CN102743768A - 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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- CN102743768A CN102743768A CN2012102308338A CN201210230833A CN102743768A CN 102743768 A CN102743768 A CN 102743768A CN 2012102308338 A CN2012102308338 A CN 2012102308338A CN 201210230833 A CN201210230833 A CN 201210230833A CN 102743768 A CN102743768 A CN 102743768A
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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 and preparation method thereof with high specific target function.
Background technology
Malignant tumor (cancer) is one of principal disease of serious threat human health, up to the present, and the human effective ways that also do not find the various malignant tumor of treatment.The method of the reduction cancer mortality of generally acknowledging is that early discovery, early treatment detect it before the cancerous cell diffusion, and effectively treat.At present, the main diagnostic techniques of all kinds of malignant tumor can only be found size greater than 1 centimetre tumor, and is powerless to littler tumor, like nuclear magnetic resonance (MRI) [Biomaterials, 2011; 32:5167-5176], computer X-ray fault imaging (CT) and positron emission tomography (PET).The medical science contrast agent can improve the detection sensitivity and the spatial resolution of these diagnostic techniquess, in order to realize earlier detection and the diagnosis to various malignant tumor, needs all kinds of high performance medical science contrast agent of development [Nat.Nanotechnol., 2010; 5:815-821].
First kind of commercial MRI contrast agent 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].What subsequently, research was more is the superparamagnetism contrast agent.The magnetic moment of superparamagnetism contrast agent and susceptibility is all much larger than human tissue structure, also much larger than the paramagnetism chelate, but minimum because of its water solublity, can only adopt homogenate or colloidal form administration.The performance and the nephrotoxicity that have liver, splenic tumor owing to this type of contrast agent little more, so extremely people's attention, focus is to select suitable medicine carrying medium, prescription, dosage form and method for preparing, and carries out property test [Biomaterials, 2011; 32:4584-4593].Brilliant researcher far away seminar of Institute of Chemistry, Academia Sinica uses FeCl
36H
2O has successfully prepared the controlled magnetic nano crystal material of size pattern, has also furtherd investigate with FeCl
36H
2O is single feedstock production 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; Have very big potential [Adv.Mater., 2005 as the 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 long blood circulation time and low bio-toxicity [Adv.Mater., 2006; 18:2553-2556].The Gu Ning of Southeast China University professor seminar has prepared the peplos microvesicle of a kind of PLA/PVA of having ELECTRODE WITH BILAYER POLYMERIC beyond the region of objective existence shell (thickness is 50-70nm); And successfully use the SPIO nanoparticle (SPION) of its embedding 12nm; Significantly improved the susceptibility of peplos microvesicle; The MRI experiment has proved its good result as contrast agent [Biomaterials, 2009 in the body; 30:3882-3890].Have the nano-particle of superparamagnetism owing to its unique magnetics and electric property, have big specific surface area, high advantages such as chemical stability, show tempting application prospect in MRI contrast agent field.
In recent years, there was research that target molecule (the ability targeting is in the chemical compound of cancerous cell, like parts such as monoclonal antibody, folic acid and galactosamines) is combined with SPIO nanoparticle (SPION), improved the targeting property of SPION tumor tissues.For example, the Shi Xiangyang of Donghua University professor seminar adopts thermal decomposition method successfully to prepare the surperficial SPIO nuclear shell type nano meter particle (Fe that is coated with silicon
3O
4SiO
2NPs), (Gd-DTPA, DTPA: diethylenetriamine pentaacetic acid) with arginine-glycine-aspartic acid oligopeptide (RGD), the MRI experiment shows this multi-functional Fe in the body with its surperficial ammonification, covalent coupling paramagnetism gadolinium complex then
3O
4SiO
2(Gd-DTPA)-the RGD nanoparticle can selectively targeted surface expression have α v β 3 to integrate plain cancerous cell [Biomaterials, 2011; 32:4584-4593].The Miguel-Sancho of Spain Univ Zaragoza professor seminar high temperature pyrolysis ferric acetyl acetonade in 2,2'-ethylenedioxybis(ethanol).; Prepared water miscible SPION, and on SPION surface coupling a kind of model antibody, detected the immunoreation of antibody-SPION complex with ELISA (ELISA); This research shows; In a kind of monoclonal antibody of SPION surface graft, can make a kind of MRI contrast agent [Chem.Mater., 2011 that tumor tissues had targeting property to the cancerous cell surface antigen; 23:2795-2802].The Kang Yantang of NUS professor seminar through Transfer Radical Polymerization (ATRP) in SPION surface coupling poly (glycidyl methacrylate)-polyethylene glycol methacrylate-styrene polymer copolymer (P (GMA-co-PEGMA)); PEGMA plays the stabilized nanoscale particle, prolongs the effect of its body-internal-circulation time; Come the part folic acid of grafting ability target cancer cell through GMA; Thereby make a kind of initiatively targeting in the MRI of tumor tissues contrast agent [Langmuir, 2012; 28:563-571].There is the polymer phospholipid parcel SPION of part folic acid in the Chang Jin of University Of Tianjin professor seminar with coupling, and has further assessed its effect as targeting type MRI contrast agent [Pharmaco1.Res., 2011; 64:410-419].Combining of target molecule (monoclonal antibody or part) and SPION all pass through in these researchs, and SPION has made contribution aspect the targeting property of tumor tissues in raising, and the early diagnosis of malignant tumor is had important scientific meaning and social economic value.
Computer X-ray fault imaging (CT) utilizes the difference of human body different tissues to the transmitance of X ray, can be carried out to picture [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].Present x-ray contrast agent has 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 the iodine [Academic Radiology, 1999 that are connected to polyethylene sheath; 6:61-65] etc., wherein, more general based on the contrast Material Injection Protocols of organic molecule iodine.This is because iodine has higher X-ray absorption coefficient [Advanced Drug Delivery Reviews, 1999; 37:159-173].Yet these iodine substances make the radiography time very short owing to being removed by kidney rapidly, have nephrotoxicity, and X ray can induce iodine substance ionization to go out iodide ion, causes toxicity.Along with the development of nano material technology and biological nano technology, novel CT contrast agent based on nano-particle is expected to improve above-mentioned shortcoming [Small, 2007; 3:333-341].The size of nano-particle little (1～100nm), can get into blood capillary [Journal of Artificial Organs, 2005 of micron-scale internal diameter; 8:77-84], therefore can get into tissue more; And, because the permeability of cancerous issue position blood capillary strengthens [American Journal of Pathology, 2000; 156:1363-1380], nano-particle can be deposited on the cancerous issue through the seepage effect more, 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 multiple malignant tumor, and the diagnostic value of tumor patient is also more and more caused concern.Over nearly 20 years, nucleic
18The 2-of fluorine labelling (fluoro-18)-2-deoxyglucose (FDG) positron emission tomography (PET) inspection method grows up gradually.FDG-PET can show the metabolic characteristics of focus, helps to distinguish the good pernicious matter of focus, and stage of tumor is also had certain help [Chinese tuberculosis and breathing magazine, 2005; 28:221-224].Bibliographical information
18F-FDG PET video picture
99mTechnetium-MDP video picture sensitiveer [Radiology, 1999; 212:803-809].
