CN102743768B - Stealth contrast-enhancing material for early diagnosis of tumors and preparation method thereof - Google Patents
Stealth contrast-enhancing material for early diagnosis of tumors and preparation method thereof Download PDFInfo
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- CN102743768B CN102743768B CN201210230833.8A CN201210230833A CN102743768B CN 102743768 B CN102743768 B CN 102743768B CN 201210230833 A CN201210230833 A CN 201210230833A CN 102743768 B CN102743768 B CN 102743768B
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Abstract
The invention discloses a stealth contrast-enhancing material for early diagnosis of tumors and a preparation method thereof. According to the invention, biodegradable nanospheres are used to embed a medical contrast agent, and target molecules specifically interacting with tumor cells are coupled on the surface of the nanospheres and are grafted with pH-sensitive high molecules. The target molecules on the surface of the nanospheres are hidden in the pH-sensitive high molecules under normal physiological conditions and can not interact with non-specific antigens or acceptors of normal cells, so the stealth contrast-enhancing material can not be non-specifically taken by normal cells; however, the target molecules on the surface of the nanospheres are exposed in an environment of tumor tissue because of contraction of high molecules and specifically interact with antigens or acceptors on the surface of tumor cells, which enables high-precision target delivery of the stealth contrast-enhancing material to tumor location to be realized, and therefore, usage amount, toxic and side effects and cost of the medical contrast agent are reduced.
Description
Technical field
The present invention relates to nano-radiography material, especially relate to a kind of nano-radiography material with high specific target function and preparation method thereof.
Background technology
Malignant tumor (cancer) is one of principal disease of serious threat human health, and up to the present, the mankind also do not find the effective ways of the various malignant tumor for the treatment of.The method of generally acknowledged reduction cancer mortality is that early discovery, early treatment detects it, and effectively treat before cancerous cell diffusion.At present, the Main Diagnosis technology of all kinds of malignant tumor can only be found the tumor that size is greater than 1 centimetre, helpless to less tumor, as nuclear magnetic resonance (MRI) [Biomaterials, 2011; 32:5167-5176], computer X-ray fault imaging (CT) and positron emission tomography (PET).Medical science contrast agent can improve detection sensitivity and the spatial resolution of these diagnostic techniquess, in order to realize earlier detection and the diagnosis to various malignant tumor, need to develop all kinds of high performance medical science contrast agent [Nat.Nanotechnol., 2010; 5:815-821].
The commercial MRI contrast agent of the first is the Gd-DTPA that the German Schering H.J.Weinmenn of company develops, and it is coordination compound [Angew.Chem.Int.Edit., 2010 of diethylenetriamine pentaacetic acid (DTPA) and Gd (III); 49:1231-1233].Subsequently, studying more is superparamagnetism contrast agent.The magnetic moment of superparamagnetism contrast agent and susceptibility is all much larger than human tissue structure, also much larger than paramagnetism chelate, but minimum because of its water solublity, can only adopt the form administration of homogenate or colloid.Performance and the nephrotoxicity become due to this type of contrast agent with liver, splenic tumor little more, therefore extremely people's attention, focus is to select suitable medicine carrying medium, formula, dosage form and preparation method, and carries out property test [Biomaterials, 2011; 32:4584-4593].The brilliant researcher FeCl of seminar far away of Institute of Chemistry, Academia Sinica
36H
2o has successfully prepared the controlled magnetic nano crystal material of size pattern, has also furtherd investigate with FeCl
36H
2o is that single raw material is prepared Fe
3o
4the mechanism of nanocrystal, this magnetic nano crystal can be advantageously applied to nuclear magnetic resonance [Angew.Chem.Int.Ed., 2005; 44:123-126]; Subsequently, they adopt " one pot reaction method " to synthesize magnetic MPEG-COOH (monocarboxyl-terminated poly (ethylene the glycol)) nanocrystal of covalent bonds, live body rat MRI experimental result shows that the magnetic nanoparticle that MPEG modifies has extraordinary biocompatibility, there are very large potential [Adv.Mater., 2005 as MRI contrast agent; 17:1001-1005]; The finishing of preparing with single step reaction has the magnetic nanometer particles of carboxyl PEG not only to have excellent MRI radiography function, and shows longer blood circulation time and low bio-toxicity [Adv.Mater., 2006; 18:2553-2556].Southeast China University turns round and look at the peplos microvesicle that peaceful teach problem group has been prepared one and have PLA/PVA ELECTRODE WITH BILAYER POLYMERIC beyond the region of objective existence shell (thickness is 50-70nm), and successfully use the Superparamagnetic Iron Oxide nanoparticle (SPION) of its embedding 12nm, significantly improve the susceptibility of peplos microvesicle, in body, MRI experimental results show that its good result as contrast agent [Biomaterials, 2009; 30:3882-3890].The nano-particle with superparamagnetism due to its unique magnetics and electric property, there is the advantages such as large specific surface area, high chemical stability, show tempting application prospect in MRI contrast agent field.
In recent years, (energy targeting is in the compound of cancerous cell by target molecule research, as parts such as monoclonal antibody, folic acid and galactosamines) and Superparamagnetic Iron Oxide nanoparticle (SPION) combination, the targeting of SPION to tumor tissues improved.For example, Donghua University's history teach problem group that faces south adopts thermal decomposition method successfully to prepare surface to be coated with the Superparamagnetic Iron Oxide nuclear shell type nano meter particle (Fe of silicon
3o
4@SiO
2nPs),, then by its surperficial ammonification, covalent coupling paramagnetism gadolinium complex (Gd-DTPA, DTPA: diethylenetriamine pentaacetic acid) and arginine-glycine-aspartic acid oligopeptide (RGD), in body, MRI experiment shows this multi-functional Fe
3o
4@SiO
2(Gd-DTPA)-selectively targeted surface expression of RGD nanoparticle energy has cancerous cell [Biomaterials, 2011 of α v β 3 integrins; 32:4584-4593].The Miguel-Sancho of Univ Zaragoza of Spain teach problem group high temperature pyrolysis ferric acetyl acetonade in 2,2'-ethylenedioxybis(ethanol)., prepare water miscible SPION, and in the coupling of SPION surface a kind of model antibody, detected the immunoreation of antibody-SPION complex by euzymelinked immunosorbent assay (ELISA) (ELISA), this research shows, in a kind of monoclonal antibody for cancerous cell surface antigen of SPION surface graft, can make a kind of MRI contrast agent [Chem.Mater., 2011 tumor tissues to targeting; 23:2795-2802].The Kang Yan of NUS hall teach problem group by Transfer Radical Polymerization (ATRP) in the coupling of SPION surface poly (glycidyl methacrylate)-polyethylene glycol methacrylate-styrene polymer copolymer (P (GMA-co-PEGMA)), PEGMA plays stabilized nanoscale particle, extends the effect of its body-internal-circulation time, carry out the part folic acid of grafting energy target cancer cell by GMA, thereby make a kind of initiatively targeting in the MRI of tumor tissues contrast agent [Langmuir, 2012; 28:563-571].University Of Tianjin's normal Tianjin teach problem group has the polymer phospholipid parcel SPION of part folic acid with coupling, and has further assessed its effect as targeting type MRI contrast agent [Pharmaco1.Res., 2011; 64:410-419].The combination of target molecule (monoclonal antibody or part) and SPION is all passed through in these researchs, and in raising, SPION has made contribution aspect the targeting of tumor tissues, and the early diagnosis of malignant tumor is had to important scientific meaning and social economic value.
