CN105816887A - CT contrast agent based on nano Pt@BSA biomimetic material and preparation method and application of CT contrast agent - Google Patents
CT contrast agent based on nano Pt@BSA biomimetic material and preparation method and application of CT contrast agent Download PDFInfo
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- 239000002872 contrast media Substances 0.000 title claims abstract description 30
- 239000002977 biomimetic material Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 81
- 108091003079 Bovine Serum Albumin Proteins 0.000 claims abstract description 72
- 229940098773 bovine serum albumin Drugs 0.000 claims abstract description 71
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 31
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- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 3
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- 206010028980 Neoplasm Diseases 0.000 description 5
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- 208000001647 Renal Insufficiency Diseases 0.000 description 1
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- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
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- PVBALTLWZVEAIO-UHFFFAOYSA-N diodone Chemical compound OC(=O)CN1C=C(I)C(=O)C(I)=C1 PVBALTLWZVEAIO-UHFFFAOYSA-N 0.000 description 1
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- 238000006703 hydration reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
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- 239000002082 metal nanoparticle Substances 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
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- 230000009054 pathological process Effects 0.000 description 1
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- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
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- 239000002096 quantum dot Substances 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
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- 210000002966 serum Anatomy 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Abstract
The invention discloses a CT contrast agent based on a nano Pt@BSA biomimetic material and a preparation method and application of the CT contrast agent. The contrast agent is composed of bovine serum albumin and nano platinum particles and characterized in that the nano platinum particles are wrapped by the bovine serum albumin, and the particle diameter of the contrast agent ranges from 1 nm to 10 nm. Compared with a traditional iodine-based micromolecular contrast agent which is clinically applied, the CT contrast agent based on the nano Pt@BSA biomimetic material has the advantages that a high X-ray absorption coefficient is achieved; the nano platinum particles wrapped by the bovine serum albumin are good in stability, water solution dispersibility and biocompatibility and long in blood staying time; surface functional modification is easy to conduct; a reaction for synthesizing the biomimetic nano material with protein as a template is conducted in a water solution, the preparation method conforms to the concept of green synthesis, and environmental pollution can be reduced to a certain extent.
Description
Technical field
The invention belongs to contrast medium technique field, be specifically related to a kind of CT contrast agent based on Pt nano particle BSA biomimetic material and its preparation method and application.
Background technology
The early stage diagnosis and treatment treatment of malignant tumor is study hotspot and the difficult point of current biomedical sector.Molecular imaging has merged molecular biochemistry, data process the multinomial technology such as nanotechnology, image procossing, image application method carries out the qualitative and quantitative study of cell and molecular level to the bioprocess under condition of living organism, cell or the physiology of molecular level and pathological process is directly displayed by image, thus probe into change biology of disease early stage, metabolism height, gene unconventionality etc. non-invasively, and then realize disease early diagnosis, at body screening active medicine and the most even Real-Time Evaluation therapeutic effect direct, quick.Because it has high specific, high sensitivity and an image resolution ratio, really qualitative, location, quantitative data can be provided for clinical diagnosis the most from now on.Wherein computed tomography (CT), lossless decomposition technology as a kind of advanced person is one of the most clinical the most frequently used detection means, compared with other detection technique, it has, and penetration power is strong, resolution is high, detection speed is fast, low price, testing result directly perceived, be not required to and the plurality of advantages such as tested article contacts.Therefore, after 20 century 70s are invented, CT has become as an important instrument on medical image, and its application is more and more extensive.
The most wide variety of CT contrast agent is containing the little molecule of iodine, such as Iopromide and iohexol etc. at present.Little yet with its molecular weight, in human kidney, energy tachymetabolism, causes its blood circulation time in vivo relatively short, thus greatly limit its application on selectively targeted imaging technique and angiography.Although the hypotoxicity having been developed at present more preferably and update and infiltrative diodone, but the most really overcome its low X-ray absorption coefficient and the characteristic of targeting modification can not be carried out.Other restriction includes: (1) toxicity: nephrotoxicity in some cases, renal failure, anaphylactic shock；(2) hyperosmosis and viscosity also can cause some bad toxic and side effects；(3) molecular weight that iodine is relatively low makes it have relatively low X-ray absorption number, thus limits the raising of its sensitivity.