For imaging patterns such as MRI, CT and PET; That optical imagery has is radiationless, characteristics cheaply, and especially near-infrared fluorescent imaging can partly realize detection and imaging to deep tissues and organ; Aspect optical imagery, have specific advantage [Nature Methods, 2009; 6:465-469].The core of optical imagery is the fluorescein contrast agent, and the problem that mainly faces comprises the transmission of profound light and luminous quantum efficiency, bleach-resistant property, excellent biological compatibility and targeting property [Biomaterials, 2009 of collection and fluorescein contrast agent; 30:5592-5600].The near infrared fluorescent dye (like phthalocyanine) that contains the tetrapyrrole group is the focus of paying close attention in recent years, makes it have application promise in clinical practice [J.Am.Chem.Soc., 2009 aspect near-infrared probe because of having good optical physics behavior; 131:2432-2433].In the design of fluorescein contrast agent, targeting property is a key issue, the most commonly utilizes drug-supplying system [SCI, 2011 of the receptor design active target tumor cell 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 property 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 generally is through binding target molecule on contrast agent (monoclonal antibody or part), thereby realizes the specificity to cancerous cell.Yet; Normal cell surface also exists heterogenetic antigen or receptor; These antigens or receptor also can combine with target molecule (monoclonal antibody or part); Thereby influenced the detection sensitivity and the spatial resolution of various diagnostic techniquess, therefore, developed and to have more that the contrast agent of high specific target function is the problem that presses for solution at present.
Summary of the invention
The invention provides a kind of early diagnosis of tumor with stealthy radiography material and preparation method thereof, described stealthy radiography material ability high specific targeted is to tumor locus.
A kind of early diagnosis of tumor is used stealthy radiography material, by biodegradable nanosphere, be embedded in the inner medical science contrast agent of said nanosphere, the pH responsive type macromolecule and the target molecule that are connected in said nanosphere surface constitute.
Described pH responsive type macromolecule is easy to change in pH5.0～6.0 scopes; Become contraction state by linear extended configuration; Make described target molecule to come out; Simultaneously pair cell has less toxicity, and described pH responsive type molecule is preferably at least a in Isopropylacrylamide-acrylic copolymer and the Isopropylacrylamide-EUDRAGIT S100, and molecular weight ranges is 2k-1000k.
Above-mentioned early diagnosis of tumor of the present invention is as shown in Figure 1 with the principle of the selectively targeted tumor cell of stealthy radiography material.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, thus should the stealth radiography material can not be by the normal cell non-specific uptake; And under the tumor tissues environment, pH value is about 5.5, and pH responsive type macromolecule can take place 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 with the 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 to be used for improving imaging resolution; The MRI contrast agent that those skilled in the art know, CT contrast agent, PET contrast agent or fluorescein contrast agent can both be applied to the present invention; In order to make described contrast agent can successfully be embedded in Biodegradable nanometer ball (abbreviation nanosphere) inside, the contrast agent particle diameter is preferably below the 15nm.
Described MRI contrast agent is preferably T for having MRI radiography materials with function
2Class MRI contrast agent and T
1Class MRI contrast agent, selected materials need have good water-solubility, described T
2Class MRI contrast agent further is preferably SPIO nanoparticle (SPION), described T
1Class MRI contrast agent further is preferably the Gd of bigger effective magnetic moment
3+, Dy
3+, Mn
2+Or Fe
3+Deng the micromolecule paramagnetic contrast medium, or form the macromolecular paramagnetic contrast agent of stable chelate, like Gd-DTPA coordination compound, Gd-DOTA coordination compound and Gd with suitable part
2O
3At least a in the nanoparticle, wherein, DTPA is a diethylenetriamine pentaacetic acid, DOTA is 1,4,7,10-tetraazacyclododecanand-N, N ', N ", the N-tetraacethyl.
Described CT contrast agent is a kind of CT of having radiography materials with function; Selected materials need have good water-solubility; Be preferably nanoparticle or micromolecular compound, further be preferably gold nano grain, gold nanorods, gold nano cage, iohexol and BaSO with CT radiography function
4In at least a.
Described PET contrast agent is preferably for improving a compounds of PET imaging resolution
18F-FDG (2-(fluoro-18)-2-deoxyglucose),
64Cu,
124I with
94At least a among the C.
Described fluorescein contrast agent is preferably phthalocyanine for improving the near infrared fluorescent dye of near-infrared optical molecular imaging.
Described nanosphere is as carrier; The embedding contrast agent is realized the effect of slow release, controlled release; Little to the human body toxic; Biodegradable nontoxic natural macromolecular or synthetic macromolecule can be applied to the present invention, and material therefor is preferably at least a in protein, oligopeptide, polysaccharide, polyethers or the polyesters macromolecule, further is preferably albumin and chitosan; Described radiography material generally uses through intravenous mode; Particle diameter can not be too big; The particle diameter of described nanosphere is preferably below the 500nm; In order to connect the above pH responsive type macromolecule and target molecule on described nanosphere surface, particle diameter can not be too little simultaneously, and the particle diameter of described nanosphere further is preferably 50-200nm.
Described target molecule is for to have the interactional chemical compound of specificity with tumor cell, and the ability targeting is preferably in monoclonal antibody, folic acid or the galactosamine at least a in cancerous cell.
Among the present invention, the described pH responsive type macromolecule in nanosphere surface is 0.2-5.0 with the number ratio of target molecule, at this moment; In normal cell tissue; Described target molecule can be hidden among the described pH responsive type macromolecule, and in the tumor tissues environment, described target molecule can come out.
The present invention also provides the method for preparing of described early diagnosis of tumor with stealth material, comprises the steps:
(1) preparation is embedded with the Biodegradable nanometer ball of medical science contrast agent;
(2) through the covalent coupling reaction described target molecule is connected on the surface of the Biodegradable nanometer ball that obtains in the step (1), obtains intermediate;
(3) on the surface of the intermediate that step (2) obtains, adopt the synthetic described pH responsive type macromolecule of living radical polymerization technique, obtain described early diagnosis of tumor and use stealth material.
The Biodegradable nanometer ball that is embedded with the medical science contrast agent in the step (1) can be through supersound method or the preparation of desolventizing method, and wherein supersound method comprises Water-In-Oil method, oil-in-water method and W/O/W multi-emulsion method again, introduces respectively below.
Water-In-Oil method: use the aqueous solution that has dissolved hydrophilic medical science contrast agent and hydrophilic film material as water; Use the organic solvent that has dissolved oil soluble emulsifying agent as oil phase; With water mix with oil phase stir carry out rough segmentation and loose after, reuse ultrasonic cell-break machine carries out emulsifying, obtains water-in-oil type nanoemulsion liquid; Under magnetic agitation, in the gained nanoemulsions, add cross-linking agent again and carry out crosslinking curing, 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; Use the aqueous solution that has dissolved water soluble emulsifier as water; After oil phase stirring mixed with water carried out rough segmentation and loose; Reuse ultrasonic cell-break machine carries out emulsifying; Obtain the oil-in-water type nanoemulsions, under magnetic agitation, in the gained nanoemulsions, add cross-linking agent again and carry out crosslinking curing, remove the Biodegradable nanometer ball that excessive cross-linking agent and emulsifying agent can obtain to be embedded with the medical science contrast agent.