Computer X-ray fault imaging (CT) utilizes the difference of the transmitance of human body different tissues to X ray, can carry out imaging [Nature Medicine, 1996 to human body and tissue; 2:473-475].The use of CT contrast agent has greatly increased discrimination [Physics in Medicine and Biology, 2002 of target tissue and surrounding tissue especially; 47:3369-3385].Current x-ray contrast agent has the diodone [Academic Radiology, 2003 that wrap into liposome; 10:475-483], dysprosium-DTPA-dextran polymer [Academic Radiology, 2002; 9:784-792], iodine polymer [Advanced Drug Delivery Reviews, 2002 of PEG parcel; 54:235-252], fluorescence bromide [Academic Radiology, 1994; 1:151-153], and be connected to iodine [Academic Radiology, 1999 of polyethylene sheath; 6:61-65] etc., wherein, the application of the contrast agent based on organic molecule iodine is more general.This is because iodine has higher X-ray absorption coefficient [Advanced Drug Delivery Reviews, 1999; 37:159-173].But these iodine substances, owing to being removed and making contrast time very short by kidney rapidly, have nephrotoxicity, and X ray can induce iodine substance to ionize out iodide ion, causes toxicity.Along with the development of nano material technology and biological nano technology, the novel CT contrast agent based on nano-particle is expected to improve above-mentioned shortcoming [Small, 2007; 3:333-341].The size little (1～100nm) of nano-particle, can enter blood capillary [Journal of Artificial Organs, 2005 of micron-scale internal diameter; 8:77-84], therefore can enter more tissue; And, because the permeability of cancerous issue position blood capillary strengthens [American Journal of Pathology, 2000; 156:1363-1380], nano-particle can be deposited in cancerous issue more by seepage effect, thereby better to cancerous region imaging [CT theory and application research, 2009; 18:15-25].
In addition, positron emission tomography (PET) has been widely used in the diagnosis of Several Kinds of Malignancy, and the diagnostic value of tumor patient is also more and more caused to concern.Over nearly 20 years, nucleic
182-(fluoro-18)-1,5-anhydroglucitols (FDG) positron emission tomographies (PET) inspection method of fluorine labelling grows up gradually.FDG-PET can show the metabolic characteristics of focus, contributes to distinguish the good pernicious matter of focus, and to tumor also have by stages certain help [Chinese tuberculosis and breathe magazine, 2005; 28:221-224].Bibliographical information
18f-FDG PET video picture
99mthe video picture of technetium-methylene diphosphonate sensitiveer [Radiology, 1999; 212:803-809].
For the imaging patterns such as MRI, CT and PET, that optical imagery has is radiationless, feature, especially near-infrared fluorescence imaging cheaply, can partly realize detection and imaging to deep tissues and organ, aspect optical imagery, there are specific advantage [Nature Methods, 2009; 6:465-469].The core of optical imagery is fluorescein contrast agent, and the problem mainly facing comprises the transmission of profound light and the luminous quantum efficiency of collection and fluorescein contrast agent, bleach-resistant, good biocompatibility and targeting [Biomaterials, 2009; 30:5592-5600].Near infrared fluorescent dye (as phthalocyanine) containing tetrapyrrole group is the focus of paying close attention in recent years, makes it aspect near-infrared probe, have good application prospect [J.Am.Chem.Soc., 2009 because having good optical physics behavior; 131:2432-2433].In the design of fluorescein contrast agent, targeting is a key issue, the most commonly utilizes initiatively drug-supplying system [SCI, 2011 of target tumor cell of receptor design of cell surface; 32:1010-1012].
According to the domestic and international present Research analysis of above-mentioned medical science radiography material, synthetic to tumor tissues have targeting radiography material, reduce contrast agent dosage, reduce toxicity and preparation cost is the major trend of research.At present, the preparation of targeting radiography material is generally by binding target molecule on contrast agent (monoclonal antibody or part), thereby realizes the specificity to cancerous cell.But, normal cell surface also exists heterogenetic antigen or receptor, these antigens or receptor also can with target molecule (monoclonal antibody or part) combination, thereby detection sensitivity and the spatial resolution of various diagnostic techniquess are affected, therefore, develop that to have more the contrast agent of high specific target function be problem in the urgent need to address at present.
Summary of the invention
The invention provides a kind of stealthy radiography material and preparation method thereof for early diagnosis of tumor, described stealthy radiography material energy high specific targeted is to tumor locus.
The stealthy radiography material of a kind of early diagnosis of tumor, is made up of biodegradable nanosphere, the medical science contrast agent that is embedded in described nanosphere inside, pH responsive type macromolecule and the target molecule that is connected in described nanosphere surface.
Described pH responsive type macromolecule is easy to change in the scope of pH5.0～6.0, become contraction state by linear extended configuration, described target molecule can be come out, cell is had to less toxicity simultaneously, described pH responsive type molecule is preferably at least one in N-isopropylacrylamide-acrylic copolymer and N-isopropylacrylamide-methacrylic acid copolymer, and molecular weight ranges is 2k-1000k.
Above-mentioned early diagnosis of tumor of the present invention with the principle of the selectively targeted tumor cell of stealthy radiography material as shown in Figure 1.Under normal physiological conditions, the pH value of body is between 7.3～7.4, the target molecule on described nanosphere surface is hidden among the pH responsive type macromolecule of linear extended configuration, can not interact with Normocellular heterogenetic antigen or receptor, therefore this stealth radiography material can not be by normal cell non-specific uptake; And under tumor tissues environment, pH value is about 5.5, pH responsive type macromolecule can occur to change mutually and shrink, the target molecule on nanosphere surface is come out, interact with the antigen of tumor cell surface or receptor generation specificity, stealthy radiography material is absorbed by tumor cell, thus realize by contrast agent height accurately targeted to tumor locus, improve detection sensitivity and spatial resolution, reduced dosage, toxic and side effects and the cost of contrast agent.
The effect of described medical science contrast agent is for improving imaging resolution, MRI contrast agent well known in the art, CT contrast agent, PET contrast agent or fluorescein contrast agent can be applied to the present invention, in order to make described contrast agent can successfully be embedded in Biodegradable nanometer ball (abbreviation nanosphere) inside, contrast agent particle diameter is preferably below 15nm.
Described MRI contrast agent is the material with MRI radiography function, is preferably T
2class MRI contrast agent and T
1class MRI contrast agent, selected materials need to have good water solublity, described T
2class MRI contrast agent is Superparamagnetic Iron Oxide nanoparticle (SPION) more preferably, described T
1class MRI contrast agent more preferably has the Gd of larger effective magnetic moment
3+, Dy
3+, Mn
2+or Fe
3+deng micromolecule paramagnetic contrast medium, or form the macromolecular paramagnetic contrast agent of stable chelate with suitable part, as Gd-DTPA coordination compound, Gd-DOTA coordination compound and Gd
2o
3at least one in nanoparticle, wherein, DTPA is diethylenetriamine pentaacetic acid, DOTA is Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand-N, N ', N ", N-tetraacethyl.
Described CT contrast agent is a kind of material of the CT of having radiography function, selected materials need to have good water solublity, be preferably nanoparticle or the micromolecular compound with CT radiography function, more preferably gold nano grain, gold nanorods, gold nano cage, iohexol and BaSO
4in at least one.
Described PET contrast agent is a compounds that can improve PET imaging resolution, is preferably
18f-FDG (2-(fluoro-18)-1,5-anhydroglucitol),
64cu,
124i and
94at least one in C.
Described fluorescein contrast agent is the near infrared fluorescent dye that can improve near-infrared optical molecular imaging, is preferably phthalocyanine.
Described nanosphere is as carrier, embedding contrast agent is realized the effect of slow release, controlled release, little to human body toxic, biodegradable nontoxic natural macromolecular or synthetic macromolecule can be applied to the present invention, material therefor is preferably at least one in protein, oligopeptide, polysaccharide, polyethers or polyesters macromolecule, more preferably albumin and chitosan; Described radiography material generally uses by intravenous mode, particle diameter can not be too large, the particle diameter of described nanosphere is preferably below 500nm, connect the above pH responsive type macromolecule and target molecule for the nanosphere surface described simultaneously, particle diameter can not be too little, more preferably 50-200nm of the particle diameter of described nanosphere.
Described target molecule is for to have the interactional compound of specificity with tumor cell, and energy targeting, in cancerous cell, is preferably at least one in monoclonal antibody, folic acid or galactosamine.
In the present invention, the pH responsive type macromolecule described in nanosphere surface with the number of target molecule than being 0.2-5.0, now, in normal cell tissue, described target molecule can be hidden among described pH responsive type macromolecule, and in tumor tissues environment, described target molecule can come out.
The present invention also provides the described early diagnosis of tumor preparation method of stealth material, comprises the steps:
(1) preparation is embedded with the Biodegradable nanometer ball of medical science contrast agent;
(2) react described target molecule is connected on the surface of the Biodegradable nanometer ball obtaining in step (1) by covalent coupling, obtain intermediate;
(3) on the surface of the intermediate obtaining in step (2), adopt the synthetic described pH responsive type macromolecule of living radical polymerization technique, obtain described early diagnosis of tumor stealth material.
