WO2014005383A1 - Invisible radiography material for early tumour diagnosis and preparation method thereof - Google Patents
Invisible radiography material for early tumour diagnosis and preparation method thereof Download PDFInfo
- Publication number
- WO2014005383A1 WO2014005383A1 PCT/CN2012/082578 CN2012082578W WO2014005383A1 WO 2014005383 A1 WO2014005383 A1 WO 2014005383A1 CN 2012082578 W CN2012082578 W CN 2012082578W WO 2014005383 A1 WO2014005383 A1 WO 2014005383A1
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- WIPO (PCT)
- Prior art keywords
- contrast agent
- cancer
- early diagnosis
- contrast
- invisible
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Definitions
- the invention relates to nano contrast materials, in particular to a nano contrast material with high specific targeting function and a preparation method thereof.
- Malignant tumors are one of the major diseases that pose a serious threat to human health. So far, humans have not found an effective way to treat various malignant tumors. Recognized methods to reduce cancer mortality are early detection, early treatment, detection of cancer cells before they spread, and effective treatment. At present, the main diagnostic techniques for various types of malignant tumors can only find that the size is greater than 1 cm of tumor, but can not do anything for smaller tumors, such as magnetic resonance imaging (MRI) [Biomaterials, 2011; 32: 5167-5176], computer X Ray tomography (CT) and positron emission tomography (PET) ). Medical contrast agents can improve the detection sensitivity and spatial resolution of these diagnostic techniques. In order to achieve early detection and diagnosis of various malignant tumors, various high-performance medical contrast agents need to be developed [Nat. Nanotechnol., 2010; 5: 815-821].
- MRI magnetic resonance imaging
- CT computer X Ray tomography
- PET positron emission tomography
- the first commercially available MRI contrast agent is Gd-DTPA, developed by HJ Weinmenn of Schering, Germany, which is a complex of diethylenetriaminepentaacetic acid (DTPA) with Gd (III) [Angew. Chem. Int. Edit., 2010; 49: 1231-1233].
- DTPA diethylenetriaminepentaacetic acid
- III Gd
- superparamagnetic contrast agents The magnetic moment and magnetic susceptibility of the superparamagnetic contrast agent are much larger than the human tissue structure, and much larger than the paramagnetic chelate compound. However, because of its extremely low water solubility, it can only be administered in the form of homogenate or colloid.
- target molecules compounds that target cancer cells, such as monoclonal antibodies, ligands such as folic acid and galactosamine
- SPION superparamagnetic iron oxide nanoparticles
- PEGMA polyglycidyl methacrylate-polyethylene glycol methacrylate copolymer
- ATRP atom transfer radical polymerization
- PEGMA plays a role in stabilizing nanoparticles and prolonging the circulation time in the body.
- GMA can be used to graft the ligand folate that can target cancer cells, thereby producing an MRI contrast agent that can actively target tumor tissues [Langmuir] , 2012; 28: 563-571].
- CT Computerized tomography
- iodine has a high X-ray absorption coefficient [Advanced Drug Delivery Reviews, 1999; 37: 159-173].
- these iodine-containing substances are rapidly cleared by the kidneys, making the contrast time short and nephrotoxic, and, X The radiation induces the iodine-containing material to ionize the iodide ion, causing toxicity.
- new nanoparticle-based CT contrast agents are expected to improve these shortcomings [Small, 2007; 3: 333-341].
- Nanoparticles are small in size (1 to 100 nm) and can enter capillaries with micron-sized inner diameters [Journal of Artificial Organs, 2005; 8: 77-84], thus allowing more access to tissues; and, due to the increased permeability of capillaries in cancerous tissues [American Journal of Pathology, 2000; 156: 1363-1380], nanoparticles can be deposited more on cancerous tissue by leakage, thus better imaging cancerous areas [CT] Theory and Applied Research, 2009; 18: 15-25].
- positron emission tomography has been widely used in the diagnosis of a variety of malignant tumors, and the diagnostic value of cancer patients has attracted more and more attention.
- fluorine-labeled radionuclide 18 2- (fluorine-18) -2-deoxy-glucose (FDG) positron emission tomography (PET) gradually developed inspection method.
- FDG-PET can show the metabolic characteristics of the lesions, help to distinguish the benign and malignant properties of the lesions, and also help the staging of the tumor [Chinese Journal of Tuberculosis and Respiratory Diseases, 2005; 28: 221-224].
- optical imaging has the characteristics of no radiation and low cost, especially near-infrared fluorescence imaging, which can partially realize the detection and imaging of deep tissues and organs, and has certain advantages in optical imaging [Nature Methods, 2009; 6: 465-469] .
- the core of optical imaging is fluorescein contrast agent.
- the main problems include the transmission and collection of deep light and the luminescence quantum efficiency, anti-bleaching, good biocompatibility and targeting of fluorescein contrast agents. [Biomaterials, 2009; 30: 5592-5600] .
- Near-infrared fluorescent dyes such as phthalocyanine
- tetrapyrrolyl groups have been the focus of attention in recent years, and have good application prospects in near-infrared probes due to their good photophysical behavior [J. Am. Chem. Soc., 2009; 131: 2432-2433] .
- Targeting is a key issue in the design of fluorescein contrast agents. The most common is the use of cell surface receptors to design a drug delivery system that actively targets tumor cells [Journal of Chemical Industry of China, 2011; 32: 1010-1012].
- targeted contrast materials are typically prepared by binding target molecules (monoclonal antibodies or ligands) to a contrast agent to achieve specificity for cancer cells.
- target molecules monoclonal antibodies or ligands
- non-specific antigens or receptors are also present on the surface of normal cells. These antigens or receptors can also bind to target molecules (monoclonal antibodies or ligands), thus affecting the detection sensitivity and spatial resolution of various diagnostic techniques. Therefore, the development of contrast agents with higher specific targeting functions is an urgent problem to be solved.
- the invention provides a stealth contrast material for early diagnosis of tumor and a preparation method thereof, and the stealth contrast material can be targeted to the tumor site with high specificity.
- a stealth contrast material for early diagnosis of tumors comprising biodegradable nanospheres, a medical contrast agent embedded inside the nanospheres, a pH sensitive polymer attached to the surface of the nanospheres, and a target molecule.
- the pH sensitive polymer is at pH 5.0 ⁇ 6.0
- the transition is prone to change from a linearly stretched state to a contracted state, so that the target molecule can be exposed while having less toxicity to the cells
- the pH-sensitive molecule is preferably isopropylacrylamide- At least one of an acrylic copolymer and an isopropylacrylamide-methacrylic acid copolymer having a molecular weight in the range of 2k to 1000k.
- FIG. 1 Shown. Under normal physiological conditions, the pH of the body is between 7.3 and 7.4, and the target molecules on the surface of the nanosphere are hidden in a linearly stretched pH-sensitive polymer.
- the stealth contrast material cannot be non-specifically taken up by normal cells; in the tumor tissue environment, the pH is about 5.5, pH Sensitive polymer A phase transition occurs and shrinks, exposing the target molecules on the surface of the nanosphere, and specifically interacting with antigens or receptors on the surface of the tumor cells, and the invisible contrast material is taken up by the tumor cells, thereby achieving high-precision targeting of the contrast agent. Delivery to the tumor site, improved Detection sensitivity and spatial resolution reduce the dose, side effects and cost of the contrast agent.
- the medical contrast agent is used to increase the imaging resolution, which is well known to those skilled in the art.
- MRI contrast agent, CT contrast agent, PET contrast agent or fluorescein contrast agent can be applied to the invention, in order to enable the contrast agent to be smoothly embedded in the biodegradable nanosphere (referred to as nanosphere), contrast agent
- the particle diameter is preferably 15 nm or less.
- the MRI contrast agent is a material having an MRI contrast function, preferably a T 2 MRI contrast agent and a T 1 type MRI contrast agent, the selected material needs to have good water solubility, and the T 2 MRI contrast agent is further Preferably, it is superparamagnetic iron oxide nanoparticles (SPION), and the T 1 -type MRI contrast agent is further preferably small in size such as Gd 3+ , Dy 3+ , Mn 2+ or Fe 3+ having a large effective magnetic moment.
- SPION superparamagnetic iron oxide nanoparticles
- a molecular paramagnetic contrast agent or a macromolecular paramagnetic contrast agent that forms a stable chelate with a suitable ligand, such as at least one of a Gd-DTPA complex, a Gd-DOTA complex, and a Gd 2 O 3 nanoparticle.
- DTPA is diethylenetriaminepentaacetic acid
- DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N",N-tetraacetic acid.
- the CT contrast agent is a material having a CT contrast function, and the selected material needs to have good water solubility, preferably a nanoparticle or a small molecule compound having a CT contrast function, further preferably a gold nanoparticle, a gold nanorod. At least one of gold nanocage, iohexol, and BaSO 4 .
- the PET contrast agent is a class of compounds capable of improving the resolution of PET imaging, preferably at least 18 F -FDG (2-(fluoro-18 )-2-deoxyglucose), 64 Cu, 124 I and 94 C One.
- the fluorescein contrast agent is a near-infrared fluorescent dye capable of improving near-infrared optical molecular imaging, preferably phthalocyanine.
- the nanosphere is used as a carrier to embed a contrast agent to achieve sustained release and controlled release.
- the non-toxic natural macromolecule or artificial synthetic polymer which is less toxic to human body and biodegradable can be applied to the present invention.
- the material is preferably at least one of a protein, an oligopeptide, a polysaccharide, a polyether or a polyester polymer, further preferably albumin and chitosan;
- the contrast material is generally used by intravenous injection, and the particle diameter cannot be too large, and the particle diameter of the nanosphere is preferably 500 nm or less, and at the same time, the pH is connected to the surface of the nanosphere.
- the particle size of the sensitive polymer and the target molecule is not too small, and the particle diameter of the nanosphere is further preferably 50-200 nm.
- the target molecule is a compound having specific interaction with tumor cells, and can be targeted to cancer cells, preferably At least one of a monoclonal antibody, folic acid or galactosamine.
- the ratio of the number of the pH-sensitive polymer to the target molecule on the surface of the nanosphere is 0.2-5.0.
- the target molecule can be concealed in the pH-sensitive polymer, and the target molecule can be exposed in the tumor tissue environment.
- the invention also provides a preparation method of the invisible material for early diagnosis of tumor, comprising the following steps:
- the biodegradable nanosphere embedded with the medical contrast agent in the step (1) can be prepared by a phacoemulsification method or a solvent removal method, wherein the ultrasonic emulsification method includes a water-in-oil method, an oil-in-water method, and a W/O/W complex.
- the milk method is introduced separately below.
- Water-in-oil method an aqueous solution in which a hydrophilic medical contrast agent and a hydrophilic membrane are dissolved is used as an aqueous phase, an organic solvent in which an oil-soluble emulsifier is dissolved is used as an oil phase, and the aqueous phase and the oil phase are mixed and stirred to be coarse. After dispersing, it is emulsified by ultrasonic cell crusher to obtain a water-in-oil type nanoemulsion, and then cross-linking is added to the obtained nano-emulsion by magnetic stirring to crosslink and solidify, and excess cross-linking agent and emulsifier can be removed. obtain.