W/O/W multi-emulsion method: use the aqueous solution that has dissolved hydrophilic medical science contrast agent as water; Use the organic solvent that has dissolved hydrophobic film material and oil soluble emulsifying agent as oil phase; With water mix with oil phase stir carry out rough segmentation and loose after; Reuse ultrasonic cell-break machine carries out emulsifying; Obtain water-in-oil type nanoemulsion liquid, again gained water-in-oil type nanoemulsion liquid is added the aqueous phase that is dissolved with water soluble emulsifier and 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 again and carry out crosslinking curing, remove the Biodegradable nanometer ball that excessive cross-linking agent and emulsifying agent can obtain to be embedded with the medical science contrast agent.
Desolventizing method: water solublity medical science contrast agent and nanosphere material oligopeptide or protein are dissolved in the NaCl aqueous solution; Drip ethanol then; The dropping process continues magnetic agitation; After solution becomes the milky suspension, add glutaraldehyde cross-linking curing nano ball, remove the Biodegradable nanometer ball that excessive cross-linking agent can obtain to be embedded with the medical science contrast agent.
Covalent coupling reaction described in the step (2) is the reaction that the functional group on terminal functional group of target molecule and nanosphere surface forms covalent chemical bond; For example: under the catalysis of EDAC (1-ethyl-(3-dimethylaminopropyl) carbodiimide), carboxyl and the amino chemical reaction that forms amide group.
When the material of nanosphere contains carboxyl (like polyglutamic acid, poly-aspartic-acid, the polypeptide that contains glutamic acid and aspartic acid and protein and contain polysaccharide of carboxyl etc.); Can select to contain parts such as amino monoclonal antibody or galactosamine as target molecule; Use the carboxyl on EDAC and NHS (N-maloyl imines) activation nanosphere surface then; Drip the target molecule solution that has terminal amino group again, make the amino covalence reaction of activatory carboxyl and target molecule form stable amido link; When the material of nanosphere contains amino (like polylysine, poly arginine, contain lysine and arginic polypeptide and protein and contain amino polysaccharide etc.); The part such as monoclonal antibody or folic acid that can select to contain carboxyl is as target molecule, takes then to make it to graft on the nanosphere surface behind the carboxyl of above method activation target molecule; For neither containing carboxyl, not containing amino Biodegradable material (like polyethers and polyesters macromolecule) again; Can adopt copolymerization method to make it to have some amino or carboxyls, be made into nanosphere and adopt above same procedure that target molecule is grafted on the nanosphere surface afterwards.
The described living radical polymerization technique of step (3) (being called controllable polymerization again) is the technology of comparative maturity in this area, can carry out according to following steps in the present invention:
At first; The catalysis that utilizes EDAC is at nanosphere surface coupling 4-chloromethyl benzoic acid (CBA) that step (2) obtains; Then sodium diethyldithiocarbamate (NaDC) is fixed on the benzyl position methyl on the described CBA, at last through ultraviolet trigger monomer Isopropylacrylamide (NIPAM), acrylic acid (AA) or methacrylic acid (MAA) living radical graft polymerization reaction on the nanosphere surface.Wherein, Macromolecule takes place to change mutually and mol ratio that the pH point that shrinks can pass through between AA (or MAA) and the NIPAM is controlled; When described mol ratio in 1: 1～50 scopes, can control described pH responsive type macromolecule and in pH5.0～6.0 scopes, change.High molecular grafting density can be controlled through the coupling amount of nanosphere surface C BA, and the coupling amount of nanosphere surface C BA can be controlled through initial concentration and the response time of CBA; High molecular chain length length (molecular weight) can be when synthetic monomeric concentration and polymerization reaction time control.
Step (3) can also realize through covalent coupling reaction, and for example, the reaction through carboxyl functional group and amido functional group is covalently coupled to pH responsive type macromolecule on the nanosphere surface that step (2) obtains.At first; It is the radical polymerization of initiator that the high molecular synthetic method of pH responsive type adopts with AIBN; Adopt segment copolymerization method to make the high molecular end of pH responsive type have several allylamines (or acrylic acid) this moment, thereby make the high molecular end of thermosensitive type have several amino (carboxyl).Then, under the catalysis of EDAC, utilize carboxyl and amino reaction that pH responsive type macromolecule is covalently coupled on the nanosphere surface.
Compare with prior art, beneficial effect of the present invention is embodied in:
(1) through the high molecular effect of pH responsive type, improved the target function of radiography material to tumor cell;
(2) reduce the consumption of contrast agent, reduced toxic and side effects and manufacturing cost.
Description of drawings
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 is for utilizing the reaction sketch map of living radical graft polymerization technique at Biodegradable nanometer ball surface synthetic isopropyl acrylamide-EUDRAGIT S100 (PNIPAM-MAA) among the embodiment 1;
Fig. 3 is the transmission electron microscope photo of albumin nanometer ball prepared among the embodiment 1;
The transmission electron microscope photo comparison diagram that Fig. 4 has the high molecular albumin nanometer of pH responsive type ball (b) for albumin nanometer ball (a) prepared among the embodiment 1 and surperficial coupling;
Fig. 5 is the quantitative analysis figure that early diagnosis of tumor prepared among the embodiment 6 is absorbed by HCC HepG2 with stealthy radiography material;
Fig. 6 is the quantitative analysis figure that early diagnosis of tumor prepared among the embodiment 11 is absorbed by cervical cancer cell HeLa with stealthy radiography material.
The specific embodiment
(1) has the preparation of the SPIO nanoparticle (SPION) of MRI radiography function
With FeCl
36H
2O (5.4g; 20mmol) and enuatrol (18.3g 60mmol) is dissolved in the mixed solvent of 40mL ethanol, 30mL deionized water and 70mL normal hexane, be heated to 70 ℃ the reaction 4h; Then mixed solution is transferred in the separatory funnel; Remove lower floor's water, upper oil phase is with 30mL deionized water wash three times, with the solid that obtains the iron oleate complex after the normal hexane evaporation.With the iron oleate complex (18g, 20mmol) and oleic acid (2.8g 10mmol) is dissolved among the 1-octadecane alkene (30g); Again with mixture heated to 320 ℃ (heating rate be 3.3 ℃/min), under argon shield after the reaction 1h, the room temperature cooling solution; Add ethanol (250mL) again; Centrifugal (6000rpm) can obtain the monodispersed SPION that particle diameter is about 14nm in ten minutes, at last with gained SPION vacuum drying, and cryopreservation (0-4 ℃).
(2) preparation of biodegradable albumin nanometer ball and to the embedding of MRI contrast agent SPION
The 10mM NaCl aqueous solution of preparation pH10.8, bovine serum albumin (BSA) aqueous solution that this solution compound concentration of reuse is 20mg/mL adds the 2.0mL dehydrated alcohol then in 2.0mL BSA aqueous solution; Rate of addition with 2.0mL/min behind the magnetic agitation 10min adds 4.0mL ethanol (volume ratio of total ethanol addition and BSA aqueous solution is 3.0); The dropping process continues magnetic agitation, adds 8% glutaraldehyde water solution (glutaraldehyde-BSA mass ratio is 0.24) crosslinking curing 24h after ethanol drip to finish immediately, adds 1.0mL glycine (40mg/mL) the excessive glutaraldehyde that neutralizes then; Behind the reaction 2.0h; To sample carry out centrifugal (20,000 * g, 20min); The gained sample is with 10mM NaCl solution washing twice, and last lyophilization 48h can obtain biodegradable albumin nanometer ball.The MRI contrast agent SPION that the first step is made is dispersed in the BSA aqueous solution of 20mg/mL, adopts above-mentionedly can make the albumin nanometer ball that is embedded with contrast agent SPION with quadrat method.