In recent years, CT contrast agent based on nano material receives the extensive concern of researcher.Since two thousand four, most is all about nanoparticle or its complex such as gold, silver, platinum, bismuth and gadoliniums based on inorganic nano-particle as the research of CT preparation.Wherein nano platinum particle is not only stable, and has chemical inertness, and it has good character in terms of self assembly, quantum size effect and catalysis and biologic applications simultaneously.Nano platinum particle is used for medical diagnosis and X ray CT preparation, be summarized as following some: (1) has higher X-ray absorption coefficient compared with conventional CT contrast agent；(2) it is prone to surface-functionalized modification, such as can be with modified antibodies target tumor；(3) nontoxic and biocompatibility is good.Based on the above, the present invention uses for reference the principle of biomineralization, with bovine serum albumin (BSA) as biological template, sodium borohydride is reducing agent, obtains hud typed bionic nano platinum composite (PtBSA) by bionic synthetic method one kettle way.The biological template bovine serum albumin (BSA) applied is a kind of globular preteins, organism serum exists in a large number, it is widely used in nanometer biotechnology, such as polymerase chain reaction (PCR), molecular image, medicine delivery, molecular self-assembling and the auxiliary synthesis etc. of metal nanoparticle.Research finds, the quantum dot that bovine serum albumin combines represents good stabilizing power, it is possible to effectively stops the generation of flocculation, and increases quantum yield and reduce cytotoxicity.
Summary of the invention
It is desirable to provide a kind of CT contrast agent based on Pt nano particle BSA biomimetic material and its preparation method and application.
The technical scheme is that
A kind of CT contrast agent based on Pt nano particle BSA biomimetic material, it is made up of bovine serum albumin (BSA) and nano-platinum particle, it is characterized in that, nano-platinum particle is wrapped up by bovine serum albumin (BSA), and the particle diameter of described contrast agent is 1～10nm.
The preparation method of above-mentioned CT contrast agent based on Pt nano particle BSA biomimetic material, comprises the following steps:
(1) bovine serum albumin (BSA) is configured to solution, adds chloroplatinic acid (H2PtCl6·6H2O) solution, stirs 5-30min；
(2) by sodium borohydride (NaBH4) it is configured to solution, it is placed in ice bath；
(3) by sodium borohydride (NaBH4) solution joins in bovine serum albumin (BSA) and platinum acid chloride solution, stirs 0.5-6h；
(4) dialysis, lyophilization processes, and obtains the nano-platinum particle pressed powder of bovine serum albumin parcel.
Described chloroplatinic acid (H2PtCl6·6H2And the mol ratio of bovine serum albumin (BSA) is 25:1-200:1 O)；
Described sodium borohydride (NaBH4) and chloroplatinic acid (H2PtCl6·6H2O) in, the mol ratio of platinum is 2:1-6:1.
The nano-platinum particle of the bovine serum albumin parcel that the present invention prepares has good stability, aqueous dispersion and biocompatibility, show good CT imaging effect, there is the body vessel imaging of excellence and to Vitro Tumor CT contrasting effects (such as lung carcinoma cell imaging), therefore, there is potential CT radiography application prospect.
The nano platinum particle assembly that the PtBSA nano-particle of present invention synthesis is wrapped up by BSA just, has higher X-ray absorption coefficient, good biocompatibility compared with traditional clinical iodine preparation and easily modifies features such as connecting a large amount of targeting groups.Wrapped up by BSA molecule outside nano-particle, this material is made to have good biocompatibility, and the abundant functional group (such as amino, carboxyl, hydroxyl etc.) itself possessed based on BSA molecule, it also can be as multi-functional interface, for the specific modification of targeted molecular.Additionally, nowadays of great interest by green bionical method nano materials, there is huge potential application prospect.Being to have plurality of advantages as templated synthesis nano material with protein, such as it has good biological safety and stability, it is adaptable to bio-imaging is studied.In a word, the inventive method is simple, and utilizes bovine serum albumin as template for the synthesis of platinum nano material, and it has some obvious advantages.First, the synthesis of material is to carry out in aqueous, and process does not use organic solvent, can reduce the pollution to environment to a certain extent.Secondly, bovine serum albumin protein is as the macromole of a kind of good biocompatibility, the nano structural material utilizing it as templated synthesis has good biocompatibility and high biological safety, and is prone to surface and modifies so that it is have a wide range of applications potentiality in biomedical imaging field.
Compared with the little molecular contrast agents of iodo (such as Iopromide and iohexol) of traditional clinical application, CT contrast agent based on Pt nano particle BSA biomimetic material has a characteristic that
1. have higher X-ray absorption coefficient.High x-ray attenuation coefficient means there is higher Contrast enhanced in relatively low-dose level.
2. the nano-platinum particle of this bovine serum albumin parcel has good stability, aqueous dispersion, biocompatibility and longer blood residence.For intravenous administration, any x-ray contrast agent must have high aqueous dispersion.This contrast agent its chemical property and pharmacokinetic property after intravenous injection is excellent, and has the body vessel imaging of excellence and to Vitro Tumor CT contrasting effects (such as lung carcinoma cell imaging).
3. it is prone to surface-functionalized modification.Wrapped up by BSA molecule outside this contrast agent, this material is made to have good biocompatibility, and the abundant functional group (such as amino, carboxyl, hydroxyl etc.) itself possessed based on BSA molecule, it also can be as multi-functional interface, for the specific modification of targeted molecular, thus carry out the targeted imaging of inside and outside tumor.