- the oil-in-water method an organic solvent in which a hydrophobic medical contrast agent and a hydrophobic film are dissolved is used as an oil phase, and an aqueous solution in which a water-soluble emulsifier is dissolved is used as an aqueous phase, and the oil phase and the aqueous phase are mixed and stirred for coarse dispersion. Then, it is emulsified by ultrasonic cell crusher to obtain an oil-in-water type nano-emulsion, and then a cross-linking agent is added to the obtained nano-emulsion under magnetic stirring to cross-link and solidify, and excess cross-linking agent and emulsifier are removed to obtain a package. Biodegradable nanospheres embedded with medical contrast agents.
- the double emulsion method an aqueous solution in which a hydrophilic medical contrast agent is dissolved is used as an aqueous phase, and an organic solvent in which a hydrophobic membrane and an oil-soluble emulsifier are dissolved is used as an oil phase, and the aqueous phase and the oil phase are mixed and stirred for coarse dispersion.
- Desolvent method dissolving water-soluble medical contrast agent and nanosphere material oligopeptide or protein in NaCl
- ethanol is added dropwise, and the magnetic stirring is continued during the dropping process.
- glutaraldehyde cross-linking and solidifying the nanospheres is added, and excess cross-linking agent is removed to obtain a medical contrast agent.
- Biodegradable nanospheres are examples of materials that are used in the aqueous solution.
- Step ( 2 The covalent coupling reaction described in the reaction is a reaction in which a functional group at the end of the target molecule forms a covalent chemical bond with a functional group on the surface of the nanosphere, for example: in EDAC ( 1-ethyl - ( 3- A chemical reaction in which a carboxyl group and an amino group form an amide group catalyzed by dimethylaminopropyl)carbodiimide.
- the material of the nanosphere contains a carboxyl group (such as polyglutamic acid, polyaspartic acid, polypeptides and proteins containing glutamic acid and aspartic acid, and polysaccharides containing carboxyl groups), a monoclonal group containing an amino group may be selected.
- a carboxyl group such as polyglutamic acid, polyaspartic acid, polypeptides and proteins containing glutamic acid and aspartic acid, and polysaccharides containing carboxyl groups
- a ligand such as an antibody or galactosamine as a target molecule
- EDAC and NHS N- Hydroxyl succinimide
- a monoclonal antibody containing a carboxyl group or a ligand such as folic acid can be selected as a target.
- Molecules then adopt the above method to activate the carboxyl group of the target molecule and graft it onto the surface of the nanosphere; for biodegradable materials (such as polyethers and polyester polymers) which contain neither carboxyl groups nor amino groups,
- the copolymerization method is carried out with some amino groups or carboxyl groups, and after the nanospheres are formed, the target molecules can be grafted on the surface of the nanospheres by the same method as above.
- Step 3 The living radical polymerization technique (also referred to as controlled polymerization) is a relatively mature technology in the art, and can be carried out in the following steps in the present invention:
- the surface of the nanosphere obtained in step (2) is coupled with 4-chloromethylbenzoic acid (CBA) by catalysis of EDAC. Then, sodium diethyldithiocarbamate (NaDC) is fixed to the benzylic methyl group on the CBA, and finally the monomer is isopropyl acrylamide (NIPAM), acrylic acid (AA). Or active radical graft polymerization of methacrylic acid (MAA) on the surface of nanospheres. Among them, the pH point at which the polymer undergoes phase transformation and shrinks can pass AA (or MAA) and NIPAM.
- CBA 4-chloromethylbenzoic acid
- NaDC sodium diethyldithiocarbamate
- AA acrylic acid
- MAA active radical graft polymerization of methacrylic acid
- the molar ratio between the two when the molar ratio is in the range of 1: 1 ⁇ 50, the pH-sensitive polymer can be controlled at pH 5.0 ⁇ 6.0. A change takes place within the scope.
- the grafting density of the polymer can be controlled by the coupling amount of CBA on the surface of the nanosphere, and the coupling amount of CBA on the surface of the nanosphere can pass CBA.
- the initial concentration and reaction time are controlled; the chain length (molecular weight) of the polymer can be controlled by the concentration of the monomer at the time of synthesis and the polymerization time.
- Step (3) can also be achieved by a covalent coupling reaction, for example, by reacting a carboxyl functional group with an amino functional group.
- the sensitive polymer is covalently coupled to the surface of the nanosphere obtained in step (2).
- the synthesis method of pH-sensitive polymer uses a radical polymerization method using AIBN as an initiator, in which case block copolymerization is used.
- the pH-sensitive polymer has a plurality of acrylamines (or acrylic acids) at one end, so that the terminal of the thermosensitive polymer has a plurality of amino groups (carboxy groups).
- EDAC electroactive electros
- FIG. 1 is a schematic diagram of a mechanism for specifically targeting cancer cells by using a stealth contrast material for early diagnosis of tumors according to the present invention
- Figure 2 shows the synthesis of isopropyl acrylamide on the surface of biodegradable nanospheres by living radical graft polymerization in Example 1.
- Figure 3 is a transmission electron micrograph of the albumin nanosphere prepared in Example 1;
- FIG 4 shows the albumin nanospheres (a) prepared in Example 1 and the surface coupled with pH. Comparison of transmission electron micrographs of sensitive macromolecular albumin nanospheres (b);
- Figure 5 is a view showing the invisible contrast material for early diagnosis of tumors prepared in Example 6 by hepatoma cells HepG2 Quantitative analysis of intake;
- Figure 6 shows the invisible angiographic material for early diagnosis of tumors prepared in Example 11 by cervical cancer cells HeLa Quantitative analysis of intake.
- the iron oleate complex (18 g, 20 mmol) and oleic acid (2.8 g, 10 mmol) were dissolved in 1-octadecene (30 g) and the mixture was heated to 320 o C (the rate of temperature increase was 3.3 o C/min), after reacting for 1 h under argon protection, cool the solution at room temperature, add ethanol (250 mL), and centrifuge (6000 rpm) for 10 minutes to obtain a monodisperse SPION with a particle size of about 14 nm. Finally, the resulting SPION is vacuum dried and stored at a low temperature (0 - 4 o C).
- - Methacrylic acid copolymer (PNIPAM-MAA), as shown in Figure 2.
- the sample (20,000 ⁇ g, 20 min), disperse the sample in 100 mL of ultrapure water, add 3.0 g of NIPAM and 200 mg of MAA, and use a 400 W UV lamp (UV wavelength 300-500). After irradiation for 1-5 hours at nm and peak value of 350 nm, the obtained composite nanoparticles are centrifuged, washed, and lyophilized to prepare a brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer, and the like. early diagnosis of cancer in invisible contrast material, may be used as T 2 weighted MRI contrast agent.
- Figure 3 is a transmission electron micrograph of the albumin nanosphere prepared in Example 1;
- Figure 4 is an albumin nanosphere (a) prepared in Example 1 and an albumin nanosphere having a pH-sensitive polymer coupled to it ( b) TEM photo comparison chart, (b) The imprinting circle on the surface of the nanosphere is evidence of successful coupling of pH-sensitive polymer on the surface of the nanosphere.
- step 1 (1) MRI contrast agent SPION was changed to PET contrast agent, 18 F -FDG was selected as medical contrast agent, preparation of biodegradable albumin nanosphere and its effect on PET contrast agent 18 F -FDG Embedding, coupling of folic acid on the surface of the albumin nanospheres, and synthesis of the pH-sensitive polymer on the surface of the albumin nanospheres are the same as in the first embodiment, and a brain cancer, kidney cancer, breast cancer, lung cancer, and ovary can be obtained.
- Invisible contrast materials for early diagnosis of cancer, uterine cancer, nasopharyngeal cancer, etc. can be used as PET contrast agents.
- Example 1 Step (1) MRI contrast agent SPION Changed to fluorescein contrast agent, selected near-infrared fluorescent dye phthalocyanine containing tetrapyrrolyl group as medical contrast agent, preparation of biodegradable albumin nanosphere and embedding of fluorescein contrast agent phthalocyanine, albumin Coupling of folic acid on the surface of nanospheres, surface of albumin nanospheres
- the synthesis of the pH-sensitive polymer is the same as in the first embodiment, and a stealth angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained.
- Fluorescein contrast agent .
- the target molecule coupled to the surface of the albumin nanosphere in the step (3) of Example 1 was changed to galactosamine, and the chemical reaction between the amino group of the galactosamine and the carboxyl group on the surface of the albumin nanosphere was catalyzed by EDAC.
- the ligand galactosamine capable of specifically targeting the liver cancer is coupled to the surface of the albumin nanosphere.
- the specific preparation method is as follows: prepare 500 ⁇ g/mL galactosamine solution with PBS as solvent, dissolve 50 mg EDAC in 10 mL galactosamine solution (ice bath), and then add 90 mL of PBS-embedded solution.
- the albumin nanosphere suspension (5.0 mg/mL) of the medical contrast agent was magnetically stirred at room temperature for 24 hours, and the sample was centrifuged (20,000 ⁇ g, 20 min), and the obtained sample was washed with PBS. Then, finally freeze-drying for 48 h can obtain albumin nanospheres with a surface coupled with ligand galactosamine and embedded with a medical contrast agent. Other steps are same as in Example 1, to prepare an early diagnosis of liver cancer in invisible contrast material, it may be used as T 2 weighted MRI contrast agent.
- SPION-AN-GAL-PM stands for internal embedding of contrast agent SPION, surface coupled with target molecule GAL and pH sensitive polymer PNIPAM-MAA (PM Albumin nanospheres (AN); SPION-AN represents albumin nanospheres (AN) encapsulating only the contrast agent SPION.
- PNIPAM-MAA PM Albumin nanospheres (AN)
- SPION-AN represents albumin nanospheres (AN) encapsulating only the contrast agent SPION.
- HepG2 cells are at pH 5.5.
- the amount of SPION-AN-GAL-PM ingested was significantly higher than that of SPION-AN-GAL-PM at pH 7.4, and significantly higher than that at pH 5.5.
- the amount of SPION-AN was significantly higher than that of SPION-AN-GAL-PM.
- the target molecule coupled to the surface of the albumin nanosphere in Example 2 was changed to galactosamine, and the preparation method was the same as that in Example 6. The other steps were the same as in Example 2, and a stealth angiography for early diagnosis of liver cancer was prepared.
- material may be used as T 1 weighted MRI contrast agent.
- the target molecule coupled to the surface of the albumin nanosphere in Example 3 was changed to galactosamine, and the specific preparation method and the embodiment 6 Similarly, the other steps are the same as in the third embodiment, and a stealth contrast material for early diagnosis of liver cancer can be obtained, which can be used as a CT contrast agent.
- the target molecule coupled to the surface of the albumin nanosphere in Example 4 was changed to galactosamine, and the specific preparation method and Example 6 Similarly, the other steps are the same as in the fourth embodiment, and a stealth contrast material for early diagnosis of liver cancer can be obtained, which can be used as a PET contrast agent.
- Example 5 The target molecule coupled to the surface of the albumin nanosphere in Example 5 was changed to galactosamine, and the specific preparation method and Example 6 Similarly, the other steps are the same as in the case of Example 5, and a stealth contrast material for early diagnosis of liver cancer can be obtained, which can be used as a fluorescein contrast agent.
- the monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer in the step (5) of Example 1 was changed to acrylic acid (AA) to synthesize a pH-sensitive polymer isopropyl group on the surface of the albumin nanosphere.
- Acrylamide-acrylic acid copolymer (PNIPAM-AA) other experimental methods and conditions are the same as in Example 1, to obtain another brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal carcinoma stealth early diagnosis of cancer and other contrast material, may be used as T 2 weighted MRI contrast agent.