(3) coupling of albumin nanometer ball surface ligand folic acid
Under the catalysis of EDAC (1-ethyl-(3-dimethylaminopropyl) carbodiimide); Utilize the chemical reaction between the amino on carboxyl and albumin nanometer ball surface of folic acid, can selectively targetedly act on the part folic acid of tissues such as the brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma in the surface coupling of albumin nanometer ball.Concrete method for preparing 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 10mL folic acid solution (ice bath), adds the albumin nanometer ball suspension (5.0mg/mL) that is embedded with SPION that 90mL is dissolved in PBS then, place the room temperature lower magnetic force to stir mixed liquor; Reacted 24 hours; To sample carry out centrifugal (20,000 * g, 20min); The gained sample is used the PBS washed twice, and last lyophilization 48h can obtain surperficial coupling has part folic acid and inner packet to be embedded with the albumin nanometer ball of SPION.
(4) albumin nanometer ball surface p H responsive type is high molecular synthetic
Adopt the surface synthetic a kind of pH responsive type macromolecule of living radical graft polymerization technique (controllable polymerization) at albumin nanometer ball (be embedded with SPION and surperficial coupling has part folic acid); Be Isopropylacrylamide-EUDRAGIT S100 (PNIPAM-MAA), as shown in Figure 2.The CBA solution of preparation 5mg/mL is dissolved in 10mL CBA solution (ice bath) with 50mg EDAC, adds 90mL albumin nanometer ball suspension (5.0mg/mL) then; Place the room temperature lower magnetic force to stir mixed liquor, reacted 24 hours, sample is carried out centrifugal (20; 000 * g, 20min), with the gained sample dispersion in the 100mL ultra-pure water; Add 3.0g NIPAM and 200mg MAA; In down irradiation 1-5 hour of 400W uviol lamp (ultraviolet wavelength 300-500nm, peak value 350nm), the gained composite nanoparticle is centrifugal, washing, lyophilizing; Thereby make early diagnosis of tumor such as a kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the MRI contrast agent of T2 weighting.
Fig. 3 is the transmission electron microscope photo of albumin nanometer ball prepared among the embodiment 1;
The transmission electron microscope photo comparison diagram that Fig. 4 has the high molecular albumin nanometer of pH responsive type ball (b) for albumin nanometer ball (a) prepared among the embodiment 1 and surperficial coupling, (b) in the trace circle on nanosphere surface be the high molecular evidence of the surperficial successful coupling pH responsive type of nanosphere.
(1) has the preparation of the paramagnetism Gd-DTPA coordination compound of MRI radiography function
Get 3g Gd
2O
3Mix with 7.3g DTPA, add water 40mL, heating and stirring and refluxing 16h, question response thing all dissolve the back temperature and reduce to room temperature; Behind filter membrane elimination impurity, add 120mL acetone, separate out white gels shape deposition; With washing with acetone 3 times, to dry to constant weight, yield is 80%.In coordination compound synthetic, the selection metallic oxide is a raw material, can be with unreacted Gd during separation
2O
3Remove by filter.
(2) preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 1 to embedding, the coupling of albumin nanometer ball surface ligand folic acid, the albumin nanometer ball surface p H responsive type of MRI contrast agent Gd-DTPA coordination compound; Can make early diagnosis of tumor such as a kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the MRI contrast agent of T1 weighting.
Embodiment 3
(1) has 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 is with the HAuCl of 0.125mL
43H
2The CTAB aqueous solution that the O aqueous solution adds 4.375mL is even, adds the NaBH of 0.500mL ice bath then
4Aqueous solution is inverted mixing 2h and is processed 5mL gold seeds liquid.Second step, the L-aqueous ascorbic acid of preparation 6.258mM, the L-aqueous ascorbic acid 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
2The O aqueous solution, gentle agitation is processed the growth-promoting media of 10mL, when the color of growth-promoting media becomes colorless from orange, adds the gold seeds liquid of 5 μ L immediately, is inverted to mix slowly to redden until the mixed liquor color.At last, mixed liquor is left standstill 24h.
(2) preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 1 to embedding, the coupling of albumin nanometer ball surface ligand folic acid, the albumin nanometer ball surface p H responsive type of CT contrast agent gold nano grain; Can make early diagnosis of tumor such as a kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Change MRI contrast agent SPION in embodiment 1 step (1) into the PET contrast agent, choosing
18F-FDG is as the medical science contrast agent, the preparation of biodegradable albumin nanometer ball and to the PET contrast agent
18The coupling of the embedding of F-FDG, albumin nanometer ball surface ligand folic acid, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 1; Can make early diagnosis of tumor such as a kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 5
Change MRI contrast agent SPION in embodiment 1 step (1) into the fluorescein contrast agent; The near infrared fluorescent dye phthalocyanine that choosing contains the tetrapyrrole group is as the medical science contrast agent; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 1 to embedding, the coupling of albumin nanometer ball surface ligand folic acid, the albumin nanometer ball surface p H responsive type of fluorescein contrast agent phthalocyanine; Can make early diagnosis of tumor such as a kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the fluorescein contrast agent.
Change the link coupled target molecule in albumin nanometer ball surface in embodiment 1 step (3) into galactosamine; Under the catalysis of EDAC; Utilize the chemical reaction between the carboxyl on amino and albumin nanometer ball surface of galactosamine, can selectively targetedly act on the part galactosamine of hepatocarcinoma in the surface coupling of albumin nanometer ball.Concrete method for preparing is summarized as follows: the galactosamine solution of preparing 500 μ g/mL with PBS as solvent; 50mg EDAC is dissolved in 10mL galactosamine solution (ice bath), adds the albumin nanometer ball suspension (5.0mg/mL) that is embedded with the medical science contrast agent that 90mL is dissolved in PBS then, place the room temperature lower magnetic force to stir mixed liquor; Reacted 24 hours; To sample carry out centrifugal (20,000 * g, 20min); The gained sample is used the PBS washed twice, and last lyophilization 48h can obtain surperficial coupling has part galactosamine and inner packet to be embedded with the albumin nanometer ball of medical science contrast agent.Other steps are identical with embodiment 1, can make a kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as T
2The MRI contrast agent of weighting.
Made early diagnosis of tumor is seen Fig. 5 with stealthy radiography material by the quantitative analysis of HCC HepG2 picked-up; Wherein, on behalf of inner packet, SPION-AN-GAL-PM be embedded with the albumin nanometer ball (AN) that contrast agent SPION, surperficial coupling have target molecule GAL and pH responsive type macromolecule PNIPAM-MAA (PM); The SPION-AN representative only is embedded with the albumin nanometer ball (AN) of contrast agent SPION.As shown in Figure 5, the amount of the HepG2 cell absorbs SPION-AN-GAL-PM when pH5.5 amount picked-up SPION-AN-GAL-PM during than pH7.4 is obviously much higher, the amount of picked-up SPION-AN during also apparently higher than pH5.5.This result shows; SPION-AN-GAL-PM can be by a large amount of specificity picked-ups of HCC when pH5.5; And when pH7.4, can only be absorbed on a small quantity by HCC because target molecule is hidden among the macromolecule, this just explains that pH responsive type macromolecule can prevent that target molecule is by the normal cell non-specific uptake.
