amount.
8. albumin nano preparation as claimed in claim 7, which is characterized in that the pharmacological active substance includes analgesic antipyretic
It is medicine, arcotic, antiasthmatic, antibiotic, antidepressants, antidiabetic, antifungal, antihypertensive, anti-inflammatory agent, antitumor
Medicine, anxiolytic, immunosuppressor, anti-migraines medicine, sedative hypnotics, antianginal drug, antipsychotic drug, antimanic drug,
Antiarrhymic, anti-arthritic, gout suppressant, anticoagulation, Thrombolytic Drugs, anti-fibrinolytic medicine, hemorheology reagent, anti-blood are small
Plate medicine, anticonvulsive drug, anti-Parkinson's drug, antihistamine antipruritic, calcium adjust medicine, antimicrobial, antiviral agent, antimicrobial, resist
It infects medicine, bronchodilators, hormone, antidiabetic drug, lipid-lowering medicine, protein, nucleic acid, promoting erythrocyte and generates medicine, antiulcer, anti-reflective
Flow medicine, antiemetic, liposoluble vitamin, mitotane, ganciclovir valine ester, nitroso ureas salt, anthracycline antibiotic or rose
One or more of rare tree alkali.
9. the preparation method of albumin nano preparation described in claim 7 or 8 characterized by comprising
S1: the albumin nanoparticle being mixed with glutathione solution, is reacted, and obtains the white egg of space structure expansion
White homogeneous solution；
S2: pharmacological active substance is added into the albumin homogeneous solution that step S1 is obtained, is sufficiently stirred, obtains albumin nano
The thick solution of preparation；
S3: the thick solution for the albumin nano preparation that step S2 is obtained is dialysed, and obtains the white of package pharmacological active substance
Protein nano preparation.
10. the albumin nanometer metric system described in the described in any item albumin nanoparticles of claim 1-3 or claim 7 or 8
Application of the agent in drug delivery.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150320837A1 (en) * | 2012-12-12 | 2015-11-12 | Massachusetts Institute Of Technology | Insulin derivatives for diabetes treatment |
| CN106158197A (en) * | 2015-04-28 | 2016-11-23 | 国家纳米科学中心 | A kind of phenylboric acid functional magnetic nano-particle with blocking group and its preparation method and application |
| CN108635570A (en) * | 2018-06-06 | 2018-10-12 | 武汉大学 | A kind of gold nanoclusters particle of response type blood glucose-control and preparation method thereof |
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2019
- 2019-02-26 CN CN201910142610.8A patent/CN109966504A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150320837A1 (en) * | 2012-12-12 | 2015-11-12 | Massachusetts Institute Of Technology | Insulin derivatives for diabetes treatment |
| CN106158197A (en) * | 2015-04-28 | 2016-11-23 | 国家纳米科学中心 | A kind of phenylboric acid functional magnetic nano-particle with blocking group and its preparation method and application |
| CN108635570A (en) * | 2018-06-06 | 2018-10-12 | 武汉大学 | A kind of gold nanoclusters particle of response type blood glucose-control and preparation method thereof |
Non-Patent Citations (3)
| Title |
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| JING WANG,ET AL.: "Size- and pathotropism-driven targeting and washout-resistant effects of boronic acid-rich protein nanoparticles for liver cancer regression", 《JOURNAL OF CONTROLLED RELEASE》 * |
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| 张兆恒: "负载雷替曲塞的HSA纳米微球的生物性能研究", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》 * |
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