- SPION-AN-FA-PA stands for internal embedding of contrast agent SPION, surface coupled with target molecule FA and pH sensitive polymer PNIPAM-AA (PA Albumin nanospheres (AN), SPION-AN represent albumin nanospheres (AN) with a contrast agent SPION embedded therein.
- PNIPAM-AA PA Albumin nanospheres
- SPION-AN represent albumin nanospheres (AN) with a contrast agent SPION embedded therein.
- HeLa cells are at pH 5.5.
- the amount of SPION-AN-FA-PA taken was significantly higher than that of SPION-AN-FA-PA at pH 7.4, and significantly higher than that at pH 5.5.
- the amount of SPION-AN was significantly higher than that of SPION-AN-FA-PA.
- the monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 2 was changed to acrylic acid (AA) to synthesize a pH-sensitive polymer isopropylacrylamide-acrylic acid on the surface of albumin nanospheres.
- Copolymer (PNIPAM-AA) other experimental methods and conditions are the same as in Example 2, and another tumor diagnosis such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal carcinoma, etc. can be obtained.
- stealth contrast material can be used as T 1 weighted MRI contrast agent.
- the monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 3 was changed to acrylic acid (AA). ), thereby synthesizing a pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer (PNIPAM-AA) on the surface of albumin nanospheres, and other experimental methods and conditions are the same as in Example 3
- PNIPAM-AA pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer
- another kind of stealth contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer and nasopharyngeal cancer can be obtained, which can be used as a CT contrast agent.
- the monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 4 was changed to acrylic acid (AA). ), thereby synthesizing a pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer (PNIPAM-AA) on the surface of albumin nanospheres, and other experimental methods and conditions are the same as in Example 4
- PNIPAM-AA pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer
- another type of brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer and other invisible contrast materials for early diagnosis can be obtained, which can be used as a PET contrast agent.
- the monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer in Example 5 was changed to acrylic acid (AA). ), thereby synthesizing a pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer (PNIPAM-AA) on the surface of albumin nanospheres, and other experimental methods and conditions are the same as in Example 5
- PNIPAM-AA pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer
- another kind of stealth contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer and nasopharyngeal cancer can be obtained, which can be used as a fluorescein contrast agent.
- the monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 6 was changed to acrylic acid (AA) to synthesize a pH-sensitive polymer isopropylacrylamide-acrylic acid on the surface of albumin nanospheres.
- AA acrylic acid
- PNIPAM-AA copolymer
- other experimental methods and conditions of Example 6 to obtain another early diagnosis of liver cancer in invisible contrast material, it may be used as T 2 weighted MRI contrast agent.
- the monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 7 was changed to acrylic acid (AA) to synthesize a pH-sensitive polymer isopropylacrylamide-acrylic acid on the surface of albumin nanospheres.
- AA acrylic acid
- the monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 8 was changed to acrylic acid (AA). ), thereby synthesizing a pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer (PNIPAM-AA) on the surface of albumin nanospheres, and other experimental methods and conditions are the same as in Example 8
- PNIPAM-AA pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer
- the monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 9 was changed to acrylic acid (AA).
- AA acrylic acid
- PNIPAM-AA pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer
- the monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 10 was changed to acrylic acid (AA). ), thereby synthesizing a pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer (PNIPAM-AA) on the surface of albumin nanospheres, and other experimental methods and conditions are the same as in Example 10
- PNIPAM-AA pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer
- the biodegradable albumin nanospheres in Example 1 were changed to chitosan nanospheres, and the preparation thereof and the embedding method for the medical contrast agent were as follows: 0.2% (w/v) chitosan solution was prepared, and the solvent was 1% (w/v) acetic acid, the medical contrast agent (same as in Example 1) was dispersed into the chitosan solution, and the pH of the solution was adjusted to 4.7-4.8 with sodium hydroxide; 0.3% (w) was prepared.
- TPP sodium tripolyphosphate
- 0.1 mL of TPP solution was added to 0.5 mL of the above chitosan solution under magnetic stirring to prepare an ion-crosslinked shell embedded with a medical contrast agent.
- Glycan nanospheres Other experimental methods and conditions are the same as in the first embodiment, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained, which can be used as T. 2 weighted MRI contrast agents.
- the biodegradable albumin nanospheres of Example 2 were changed to chitosan nanospheres, and the preparation thereof and the embedding method for the medical contrast agent (same as in Example 2) were the same as in Example 21, and other experimental methods and conditions.
- the medical contrast agent (same as in Example 2) were the same as in Example 21, and other experimental methods and conditions.
- As in Example 2, can be prepared another early diagnosis of cancer, brain cancer, renal cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal stealth contrast material can be used as MRI contrast T 1 weighted Agent.
- Example 3 The biodegradable albumin nanospheres of Example 3 were changed to chitosan nanospheres, and their preparation and medical contrast agents (with Example 3)
- the same method of embedding is the same as in Example 21, other experimental methods and conditions and Example 3
- another kind of stealth contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer and nasopharyngeal cancer can be obtained, which can be used as a CT contrast agent.
- the biodegradable albumin nanospheres of Example 4 were changed to chitosan nanospheres, and their preparation and medical contrast agents (with Example 4)
- the same method of embedding is the same as in Example 21, other experimental methods and conditions and Example 4
- another type of brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer and other invisible contrast materials for early diagnosis can be obtained, which can be used as a PET contrast agent.
- the biodegradable albumin nanospheres of Example 5 were changed to chitosan nanospheres, and their preparation and medical contrast agents (with Example 5)
- the same method of embedding is the same as in Example 21, other experimental methods and conditions and Example 5
- another kind of stealth contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer and nasopharyngeal cancer can be obtained, which can be used as a fluorescein contrast agent.
- Example 11 The biodegradable albumin nanospheres of Example 11 were changed to chitosan nanospheres, and the preparation thereof and the embedding method for the medical contrast agent (same as in Example 11) were the same as in Example 21, and other experimental methods and conditions.
- the medical contrast agent (same as in Example 11) were the same as in Example 21, and other experimental methods and conditions.
- T 2 weighted MRI contrast Agent to obtain another early diagnosis of cancer, brain cancer, renal cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal invisible with contrast material.
- the biodegradable albumin nanospheres of Example 12 were changed to chitosan nanospheres, and the preparation thereof and the embedding method for the medical contrast agent (same as in Example 12) were the same as in Example 21, and other experimental methods and conditions.
- Example 12 to obtain another early diagnosis of cancer, brain cancer, renal cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal stealth contrast material can be used as MRI contrast T 1 weighted Agent.
- Example 13 The biodegradable albumin nanospheres of Example 13 were changed to chitosan nanospheres, and their preparation and medical contrast agents (and Example 13)
- the same method of embedding is the same as in Example 21, other experimental methods and conditions and Example 13
- another kind of stealth contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer and nasopharyngeal cancer can be obtained, which can be used as a CT contrast agent.
- Example 14 The biodegradable albumin nanospheres of Example 14 were changed to chitosan nanospheres, their preparation and for medical contrast agents (and Example 14)
- the same method of embedding is the same as in Example 21, and other experimental methods and conditions and examples 14
- another type of brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer and other invisible contrast materials for early diagnosis can be obtained, which can be used as a PET contrast agent.
- the biodegradable albumin nanospheres of Example 15 were changed to chitosan nanospheres, and their preparation and medical contrast agents (with Example 15)
- the same method of embedding is the same as in Example 21, and other experimental methods and conditions and examples 15
- another kind of stealth contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer and nasopharyngeal cancer can be obtained, which can be used as a fluorescein contrast agent.
- the MRI contrast agent Gd-DTPA complex in Example 2 was changed to a commercially available Gd-DOTA complex, the preparation of biodegradable albumin nanospheres and the embedding of the MRI contrast agent Gd-DOTA complex
- the coupling of folic acid on the surface of the albumin nanospheres and the synthesis of the pH-sensitive polymer on the surface of the albumin nanospheres are the same as in the second embodiment, and another brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer can be obtained.
- uterine cancer, nasopharyngeal cancer early diagnosis invisible contrast material can be used as T 1 weighted MRI contrast agent.
- the MRI contrast agent Gd-DTPA complex in Example 7 was changed to a commercially available Gd-DOTA complex, the preparation of biodegradable albumin nanospheres and its embedding of MRI contrast agent Gd-DOTA complex
- the coupling of the galactosamine on the surface of the albumin nanospheres and the pH-sensitive polymer on the surface of the albumin nanospheres are the same as in the case of Example 7, and another invisible angiographic material for early diagnosis of liver cancer can be obtained.
- the MRI contrast agent Gd-DTPA complex in Example 12 was changed to a commercially available Gd-DOTA complex, the preparation of biodegradable albumin nanospheres and the embedding of the MRI contrast agent Gd-DOTA complex
- the coupling of folic acid on the surface of the albumin nanospheres and the pH-sensitive polymer on the surface of the albumin nanospheres are the same as in the case of Example 12, and another brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer can be obtained.
- uterine cancer, nasopharyngeal cancer early diagnosis invisible contrast material can be used as T 1 weighted MRI contrast agent.
- the MRI contrast agent Gd-DTPA complex in Example 17 was changed to a commercially available Gd-DOTA complex, the preparation of biodegradable albumin nanospheres and the embedding of the MRI contrast agent Gd-DOTA complex
- the coupling of galactosamine on the surface of the albumin nanospheres and the pH-sensitive polymer on the surface of the albumin nanospheres are the same as in Example 17, and another invisible angiographic material for early diagnosis of liver cancer can be obtained.
- the MRI contrast agent Gd-DTPA complex in Example 22 was changed to a commercially available Gd-DOTA complex, and the preparation of the biodegradable chitosan nanosphere and its package for the MRI contrast agent Gd-DOTA complex
- the coupling of the surface ligand of the chitosan nanospheres and the synthesis of the pH-sensitive polymer on the surface of the albumin nanospheres are the same as in the case of Example 22, and another brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer early diagnosis invisible contrast material can be used as T 1 weighted MRI contrast agent.
- the MRI contrast agent Gd-DTPA complex in Example 27 was changed to a commercially available Gd-DOTA complex, and the preparation of the biodegradable chitosan nanosphere and its package for the MRI contrast agent Gd-DOTA complex
- the coupling of the surface ligand of the chitosan nanospheres and the synthesis of the pH-sensitive polymer on the surface of the albumin nanospheres are the same as in the case of Example 27, and another brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer early diagnosis invisible contrast material can be used as T 1 weighted MRI contrast agent.
- the MRI contrast agent Gd-DTPA complex in Example 2 was changed to Gd 2 O 3 nanoparticles, and the specific preparation method was as follows: 6.0 mmol GdCl 3 .6H 2 O was added to 30 mL of DEG, and magnetic stirring was continued for the silicone oil. Heat in the oil bath at 140-160 °C for 1 h, then add 30 mL of DEG solution containing 7.5 mmol NaOH. After the reaction is completely dissolved, the temperature of the oil bath is raised to 180 °C and reacted for 4 h with rapid stirring.
- Preparation of biodegradable albumin nanospheres and its application to MRI contrast agent Gd 2 O 3 nanoparticles, coupling of albumin nanosphere surface ligand folic acid, synthesis of albumin nanosphere surface pH sensitive polymer As in Example 2, can be prepared another early diagnosis of cancer, brain cancer, renal cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal stealth contrast material can be used as MRI contrast T 1 weighted Agent.