Embodiment 7
Change the link coupled target molecule in albumin nanometer ball surface among the embodiment 2 into galactosamine, concrete method for preparing is identical with embodiment 6, and other steps are identical with embodiment 2, can make a kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as T
1The MRI contrast agent of weighting.
Embodiment 8
Change the link coupled target molecule in albumin nanometer ball surface among the embodiment 3 into galactosamine, concrete method for preparing is identical with embodiment 6, and other steps are identical with embodiment 3, can make a kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 9
Change the link coupled target molecule in albumin nanometer ball surface among the embodiment 4 into galactosamine, concrete method for preparing is identical with embodiment 6, and other steps are identical with embodiment 4, can make a kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 10
Change the link coupled target molecule in albumin nanometer ball surface among the embodiment 5 into galactosamine, concrete method for preparing is identical with embodiment 6, and other steps are identical with embodiment 5, can make a kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the fluorescein contrast agent.
Embodiment 11
Change the monomer methacrylic acid (MAA) the during Polymer Synthesizing of pH responsive type in embodiment 1 step (5) into acrylic acid (AA); Thereby synthetic a kind of pH responsive type macromolecule Isopropylacrylamide-acrylic copolymer (PNIPAM-AA) on albumin nanometer ball surface; Other experimental techniques are all identical with embodiment 1 with condition; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the MRI contrast agent of T2 weighting.
Made early diagnosis of tumor is seen Fig. 6 with stealthy radiography material by the quantitative analysis of cervical cancer cell HeLa picked-up; Wherein, On behalf of inner packet, SPION-AN-FA-PA be embedded with the albumin nanometer ball (AN) that contrast agent SPION, surperficial coupling have target molecule FA and pH responsive type macromolecule PNIPAM-AA (PA), and on behalf of inner packet, SPION-AN be embedded with the albumin nanometer ball (AN) of contrast agent SPION.As shown in Figure 6, the amount of the HeLa cell absorbs SPION-AN-FA-PA when pH5.5 amount picked-up SPION-AN-FA-PA during than pH7.4 is obviously much higher, the amount of picked-up SPION-AN during also apparently higher than pH5.5.This result shows; SPION-AN-FA-PA can be by a large amount of specificity picked-ups of cervical cancer cell when pH5.5; And when pH7.4, can only be absorbed on a small quantity by cervical cancer cell because target molecule is hidden among the macromolecule, this just explains that pH responsive type macromolecule can prevent that target molecule is by the normal cell non-specific uptake.
Embodiment 12
Change the monomer methacrylic acid (MAA) the during Polymer Synthesizing of pH responsive type among the embodiment 2 into acrylic acid (AA); Thereby synthetic a kind of pH responsive type macromolecule Isopropylacrylamide-acrylic copolymer (PNIPAM-AA) on albumin nanometer ball surface; Other experimental techniques are all identical with embodiment 2 with condition; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as T
1The MRI contrast agent of weighting.
Embodiment 13
Change the monomer methacrylic acid (MAA) the during Polymer Synthesizing of pH responsive type among the embodiment 3 into acrylic acid (AA); Thereby synthetic a kind of pH responsive type macromolecule Isopropylacrylamide-acrylic copolymer (PNIPAM-AA) on albumin nanometer ball surface; Other experimental techniques are all identical with embodiment 3 with condition; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 14
Change the monomer methacrylic acid (MAA) the during Polymer Synthesizing of pH responsive type among the embodiment 4 into acrylic acid (AA); Thereby synthetic a kind of pH responsive type macromolecule Isopropylacrylamide-acrylic copolymer (PNIPAM-AA) on albumin nanometer ball surface; Other experimental techniques are all identical with embodiment 4 with condition; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 15
Change the monomer methacrylic acid (MAA) the during Polymer Synthesizing of pH responsive type among the embodiment 5 into acrylic acid (AA); Thereby synthetic a kind of pH responsive type macromolecule Isopropylacrylamide-acrylic copolymer (PNIPAM-AA) on albumin nanometer ball surface; Other experimental techniques are all identical with embodiment 5 with condition; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the fluorescein contrast agent.
Embodiment 16
Change the monomer methacrylic acid (MAA) the during Polymer Synthesizing of pH responsive type among the embodiment 6 into acrylic acid (AA); Thereby synthetic a kind of pH responsive type macromolecule Isopropylacrylamide-acrylic copolymer (PNIPAM-AA) on albumin nanometer ball surface; Other experimental techniques are all identical with embodiment 6 with condition; Can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as T
2The MRI contrast agent of weighting.
Embodiment 17
Change the monomer methacrylic acid (MAA) the during Polymer Synthesizing of pH responsive type among the embodiment 7 into acrylic acid (AA); Thereby synthetic a kind of pH responsive type macromolecule Isopropylacrylamide-acrylic copolymer (PNIPAM-AA) on albumin nanometer ball surface; Other experimental techniques are all identical with embodiment 7 with condition; Can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as T
1The MRI contrast agent of weighting.
Embodiment 18
Change the monomer methacrylic acid (MAA) the during Polymer Synthesizing of pH responsive type among the embodiment 8 into acrylic acid (AA); Thereby synthetic a kind of pH responsive type macromolecule Isopropylacrylamide-acrylic copolymer (PNIPAM-AA) on albumin nanometer ball surface; Other experimental techniques are all identical with embodiment 8 with condition; Can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 19
Change the monomer methacrylic acid (MAA) the during Polymer Synthesizing of pH responsive type among the embodiment 9 into acrylic acid (AA); Thereby synthetic a kind of pH responsive type macromolecule Isopropylacrylamide-acrylic copolymer (PNIPAM-AA) on albumin nanometer ball surface; Other experimental techniques are all identical with embodiment 9 with condition; Can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 20
Change the monomer methacrylic acid (MAA) the during Polymer Synthesizing of pH responsive type among the embodiment 10 into acrylic acid (AA); Thereby synthetic a kind of pH responsive type macromolecule Isopropylacrylamide-acrylic copolymer (PNIPAM-AA) on albumin nanometer ball surface; Other experimental techniques are all identical with embodiment 10 with condition; Can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the fluorescein contrast agent.
Embodiment 21
Change biodegradable albumin nanometer ball among the embodiment 1 into the chitosan nano ball; Its preparation and following: the chitosan solution of preparation 0.2% (w/v) to the embedding method of medical science contrast agent; Solvent is the acetic acid of 1% (w/v); Medical science contrast agent (identical with embodiment 1) is dispersed in the chitosan solution, the pH value of this solution is transferred 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as T
2The MRI contrast agent of weighting.
Embodiment 22
Change biodegradable albumin nanometer ball among the embodiment 2 into the 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as T
1The MRI contrast agent of weighting.
Embodiment 23
Change biodegradable albumin nanometer ball among the embodiment 3 into the 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 24
Change biodegradable albumin nanometer ball among the embodiment 4 into the 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 25
Change biodegradable albumin nanometer ball among the embodiment 5 into the 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the fluorescein contrast agent.