4. the reaction of the bionical nano material with protein as templated synthesis is carried out in aqueous, meets the thought of green syt, it is possible to reduce the pollution to environment to a certain extent.
Accompanying drawing explanation
In Fig. 1, the transmission electron microscope (a) of Pt nano particle BSA biomimetic material and (c), grain size distribution (b) and uv absorption figure (d).
Fig. 2 shows the cytotoxicity test result of Pt nano particle BSA biomimetic material.
In Fig. 3, Pt nano particle BSA biomimetic material and CT radiography picture (a) of Iopromide and corresponding CT value (b), wherein 1 is Pt nano particle BSA biomimetic material, and 2 is Iopromide.
Detailed description of the invention
Provide present pre-ferred embodiments below in conjunction with the accompanying drawings, to describe technical scheme in detail.
Embodiment:
(1) experiment reagent
Bovine serum albumin (the BSA of 99% lyophilizing, molecular weight～66.4kDa), dimethyl sulfoxide (DMSO), 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromide (MTT) buys from Sigma-Aldrich company.Hyclone (FBS), 1640 cell culture mediums are purchased from Shanghai Baihuishen Biotechnology Co., Ltd..Six hydration chloroplatinic acid (H2PtCl6·6H2O), sodium borohydride (NaBH4), dehydrated alcohol (CH3CH2Etc. OH) other commercially available chemically pure reagent is purchased from Solution on Chemical Reagents in Shanghai company.A549 cell is provided by Chinese Academy of Sciences's Shanghai cell.Experiment water used is deionized water (18.2M Ω).
(2) preparation of Pt nano particle BSA biomimetic material
Utilize the BSA solution that the bovine serum albumin of lyophilizing is 26mg/mL with deionized water preparation 30mL concentration, be rapidly added, under continuing magnetic force stirs, the platinum acid chloride solution that 30mL concentration is 19.3mM.It is slowly added to 0.112gNaBH after continuing stirring 10min4(being dissolved in 2mL frozen water), is stirred vigorously 30min.Then the product dialysis 8h that will obtain, is finally placed in last product in freezer dryer and is dried.The bionic nano alloy platinum material (PtBSA) taking the surface parcel bovine serum albumin prepared in right amount is dissolved in wiring solution-forming in PBS, utilizes ICP to be accurately positioned wherein platinum content, and is stored in 4 DEG C of refrigerators stand-by.
Fig. 1 is the transmission electron microscope of Pt nano particle BSA biomimetic material, grain size distribution and uv absorption figure.The Pt nano particle BSA biomimetic material mean diameter that the present invention prepares as can be seen from Figure 1 is about 2nm, and can be seen that its surface is wrapped up by BSA by light and shade difference under high power lens.In ultra-violet absorption spectrum, the absworption peak of about 280nm is the characteristic absorption of BSA, further demonstrates Pt nanoparticle and is wrapped up by BSA.
(3) the bio-safety Journal of Sex Research of Pt nano particle BSA biomimetic material
MTT analytic process is used to study the biocompatibility of bionic nano gold copper-base alloy.First inoculating 8000 A549 cells in each hole of two 96 porocyte culture plates, at 37 DEG C, overnight incubation under the conditions of 5%CO2, now cell is in well-grown logarithmic (log) phase.Then discard old culture medium, every hole rejoin containing variable concentrations platinum complete medium (Concentraton gradient is 0,0.01,0.05,0.1,0.3,0.6,1.2,2.5mM) 100 μ L, cellar culture 24h and 48h.Set 4 multiple holes and blank group simultaneously.After terminating cultivating, supernatant is discarded, every hole adds 100 μ L1mg/mLMTT solution, hatch 4h for 37 DEG C, again supernatant is discarded, every hole adds 100 μ LDMSO, surveys the light absorption value (OD value) in each hole at 490nm with enzyme-linked immunosorbent assay instrument after 37 DEG C of shaking table 10min, and data obtain cell survival rate and the graph of a relation hatching between concentration after processing.
Fig. 2 is the survival rate of cell after A549 cell is hatched with variable concentrations PtBSA 24 hours and 48 hours respectively, and untreated cell is as a comparison.The present invention activity of the A549 cell after mtt assay detection and bionic nano alloy platinum material effect, thus evaluate the biological safety of bionic nano alloy platinum material.Result shows that bionic nano alloy platinum material is little, even if cell survival rate stills remain in about 80% when Cmax 2.5mM on the impact of A549 cell survival rate.But what is interesting is, it has been found that hatching the survival rate of cell after 48h when cell altogether with material and raise on the contrary compared with hatching 24h, this is possibly due to BSA is that cell growth provides a good interface.MTT result shows that bionic nano alloy platinum material involved in the present invention is little to A549 cytotoxicity, and good biocompatibility has potential using value in terms of biomedical imaging.Experiment displays that the Pt nano particle BSA biomimetic material that the present invention relates to is respectively provided with good dispersibility in water, 1640 culture medium and PBS buffer solution (pH7.4).