- Example 7 The MRI contrast agent Gd-DTPA complex in Example 7 was changed to Gd 2 O 3 nanoparticles, and the specific preparation method was the same as in Example 37.
- Preparation of Biodegradable Albumin Nanospheres and Encapsulation of MRI Contrast Agent Gd 2 O 3 Nanoparticles, Coupling of Albumin Nanosphere Surface Ligand Galactosamine, Albumin Nanosphere Surface pH Sensitive Polymer The synthesis of the same as in Example 7 can be used to obtain another invisible contrast material for early diagnosis of liver cancer, which can be used as a T1-weighted MRI contrast agent.
- the MRI contrast agent Gd-DTPA complex in Example 12 was changed to Gd 2 O 3 nanoparticles, and the specific preparation method was the same as in Example 37.
- to obtain another early diagnosis of cancer brain cancer, renal cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal stealth contrast material can be used as MRI contrast T 1 weighted Agent.
- the MRI contrast agent Gd-DTPA complex in Example 17 was changed to Gd 2 O 3 nanoparticles, and the specific preparation method was the same as in Example 37.
- Preparation of Biodegradable Albumin Nanospheres and Encapsulation of MRI Contrast Agent Gd 2 O 3 Nanoparticles, Coupling of Albumin Nanosphere Surface Ligand Galactosamine, Albumin Nanosphere Surface pH Sensitive Polymer synthesis same as in Example 17, to obtain another early diagnosis of liver cancer in invisible contrast material can be used as T 1 weighted MRI contrast agent.
- the MRI contrast agent Gd-DTPA complex in Example 22 was changed to Gd 2 O 3 nanoparticles, and the specific preparation method was the same as in Example 37.
- Preparation of biodegradable chitosan nanospheres and its embedding of MRI contrast agent Gd 2 O 3 nanoparticles, coupling of surface ligands of chitosan nanospheres, and pH sensitivity of chitosan nanospheres The synthesis of the molecule is the same as in Example 22, and another invisible contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained, which can be used as T 1 weighting.
- MRI contrast agent is another invisible contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer.
- Example 27 The MRI contrast agent Gd-DTPA complex in Example 27 was changed to Gd 2 O 3 nanoparticles, and the specific preparation method was the same as in Example 37.
- Preparation of biodegradable chitosan nanospheres and its embedding of MRI contrast agent Gd 2 O 3 nanoparticles, coupling of surface ligands of chitosan nanospheres, and pH sensitivity of chitosan nanospheres The synthesis of the molecule is the same as in Example 27, and another invisible contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained, which can be used as T 1 weighting.
- MRI contrast agent MRI contrast agent.
- the reducing agent NaBH 4 for preparing the gold nanoparticles in Example 3 was changed to sodium citrate, and the specific preparation method was as follows: 50 mL of ultrapure water was added to a 100 mL round bottom flask, and 2.5 mL of 5 was added under rapid magnetic stirring. mM HAuCl 4 solution, heated in boiling water, then add 0.5, 0.625, 1.0 or 2.0 mL of sodium citrate solution (1%), the reaction is continued in a boiling water bath for 10 min, and finally stirred at room temperature to cool down, you can get Gold nanoparticles with particle sizes of 38, 35, 16, and 14 nm, respectively. Larger gold nanoparticles (100 nm) can be synthesized from 14 nm gold nanoparticles.
- the specific preparation method is as follows: 0.75 mL of 14 nm gold nanoparticles are added to 97.25 mL of ultrapure water, then 1.0 mL is added. 1% (w/v) of HAuCl 4 •3H 2 O solution, stir rapidly at room temperature, add 0.22 mL of 1% sodium citrate, add 1.0 mL of 0.03 M hydroquinone, and stir overnight. 100 nm gold nanoparticles.
- the reducing agent NaBH 4 for preparing gold nanoparticles in Example 8 was changed to sodium citrate, and the specific preparation method was the same as in Example 43.
- Preparation of Biodegradable Albumin Nanospheres and Encapsulation of Five Different Particle Size Gold Nanoparticles, Coupling of Albumin Nanosphere Surface Ligand Galactosamine, Albumin Nanosphere Surface pH Sensitive The synthesis of the polymer is the same as in Example 8, and another four kinds of invisible contrast materials for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
- Example 3 Replace the CT contrast agent gold nanoparticles in Example 3 with a commercially available CT Preparation of contrast agent iohexol, biodegradable albumin nanospheres and its encapsulation of CT contrast agent iohexol, coupling of folic acid on the surface of albumin nanospheres, pH of albumin nanospheres
- CT contrast agent is the same as in Example 3, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained.
- CT contrast agent is the same as in Example 3, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer.
- Example 8 Replace the CT contrast agent gold nanoparticles in Example 8 with a commercially available CT Preparation of contrast agent iohexol, biodegradable albumin nanospheres and its encapsulation of CT contrast agent iohexol, coupling of galactosamine on the surface of albumin nanospheres, pH of albumin nanospheres
- CT contrast agent iohexol a commercially available CT Preparation of contrast agent iohexol, biodegradable albumin nanospheres and its encapsulation of CT contrast agent iohexol, coupling of galactosamine on the surface of albumin nanospheres, pH of albumin nanospheres
- the synthesis of the sensitive polymer is the same as in the case of Example 8, and another stealth contrast material for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
- Example 13 Replace the CT contrast agent gold nanoparticles in Example 13 with a commercially available CT Preparation of contrast agent iohexol, biodegradable albumin nanospheres and its encapsulation of CT contrast agent iohexol, coupling of folic acid on the surface of albumin nanospheres, pH of albumin nanospheres
- CT contrast agent is the same as in Example 13, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained.
- CT contrast agent is the same as in Example 13, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer.
- Example 18 Replace the CT contrast agent gold nanoparticles in Example 18 with a commercially available CT Preparation of contrast agent iohexol, biodegradable albumin nanospheres and its encapsulation of CT contrast agent iohexol, coupling of galactosamine on the surface of albumin nanospheres, pH of albumin nanospheres
- CT contrast agent iohexol Preparation of contrast agent iohexol, biodegradable albumin nanospheres and its encapsulation of CT contrast agent iohexol, coupling of galactosamine on the surface of albumin nanospheres, pH of albumin nanospheres
- the synthesis of the sensitive polymer is the same as in Example 18, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
- Example 23 Replace the CT contrast agent gold nanoparticles in Example 23 with a commercially available CT Preparation of contrast agent iohexol, biodegradable chitosan nanospheres and its encapsulation of CT contrast agent iohexol, coupling of surface ligands of chitosan nanospheres, pH of chitosan nanospheres
- CT contrast agent is the same as in Example 23, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained.
- CT contrast agent is the same as in Example 23, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer.
- Example 28 Replace the CT contrast agent gold nanoparticles in Example 28 with a commercially available CT Preparation of contrast agent iohexol, biodegradable chitosan nanospheres and its encapsulation of CT contrast agent iohexol, coupling of surface ligands of chitosan nanospheres, pH of chitosan nanospheres
- CT contrast agent is the same as in Example 28, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained.
- CT contrast agent is the same as in Example 28, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer.
- Example 3 Replace the CT contrast agent gold nanoparticles in Example 3 with a commercially available CT Contrast agent barium sulfate suspension, preparation of biodegradable albumin nanospheres and its encapsulation of CT contrast agent barium sulfate, folic acid coupling of albumin nanosphere surface ligand, albumin nanosphere surface pH
- CT contrast agent a commercially available CT Contrast agent barium sulfate suspension, preparation of biodegradable albumin nanospheres and its encapsulation of CT contrast agent barium sulfate, folic acid coupling of albumin nanosphere surface ligand, albumin nanosphere surface pH
- CT contrast agent is the same as in Example 3, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer.
- Example 8 Replace the CT contrast agent gold nanoparticles in Example 8 with a commercially available CT Contrast agent barium sulfate suspension, preparation of biodegradable albumin nanospheres and its encapsulation of CT contrast agent barium sulfate, coupling of galactosamine on the surface of albumin nanospheres, surface pH of albumin nanospheres
- the synthesis of the sensitive polymer is the same as in the case of Example 8, and another stealth contrast material for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
- Example 13 Replace the CT contrast agent gold nanoparticles in Example 13 with a commercially available CT Contrast agent barium sulfate suspension, preparation of biodegradable albumin nanospheres and its encapsulation of CT contrast agent barium sulfate, folic acid coupling of albumin nanosphere surface ligand, albumin nanosphere surface pH
- CT contrast agent a commercially available CT Contrast agent barium sulfate suspension, preparation of biodegradable albumin nanospheres and its encapsulation of CT contrast agent barium sulfate, folic acid coupling of albumin nanosphere surface ligand, albumin nanosphere surface pH
- CT contrast agent is the same as in Example 13, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer.
- Example 18 Replace the CT contrast agent gold nanoparticles in Example 18 with a commercially available CT Contrast agent barium sulfate suspension, preparation of biodegradable albumin nanospheres and its encapsulation of CT contrast agent barium sulfate, coupling of galactosamine on the surface of albumin nanospheres, surface pH of albumin nanospheres
- the synthesis of the sensitive polymer is the same as in Example 18, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
- Example 23 Replace the CT contrast agent gold nanoparticles in Example 23 with a commercially available CT Contrast agent barium sulfate suspension, preparation of biodegradable chitosan nanospheres and its encapsulation of CT contrast agent barium sulfate, coupling of surface ligands of chitosan nanospheres, and surface of chitosan nanospheres pH
- the synthesis of the sensitive polymer is the same as in Example 23, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained.
- CT contrast agent is the same as in Example 23, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer.
- Example 28 Replace the CT contrast agent gold nanoparticles in Example 28 with a commercially available CT Contrast agent barium sulfate suspension, preparation of biodegradable chitosan nanospheres and its encapsulation of CT contrast agent barium sulfate, coupling of surface ligands of chitosan nanospheres, and surface of chitosan nanospheres pH
- the synthesis of the sensitive polymer is the same as in Example 28, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained.
- CT contrast agent is the same as in Example 28, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer.
- the PET contrast agent 18 F -FDG in Example 4 was changed to 64 Cu, the preparation of biodegradable albumin nanospheres and the entrapment of PET contrast agent 64 Cu and the coupling of folic acid on the surface of albumin nanospheres.
- the synthesis of the pH-sensitive polymer on the surface of albumin nanospheres is the same as in the case of Example 4, and an early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained.
- Invisible contrast material can be used as a PET contrast agent.
- the preparation of the PET contrast agent 18 F -FDG in Example 9 was changed to 64 Cu, the preparation of biodegradable albumin nanospheres and the entrapment of the PET contrast agent 64 Cu, the surface ligand of the albumin nanospheres, galactosamine
- the synthesis of the pH-sensitive polymer on the surface of the coupled and albumin nanospheres is the same as in Example 9, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a PET contrast agent.
- the PET contrast agent 18 F -FDG in Example 14 was changed to 64 Cu, the preparation of biodegradable albumin nanospheres and the entrapment of PET contrast agent 64 Cu and the coupling of folic acid on the surface of albumin nanospheres.
- the synthesis of the pH-sensitive polymer on the surface of albumin nanospheres is the same as in Example 14, and another tumor for brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer, etc. can be prepared for early diagnosis.