Embodiment 26
Change biodegradable albumin nanometer ball among the embodiment 11 into the 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as T
2The MRI contrast agent of weighting.
Embodiment 27
Change biodegradable albumin nanometer ball among the embodiment 12 into the 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as T
1The MRI contrast agent of weighting.
Embodiment 28
Change biodegradable albumin nanometer ball among the embodiment 13 into the 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 29
Change biodegradable albumin nanometer ball among the embodiment 14 into the 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 30
Change biodegradable albumin nanometer ball among the embodiment 15 into the 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the fluorescein contrast agent.
Embodiment 31
Make the MRI contrast agent Gd-DTPA coordination compound among the embodiment 2 into business-like Gd-DOTA coordination compound; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 2 to embedding, the coupling of albumin nanometer ball surface ligand folic acid, the albumin nanometer ball surface p H responsive type of MRI contrast agent Gd-DOTA coordination compound; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as T
1The MRI contrast agent of weighting.
Embodiment 32
Make the MRI contrast agent Gd-DTPA coordination compound among the embodiment 7 into business-like Gd-DOTA coordination compound; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 7 to embedding, the coupling of albumin nanometer ball surface ligand galactosamine, the albumin nanometer ball surface p H responsive type of MRI contrast agent Gd-DOTA coordination compound; Can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as T
1The MRI contrast agent of weighting.
Embodiment 33
Make the MRI contrast agent Gd-DTPA coordination compound among the embodiment 12 into business-like Gd-DOTA coordination compound; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 12 to embedding, the coupling of albumin nanometer ball surface ligand folic acid, the albumin nanometer ball surface p H responsive type of MRI contrast agent Gd-DOTA coordination compound; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as T
1The MRI contrast agent of weighting.
Embodiment 34
Make the MRI contrast agent Gd-DTPA coordination compound among the embodiment 17 into business-like Gd-DOTA coordination compound; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 17 to embedding, the coupling of albumin nanometer ball surface ligand galactosamine, the albumin nanometer ball surface p H responsive type of MRI contrast agent Gd-DOTA coordination compound; Can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as T
1The MRI contrast agent of weighting.
Embodiment 35
Make the MRI contrast agent Gd-DTPA coordination compound among the embodiment 22 into business-like Gd-DOTA coordination compound; The preparation of biodegradable chitosan nanosphere and high molecular synthetic identical with embodiment 22 to embedding, the coupling of chitosan nano ball surface ligand folic acid, the albumin nanometer ball surface p H responsive type of MRI contrast agent Gd-DOTA coordination compound; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as T
1The MRI contrast agent of weighting.
Embodiment 36
Make the MRI contrast agent Gd-DTPA coordination compound among the embodiment 27 into business-like Gd-DOTA coordination compound; The preparation of biodegradable chitosan nanosphere and high molecular synthetic identical with embodiment 27 to embedding, the coupling of chitosan nano ball surface ligand folic acid, the albumin nanometer ball surface p H responsive type of MRI contrast agent Gd-DOTA coordination compound; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as T
1The MRI contrast agent of weighting.
Embodiment 37
Make the MRI contrast agent Gd-DTPA coordination compound among the embodiment 2 into Gd
2O
3Nanoparticle, concrete method for preparing is following: with 6.0mmol GdCl
3.6H
2O adds among the DEG of 30mL, continues magnetic agitation, and 140-160 ℃ of heating 1h adds the DEG solution that 30mL contains 7.5mmol NaOH then in the silicone oil oil bath, after reactant dissolves fully, oil bath temperature is warming up to 180 ℃, reaction 4h under stirring fast.
The preparation of biodegradable albumin nanometer ball and to MRI contrast agent Gd
2O
3The coupling of the embedding of nanoparticle, albumin nanometer ball surface ligand folic acid, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 2; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as T
1The MRI contrast agent of weighting.
Embodiment 38
Make the MRI contrast agent Gd-DTPA coordination compound among the embodiment 7 into Gd
2O
3Nanoparticle, concrete method for preparing is identical with embodiment 37.The preparation of biodegradable albumin nanometer ball and to MRI contrast agent Gd
2O
3The coupling of the embedding of nanoparticle, albumin nanometer ball surface ligand galactosamine, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 7; Can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the MRI contrast agent of T1 weighting.
Embodiment 39
Make the MRI contrast agent Gd-DTPA coordination compound among the embodiment 12 into Gd
2O
3Nanoparticle, concrete method for preparing is identical with embodiment 37.The preparation of biodegradable albumin nanometer ball and to MRI contrast agent Gd
2O
3The coupling of the embedding of nanoparticle, albumin nanometer ball surface ligand folic acid, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 12; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the MRI contrast agent of T1 weighting.
Embodiment 40
Make the MRI contrast agent Gd-DTPA coordination compound among the embodiment 17 into Gd
2O
3Nanoparticle, concrete method for preparing is identical with embodiment 37.The preparation of biodegradable albumin nanometer ball and to MRI contrast agent Gd
2O
3The coupling of the embedding of nanoparticle, albumin nanometer ball surface ligand galactosamine, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 17; Can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the MRI contrast agent of T1 weighting.
Embodiment 41
Make the MRI contrast agent Gd-DTPA coordination compound among the embodiment 22 into Gd
2O
3Nanoparticle, concrete method for preparing is identical with embodiment 37.The preparation of biodegradable chitosan nanosphere and to MRI contrast agent Gd
2O
3The coupling of the embedding of nanoparticle, 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the MRI contrast agent of T1 weighting.
Embodiment 42
Make the MRI contrast agent Gd-DTPA coordination compound among the embodiment 27 into Gd
2O
3Nanoparticle, concrete method for preparing is identical with embodiment 37.The preparation of biodegradable chitosan nanosphere and to MRI contrast agent Gd
2O
3The coupling of the embedding of nanoparticle, 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the MRI contrast agent of T1 weighting.
Embodiment 43
Reducing agent NaBH with preparation gold nano grain among the embodiment 3
4Change sodium citrate into, concrete method for preparing is following: in the round-bottomed flask of 100mL, add the 50mL ultra-pure water, under quick magnetic agitation, add the 5mM HAuCl of 2.5mL
4Solution; Heating in boiling water is abundant adds 0.5,0.625,1.0 or the sodium citrate solution (1%) of 2.0mL then, is reflected to continue 10min in the boiling water bath; At room temperature stir cooling at last, can obtain that particle diameter is respectively 38,35,16, the gold nano grain of 14nm.Bigger gold nano grain (100nm) can 14nm gold nano grain be that seed synthesizes, concrete method for preparing is following: the gold nano grain of getting the 14nm of 0.75mL adds in the 97.25mL ultra-pure water, adds the HAuCl of 1.0mL 1% (w/v) then
43H
2O solution at room temperature stirs fast, adds 1% sodium citrate of 0.22mL, adds the 0.03M hydroquinone of 1.0mL again, stirred overnight, thus make the gold nano grain of 100nm.