The Biodegradable nanometer ball that is embedded with medical science contrast agent in step (1) can be standby by supersound method or desolventizing legal system, and wherein supersound method comprises again Water-In-Oil method, oil-in-water method and W/O/W multi-emulsion method, is introduced respectively below.
Water-In-Oil method: use the aqueous solution that has dissolved hydrophilic medical science contrast agent and hydrophilic film material as water, with the organic solvent that has dissolved oil soluble emulsifying agent as oil phase, by water and oil phase mix and blend carry out rough segmentation loose after, carry out emulsifying with ultrasonic cell-break machine again, obtain water-in-oil type nanoemulsion liquid, under magnetic agitation, in gained nanoemulsions, add cross-linking agent to carry out crosslinking curing again, removing excessive cross-linking agent and emulsifying agent can obtain.
Oil-in-water method: use the organic solvent that has dissolved hydrophobicity medical science contrast agent and hydrophobic film material as oil phase, with the aqueous solution that has dissolved water soluble emulsifier as water, by stirring mixed with water oil phase carry out rough segmentation loose after, carry out emulsifying with ultrasonic cell-break machine again, obtain oil-in-water type nanoemulsions, under magnetic agitation, in gained nanoemulsions, add cross-linking agent to carry out crosslinking curing again, remove excessive cross-linking agent and emulsifying agent and can obtain the Biodegradable nanometer ball that is embedded with medical science contrast agent.
W/O/W multi-emulsion method: use the aqueous solution that has dissolved hydrophilic medical science contrast agent as water, with the organic solvent that has dissolved hydrophobic film material and oil soluble emulsifying agent as oil phase, by water and oil phase mix and blend carry out rough segmentation loose after, carry out emulsifying with ultrasonic cell-break machine again, obtain water-in-oil type nanoemulsion liquid, again gained water-in-oil type nanoemulsion liquid is added and in the water that is dissolved with water soluble emulsifier, carry out ultrasonic emulsification, thereby obtain W/O/W type nanoemulsions, under magnetic agitation, in gained W/O/W type nanoemulsions, add cross-linking agent to carry out crosslinking curing again, remove excessive cross-linking agent and emulsifying agent and can obtain the Biodegradable nanometer ball that is embedded with medical science contrast agent.
Desolventizing method: water solublity medical science contrast agent and nanosphere material oligopeptide or protein are dissolved in NaCl aqueous solution, then drip ethanol, dropping process continues magnetic agitation, after solution becomes milky suspension, add glutaraldehyde cross-linking curing nano ball, remove excessive cross-linking agent and can obtain the Biodegradable nanometer ball that is embedded with medical science contrast agent.
Covalent coupling reaction reacting for the functional group of target molecule end and the functional group on nanosphere surface formation covalent chemical bond described in step (2), for example: under the catalysis of EDAC (1-ethyl-(3-dimethylaminopropyl) carbodiimide), carboxyl and the amino chemical reaction that forms amide group.
In the time that the material of nanosphere contains carboxyl (as polyglutamic acid, poly-aspartic-acid, the peptide and protein that contains glutamic acid and aspartic acid and polysaccharide of containing carboxyl etc.), can select to contain the amino part such as monoclonal antibody or galactosamine as target molecule, then use the carboxyl on EDAC and NHS (N-maloyl imines) activation nanosphere surface, drip again the target molecule solution with terminal amino group, make the carboxyl of activation react the stable amido link of formation with the amino covalence of target molecule; In the time that the material of nanosphere contains amino (as polylysine, poly arginine, contain lysine and arginic peptide and protein and contain amino polysaccharide etc.), can select the part such as monoclonal antibody or folic acid that contains carboxyl as target molecule, then take to make it to graft on nanosphere surface after the carboxyl of above method activation target molecule; For neither containing carboxyl, not containing amino Biodegradable material (as polyethers and polyesters macromolecule) again, can adopt copolymerization method to make it with some amino or carboxyl, be made into nanosphere and adopt above same procedure can make target molecule graft on nanosphere surface afterwards.
The described living radical polymerization technique (being called again controllable polymerization) of step (3) is the technology of comparative maturity in this area, can carry out according to following steps in the present invention:
First, the nanosphere surface coupling 4-chloromethyl benzoic acid (CBA) that utilizes the catalysis of EDAC to obtain in step (2), then sodium diethyldithiocarbamate (NaDC) is fixed on the benzyl position methyl on described CBA, finally the living radical graft polymerization reaction on nanosphere surface by ultraviolet trigger monomer N-isopropylacrylamide (NIPAM), acrylic acid (AA) or methacrylic acid (MAA).Wherein, macromolecule occurs to change mutually and the pH point that shrinks can pass through the mol ratio control between AA (or MAA) and NIPAM, when described mol ratio is in 1: 1～50 scopes, can control described pH responsive type macromolecule and change in the scope of pH5.0～6.0.High molecular grafting density can be passed through the coupling amount control of nanosphere surface C BA, and the coupling amount of nanosphere surface C BA can be controlled by the initial concentration of CBA and response time; High molecular chain length length (molecular weight) can be controlled by concentration and the polymerization reaction time of monomer when synthetic.
Step (3) can also be reacted realization by covalent coupling, for example, by reacting of carboxyl functional group and amido functional group, pH responsive type macromolecule is covalently coupled on the nanosphere surface that step (2) obtains.First, the high molecular synthetic method of pH responsive type adopts the radical polymerization take AIBN as initiator, now adopt segment copolymerization method to make the high molecular one end of pH responsive type there are several allylamines (or acrylic acid), thereby make the high molecular end of thermosensitive type there is several amino (carboxyl).Then,, under the catalysis of EDAC, utilize carboxyl with amino reacting, pH responsive type macromolecule to be covalently coupled on nanosphere surface.
Compared with the existing technology, beneficial effect of the present invention is embodied in:
(1) by the high molecular effect of pH responsive type, improved the target function to tumor cell to radiography material;
(2) reduce the consumption of contrast agent, reduced toxic and side effects and manufacturing cost.
Accompanying drawing explanation
Fig. 1 is the mechanism figure of early diagnosis of tumor of the present invention with the selectively targeted cancerous cell of stealthy radiography material;
Fig. 2 utilizes the reaction schematic diagram of living radical graft polymerization technique in Biodegradable nanometer ball surface synthetic isopropyl acrylamide-methacrylic acid copolymer (PNIPAM-MAA) in embodiment 1;
Fig. 3 is the transmission electron microscope photo of albumin nanospheres prepared in embodiment 1;
Fig. 4 is the transmission electron microscope photo comparison diagram that albumin nanospheres (a) prepared in embodiment 1 and surperficial coupling have the high molecular albumin nanospheres of pH responsive type (b);
Fig. 5 is the quantitative analysis figure that early diagnosis of tumor prepared in embodiment 6 is absorbed by hepatoma carcinoma cell HepG2 with stealthy radiography material;
Fig. 6 is the quantitative analysis figure that early diagnosis of tumor prepared in embodiment 11 is absorbed by cervical cancer cell HeLa with stealthy radiography material.
The specific embodiment
(1) there is the preparation of the Superparamagnetic Iron Oxide nanoparticle (SPION) of MRI radiography function
By FeCl
36H
2o (5.4g, 20mmol) and enuatrol (18.3g, 60mmol) be dissolved in the mixed solvent of 40mL ethanol, 30mL deionized water and 70mL normal hexane, be heated to 70 ℃ of reaction 4h, then mixed solution is transferred in separatory funnel, remove lower floor's water, upper oil phase 30mL deionized water wash three times, will obtain the solid of iron oleate complex after normal hexane evaporation.By iron oleate complex (18g; 20mmol) and oleic acid (2.8g; 10mmol) be dissolved among 1-octadecane alkene (30g); again mixture is heated to 320 ℃ (heating rate is 3.3 ℃/min); react 1h under argon shield after; room temperature cooling solution; add again ethanol (250mL); centrifugal (6000rpm) can obtain the monodispersed SPION that particle diameter is about 14nm for ten minutes; finally by gained SPION vacuum drying, cryopreservation (0-4 ℃).