- Invisible contrast material can be used as a PET contrast agent.
- the PET contrast agent 18 F -FDG in Example 19 was changed to 64 Cu, the preparation of biodegradable albumin nanospheres and its encapsulation of PET contrast agent 64 Cu, albumin nanosphere surface ligand galactosamine
- the synthesis of the pH-sensitive polymer on the surface of the coupled and albumin nanospheres is the same as in Example 19, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a PET contrast agent.
- PET contrast agent 18 F -FDG in Example 24 to 64 Cu preparation of biodegradable chitosan nanospheres and encapsulation of PET contrast agent 64 Cu, surface ligand of folic acid nanospheres folic acid
- the synthesis of the pH-sensitive polymer on the surface of the coupled chitosan nanosphere is the same as in Example 24, and another tumor of brain, kidney, breast, lung, ovarian, uterine, nasopharyngeal, etc. can be obtained.
- Invisible contrast materials for early diagnosis can be used as PET contrast agents.
- the PET contrast agent 18 F -FDG in Example 29 was changed to 64 Cu, the preparation of biodegradable chitosan nanospheres and the encapsulation of PET contrast agent 64 Cu and the surface ligand of chitosan nanospheres.
- the synthesis of the pH-sensitive polymer on the surface of the coupled chitosan nanospheres is the same as in Example 29, and another tumor such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal carcinoma, etc. can be obtained.
- Invisible contrast materials for early diagnosis can be used as PET contrast agents.
- the PET contrast agent 18 F -FDG in Example 4 was changed to 124 I , the preparation of biodegradable albumin nanospheres and the entrapment of PET contrast agent 124 I and the coupling of albumin nanosphere surface ligand folic acid
- the synthesis of the pH-sensitive polymer on the surface of albumin nanospheres is the same as in the case of Example 4, and an early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained.
- Invisible contrast material can be used as a PET contrast agent.
- the PET contrast agent 18 F -FDG in Example 9 was changed to 124 I , the preparation of biodegradable albumin nanospheres and its encapsulation of PET contrast agent 124 I , albumin nanosphere surface ligand galactosamine
- the synthesis of the pH-sensitive polymer on the surface of the coupled and albumin nanospheres is the same as in Example 9, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a PET contrast agent.
- the PET contrast agent 18 F -FDG in Example 14 was changed to 124 I , the preparation of biodegradable albumin nanospheres and the entrapment of PET contrast agent 124 I and the coupling of albumin nanosphere surface ligand folic acid
- the synthesis of the pH-sensitive polymer on the surface of albumin nanospheres is the same as in Example 14, and another tumor for brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer, etc. can be prepared for early diagnosis.
- Invisible contrast material can be used as a PET contrast agent.
- the PET contrast agent 18 F -FDG in Example 19 was changed to 124 I , the preparation of biodegradable albumin nanospheres and its encapsulation of PET contrast agent 124 I , albumin nanosphere surface ligand galactosamine
- the synthesis of the pH-sensitive polymer on the surface of the coupled and albumin nanospheres is the same as in Example 19, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a PET contrast agent.
- the PET contrast agent 18 F -FDG in Example 24 was changed to 124 I , the preparation of biodegradable chitosan nanospheres and the entrapment of PET contrast agent 124 I , the surface ligand of folic acid nanospheres folic acid
- the synthesis of the pH-sensitive polymer on the surface of the coupled chitosan nanosphere is the same as in Example 24, and another tumor of brain, kidney, breast, lung, ovarian, uterine, nasopharyngeal, etc. can be obtained.
- Invisible contrast materials for early diagnosis can be used as PET contrast agents.
- the PET contrast agent 18 F -FDG in Example 29 was changed to 124 I , the preparation of biodegradable chitosan nanospheres and the entrapment of PET contrast agent 124 I , the surface ligand of folic acid nanospheres folic acid
- the synthesis of the pH-sensitive polymer on the surface of the coupled chitosan nanospheres is the same as in Example 29, and another tumor such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal carcinoma, etc. can be obtained.
- Invisible contrast materials for early diagnosis can be used as PET contrast agents.
- the PET contrast agent 18 F -FDG in Example 4 was changed to 94 Tc , the preparation of biodegradable albumin nanospheres and the entrapment of PET contrast agent 94 Tc and the coupling of folic acid on the surface of albumin nanospheres.
- the synthesis of the pH-sensitive polymer on the surface of albumin nanospheres is the same as in the case of Example 4, and an early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained.
- Invisible contrast material can be used as a PET contrast agent.
- the PET contrast agent 18 F -FDG in Example 9 was changed to 94 Tc , the preparation of biodegradable albumin nanospheres and its encapsulation of PET contrast agent 94 Tc , albumin nanosphere surface ligand galactosamine
- the synthesis of the pH-sensitive polymer on the surface of the coupled and albumin nanospheres is the same as in Example 9, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a PET contrast agent.
- the PET contrast agent 18 F -FDG in Example 14 was changed to 94 Tc , the preparation of biodegradable albumin nanospheres and the entrapment of PET contrast agent 94 Tc and the coupling of albumin nanosphere surface ligand folic acid
- the synthesis of the pH-sensitive polymer on the surface of albumin nanospheres is the same as in Example 14, and another tumor for brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer, etc. can be prepared for early diagnosis.
- Invisible contrast material can be used as a PET contrast agent.
- the PET contrast agent 18 F -FDG in Example 19 was changed to 94 Tc , the preparation of biodegradable albumin nanospheres and its encapsulation of PET contrast agent 94 Tc , albumin nanosphere surface ligand galactosamine
- the synthesis of the pH-sensitive polymer on the surface of the coupled and albumin nanospheres is the same as in Example 19, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a PET contrast agent.
- the PET contrast agent 18 F -FDG in Example 24 was changed to 94 Tc , the preparation of biodegradable chitosan nanospheres and its encapsulation of PET contrast agent 94 Tc , the surface ligand of folic acid nanospheres folic acid
- the synthesis of the pH-sensitive polymer on the surface of the coupled chitosan nanosphere is the same as in Example 24, and another tumor of brain, kidney, breast, lung, ovarian, uterine, nasopharyngeal, etc. can be obtained.
- Invisible contrast materials for early diagnosis can be used as PET contrast agents.
- the PET contrast agent 18 F -FDG in Example 29 was changed to 94 Tc , the preparation of biodegradable chitosan nanospheres and its encapsulation of PET contrast agent 94 Tc , the surface ligand of folic acid nanospheres folic acid
- the synthesis of the pH-sensitive polymer on the surface of the coupled chitosan nanospheres is the same as in Example 29, and another tumor such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal carcinoma, etc. can be obtained.
- Invisible contrast materials for early diagnosis can be used as PET contrast agents.
- the gold nanoparticles prepared in Example 3 were changed to gold nano cages, and the preparation method was as follows: 3 mL of 0.75 mM HAuCl 4 and 3 mL of 0.03 M HMT (hexamethylenetetramine) were mixed, and the solution color was light yellow. It became transparent. Then, add 3 mL of 0.3 M PVP (polyvinylpyrrolidone) and 100 ⁇ L of 0.01 M AgNO3. After gentle stirring, add 50 ⁇ L of 0.08 M ascorbic acid, stir the mixed solution for 10 s, and let stand at room temperature for 12 h. After centrifugation, a gold nanocage is obtained.
- 3 mL of 0.75 mM HAuCl 4 and 3 mL of 0.03 M HMT (hexamethylenetetramine) were mixed, and the solution color was light yellow. It became transparent. Then, add 3 mL of 0.3 M PVP (polyvinylpyrrolidone) and 100 ⁇ L
- the gold nanoparticles prepared in Example 8 were changed to gold nano cages, and the specific preparation method and examples 75 The same, the preparation of biodegradable albumin nanospheres and the embedding of the above gold nanocage, the coupling of the albumin nanosphere surface ligand galactosamine, the synthesis of the albumin nanosphere surface pH sensitive polymer and Example 8 In the same way, another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
- the gold nanoparticles prepared in Example 3 were changed to gold nanorods, and the preparation method was as follows: 20 mL of a 0.1 M NaBH 4 solution containing 0.25 mM HAuCl 4 and 0.25 mM sodium citrate solution and 0.6 mL ice bath while stirring was prepared. After adding NaBH 4 , the solution will quickly turn purple and gold nanoparticles will form.
- the gold nanoparticles can be used as gold nano seeds within 2-5 h after synthesizing the gold nanoparticles.
- the gold nanoparticles prepared in Example 8 were changed to gold nanorods, and the specific preparation method and examples 77 The same, the preparation of biodegradable albumin nanospheres and the embedding of the above gold nanorods, the coupling of galactosamine on the surface of albumin nanospheres, and the synthesis of pH-sensitive polymers on the surface of albumin nanospheres Example 8 In the same way, another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
Abstract
Disclosed are an invisible radiography material for early tumour diagnosis and the preparation method thereof. The method comprises the following steps: employing a biodegradable nanosphere to embed a medical contrast medium; coupling a target molecule which specifically interacts with a tumour cell on the surface of the nanosphere; and grafting a pH sensitive macromolecule which is a macromolecule compound contracted between pH 5.0-6.0.
Description
本发明涉及纳米造影材料，尤其是涉及一种具有高特异性靶向功能的纳米造影材料及其制备方法。 The invention relates to nano contrast materials, in particular to a nano contrast material with high specific targeting function and a preparation method thereof.
恶性肿瘤（癌症）是严重威胁人类健康的主要疾病之一，到目前为止，人类还没有找到治疗各种恶性肿瘤的有效方法。公认的降低癌症死亡率的方法是，早发现、早治疗，在癌细胞扩散前对其进行检测，并进行有效治疗。目前，各类恶性肿瘤的主要诊断技术只能发现尺寸大于
1 厘米 的肿瘤，对更小的肿瘤却无能为力，如磁共振成像（ MRI ） [Biomaterials, 2011; 32: 5167-5176] 、计算机 X
射线断层成像（ CT ）和正电子发射断层成像（ PET
）。医学造影剂能提高这些诊断技术的检测灵敏度与空间分辨率，为了实现对各种恶性肿瘤的早期检测与诊断，需要发展各类高性能的医学造影剂 [Nat.
Nanotechnol., 2010; 5: 815-821] 。
Malignant tumors (cancers) are one of the major diseases that pose a serious threat to human health. So far, humans have not found an effective way to treat various malignant tumors. Recognized methods to reduce cancer mortality are early detection, early treatment, detection of cancer cells before they spread, and effective treatment. At present, the main diagnostic techniques for various types of malignant tumors can only find that the size is greater than
1 cm of tumor, but can not do anything for smaller tumors, such as magnetic resonance imaging (MRI) [Biomaterials, 2011; 32: 5167-5176], computer X
Ray tomography (CT) and positron emission tomography (PET)
). Medical contrast agents can improve the detection sensitivity and spatial resolution of these diagnostic techniques. In order to achieve early detection and diagnosis of various malignant tumors, various high-performance medical contrast agents need to be developed [Nat.
Nanotechnol., 2010; 5: 815-821].