The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 3 to embedding, the coupling of albumin nanometer ball surface ligand folic acid, the albumin nanometer ball surface p H responsive type of the gold nano grain of above-mentioned five kinds of different-grain diameters; Can make early diagnosis of tumor such as other four kinds of brain cancers, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 44
Reducing agent NaBH with preparation gold nano grain among the embodiment 8
4Change sodium citrate into, concrete method for preparing is identical with embodiment 43.The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 8 to embedding, the coupling of albumin nanometer ball surface ligand galactosamine, the albumin nanometer ball surface p H responsive type of the gold nano grain of made five kinds of different-grain diameters; Can make other four kinds of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 45
CT contrast agent gold nano grain among the embodiment 3 is changed to business-like CT contrast agent iohexol; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 3 to embedding, the coupling of albumin nanometer ball surface ligand folic acid, the albumin nanometer ball surface p H responsive type of CT contrast agent iohexol; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 46
CT contrast agent gold nano grain among the embodiment 8 is changed to business-like CT contrast agent iohexol; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 8 to embedding, the coupling of albumin nanometer ball surface ligand galactosamine, the albumin nanometer ball surface p H responsive type of CT contrast agent iohexol; Can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 47
CT contrast agent gold nano grain among the embodiment 13 is changed to business-like CT contrast agent iohexol; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 13 to embedding, the coupling of albumin nanometer ball surface ligand folic acid, the albumin nanometer ball surface p H responsive type of CT contrast agent iohexol; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 48
CT contrast agent gold nano grain among the embodiment 18 is changed to business-like CT contrast agent iohexol; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 18 to embedding, the coupling of albumin nanometer ball surface ligand galactosamine, the albumin nanometer ball surface p H responsive type of CT contrast agent iohexol; Can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 49
CT contrast agent gold nano grain among the embodiment 23 is changed to business-like CT contrast agent iohexol; The preparation of biodegradable chitosan nanosphere and high molecular synthetic identical with embodiment 23 to embedding, the coupling of chitosan nano ball surface ligand folic acid, the chitosan nano ball surface p H responsive type of CT contrast agent iohexol; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 50
CT contrast agent gold nano grain among the embodiment 28 is changed to business-like CT contrast agent iohexol; The preparation of biodegradable chitosan nanosphere and high molecular synthetic identical with embodiment 28 to embedding, the coupling of chitosan nano ball surface ligand folic acid, the chitosan nano ball surface p H responsive type of CT contrast agent iohexol; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 51
CT contrast agent gold nano grain among the embodiment 3 is changed to business-like CT contrast agent Actybaryte; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 3 to embedding, the coupling of albumin nanometer ball surface ligand folic acid, the albumin nanometer ball surface p H responsive type of CT contrast agent Barium Sulfate; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 52
CT contrast agent gold nano grain among the embodiment 8 is changed to business-like CT contrast agent Actybaryte; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 8 to embedding, the coupling of albumin nanometer ball surface ligand galactosamine, the albumin nanometer ball surface p H responsive type of CT contrast agent Barium Sulfate; Can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 53
CT contrast agent gold nano grain among the embodiment 13 is changed to business-like CT contrast agent Actybaryte; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 13 to embedding, the coupling of albumin nanometer ball surface ligand folic acid, the albumin nanometer ball surface p H responsive type of CT contrast agent Barium Sulfate; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 54
CT contrast agent gold nano grain among the embodiment 18 is changed to business-like CT contrast agent Actybaryte; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 18 to embedding, the coupling of albumin nanometer ball surface ligand galactosamine, the albumin nanometer ball surface p H responsive type of CT contrast agent Barium Sulfate; Can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 55
CT contrast agent gold nano grain among the embodiment 23 is changed to business-like CT contrast agent Actybaryte; The preparation of biodegradable chitosan nanosphere and high molecular synthetic identical with embodiment 23 to embedding, the coupling of chitosan nano ball surface ligand folic acid, the chitosan nano ball surface p H responsive type of CT contrast agent Barium Sulfate; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 56
CT contrast agent gold nano grain among the embodiment 28 is changed to business-like CT contrast agent Actybaryte; The preparation of biodegradable chitosan nanosphere and high molecular synthetic identical with embodiment 28 to embedding, the coupling of chitosan nano ball surface ligand folic acid, the chitosan nano ball surface p H responsive type of CT contrast agent Barium Sulfate; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 57
With PET contrast agent among the embodiment 4
18F-FDG is changed to
64Cu, the preparation of biodegradable albumin nanometer ball and to the PET contrast agent
64The coupling of the embedding of Cu, albumin nanometer ball surface ligand folic acid, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 4; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 58
With PET contrast agent among the embodiment 9
18F-FDG is changed to
64Cu, the preparation of biodegradable albumin nanometer ball and to the PET contrast agent
64The coupling of the embedding of Cu, albumin nanometer ball surface ligand galactosamine, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 9, can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 59
With PET contrast agent among the embodiment 14
18F-FDG is changed to
64Cu, the preparation of biodegradable albumin nanometer ball and to the PET contrast agent
64The coupling of the embedding of Cu, albumin nanometer ball surface ligand folic acid, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 14; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 60
With PET contrast agent among the embodiment 19
18F-FDG is changed to
64Cu, the preparation of biodegradable albumin nanometer ball and to the PET contrast agent
64The coupling of the embedding of Cu, albumin nanometer ball surface ligand galactosamine, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 19, can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 61
With PET contrast agent among the embodiment 24
18F-FDG is changed to
64Cu, the preparation of biodegradable chitosan nanosphere and to the PET contrast agent
64The coupling of the embedding of Cu, 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 62
With PET contrast agent among the embodiment 29
18F-FDG is changed to
64Cu, the preparation of biodegradable chitosan nanosphere and to the PET contrast agent
64The coupling of the embedding of Cu, 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 63
With PET contrast agent among the embodiment 4
18F-FDG is changed to
124I, the preparation of biodegradable albumin nanometer ball and to the PET contrast agent
124The coupling of the embedding of I, albumin nanometer ball surface ligand folic acid, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 4; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 64
With PET contrast agent among the embodiment 9
18F-FDG is changed to
124I, the preparation of biodegradable albumin nanometer ball and to the PET contrast agent
124The coupling of the embedding of I, albumin nanometer ball surface ligand galactosamine, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 9, can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 65
With PET contrast agent among the embodiment 14
18F-FDG is changed to
124I, the preparation of biodegradable albumin nanometer ball and to the PET contrast agent
124The coupling of the embedding of I, albumin nanometer ball surface ligand folic acid, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 14; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 66
With PET contrast agent among the embodiment 19
18F-FDG is changed to
124I, the preparation of biodegradable albumin nanometer ball and to the PET contrast agent
124The coupling of the embedding of I, albumin nanometer ball surface ligand galactosamine, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 19, can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 67
With PET contrast agent among the embodiment 24
18F-FDG is changed to
124I, the preparation of biodegradable chitosan nanosphere and to the PET contrast agent
124The coupling of the embedding of I, 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 68
With PET contrast agent among the embodiment 29
18F-FDG is changed to
124I, the preparation of biodegradable chitosan nanosphere and to the PET contrast agent
124The coupling of the embedding of I, 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 69
With PET contrast agent among the embodiment 4
18F-FDG is changed to
94Tc, the preparation of biodegradable albumin nanometer ball and to the PET contrast agent
94The coupling of the embedding of Tc, albumin nanometer ball surface ligand folic acid, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 4; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 70
With PET contrast agent among the embodiment 9
18F-FDG is changed to
94Tc, the preparation of biodegradable albumin nanometer ball and to the PET contrast agent
94The coupling of the embedding of Tc, albumin nanometer ball surface ligand galactosamine, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 9, can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 71
With PET contrast agent among the embodiment 14
18F-FDG is changed to
94Tc, the preparation of biodegradable albumin nanometer ball and to the PET contrast agent
94The coupling of the embedding of Tc, albumin nanometer ball surface ligand folic acid, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 14; Can make early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 72
With PET contrast agent among the embodiment 19
18F-FDG is changed to
94Tc, the preparation of biodegradable albumin nanometer ball and to the PET contrast agent
94The coupling of the embedding of Tc, albumin nanometer ball surface ligand galactosamine, albumin nanometer ball surface p H responsive type are high molecular synthetic identical with embodiment 19, can make another kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 73
With PET contrast agent among the embodiment 24
18F-FDG is changed to
94Tc, the preparation of biodegradable chitosan nanosphere and to the PET contrast agent
94The coupling of the embedding of Tc, 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 74
With PET contrast agent among the embodiment 29
18F-FDG is changed to
94Tc, the preparation of biodegradable chitosan nanosphere and to the PET contrast agent
94The coupling of the embedding of Tc, 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 early diagnosis of tumor such as the another kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the PET contrast agent.