(2) preparation of biodegradable albumin nanospheres and the embedding to MRI contrast agent SPION thereof
The 10mM NaCl aqueous solution of preparation pH10.8, bovine serum albumin (BSA) aqueous solution that is 20mg/mL by this solution preparation concentration again, then in 2.0mL BSA aqueous solution, add 2.0mL dehydrated alcohol, after magnetic agitation 10min, add 4.0mL ethanol (volume ratio of total ethanol addition and BSA aqueous solution is as 3.0) take the rate of addition of 2.0mL/min, dropping process continues magnetic agitation, ethanol adds 8% glutaraldehyde water solution (glutaraldehyde-BSA mass ratio is 0.24) crosslinking curing 24h immediately after dripping and finishing, then add 1.0mL glycine (40mg/mL) to neutralize excessive glutaraldehyde, after reaction 2.0h, sample is carried out to centrifugal (20, 000 × g, 20min), twice of 10mM NaCl solution washing of gained sample, last lyophilization 48h can obtain biodegradable albumin nanospheres.The MRI contrast agent SPION that the first step is made is dispersed in the BSA aqueous solution of 20mg/mL, adopts above-mentioned same method can make the albumin nanospheres that is embedded with contrast agent SPION.
(3) coupling of albumin nanospheres surface ligand folic acid
Under the catalysis of EDAC (1-ethyl-(3-dimethylaminopropyl) carbodiimide), utilize the chemical reaction between the carboxyl of folic acid and the amino on albumin nanospheres surface, can selectively targetedly act on the part folic acid of the tissues such as the brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma in albumin nanospheres surface coupling.Concrete preparation method is summarized as follows: the folic acid solution of preparing 500 μ g/mL with phosphate buffer (PBS) as solvent, 50mg EDAC is dissolved in to 10mL folic acid solution (ice bath), then add 90mL to be dissolved in the albumin nanospheres suspension (5.0mg/mL) that is embedded with SPION of PBS, mixed liquor is placed in to room temperature lower magnetic force to be stirred, react 24 hours, sample is carried out to centrifugal (20, 000 × g, 20min), gained sample PBS washed twice, last lyophilization 48h can obtain surperficial coupling part folic acid, and the inner albumin nanospheres that is embedded with SPION.
(4) albumin nanospheres surface p H responsive type is high molecular synthetic
Adopt living radical graft polymerization technique (controllable polymerization) at the synthetic a kind of pH responsive type macromolecule in the surface of albumin nanospheres (be embedded with SPION and surperficial coupling has part folic acid), be N-isopropylacrylamide-methacrylic acid copolymer (PNIPAM-MAA), as shown in Figure 2.The CBA solution of preparation 5mg/mL, 50mg EDAC is dissolved in to 10mL CBA solution (ice bath), then add 90mL albumin nanospheres suspension (5.0mg/mL), mixed liquor is placed in to room temperature lower magnetic force to be stirred, react 24 hours, sample is carried out to centrifugal (20, 000 × g, 20min), by gained sample dispersion in 100mL ultra-pure water, add 3.0g NIPAM and 200mg MAA, at 400W uviol lamp (ultraviolet wavelength 300-500nm, peak value 350nm) the lower 1-5 hour that irradiates, by centrifugal gained composite nanoparticle, washing, lyophilizing, thereby make a kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, the stealthy radiography material of the early diagnosis of tumor such as nasopharyngeal carcinoma, can be used as the MRI contrast agent of T2 weighting.
Fig. 3 is the transmission electron microscope photo of albumin nanospheres prepared in embodiment 1;
Fig. 4 is the transmission electron microscope photo comparison diagram that albumin nanospheres (a) prepared in embodiment 1 and surperficial coupling have the high molecular albumin nanospheres of pH responsive type (b), (b) in the trace circle on nanosphere surface be the high molecular evidence of the nanosphere successful coupling pH responsive type in surface.
(1) there is the preparation of the paramagnetism Gd-DTPA coordination compound of MRI radiography function
Get 3g Gd
2o
3mix with 7.3g DTPA, the 40mL that adds water, heating stirring and refluxing 16h, after question response thing all dissolves, temperature is down to room temperature, with after filter membrane elimination impurity, add 120mL acetone, separate out white gels shape precipitation, with washing with acetone 3 times, to dry to constant weight, yield is 80%.In coordination compound synthetic, selection metal-oxide is raw material, can be by unreacted Gd when separation
2o
3remove by filter.
(2) coupling of the preparation of biodegradable albumin nanospheres and the embedding to MRI contrast agent Gd-DTPA coordination compound thereof, albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 1, can make the stealthy radiography materials of early diagnosis of tumor such as a kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as the MRI contrast agent of T1 weighting.
Embodiment 3
(1) there is the preparation of the gold nano grain of CT radiography function
The first step, the NaBH of preparation 10mM
4the HAuCl of aqueous solution, 10mM
43H
2the CTAB aqueous solution of O aqueous solution and 75mM, by the HAuCl of 0.125mL
43H
2o aqueous solution adds the CTAB aqueous solution of 4.375mL even, then adds the NaBH of 0.500mL ice bath
4aqueous solution, is inverted mixing 2h and makes 5mL gold seeds liquid.Second step, the L-AA aqueous solution of preparation 6.258mM, the L-AA aqueous solution of getting 9.587mL adds the CTAB aqueous solution of the 75mM of 0.213mL, and then adds the HAuCl of the 10mM of 0.2mL
43H
2o aqueous solution, gentle agitation, makes the growth-promoting media of 10mL, when the color of growth-promoting media becomes colorless from orange, adds immediately the gold seeds liquid of 5 μ L, is inverted and mixes until mixed liquor color slowly reddens.Finally, mixed liquor is left standstill to 24h.
(2) coupling of the preparation of biodegradable albumin nanospheres and the embedding to CT contrast agent gold nano grain thereof, albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 1, can make the stealthy radiography materials of early diagnosis of tumor such as a kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Change MRI contrast agent SPION in embodiment 1 step (1) into PET contrast agent, choosing
18f-FDG is as medical science contrast agent, the preparation of biodegradable albumin nanospheres and to PET contrast agent
18the embedding of F-FDG, the coupling of albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 1, can make the stealthy radiography materials of early diagnosis of tumor such as a kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 5
Change MRI contrast agent SPION in embodiment 1 step (1) into fluorescein contrast agent, choosing contains the near infrared fluorescent dye phthalocyanine of tetrapyrrole group as medical science contrast agent, the preparation of biodegradable albumin nanospheres and the embedding to fluorescein contrast agent phthalocyanine thereof, the coupling of albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type is high molecular synthetic identical with embodiment 1, can make a kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, the stealthy radiography material of the early diagnosis of tumor such as nasopharyngeal carcinoma, can be used as fluorescein contrast agent.
Change the target molecule of albumin nanospheres surface coupling in embodiment 1 step (3) into galactosamine, under the catalysis of EDAC, utilize the chemical reaction between the amino of galactosamine and the carboxyl on albumin nanospheres surface, can selectively targetedly act on the part galactosamine of hepatocarcinoma in albumin nanospheres surface coupling.Concrete preparation method is summarized as follows: the galactosamine solution of preparing 500 μ g/mL with PBS as solvent, 50mg EDAC is dissolved in to 10mL galactosamine solution (ice bath), then add 90mL to be dissolved in the albumin nanospheres suspension (5.0mg/mL) that is embedded with medical science contrast agent of PBS, mixed liquor is placed in to room temperature lower magnetic force to be stirred, react 24 hours, sample is carried out to centrifugal (20, 000 × g, 20min), gained sample PBS washed twice, last lyophilization 48h can obtain surperficial coupling part galactosamine, and the inner albumin nanospheres that is embedded with medical science contrast agent.Other steps are identical with embodiment 1, can make the stealthy radiography material of a kind of hepatocarcinoma early diagnosis, can be used as T
2the MRI contrast agent of weighting.