第一种商用 MRI 造影剂是德国 Schering 公司 H.J.Weinmenn 研制开发的
Gd-DTPA ，它是二乙三胺五乙酸（ DTPA ）与 Gd （Ⅲ）的配合物 [Angew. Chem. Int. Edit., 2010; 49:
1231-1233]
。随后，研究较多的是超顺磁性造影剂。超顺磁性造影剂的磁矩和磁化率均远大于人体组织结构，也远大于顺磁性螯合物，但因其水溶性极小，只能采用匀浆或胶体的形式给药。由于此类造影剂多具有趋肝、脾肿瘤的性能且肾毒性小，故倍受人们的重视，工作重点是选择适当的载药介质、配方、剂型和制备方法，并进行性质试验
[Biomaterials, 2011; 32: 4584-4593] 。中国科学院化学研究所高明远研究员课题组用
FeCl3•6H2O 成功地制备了尺寸形貌可控的磁性纳米晶体材料，还深入探索了以
FeCl3•6H2O 为单一原料制备 Fe3O4
纳米晶体的机理，该磁性纳米晶体可以很好地应用于磁共振成像 [Angew. Chem. Int. Ed., 2005; 44: 123-126]
；随后，他们采用'一锅反应法'合成了共价键结合的磁性 MPEG-COOH （ monocarboxyl-terminated poly (ethylene
glycol) ）纳米晶体，活体大鼠 MRI 实验结果表明 MPEG 修饰的磁性纳米颗粒具有非常好的生物相容性，作为 MRI 造影剂具有很大的潜能 [Adv.
Mater., 2005; 17: 1001-1005] ；用一步反应制备出的表面修饰有羧基 PEG 的磁性纳米微粒不仅具有优异的 MRI
造影功能，而且表现出较长的血液循环时间和低生物毒性 [Adv. Mater., 2006; 18: 2553-2556]
。东南大学顾宁教授课题组制备了一种具有 PLA/PVA 双层聚合物外壳（厚度为 50-70 nm ）的包膜微泡，并成功用其包埋 12 nm
的超顺磁性氧化铁纳米粒子（ SPION ），显著提高了包膜微泡的磁化率，体内 MRI 实验证明了其作为造影剂的良好效果 [Biomaterials,
2009; 30: 3882-3890] 。具有超顺磁性的纳米颗粒由于其独特的磁学和电学性能、具有大的比表面积、高的化学稳定性等优点，在 MRI
造影剂领域表现出诱人的应用前景。 The first commercially available MRI contrast agent is Gd-DTPA, developed by HJ Weinmenn of Schering, Germany, which is a complex of diethylenetriaminepentaacetic acid (DTPA) with Gd (III) [Angew. Chem. Int. Edit., 2010; 49: 1231-1233]. Subsequently, more research was done on superparamagnetic contrast agents. The magnetic moment and magnetic susceptibility of the superparamagnetic contrast agent are much larger than the human tissue structure, and much larger than the paramagnetic chelate compound. However, because of its extremely low water solubility, it can only be administered in the form of homogenate or colloid. Because these contrast agents have the properties of hepatic and spleen tumors and have low nephrotoxicity, they have received much attention. The focus of work is to select appropriate drug-loading media, formulations, dosage forms and preparation methods, and conduct qualitative tests [Biomaterials, 2011; 32: 4584-4593]. Gao Mingyuan, a researcher at the Institute of Chemistry, Chinese Academy of Sciences, successfully prepared magnetic nanocrystals with controlled size and morphology using FeCl 3 •6H 2 O, and further explored the preparation of Fe 3 O with FeCl 3 •6H 2 O as a single raw material. The mechanism of 4 nanocrystals, which can be well applied to magnetic resonance imaging [Angew. Chem. Int. Ed., 2005; 44: 123-126]; subsequently, they synthesized using a one-pot reaction method. Covalently bonded magnetic MPEG-COOH (monocarboxyl-terminated poly (ethylene glycol)) nanocrystals. The results of MRI experiments in living rats indicate that MPEG-modified magnetic nanoparticles have very good biocompatibility and are very useful as MRI contrast agents. Large potential [Adv. Mater., 2005; 17: 1001-1005]; magnetic nanoparticles prepared by one-step reaction with carboxyl-modified PEG not only have excellent MRI contrast but also exhibit long blood circulation time And low biotoxicity [Adv. Mater., 2006; 18: 2553-2556]. Professor Gu Ning of Southeast University prepared a coated microbubble with PLA/PVA double-layer polymer shell (thickness 50-70 nm) and successfully used it to embed 12 nm superparamagnetic iron oxide nanoparticles. (SPION) significantly increased the magnetic susceptibility of the envelope microbubbles, and in vivo MRI experiments demonstrated its good effect as a contrast agent [Biomaterials, 2009; 30: 3882-3890]. Nanoparticles with superparamagnetic properties have attractive application prospects in the field of MRI contrast agents due to their unique magnetic and electrical properties, large specific surface area, and high chemical stability.
近几年，有研究将靶分子（能靶向作用于癌细胞的化合物，如单克隆抗体、叶酸和半乳糖胺等配体）与超顺磁性氧化铁纳米粒子（ SPION ）结合，提高了 SPION
对肿瘤组织的靶向性。例如，东华大学史向阳教授课题组采用热分解法成功地制备了表面镀有硅的超顺磁性氧化铁核壳型纳米粒子（
Fe3O4@SiO2 NPs ），然后将其表面氨化、共价偶联顺磁性钆复合物（
Gd-DTPA, DTPA: 二乙三胺五乙酸）与精氨酸 - 甘氨酸 - 天冬氨酸寡肽（ RGD ），体内 MRI 实验表明该多功能
Fe3O4@SiO2(Gd-DTPA)-RGD 纳米粒子能特异性靶向表面表达有 αvβ3
整合素的癌细胞 [Biomaterials, 2011; 32: 4584-4593] 。西班牙萨拉戈萨大学 Miguel-Sancho
教授课题组在三甘醇中高温热解乙酰丙酮铁，制备了水溶性的 SPION ，并在 SPION 表面偶联了一种模型抗体，用酶联免疫法（ ELISA ）检测了抗体
-SPION 复合物的免疫反应，该研究表明，在 SPION 表面嫁接一种针对癌细胞表面抗原的单克隆抗体，可以制得一种对肿瘤组织具有靶向性的 MRI 造影剂
[Chem. Mater., 2011; 23: 2795-2802] 。新加坡国立大学康燕堂教授课题组通过原子转移自由基聚合法（ ATRP ）在 SPION
表面偶联了聚甲基丙烯酸缩水甘油酯 - 聚乙二醇甲基丙烯酸酯共聚物（ P(GMA-co-PEGMA) ）， PEGMA
起到稳定纳米粒子、延长其体内循环时间的作用，通过 GMA 来嫁接能靶向癌细胞的配体叶酸，从而制得一种能主动靶向作用于肿瘤组织的 MRI 造影剂
[Langmuir, 2012; 28: 563-571] 。天津大学常津教授课题组用偶联有配体叶酸的聚合物磷脂包裹 SPION ，并进一步评估了其作为靶向型
MRI 造影剂的效果 [Pharmacol. Res., 2011; 64: 410-419] 。这些研究都通过靶分子（单克隆抗体或配体）与 SPION
的结合，在提高 SPION 对肿瘤组织的靶向性方面做出了贡献，对恶性肿瘤的早期诊断具有重要的科学意义与社会经济价值。 In recent years, studies have been conducted to combine target molecules (compounds that target cancer cells, such as monoclonal antibodies, ligands such as folic acid and galactosamine) with superparamagnetic iron oxide nanoparticles (SPION) to improve SPION. Targeting to tumor tissue. For example, Professor Shi Xiangyang from Donghua University successfully prepared superparamagnetic iron oxide core-shell nanoparticles (Fe 3 O 4 @SiO 2 NPs ) coated with silicon on the surface by thermal decomposition method, and then aminated them on the surface. Covalently coupled with a paramagnetic ruthenium complex (Gd-DTPA, DTPA: diethylenetriamine pentaacetic acid) and arginine-glycine-aspartate oligopeptide (RDD), in vivo MRI experiments show that the multifunctional Fe 3 O 4 @SiO 2 (Gd-DTPA)-RGD nanoparticles can specifically target cancer cells surface-expressing αvβ3 integrin [Biomaterials, 2011; 32: 4584-4593]. Prof. Miguel-Sancho from the University of Zaragoza, Spain, pyrolyzed iron acetylacetonate in triethylene glycol to prepare water-soluble SPION, and coupled a model antibody on the surface of SPION, using enzyme-linked immunosorbent assay (ELISA). The immune response of the antibody-SPION complex was examined. This study showed that a monoclonal antibody against cancer cell surface antigen was grafted on the surface of SPION to produce a MRI contrast agent that is targeted to tumor tissues [Chem Mater., 2011; 23: 2795-2802]. Prof. Kang Yantang from the National University of Singapore coupled a polyglycidyl methacrylate-polyethylene glycol methacrylate copolymer (P(GMA-co-PEGMA) on the SPION surface by atom transfer radical polymerization (ATRP). PEGMA plays a role in stabilizing nanoparticles and prolonging the circulation time in the body. GMA can be used to graft the ligand folate that can target cancer cells, thereby producing an MRI contrast agent that can actively target tumor tissues [Langmuir] , 2012; 28: 563-571]. Professor Chang Jin of Tianjin University wrapped SPION with polymer phospholipids conjugated with ligand folic acid and further evaluated its effect as a targeted MRI contrast agent [Pharmacol. Res., 2011; 64: 410-419]. These studies have contributed to the enhancement of SPION's targeting to tumor tissues through the combination of target molecules (monoclonal antibodies or ligands) with SPION, and have important scientific and socioeconomic value for the early diagnosis of malignant tumors. .
计算机 X 射线断层成像（ CT ）利用人体不同组织对 X 射线的透过率的不同，可以对人体和组织进行成像
[Nature Medicine, 1996; 2: 473-475] 。 CT 造影剂的使用更是极大地增加了靶组织与周围组织的区分度 [Physics in
Medicine and Biology, 2002; 47: 3369-3385] 。目前的 X 射线造影剂有包入脂质体的碘造影剂 [Academic
Radiology, 2003; 10: 475-483] ，镝 -DTPA- 右旋糖苷聚合体 [Academic Radiology, 2002; 9:
784-792] ， PEG 包裹的碘聚合物 [Advanced Drug Delivery Reviews, 2002; 54: 235-252]
，荧光溴化物 [Academic Radiology, 1994; 1: 151-153] ，以及连接到聚乙烯壳的碘 [Academic Radiology,
1999; 6: 61-65] 等，其中，基于有机小分子碘的造影剂的应用更为普遍。这是因为碘具有较高的 X 射线吸收系数 [Advanced Drug
Delivery Reviews, 1999; 37: 159-173] 。然而，这些含碘物质由于迅速被肾脏清除而使得造影时间很短，具有肾毒性，而且， X
射线会诱导含碘物质电离出碘离子，造成毒性。随着纳米材料技术和生物纳米技术的发展，新型基于纳米颗粒的 CT 造影剂有望改善上述缺点 [Small, 2007;
3: 333-341] 。纳米颗粒的尺寸小（ 1 ～ 100 nm ），可以进入微米尺寸内径的毛细血管 [Journal of Artificial
Organs, 2005; 8: 77-84] ，因此能更多地进入组织；而且，由于癌变组织部位毛细血管的通透性增强 [American Journal of
Pathology, 2000; 156: 1363-1380] ，纳米颗粒可以通过渗漏作用更多地沉积在癌变组织上，从而更好地对癌变区域成像 [CT
理论与应用研究， 2009 ； 18 ： 15-25] 。 Computerized tomography (CT) can image humans and tissues by using different X-ray transmittances from different tissues of the human body.