(4) the CT imaging performance research of Pt nano particle BSA biomimetic material
Being scattered in PBS solution by PtBSA, be configured to the PBS solution of variable concentrations gradient bionic nano alloy platinum material, the platinum containing amount controlling each concentration group is followed successively by: 0,1,2,3,6 and 12mM, is respectively placed in 1.5mLEP pipe stand-by.
GE company gem CT (DiscoveryCT750HD, Milwaukee, USA) is used to be scanned, the CT imaging effect of the PBS solution under test variable concentrations.Selecting FOV=25.0cm, thickness=0.625mm, scan pattern, the tube voltage 120kVp of bulb, milliampere is fixedly installed, and on 6 groups of images of scanning, selected identical aspect, chooses the region of interest of formed objects, measures the CT value of region of interest.Imagery exploitation GSIViewer browser processes.Fig. 3 is the CT contrast imaging comparison diagram of Pt nano particle BSA biomimetic material and Iopromide, Pt nano particle BSA biomimetic material CT imaging effect the most involved in the present invention is significantly larger than the conventional iodine preparation Iopromide of clinic, when molar concentration is 12mM, the imaging effect of Pt nano particle BSA biomimetic material is close to 3 times of iodine preparation Iopromide.And the Pt nano particle BSA biomimetic material prepared has Vitro Tumor CT contrasting effects (such as lung carcinoma cell imaging) and the body vessel imaging effect of excellence as CT contrast agent, has potential application prospect in Biologic Medical Image field.
Claims (5)
1. a CT contrast agent based on Pt nano particle BSA biomimetic material, it is made up of bovine serum albumin (BSA) and nano-platinum particle, it is characterized in that, nano-platinum particle is wrapped up by bovine serum albumin (BSA), and the particle diameter of described contrast agent is 1～10nm.
The preparation method of CT contrast agent based on Pt nano particle BSA biomimetic material the most according to claim 1, comprises the following steps:
(1) bovine serum albumin (BSA) is configured to solution, adds chloroplatinic acid (H2PtCl6·6H2O) solution, stirs 5-30min；
(2) by sodium borohydride (NaBH4) it is configured to solution, it is placed in ice bath；
(3) by sodium borohydride (NaBH4) solution joins in bovine serum albumin (BSA) and platinum acid chloride solution, stirs 0.5-6h；
(4) dialysis, lyophilization processes, and obtains the nano-platinum particle pressed powder of bovine serum albumin parcel.
The preparation method of CT contrast agent based on Pt nano particle BSA biomimetic material the most according to claim 1, described chloroplatinic acid (H2PtCl6·6H2And the mol ratio of bovine serum albumin (BSA) is 25:1-200:1 O).
The preparation method of CT contrast agent based on Pt nano particle BSA biomimetic material the most according to claim 1, described sodium borohydride (NaBH4) and chloroplatinic acid (H2PtCl6·6H2O) in, the mol ratio of platinum is 2:1-6:1.
5. the CT contrast agent described in claim 1 is used for CT radiography.
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| CN108115127A (en) * | 2017-11-29 | 2018-06-05 | 上海师范大学 | A kind of Nanometer Copper biomimetic material and preparation method and application |
| CN108226048A (en) * | 2017-12-31 | 2018-06-29 | 厦门大学 | Nano particle and its synthesis and application with aggregation inducing light absorption enhancing phenomenon |
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| CN104209506A (en) * | 2013-08-22 | 2014-12-17 | 福建医科大学 | Platinum nanoparticle-bovine serum albumin core shell structure and preparation method thereof |
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| CN104209506A (en) * | 2013-08-22 | 2014-12-17 | 福建医科大学 | Platinum nanoparticle-bovine serum albumin core shell structure and preparation method thereof |
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| SHANG-WEI CHOU等: ""In Vitro and in Vivo Studies of FePt Nanoparticles for Dual Modal CT/MRI Molecular Imaging", 《JACS》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108115127A (en) * | 2017-11-29 | 2018-06-05 | 上海师范大学 | A kind of Nanometer Copper biomimetic material and preparation method and application |
| CN108226048A (en) * | 2017-12-31 | 2018-06-29 | 厦门大学 | Nano particle and its synthesis and application with aggregation inducing light absorption enhancing phenomenon |
| CN108226048B (en) * | 2017-12-31 | 2020-07-03 | 厦门大学 | Nano-particles with aggregation-induced light absorption enhancement phenomenon and synthesis method thereof |
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