Made early diagnosis of tumor is shown in Fig. 5 with the quantitative analysis that stealthy radiography material is absorbed by hepatoma carcinoma cell HepG2, wherein, SPION-AN-GAL-PM represents that inside is embedded with contrast agent SPION, surperficial coupling and has the albumin nanospheres (AN) of target molecule GAL and pH responsive type macromolecule PNIPAM-MAA (PM); SPION-AN representative is only embedded with the albumin nanospheres (AN) of contrast agent SPION.As shown in Figure 5, the amount that the amount that HepG2 cell absorbs SPION-AN-GAL-PM in the time of pH5.5 is absorbed SPION-AN-GAL-PM during than pH7.4 is much higher, the amount of absorbing SPION-AN during also apparently higher than pH5.5 obviously.This result shows, SPION-AN-GAL-PM can be absorbed by a large amount of specificitys of hepatoma carcinoma cell in the time of pH5.5, and in the time of pH7.4 because target molecule is hidden among macromolecule and can only be absorbed on a small quantity by hepatoma carcinoma cell, this just illustrates that pH responsive type macromolecule can prevent that target molecule is by normal cell non-specific uptake.
Embodiment 7
Change the target molecule of albumin nanospheres surface coupling in embodiment 2 into galactosamine, concrete preparation method is identical with embodiment 6, and other steps are identical with embodiment 2, can make the stealthy radiography material of a kind of hepatocarcinoma early diagnosis, can be used as T
1the MRI contrast agent of weighting.
Embodiment 8
Change the target molecule of albumin nanospheres surface coupling in embodiment 3 into galactosamine, concrete preparation method is identical with embodiment 6, and other steps are identical with embodiment 3, can make the stealthy radiography material of a kind of hepatocarcinoma early diagnosis, can be used as CT contrast agent.
Embodiment 9
Change the target molecule of albumin nanospheres surface coupling in embodiment 4 into galactosamine, concrete preparation method is identical with embodiment 6, and other steps are identical with embodiment 4, can make the stealthy radiography material of a kind of hepatocarcinoma early diagnosis, can be used as PET contrast agent.
Embodiment 10
Change the target molecule of albumin nanospheres surface coupling in embodiment 5 into galactosamine, concrete preparation method is identical with embodiment 6, and other steps are identical with embodiment 5, can make the stealthy radiography material of a kind of hepatocarcinoma early diagnosis, can be used as fluorescein contrast agent.
Embodiment 11
Monomer methacrylic acid (MAA) during by the middle pH responsive type Polymer Synthesizing of embodiment 1 step (5) changes acrylic acid (AA) into, thereby at the synthetic a kind of pH responsive type macromolecule N-isopropylacrylamide-acrylic copolymer (PNIPAM-AA) in albumin nanospheres surface, other experimental techniques are all identical with embodiment 1 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as the MRI contrast agent of T2 weighting.
Made early diagnosis of tumor is shown in Fig. 6 with the quantitative analysis that stealthy radiography material is absorbed by cervical cancer cell HeLa, wherein, SPION-AN-FA-PA represents that inside is embedded with contrast agent SPION, surperficial coupling and has the albumin nanospheres (AN) of target molecule FA and pH responsive type macromolecule PNIPAM-AA (PA), SPION-AN to represent the inner albumin nanospheres (AN) that is embedded with contrast agent SPION.As shown in Figure 6, the amount that the amount that HeLa cell absorbs SPION-AN-FA-PA in the time of pH5.5 is absorbed SPION-AN-FA-PA during than pH7.4 is much higher, the amount of absorbing SPION-AN during also apparently higher than pH5.5 obviously.This result shows, SPION-AN-FA-PA can be absorbed by a large amount of specificitys of cervical cancer cell in the time of pH5.5, and in the time of pH7.4 because target molecule is hidden among macromolecule and can only be absorbed on a small quantity by cervical cancer cell, this just illustrates that pH responsive type macromolecule can prevent that target molecule is by normal cell non-specific uptake.
Embodiment 12
Change the monomer methacrylic acid (MAA) when the Polymer Synthesizing of pH responsive type in embodiment 2 into acrylic acid (AA), thereby at the synthetic a kind of pH responsive type macromolecule N-isopropylacrylamide-acrylic copolymer (PNIPAM-AA) in albumin nanospheres surface, other experimental techniques are all identical with embodiment 2 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as T
1the MRI contrast agent of weighting.
Embodiment 13
Change the monomer methacrylic acid (MAA) when the Polymer Synthesizing of pH responsive type in embodiment 3 into acrylic acid (AA), thereby at the synthetic a kind of pH responsive type macromolecule N-isopropylacrylamide-acrylic copolymer (PNIPAM-AA) in albumin nanospheres surface, other experimental techniques are all identical with embodiment 3 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Embodiment 14
Change the monomer methacrylic acid (MAA) when the Polymer Synthesizing of pH responsive type in embodiment 4 into acrylic acid (AA), thereby at the synthetic a kind of pH responsive type macromolecule N-isopropylacrylamide-acrylic copolymer (PNIPAM-AA) in albumin nanospheres surface, other experimental techniques are all identical with embodiment 4 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 15
Change the monomer methacrylic acid (MAA) when the Polymer Synthesizing of pH responsive type in embodiment 5 into acrylic acid (AA), thereby at the synthetic a kind of pH responsive type macromolecule N-isopropylacrylamide-acrylic copolymer (PNIPAM-AA) in albumin nanospheres surface, other experimental techniques are all identical with embodiment 5 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as fluorescein contrast agent.
Embodiment 16
Change the monomer methacrylic acid (MAA) when the Polymer Synthesizing of pH responsive type in embodiment 6 into acrylic acid (AA), thereby at the synthetic a kind of pH responsive type macromolecule N-isopropylacrylamide-acrylic copolymer (PNIPAM-AA) in albumin nanospheres surface, other experimental techniques are all identical with embodiment 6 with condition, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as T
2the MRI contrast agent of weighting.
Embodiment 17
Change the monomer methacrylic acid (MAA) when the Polymer Synthesizing of pH responsive type in embodiment 7 into acrylic acid (AA), thereby at the synthetic a kind of pH responsive type macromolecule N-isopropylacrylamide-acrylic copolymer (PNIPAM-AA) in albumin nanospheres surface, other experimental techniques are all identical with embodiment 7 with condition, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as T
1the MRI contrast agent of weighting.
Embodiment 18
Change the monomer methacrylic acid (MAA) when the Polymer Synthesizing of pH responsive type in embodiment 8 into acrylic acid (AA), thereby at the synthetic a kind of pH responsive type macromolecule N-isopropylacrylamide-acrylic copolymer (PNIPAM-AA) in albumin nanospheres surface, other experimental techniques are all identical with embodiment 8 with condition, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as CT contrast agent.
Embodiment 19
Change the monomer methacrylic acid (MAA) when the Polymer Synthesizing of pH responsive type in embodiment 9 into acrylic acid (AA), thereby at the synthetic a kind of pH responsive type macromolecule N-isopropylacrylamide-acrylic copolymer (PNIPAM-AA) in albumin nanospheres surface, other experimental techniques are all identical with embodiment 9 with condition, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as PET contrast agent.
Embodiment 20
Change the monomer methacrylic acid (MAA) when the Polymer Synthesizing of pH responsive type in embodiment 10 into acrylic acid (AA), thereby at the synthetic a kind of pH responsive type macromolecule N-isopropylacrylamide-acrylic copolymer (PNIPAM-AA) in albumin nanospheres surface, other experimental techniques are all identical with embodiment 10 with condition, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as fluorescein contrast agent.
Embodiment 21
Change biodegradable albumin nanospheres in embodiment 1 into chitosan nano ball, its preparation and as follows to the embedding method of medical science contrast agent: the chitosan solution of preparation 0.2% (w/v), solvent is the acetic acid of 1% (w/v), medical science contrast agent (identical with embodiment 1) is dispersed in chitosan solution, the pH value of this solution is adjusted to 4.7-4.8 with sodium hydroxide; Sodium tripolyphosphate (TPP) aqueous solution of preparation 0.3% (w/v); Under magnetic agitation, in the above-mentioned chitosan solution of 0.5mL, add the TPP solution of 0.1mL, thereby make ionomer embedding the chitosan nano ball of medical science contrast agent.Other experimental techniques are identical with embodiment 1 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as T
2the MRI contrast agent of weighting.
Embodiment 22
Change biodegradable albumin nanospheres in embodiment 2 into chitosan nano ball, its preparation and identical with embodiment 21 to the embedding method of medical science contrast agent (identical with embodiment 2), other experimental techniques are identical with embodiment 2 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as T
1the MRI contrast agent of weighting.