[Nature Medicine, 1996; 2: 473-475]. The use of CT contrast agents greatly increases the discrimination between target tissue and surrounding tissues [Physics in
Medicine and Biology, 2002; 47: 3369-3385]. Current X-ray contrast agents have iodine contrast agents encapsulated in liposomes [Academic
Radiology, 2003; 10: 475-483], 镝-DTPA-dextran aggregate [Academic Radiology, 2002; 9:
784-792], PEG-coated iodine polymer [Advanced Drug Delivery Reviews, 2002; 54: 235-252]
, fluorescent bromide [Academic Radiology, 1994; 1: 151-153], and iodine attached to a polyethylene shell [Academic Radiology,
1999; 6: 61-65], etc. Among them, the application of contrast agents based on organic small molecule iodine is more common. This is because iodine has a high X-ray absorption coefficient [Advanced Drug
Delivery Reviews, 1999; 37: 159-173]. However, these iodine-containing substances are rapidly cleared by the kidneys, making the contrast time short and nephrotoxic, and, X
The radiation induces the iodine-containing material to ionize the iodide ion, causing toxicity. With the development of nanomaterial technology and bio-nanotechnology, new nanoparticle-based CT contrast agents are expected to improve these shortcomings [Small, 2007;
3: 333-341]. Nanoparticles are small in size (1 to 100 nm) and can enter capillaries with micron-sized inner diameters [Journal of Artificial
Organs, 2005; 8: 77-84], thus allowing more access to tissues; and, due to the increased permeability of capillaries in cancerous tissues [American Journal of
Pathology, 2000; 156: 1363-1380], nanoparticles can be deposited more on cancerous tissue by leakage, thus better imaging cancerous areas [CT]
Theory and Applied Research, 2009; 18: 15-25].
另外，正电子发射断层成像（ PET
）已广泛应用于多种恶性肿瘤的诊断，对肿瘤患者的诊断价值也越来越引起关注。近 20 年来，核素 18 氟标记的 2- （氟 -18 ）
-2- 脱氧葡萄糖（ FDG ）正电子发射断层成像（ PET ）检查方法渐渐发展起来。 FDG-PET
可以显示病灶的代谢特征，有助于区别病灶的良恶性质，且对肿瘤的分期也有一定的帮助 [ 中华结核和呼吸杂志， 2005 ； 28 ： 221-224] 。文献报道
18 F -FDG PET 显像较 99m 锝 - 亚甲基二磷酸盐显像更灵敏 [Radiology, 1999;
212: 803-809] 。 In addition, positron emission tomography (PET) has been widely used in the diagnosis of a variety of malignant tumors, and the diagnostic value of cancer patients has attracted more and more attention. The past 20 years, fluorine-labeled radionuclide 18 2- (fluorine-18) -2-deoxy-glucose (FDG) positron emission tomography (PET) gradually developed inspection method. FDG-PET can show the metabolic characteristics of the lesions, help to distinguish the benign and malignant properties of the lesions, and also help the staging of the tumor [Chinese Journal of Tuberculosis and Respiratory Diseases, 2005; 28: 221-224]. The literature reports that 18 F-FDG PET imaging is more sensitive than 99m锝-methylene diphosphate imaging [Radiology, 1999; 212: 803-809].
相对于 MRI 、 CT 和 PET
等成像模式而言，光学成像具有无辐射、低成本的特点，尤其是近红外荧光成像，可以部分实现对深层组织和器官的探测和成像，在光学成像方面具有特定的优势 [Nature
Methods, 2009; 6: 465-469]
。光学成像的核心是荧光素造影剂，主要面临的问题包括深层次光的传输和采集以及荧光素造影剂的发光量子效率、抗漂白性、良好的生物相容性和靶向性
[Biomaterials, 2009; 30: 5592-5600]
。含四吡咯基团的近红外荧光染料（如酞菁）是近年来关注的焦点，因具有良好的光物理行为使其在近红外探针方面具有较好的应用前景 [J. Am. Chem.
Soc., 2009; 131: 2432-2433]
。在荧光素造影剂的设计中，靶向性是一个关键问题，最为常见的是利用细胞表面的受体设计主动靶向肿瘤细胞的给药*** [ 高等学校化学学报， 2011 ； 32 ：
1010-1012] 。 Relative to MRI, CT and PET
In terms of imaging mode, optical imaging has the characteristics of no radiation and low cost, especially near-infrared fluorescence imaging, which can partially realize the detection and imaging of deep tissues and organs, and has certain advantages in optical imaging [Nature
Methods, 2009; 6: 465-469]
. The core of optical imaging is fluorescein contrast agent. The main problems include the transmission and collection of deep light and the luminescence quantum efficiency, anti-bleaching, good biocompatibility and targeting of fluorescein contrast agents.
[Biomaterials, 2009; 30: 5592-5600]
. Near-infrared fluorescent dyes (such as phthalocyanine) containing tetrapyrrolyl groups have been the focus of attention in recent years, and have good application prospects in near-infrared probes due to their good photophysical behavior [J. Am. Chem.
Soc., 2009; 131: 2432-2433]
. Targeting is a key issue in the design of fluorescein contrast agents. The most common is the use of cell surface receptors to design a drug delivery system that actively targets tumor cells [Journal of Chemical Industry of China, 2011; 32:
1010-1012].
根据上述医学造影材料的国内外研究现状分析，合成对肿瘤组织具有靶向性的造影材料、减小造影剂的用药剂量、降低毒性和制备成本是研究的主要趋势。目前，靶向造影材料的制备一般是通过在造影剂上结合靶分子（单克隆抗体或配体），从而实现对癌细胞的特异性。然而，正常的细胞表面也存在着非特异性抗原或者受体，这些抗原或受体也能与靶分子（单克隆抗体或配体）结合，从而影响了各种诊断技术的检测灵敏度与空间分辨率，因此，发展出具有更高特异性靶向功能的造影剂是目前迫切需要解决的问题。
According to the analysis of the domestic and international research status of the above-mentioned medical contrast materials, it is the main trend of the research to synthesize the contrast materials which have targeted tumor tissues, reduce the dosage of the contrast agent, reduce the toxicity and the preparation cost. Currently, targeted contrast materials are typically prepared by binding target molecules (monoclonal antibodies or ligands) to a contrast agent to achieve specificity for cancer cells. However, non-specific antigens or receptors are also present on the surface of normal cells. These antigens or receptors can also bind to target molecules (monoclonal antibodies or ligands), thus affecting the detection sensitivity and spatial resolution of various diagnostic techniques. Therefore, the development of contrast agents with higher specific targeting functions is an urgent problem to be solved.
本发明提供了一种肿瘤早期诊断用隐形造影材料及其制备方法，所述的隐形造影材料能高特异性靶向输送至肿瘤部位。
The invention provides a stealth contrast material for early diagnosis of tumor and a preparation method thereof, and the stealth contrast material can be targeted to the tumor site with high specificity.
一种肿瘤早期诊断用隐形造影材料，由可生物降解的纳米球、包埋于所述纳米球内部的医学造影剂、连接于所述纳米球表面的 pH 敏感型高分子和靶分子构成。
A stealth contrast material for early diagnosis of tumors, comprising biodegradable nanospheres, a medical contrast agent embedded inside the nanospheres, a pH sensitive polymer attached to the surface of the nanospheres, and a target molecule.
所述的 pH 敏感型高分子 在 pH5.0~6.0
范围内易于发生转变，由线形伸展状态变成收缩状态，使得所述的靶分子能够暴露出来，同时对细胞具有较小的毒性，所述的 pH 敏感型分子优选为 异丙基丙烯酰胺 -
丙烯酸共聚物和异丙基丙烯酰胺 - 甲基丙烯酸共聚物中的至少一种 ，分子量范围为 2k-1000k 。 The pH sensitive polymer is at pH 5.0~6.0
The transition is prone to change from a linearly stretched state to a contracted state, so that the target molecule can be exposed while having less toxicity to the cells, and the pH-sensitive molecule is preferably isopropylacrylamide-
At least one of an acrylic copolymer and an isopropylacrylamide-methacrylic acid copolymer having a molecular weight in the range of 2k to 1000k.
本发明的上述肿瘤早期诊断用隐形造影材料特异性靶向肿瘤细胞的原理如图 1
所示。在正常生理条件下，机体的 pH 值在 7.3 ～ 7.4 之间， 所述的 纳米球表面的靶分子隐藏在 线形伸展状态的 pH 敏感型高分子
之中，不能与正常细胞的非特异性抗原或受体发生相互作用，故该隐形造影材料不能被正常细胞非特异性摄取；而在肿瘤组织环境下， pH 值约为 5.5 ， pH
敏感型高分子
会发生相转变而收缩，使纳米球表面的靶分子暴露出来，与肿瘤细胞表面的抗原或受体发生特异性相互作用，隐形造影材料被肿瘤细胞摄取，从而实现将造影剂高精准地靶向输送至肿瘤部位，提高了
检测灵敏度与空间分辨率， 降低造影剂的用药剂量、毒副作用和成本。 The principle of the above-mentioned tumor early diagnosis using the stealth angiography material to specifically target tumor cells of the present invention is shown in FIG. 1 .
Shown. Under normal physiological conditions, the pH of the body is between 7.3 and 7.4, and the target molecules on the surface of the nanosphere are hidden in a linearly stretched pH-sensitive polymer.
Among them, it cannot interact with non-specific antigens or receptors of normal cells, so the stealth contrast material cannot be non-specifically taken up by normal cells; in the tumor tissue environment, the pH is about 5.5, pH
Sensitive polymer
A phase transition occurs and shrinks, exposing the target molecules on the surface of the nanosphere, and specifically interacting with antigens or receptors on the surface of the tumor cells, and the invisible contrast material is taken up by the tumor cells, thereby achieving high-precision targeting of the contrast agent. Delivery to the tumor site, improved
Detection sensitivity and spatial resolution reduce the dose, side effects and cost of the contrast agent.
所述的医学造影剂的作用是用来提高成像分辨率，本领域人员熟知的
MRI造影剂、CT造影剂、PET造影剂或荧光素造影剂都能应用于本发明，为了使得所述的造影剂能顺利地包埋于可生物降解纳米球（简称纳米球）内部，造影剂粒径优选为15nm以下。 The medical contrast agent is used to increase the imaging resolution, which is well known to those skilled in the art.
MRI contrast agent, CT contrast agent, PET contrast agent or fluorescein contrast agent can be applied to the invention, in order to enable the contrast agent to be smoothly embedded in the biodegradable nanosphere (referred to as nanosphere), contrast agent The particle diameter is preferably 15 nm or less.