Embodiment 75
Change preparation gold nano grain among the embodiment 3 into the gold nano cage, concrete method for preparing is following: with the HAuCl of 3mL 0.75mM
4HMT (hexamethylenetetramine) mixing with 3mL 0.03M; Solution colour becomes transparently by pale yellow, then, adds the PVP (polyvinylpyrrolidone) of 3mL 0.3M and the AgNO3 of 100 μ L 0.01M; Add 50 μ L 0.08M ascorbic acid after the gentle agitation; Mixed solution is stirred 10s, and room temperature leaves standstill 12h centrifuge washing afterwards, can obtain the gold nano cage.
The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 3 to embedding, the coupling of albumin nanometer ball surface ligand folic acid, the albumin nanometer ball surface p H responsive type of above-mentioned gold nano cage; Can make early diagnosis of tumor such as other a kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 76
Change preparation gold nano grain among the embodiment 8 into the gold nano cage; Concrete method for preparing is identical with embodiment 75; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 8 to embedding, the coupling of albumin nanometer ball surface ligand galactosamine, the albumin nanometer ball surface p H responsive type of above-mentioned gold nano cage; Can make other a kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 77
Change preparation gold nano grain among the embodiment 3 into gold nanorods, concrete method for preparing is following: preparation 20mL contains 0.25mM HAuCl
4With the 0.25mM sodium citrate solution, add the 0.1M NaBH of 0.6mL ice bath while stirring
4Solution adds NaBH
4Back solution can become purple rapidly, and golden nanometer particle forms.In the 2-5h, this golden nanometer particle can be used as the gold nano seed behind synthetic this golden nanometer particle.Preparation 10mL contains 0.25mM HAuCl
4Growth solution with 0.1M CTAB (cetyl trimethyl ammonium bromide); The 0.1M new system ascorbic acid solution that adds 0.05mL; And then adding 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 preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 3 to embedding, the coupling of albumin nanometer ball surface ligand folic acid, the albumin nanometer ball surface p H responsive type of above-mentioned gold nanorods; Can make early diagnosis of tumor such as other a kind of brain cancer, renal carcinoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, uterus carcinoma, nasopharyngeal carcinoma and use stealthy radiography material, can be used as the CT contrast agent.
Embodiment 78
Change preparation gold nano grain among the embodiment 8 into gold nanorods; Concrete method for preparing is identical with embodiment 77; The preparation of biodegradable albumin nanometer ball and high molecular synthetic identical with embodiment 8 to embedding, the coupling of albumin nanometer ball surface ligand galactosamine, the albumin nanometer ball surface p H responsive type of above-mentioned gold nanorods; Can make other a kind of hepatocarcinoma early diagnosis and use stealthy radiography material, can be used as the CT contrast agent.
Claims (10)
1. an early diagnosis of tumor is used stealthy radiography material; It is characterized in that, by the Biodegradable nanometer ball, be embedded in the inner medical science contrast agent of described Biodegradable nanometer ball, the target molecule and the pH responsive type macromolecule that are connected in described Biodegradable nanometer ball surface constitute.
2. early diagnosis of tumor according to claim 1 is used stealthy radiography material, it is characterized in that, the macromolecular compound of described pH responsive type macromolecule in pH5.0～6.0 scopes, shrinking.
3. early diagnosis of tumor according to claim 1 and 2 is used stealthy radiography material; It is characterized in that; Described pH responsive type macromolecule is at least a in Isopropylacrylamide-acrylic copolymer and the Isopropylacrylamide-EUDRAGIT S100, and molecular weight ranges is 2k-1000k.
4. early diagnosis of tumor according to claim 1 is used stealthy radiography material, it is characterized in that, described medical science contrast agent is MRI contrast agent, CT contrast agent, PET contrast agent or fluorescein contrast agent, and the particle diameter of described medical science contrast agent is below the 15nm.
5. early diagnosis of tumor according to claim 4 is used stealthy radiography material, it is characterized in that, described MRI contrast agent is selected from SPIO nanoparticle, paramagnetism Gd-DTPA coordination compound, Gd-DOTA coordination compound and Gd
2O
3At least a in the nanoparticle;
Described CT contrast agent is selected from least a in iohexol, Barium Sulfate, gold nano grain, gold nanorods and the gold nano cage;
Described PET contrast agent is selected from
18F-FDG,
64Cu,
124I with
94At least a among the C;
Described fluorescein contrast agent is a phthalocyanine.
6. early diagnosis of tumor according to claim 1 is used stealthy radiography material; It is characterized in that; The material of described Biodegradable nanometer ball is selected from least a in oligopeptide, protein, polysaccharide, polyethers, the polyesters macromolecule, and the particle diameter of described Biodegradable nanometer ball is below the 500nm.
7. early diagnosis of tumor according to claim 1 is used stealthy radiography material, it is characterized in that, described target molecule is selected from monoclonal antibody, folic acid or the galactosamine at least a.
8. early diagnosis of tumor according to claim 1 is used stealthy radiography material, it is characterized in that, described pH responsive type macromolecule is 0.2-5.0 with the number ratio of target molecule.
9. the arbitrary described early diagnosis of tumor of claim 1～8 is characterized in that with the method for preparing of stealthy radiography material, comprises the steps:
(1) preparation is embedded with the Biodegradable nanometer ball of medical science contrast agent;
(2) through the covalent coupling reaction described target molecule is connected on the surface of the Biodegradable nanometer ball that obtains in the step (1), obtains intermediate;
(3) on the surface of the intermediate that step (2) obtains, adopt the synthetic described pH responsive type macromolecule of living radical polymerization technique, obtain described early diagnosis of tumor and use stealth material.
10. early diagnosis of tumor according to claim 9 is characterized in that with the method for preparing of stealthy radiography material step (3) replaces with:
PH responsive type macromolecule is connected on the surface of the intermediate that step (2) obtains through covalent coupling reaction, obtains described early diagnosis of tumor and use stealthy radiography material.
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