Embodiment 23
Change biodegradable albumin nanospheres in embodiment 3 into chitosan nano ball, its preparation and identical with embodiment 21 to the embedding method of medical science contrast agent (identical with embodiment 3), other experimental techniques are identical with embodiment 3 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Embodiment 24
Change biodegradable albumin nanospheres in embodiment 4 into chitosan nano ball, its preparation and identical with embodiment 21 to the embedding method of medical science contrast agent (identical with embodiment 4), other experimental techniques are identical with embodiment 4 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 25
Change biodegradable albumin nanospheres in embodiment 5 into chitosan nano ball, its preparation and identical with embodiment 21 to the embedding method of medical science contrast agent (identical with embodiment 5), other experimental techniques are identical with embodiment 5 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as fluorescein contrast agent.
Embodiment 26
Change biodegradable albumin nanospheres in embodiment 11 into chitosan nano ball, its preparation and identical with embodiment 21 to the embedding method of medical science contrast agent (identical with embodiment 11), other experimental techniques are identical with embodiment 11 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as T
2the MRI contrast agent of weighting.
Embodiment 27
Change biodegradable albumin nanospheres in embodiment 12 into chitosan nano ball, its preparation and identical with embodiment 21 to the embedding method of medical science contrast agent (identical with embodiment 12), other experimental techniques are identical with embodiment 12 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as T
1the MRI contrast agent of weighting.
Embodiment 28
Change biodegradable albumin nanospheres in embodiment 13 into chitosan nano ball, its preparation and identical with embodiment 21 to the embedding method of medical science contrast agent (identical with embodiment 13), other experimental techniques are identical with embodiment 13 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Embodiment 29
Change biodegradable albumin nanospheres in embodiment 14 into chitosan nano ball, its preparation and identical with embodiment 21 to the embedding method of medical science contrast agent (identical with embodiment 14), other experimental techniques are identical with embodiment 14 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 30
Change biodegradable albumin nanospheres in embodiment 15 into chitosan nano ball, its preparation and identical with embodiment 21 to the embedding method of medical science contrast agent (identical with embodiment 15), other experimental techniques are identical with embodiment 15 with condition, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as fluorescein contrast agent.
Embodiment 31
Make the MRI contrast agent Gd-DTPA coordination compound in embodiment 2 into business-like Gd-DOTA coordination compound, the coupling of the preparation of biodegradable albumin nanospheres and the embedding to MRI contrast agent Gd-DOTA coordination compound thereof, albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 2, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as T
1the MRI contrast agent of weighting.
Embodiment 32
Make the MRI contrast agent Gd-DTPA coordination compound in embodiment 7 into business-like Gd-DOTA coordination compound, the coupling of the preparation of biodegradable albumin nanospheres and the embedding to MRI contrast agent Gd-DOTA coordination compound thereof, albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 7, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as T
1the MRI contrast agent of weighting.
Embodiment 33
Make the MRI contrast agent Gd-DTPA coordination compound in embodiment 12 into business-like Gd-DOTA coordination compound, the coupling of the preparation of biodegradable albumin nanospheres and the embedding to MRI contrast agent Gd-DOTA coordination compound thereof, albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 12, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as T
1the MRI contrast agent of weighting.
Embodiment 34
Make the MRI contrast agent Gd-DTPA coordination compound in embodiment 17 into business-like Gd-DOTA coordination compound, the coupling of the preparation of biodegradable albumin nanospheres and the embedding to MRI contrast agent Gd-DOTA coordination compound thereof, albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 17, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as T
1the MRI contrast agent of weighting.
Embodiment 35
Make the MRI contrast agent Gd-DTPA coordination compound in embodiment 22 into business-like Gd-DOTA coordination compound, the coupling of the preparation of biodegradable chitosan nano ball and the embedding to MRI contrast agent Gd-DOTA coordination compound thereof, chitosan nano ball surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 22, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as T
1the MRI contrast agent of weighting.
Embodiment 36
Make the MRI contrast agent Gd-DTPA coordination compound in embodiment 27 into business-like Gd-DOTA coordination compound, the coupling of the preparation of biodegradable chitosan nano ball and the embedding to MRI contrast agent Gd-DOTA coordination compound thereof, chitosan nano ball surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 27, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as T
1the MRI contrast agent of weighting.
Embodiment 37
Make the MRI contrast agent Gd-DTPA coordination compound in embodiment 2 into Gd
2o
3nanoparticle, concrete preparation method is as follows: by 6.0mmol GdCl
3.6H
2o adds in the DEG of 30mL, continues magnetic agitation, 140-160 ℃ of heating 1h in silicone oil oil bath, and the DEG solution that then adds 30mL to contain 7.5mmol NaOH, after reactant dissolves completely, is warming up to 180 ℃ by oil bath temperature, under rapid stirring, reacts 4h.
The preparation of biodegradable albumin nanospheres and to MRI contrast agent Gd
2o
3the embedding of nanoparticle, the coupling of albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 2, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as T
1the MRI contrast agent of weighting.
Embodiment 38
Make the MRI contrast agent Gd-DTPA coordination compound in embodiment 7 into Gd
2o
3nanoparticle, concrete preparation method is identical with embodiment 37.The preparation of biodegradable albumin nanospheres and to MRI contrast agent Gd
2o
3the embedding of nanoparticle, the coupling of albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 7, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as the MRI contrast agent of T1 weighting.
Embodiment 39
Make the MRI contrast agent Gd-DTPA coordination compound in embodiment 12 into Gd
2o
3nanoparticle, concrete preparation method is identical with embodiment 37.The preparation of biodegradable albumin nanospheres and to MRI contrast agent Gd
2o
3the embedding of nanoparticle, the coupling of albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 12, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as the MRI contrast agent of T1 weighting.
Embodiment 40
Make the MRI contrast agent Gd-DTPA coordination compound in embodiment 17 into Gd
2o
3nanoparticle, concrete preparation method is identical with embodiment 37.The preparation of biodegradable albumin nanospheres and to MRI contrast agent Gd
2o
3the embedding of nanoparticle, the coupling of albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 17, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as the MRI contrast agent of T1 weighting.
Embodiment 41
Make the MRI contrast agent Gd-DTPA coordination compound in embodiment 22 into Gd
2o
3nanoparticle, concrete preparation method is identical with embodiment 37.The preparation of biodegradable chitosan nano ball and to MRI contrast agent Gd
2o
3the embedding of nanoparticle, the coupling of chitosan nano ball surface ligand folic acid, chitosan nano ball surface p H responsive type are high molecular synthetic identical with embodiment 22, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as the MRI contrast agent of T1 weighting.
Embodiment 42
Make the MRI contrast agent Gd-DTPA coordination compound in embodiment 27 into Gd
2o
3nanoparticle, concrete preparation method is identical with embodiment 37.The preparation of biodegradable chitosan nano ball and to MRI contrast agent Gd
2o
3the embedding of nanoparticle, the coupling of chitosan nano ball surface ligand folic acid, chitosan nano ball surface p H responsive type are high molecular synthetic identical with embodiment 27, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as the MRI contrast agent of T1 weighting.
Embodiment 43
The reducing agent NaBH of gold nano grain will be prepared in embodiment 3
4change sodium citrate into, concrete preparation method is as follows: in the round-bottomed flask of 100mL, add 50mL ultra-pure water, add the 5mM HAuCl of 2.5mL under quick magnetic agitation
4solution, in the abundant middle heating of boiling water, then add 0.5,0.625,1.0 or the sodium citrate solution (1%) of 2.0mL, reaction continues 10min in boiling water bath, finally at room temperature stir cooling, can obtain that particle diameter is respectively 38,35,16, the gold nano grain of 14nm.Larger gold nano grain (100nm) can 14nm gold nano grain be that seed synthesizes, concrete preparation method is as follows: the gold nano grain of getting the 14nm of 0.75mL adds in 97.25mL ultra-pure water, then adds the HAuCl of 1.0mL 1% (w/v)
43H
2o solution, at room temperature rapid stirring, adds 1% sodium citrate of 0.22mL, then adds the 0.03M hydroquinone of 1.0mL, and stirring is spent the night, thereby makes the gold nano grain of 100nm.
The embedding of the preparation of biodegradable albumin nanospheres and the gold nano grain to above-mentioned five kinds of different-grain diameters thereof, the coupling of albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 3, can make the stealthy radiography materials of early diagnosis of tumor such as other four kinds of brain cancers, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Embodiment 44
The reducing agent NaBH of gold nano grain will be prepared in embodiment 8
4change sodium citrate into, concrete preparation method is identical with embodiment 43.The embedding of the preparation of biodegradable albumin nanospheres and the gold nano grain to made five kinds of different-grain diameters thereof, the coupling of albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 8, can make other four kinds of stealthy radiography materials of hepatocarcinoma early diagnosis, can be used as CT contrast agent.
Embodiment 45
CT contrast agent gold nano grain in embodiment 3 is changed to business-like CT contrast agent iohexol; the coupling of the preparation of biodegradable albumin nanospheres and the embedding to CT contrast agent iohexol thereof, albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 3; can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Embodiment 46
CT contrast agent gold nano grain in embodiment 8 is changed to business-like CT contrast agent iohexol; the coupling of the preparation of biodegradable albumin nanospheres and the embedding to CT contrast agent iohexol thereof, albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 8; can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as CT contrast agent.
Embodiment 47
CT contrast agent gold nano grain in embodiment 13 is changed to business-like CT contrast agent iohexol; the coupling of the preparation of biodegradable albumin nanospheres and the embedding to CT contrast agent iohexol thereof, albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 13; can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Embodiment 48
CT contrast agent gold nano grain in embodiment 18 is changed to business-like CT contrast agent iohexol; the coupling of the preparation of biodegradable albumin nanospheres and the embedding to CT contrast agent iohexol thereof, albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 18; can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as CT contrast agent.
Embodiment 49
CT contrast agent gold nano grain in embodiment 23 is changed to business-like CT contrast agent iohexol; the coupling of the preparation of biodegradable chitosan nano ball and the embedding to CT contrast agent iohexol thereof, chitosan nano ball surface ligand folic acid, chitosan nano ball surface p H responsive type are high molecular synthetic identical with embodiment 23; can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Embodiment 50
CT contrast agent gold nano grain in embodiment 28 is changed to business-like CT contrast agent iohexol; the coupling of the preparation of biodegradable chitosan nano ball and the embedding to CT contrast agent iohexol thereof, chitosan nano ball surface ligand folic acid, chitosan nano ball surface p H responsive type are high molecular synthetic identical with embodiment 28; can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Embodiment 51
CT contrast agent gold nano grain in embodiment 3 is changed to business-like CT contrast agent Actybaryte; the coupling of the preparation of biodegradable albumin nanospheres and the embedding to CT contrast agent barium sulfate thereof, albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 3; can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Embodiment 52
CT contrast agent gold nano grain in embodiment 8 is changed to business-like CT contrast agent Actybaryte; the coupling of the preparation of biodegradable albumin nanospheres and the embedding to CT contrast agent barium sulfate thereof, albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 8; can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as CT contrast agent.
Embodiment 53
CT contrast agent gold nano grain in embodiment 13 is changed to business-like CT contrast agent Actybaryte; the coupling of the preparation of biodegradable albumin nanospheres and the embedding to CT contrast agent barium sulfate thereof, albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 13; can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Embodiment 54
CT contrast agent gold nano grain in embodiment 18 is changed to business-like CT contrast agent Actybaryte; the coupling of the preparation of biodegradable albumin nanospheres and the embedding to CT contrast agent barium sulfate thereof, albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 18; can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as CT contrast agent.
Embodiment 55
CT contrast agent gold nano grain in embodiment 23 is changed to business-like CT contrast agent Actybaryte; the coupling of the preparation of biodegradable chitosan nano ball and the embedding to CT contrast agent barium sulfate thereof, chitosan nano ball surface ligand folic acid, chitosan nano ball surface p H responsive type are high molecular synthetic identical with embodiment 23; can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Embodiment 56
CT contrast agent gold nano grain in embodiment 28 is changed to business-like CT contrast agent Actybaryte; the coupling of the preparation of biodegradable chitosan nano ball and the embedding to CT contrast agent barium sulfate thereof, chitosan nano ball surface ligand folic acid, chitosan nano ball surface p H responsive type are high molecular synthetic identical with embodiment 28; can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Embodiment 57
By PET contrast agent in embodiment 4
18f-FDG is changed to
64cu, the preparation of biodegradable albumin nanospheres and to PET contrast agent
64the embedding of Cu, the coupling of albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 4, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 58
By PET contrast agent in embodiment 9
18f-FDG is changed to
64cu, the preparation of biodegradable albumin nanospheres and to PET contrast agent
64the embedding of Cu, the coupling of albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 9, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as PET contrast agent.
Embodiment 59
By PET contrast agent in embodiment 14
18f-FDG is changed to
64cu, the preparation of biodegradable albumin nanospheres and to PET contrast agent
64the embedding of Cu, the coupling of albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 14, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 60
By PET contrast agent in embodiment 19
18f-FDG is changed to
64cu, the preparation of biodegradable albumin nanospheres and to PET contrast agent
64the embedding of Cu, the coupling of albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 19, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as PET contrast agent.
Embodiment 61
By PET contrast agent in embodiment 24
18f-FDG is changed to
64cu, the preparation of biodegradable chitosan nano ball and to PET contrast agent
64the embedding of Cu, the coupling of chitosan nano ball surface ligand folic acid, chitosan nano ball surface p H responsive type are high molecular synthetic identical with embodiment 24, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 62
By PET contrast agent in embodiment 29
18f-FDG is changed to
64cu, the preparation of biodegradable chitosan nano ball and to PET contrast agent
64the embedding of Cu, the coupling of chitosan nano ball surface ligand folic acid, chitosan nano ball surface p H responsive type are high molecular synthetic identical with embodiment 29, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 63
By PET contrast agent in embodiment 4
18f-FDG is changed to
124i, the preparation of biodegradable albumin nanospheres and to PET contrast agent
124the embedding of I, the coupling of albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 4, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 64
By PET contrast agent in embodiment 9
18f-FDG is changed to
124i, the preparation of biodegradable albumin nanospheres and to PET contrast agent
124the embedding of I, the coupling of albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 9, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as PET contrast agent.
Embodiment 65
By PET contrast agent in embodiment 14
18f-FDG is changed to
124i, the preparation of biodegradable albumin nanospheres and to PET contrast agent
124the embedding of I, the coupling of albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 14, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 66
By PET contrast agent in embodiment 19
18f-FDG is changed to
124i, the preparation of biodegradable albumin nanospheres and to PET contrast agent
124the embedding of I, the coupling of albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 19, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as PET contrast agent.
Embodiment 67
By PET contrast agent in embodiment 24
18f-FDG is changed to
124i, the preparation of biodegradable chitosan nano ball and to PET contrast agent
124the embedding of I, the coupling of chitosan nano ball surface ligand folic acid, chitosan nano ball surface p H responsive type are high molecular synthetic identical with embodiment 24, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 68
By PET contrast agent in embodiment 29
18f-FDG is changed to
124i, the preparation of biodegradable chitosan nano ball and to PET contrast agent
124the embedding of I, the coupling of chitosan nano ball surface ligand folic acid, chitosan nano ball surface p H responsive type are high molecular synthetic identical with embodiment 29, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 69
By PET contrast agent in embodiment 4
18f-FDG is changed to
94tc, the preparation of biodegradable albumin nanospheres and to PET contrast agent
94the embedding of Tc, the coupling of albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 4, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 70
By PET contrast agent in embodiment 9
18f-FDG is changed to
94tc, the preparation of biodegradable albumin nanospheres and to PET contrast agent
94the embedding of Tc, the coupling of albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 9, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as PET contrast agent.
Embodiment 71
By PET contrast agent in embodiment 14
18f-FDG is changed to
94tc, the preparation of biodegradable albumin nanospheres and to PET contrast agent
94the embedding of Tc, the coupling of albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 14, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 72
By PET contrast agent in embodiment 19
18f-FDG is changed to
94tc, the preparation of biodegradable albumin nanospheres and to PET contrast agent
94the embedding of Tc, the coupling of albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 19, can make the stealthy radiography material of another kind of hepatocarcinoma early diagnosis, can be used as PET contrast agent.
Embodiment 73
By PET contrast agent in embodiment 24
18f-FDG is changed to
94tc, the preparation of biodegradable chitosan nano ball and to PET contrast agent
94the embedding of Tc, the coupling of chitosan nano ball surface ligand folic acid, chitosan nano ball surface p H responsive type are high molecular synthetic identical with embodiment 24, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 74
By PET contrast agent in embodiment 29
18f-FDG is changed to
94tc, the preparation of biodegradable chitosan nano ball and to PET contrast agent
94the embedding of Tc, the coupling of chitosan nano ball surface ligand folic acid, chitosan nano ball surface p H responsive type are high molecular synthetic identical with embodiment 29, can make the stealthy radiography materials of early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as PET contrast agent.
Embodiment 75
Change prepare gold nano grain in embodiment 3 as gold nano cage into, concrete preparation method is as follows: by the HAuCl of 3mL 0.75mM
4mix with the HMT (hexamethylenetetramine) of 3mL 0.03M, solution colour from pale yellow become transparent, then, add the PVP (polyvinylpyrrolidone) of 3mL 0.3M and the AgNO3 of 100 μ L 0.01M, after gentle agitation, add 50 μ L 0.08M ascorbic acid, mixed solution is stirred to 10s, and room temperature leaves standstill 12h centrifuge washing afterwards, can obtain gold nano cage.
The coupling of the preparation of biodegradable albumin nanospheres and the embedding to above-mentioned gold nano cage thereof, albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 3, can make the stealthy radiography materials of early diagnosis of tumor such as another brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Embodiment 76
Change prepare gold nano grain in embodiment 8 as gold nano cage into, concrete preparation method is identical with embodiment 75, the coupling of the preparation of biodegradable albumin nanospheres and the embedding to above-mentioned gold nano cage thereof, albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 8, can make the stealthy radiography material of another hepatocarcinoma early diagnosis, can be used as CT contrast agent.
Embodiment 77
Change prepare gold nano grain in embodiment 3 as gold nanorods into, concrete preparation method is as follows: preparation 20mL contains 0.25mM HAuCl
4with 0.25mM sodium citrate solution, add while stirring the 0.1M NaBH of 0.6mL ice bath
4solution, adds NaBH
4rear solution can become rapidly purple, and golden nanometer particle forms.After synthetic this golden nanometer particle, in 2-5h, this golden nanometer particle can be used as gold nano seed.Preparation 10mL contains 0.25mM HAuCl
4growth solution with 0.1M CTAB (cetyl trimethyl ammonium bromide), add the 0.1M new system ascorbic acid solution of 0.05mL, and then add the 3.5nm gold nano seed of 0.025mL, standing and reacting 48h, can make golden draw ratio (aspect ratio) and be 3.0 gold nanorods.
The coupling of the preparation of biodegradable albumin nanospheres and the embedding to above-mentioned gold nanorods thereof, albumin nanospheres surface ligand folic acid, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 3, can make the stealthy radiography materials of early diagnosis of tumor such as another brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma, can be used as CT contrast agent.
Embodiment 78
Change prepare gold nano grain in embodiment 8 as gold nanorods into, concrete preparation method is identical with embodiment 77, the coupling of the preparation of biodegradable albumin nanospheres and the embedding to above-mentioned gold nanorods thereof, albumin nanospheres surface ligand galactosamine, albumin nanospheres surface p H responsive type are high molecular synthetic identical with embodiment 8, can make the stealthy radiography material of another hepatocarcinoma early diagnosis, can be used as CT contrast agent.
Claims (9)
1. the stealthy radiography material of early diagnosis of tumor, it is characterized in that, formed by Biodegradable nanometer ball, the medical science contrast agent that is embedded in described Biodegradable nanometer ball inside, target molecule and the pH responsive type macromolecule that is connected in described Biodegradable nanometer ball surface;
Wherein, described medical science contrast agent is MRI contrast agent, CT contrast agent, PET contrast agent or fluorescein contrast agent;
Described pH responsive type macromolecule is the macromolecular compound shrinking in the scope of pH5.0～6.0, and described pH responsive type macromolecule is at least one in N-isopropylacrylamide-acrylic copolymer and N-isopropylacrylamide-methacrylic acid copolymer, and molecular weight ranges is 2k-1000k;
The material of described Biodegradable nanometer ball is selected from least one in oligopeptide, protein, polysaccharide, polyethers, polyesters macromolecule, and the particle diameter of described Biodegradable nanometer ball is below 500nm;
And under normal physiological conditions, the pH value of body is between 7.3～7.4, the target molecule on described nanosphere surface is hidden among the pH responsive type macromolecule of linear extended configuration; Described pH responsive type macromolecule changes in the scope of pH5.0～6.0, becomes contraction state by linear extended configuration, and described target molecule can be come out.
2. the stealthy radiography material of early diagnosis of tumor according to claim 1, is characterized in that, described pH responsive type macromolecule is N-isopropylacrylamide-acrylic copolymer.
3. the stealthy radiography material of early diagnosis of tumor according to claim 1, is characterized in that, the particle diameter of described medical science contrast agent is below 15nm.
4. the stealthy radiography material of early diagnosis of tumor according to claim 3, is characterized in that, described MRI contrast agent is selected from Superparamagnetic Iron Oxide nanoparticle, paramagnetism Gd-DTPA coordination compound, Gd-DOTA coordination compound and Gd
2o
3at least one in nanoparticle;
Described CT contrast agent is selected from least one in iohexol, barium sulfate, gold nano grain, gold nanorods and gold nano cage;
Described PET contrast agent is selected from
18f-FDG,
64cu,
124i and
94at least one in C;
Described fluorescein contrast agent is phthalocyanine.
5. the stealthy radiography material of early diagnosis of tumor according to claim 1, is characterized in that, the particle diameter of described Biodegradable nanometer ball is 50-200nm.
6. the stealthy radiography material of early diagnosis of tumor according to claim 1, is characterized in that, described target molecule is selected from least one in monoclonal antibody, folic acid or galactosamine.
7. the stealthy radiography material of early diagnosis of tumor according to claim 1, is characterized in that, described pH responsive type macromolecule is 0.2-5.0 with the number of target molecule ratio.
8. a preparation method for stealthy radiography material for the arbitrary described early diagnosis of tumor of claim 1～7, is characterized in that, comprises the steps:
(1) preparation is embedded with the Biodegradable nanometer ball of medical science contrast agent;
(2) react described target molecule is connected on the surface of the Biodegradable nanometer ball obtaining in step (1) by covalent coupling, obtain intermediate;
(3) on the surface of the intermediate obtaining in step (2), adopt the synthetic described pH responsive type macromolecule of living radical polymerization technique, obtain described early diagnosis of tumor stealth material.
9. the preparation method of stealthy radiography material for early diagnosis of tumor according to claim 8, is characterized in that, step (3) replaces with:
PH responsive type macromolecule is reacted on the surface that is connected to the intermediate that step (2) obtains by covalent coupling, obtain the described stealthy radiography material of early diagnosis of tumor.
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| CN103446588B (en) * | 2013-07-24 | 2015-12-02 | 中国科学院宁波材料技术与工程研究所 | Targeting type diagnosis and treatment coupling medicine and its preparation method and application |
| CN104368007A (en) * | 2013-08-12 | 2015-02-25 | 于湛 | Injectable protein-based drug-loading micro nano material with flower-shaped structure, inner ear trans-membrane drug-delivery sustain-released preparation and preparation method thereof |
| CN104623697B (en) * | 2015-02-08 | 2017-03-22 | 中国科学院武汉物理与数学研究所 | Method for preparing polymeric micelle type magnetic resonance contrast agent based on human physiological temperature response |
| CN108872172B (en) * | 2018-06-21 | 2021-05-25 | 东南大学 | BSA-based super-resolution imaging probe and preparation method and application thereof |
| CN111558040B (en) * | 2020-04-17 | 2021-03-26 | 华南农业大学 | High-molecular self-healing gel integrating magnetic resonance imaging and photothermal therapy and preparation and application thereof |
| CN112338199B (en) * | 2020-10-20 | 2022-05-31 | 华中科技大学同济医学院附属协和医院 | Preparation method and application of gold nanocages |
| CN114949261B (en) * | 2022-05-05 | 2024-06-04 | 南方医科大学南方医院 | Iron gadolinium nano-composite and preparation method and application thereof |
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