所述的 MRI 造影剂为具有 MRI 造影功能的材料，优选为 T2 类
MRI 造影剂和 T1 类 MRI 造影剂，所选材料需要具有良好的水溶性，所述的 T2 类 MRI
造影剂进一步优选为超顺磁性氧化铁纳米粒子（ SPION ），所述的 T1 类 MRI 造影剂进一步优选为有较大的有效磁矩的
Gd3+ 、 Dy3+ 、 Mn2+ 或 Fe3+
等小分子顺磁性造影剂，或与适当的配体形成稳定的螯合物的大分子顺磁性造影剂，如 Gd-DTPA 配合物、 Gd-DOTA 配合物和
Gd2O3 纳米粒子中的至少一种，其中， DTPA 为二乙三胺五乙酸， DOTA 为 1,4,7,10-
四氮杂环十二烷 -N,N′,N″,N- 四乙酸。 The MRI contrast agent is a material having an MRI contrast function, preferably a T 2 MRI contrast agent and a T 1 type MRI contrast agent, the selected material needs to have good water solubility, and the T 2 MRI contrast agent is further Preferably, it is superparamagnetic iron oxide nanoparticles (SPION), and the T 1 -type MRI contrast agent is further preferably small in size such as Gd 3+ , Dy 3+ , Mn 2+ or Fe 3+ having a large effective magnetic moment. a molecular paramagnetic contrast agent, or a macromolecular paramagnetic contrast agent that forms a stable chelate with a suitable ligand, such as at least one of a Gd-DTPA complex, a Gd-DOTA complex, and a Gd 2 O 3 nanoparticle. Wherein DTPA is diethylenetriaminepentaacetic acid and DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N",N-tetraacetic acid.
所述的 CT 造影剂是一种具有 CT 造影功能的材料，所选材料需要具有良好的水溶性，优选为具有
CT 造影功能的纳米粒子或小分子化合物，进一步优选为金纳米颗粒、金纳米棒、金纳米笼子、碘海醇和 BaSO4 中的至少一种。The CT contrast agent is a material having a CT contrast function, and the selected material needs to have good water solubility, preferably a nanoparticle or a small molecule compound having a CT contrast function, further preferably a gold nanoparticle, a gold nanorod. At least one of gold nanocage, iohexol, and BaSO 4 .
所述的 PET 造影剂为能提高 PET 成像分辨率的一类化合物，优选为
18 F -FDG （ 2- （氟 -18 ） -2- 脱氧葡萄糖）、 64 Cu 、 124 I
和 94 C 中的至少一种。The PET contrast agent is a class of compounds capable of improving the resolution of PET imaging, preferably at least 18 F -FDG (2-(fluoro-18 )-2-deoxyglucose), 64 Cu, 124 I and 94 C One.
所述的荧光素造影剂为能提高近红外光学分子成像的近红外荧光染料，优选为酞菁。 The fluorescein contrast agent is a near-infrared fluorescent dye capable of improving near-infrared optical molecular imaging, preferably phthalocyanine.
所述的纳米球作为载体，包埋造影剂实现缓释、控释的作用，对人体毒害性小，可生物降解的无毒的天然大分子或人工合成高分子都可以应用于本发明，所用材料优选为蛋白质、寡肽、多糖、聚醚类或聚酯类高分子中的至少一种，进一步优选为白蛋白和壳聚糖；
所述的造影材料一般通过静脉注射的方式使用，粒径不能太大，所述的纳米球的粒径优选为 500 nm 以下，同时为了在所述的纳米球表面连接上所述的 pH
敏感型高分子和靶分子，粒径不能太小，所述的纳米球的粒径进一步优选为 50-200 nm 。
The nanosphere is used as a carrier to embed a contrast agent to achieve sustained release and controlled release. The non-toxic natural macromolecule or artificial synthetic polymer which is less toxic to human body and biodegradable can be applied to the present invention. The material is preferably at least one of a protein, an oligopeptide, a polysaccharide, a polyether or a polyester polymer, further preferably albumin and chitosan;
The contrast material is generally used by intravenous injection, and the particle diameter cannot be too large, and the particle diameter of the nanosphere is preferably 500 nm or less, and at the same time, the pH is connected to the surface of the nanosphere.
The particle size of the sensitive polymer and the target molecule is not too small, and the particle diameter of the nanosphere is further preferably 50-200 nm.
所述的靶分子为 与肿瘤细胞有特异性相互作用的化合物，能 靶向作用于癌细胞，优选为
单克隆抗体、叶酸或半乳糖胺中至少一种。 The target molecule is a compound having specific interaction with tumor cells, and can be targeted to cancer cells, preferably
At least one of a monoclonal antibody, folic acid or galactosamine.
本发明中，纳米球表面所述的pH敏感型高分子与靶分子的数目比为0.2-5.0,
此时，在正常的细胞组织中，所述的靶分子能够隐藏在所述的pH敏感型高分子之中，在肿瘤组织环境中，所述的靶分子能够暴露出来。 In the present invention, the ratio of the number of the pH-sensitive polymer to the target molecule on the surface of the nanosphere is 0.2-5.0.
At this time, in normal cell tissues, the target molecule can be concealed in the pH-sensitive polymer, and the target molecule can be exposed in the tumor tissue environment.
本发明还提供了 所述的肿瘤早期诊断用隐形材料的制备方法，包括如下步骤： The invention also provides a preparation method of the invisible material for early diagnosis of tumor, comprising the following steps:
（ 1 ）制备包埋有医学造影剂的可生物降解纳米球； (1) preparing biodegradable nanospheres embedded with a medical contrast agent;
（ 2 ）通过共价偶联反应将所述的靶分子连接到步骤（ 1
）中得到的可生物降解纳米球的表面上，得到中间体； (2) attaching the target molecule to the step by a covalent coupling reaction (1)
An intermediate is obtained on the surface of the biodegradable nanosphere obtained;
（ 3 ）在步骤（ 2 ）得到的中间体的表面上，采用活性自由基聚合技术合成所述的 pH
敏感型高分子，得到所述的肿瘤早期诊断用隐形材料。 (3) synthesizing the pH by living radical polymerization technique on the surface of the intermediate obtained in the step (2)
The sensitive polymer obtains the invisible material for early diagnosis of the tumor.
步骤（1）中包埋有医学造影剂的可生物降解纳米球可以通过超声乳化法或者脱溶剂法制备，其中超声乳化法又包括油包水法、水包油法和W/O/W复乳法，下面分别进行介绍。
The biodegradable nanosphere embedded with the medical contrast agent in the step (1) can be prepared by a phacoemulsification method or a solvent removal method, wherein the ultrasonic emulsification method includes a water-in-oil method, an oil-in-water method, and a W/O/W complex. The milk method is introduced separately below.
油包水法：用溶解了亲水性医学造影剂和亲水性膜材的水溶液作为水相，用溶解了油溶性乳化剂的有机溶剂作为油相，将水相与油相混合搅拌进行粗分散后，再用超声波细胞破碎机进行乳化，获得油包水型纳米乳液，再在磁力搅拌下向所得纳米乳液中加入交联剂进行交联固化，除去过量的交联剂和乳化剂即可获得。
Water-in-oil method: an aqueous solution in which a hydrophilic medical contrast agent and a hydrophilic membrane are dissolved is used as an aqueous phase, an organic solvent in which an oil-soluble emulsifier is dissolved is used as an oil phase, and the aqueous phase and the oil phase are mixed and stirred to be coarse. After dispersing, it is emulsified by ultrasonic cell crusher to obtain a water-in-oil type nanoemulsion, and then cross-linking is added to the obtained nano-emulsion by magnetic stirring to crosslink and solidify, and excess cross-linking agent and emulsifier can be removed. obtain.
水包油法：用溶解了疏水性医学造影剂和疏水性膜材的有机溶剂作为油相，用溶解了水溶性乳化剂的水溶液作为水相，将油相与水相混合搅拌进行粗分散后，再用超声波细胞破碎机进行乳化，获得水包油型纳米乳液，再在磁力搅拌下向所得纳米乳液中加入交联剂进行交联固化，除去过量的交联剂和乳化剂即可获得包埋有医学造影剂的可生物降解纳米球。
The oil-in-water method: an organic solvent in which a hydrophobic medical contrast agent and a hydrophobic film are dissolved is used as an oil phase, and an aqueous solution in which a water-soluble emulsifier is dissolved is used as an aqueous phase, and the oil phase and the aqueous phase are mixed and stirred for coarse dispersion. Then, it is emulsified by ultrasonic cell crusher to obtain an oil-in-water type nano-emulsion, and then a cross-linking agent is added to the obtained nano-emulsion under magnetic stirring to cross-link and solidify, and excess cross-linking agent and emulsifier are removed to obtain a package. Biodegradable nanospheres embedded with medical contrast agents.
W/O/W
复乳法：用溶解了亲水性医学造影剂的水溶液作为水相，用溶解了疏水性膜材和油溶性乳化剂的有机溶剂作为油相，将水相与油相混合搅拌进行粗分散后，再用超声波细胞破碎机进行乳化，获得油包水型纳米乳液，再将所得油包水型纳米乳液加入溶有水溶性乳化剂的水相中进行超声乳化，从而获得
W/O/W 型纳米乳液，再在磁力搅拌下向所得 W/O/W
型纳米乳液中加入交联剂进行交联固化，除去过量的交联剂和乳化剂即可获得包埋有医学造影剂的可生物降解纳米球。 W/O/W
The double emulsion method: an aqueous solution in which a hydrophilic medical contrast agent is dissolved is used as an aqueous phase, and an organic solvent in which a hydrophobic membrane and an oil-soluble emulsifier are dissolved is used as an oil phase, and the aqueous phase and the oil phase are mixed and stirred for coarse dispersion. And then emulsified with an ultrasonic cell crusher to obtain a water-in-oil type nanoemulsion, and then the obtained water-in-oil type nanoemulsion is added to an aqueous phase in which a water-soluble emulsifier is dissolved, and emulsified, thereby obtaining
W/O/W type nanoemulsion, and then obtained under magnetic stirring to obtain W/O/W
The cross-linking curing is carried out by adding a crosslinking agent to the nano-emulsion, and the biodegradable nanosphere embedded with the medical contrast agent can be obtained by removing excess cross-linking agent and emulsifier.
脱溶剂法：将水溶性医学造影剂和纳米球材料寡肽或蛋白质溶于 NaCl
水溶液中，然后滴加乙醇，滴加过程持续磁力搅拌，当溶液变成乳白色悬浊液后加入戊二醛交联固化纳米球，除去过量的交联剂即可获得包埋有医学造影剂的可生物降解纳米球。
Desolvent method: dissolving water-soluble medical contrast agent and nanosphere material oligopeptide or protein in NaCl
In the aqueous solution, ethanol is added dropwise, and the magnetic stirring is continued during the dropping process. When the solution becomes a milky white suspension, glutaraldehyde cross-linking and solidifying the nanospheres is added, and excess cross-linking agent is removed to obtain a medical contrast agent. Biodegradable nanospheres.
步骤（ 2
）中所述的共价偶联反应为靶分子末端的官能团与纳米球表面的官能团形成共价化学键的反应，例如：在 EDAC （ 1- 乙基 - （ 3-
二甲基氨基丙基）碳二亚胺）的催化下，羧基和氨基形成酰胺基团的化学反应。 Step ( 2
The covalent coupling reaction described in the reaction is a reaction in which a functional group at the end of the target molecule forms a covalent chemical bond with a functional group on the surface of the nanosphere, for example: in EDAC ( 1-ethyl - ( 3-
A chemical reaction in which a carboxyl group and an amino group form an amide group catalyzed by dimethylaminopropyl)carbodiimide.
当纳米球的材料含有羧基时（如聚谷氨酸、聚天门冬氨酸、含有谷氨酸和天门冬氨酸的多肽和蛋白质、以及含有羧基的多糖等），可以选择含有氨基的单克隆抗体或半乳糖胺等配体作为靶分子，然后用
EDAC 和 NHS （ N-
羟基丁二酰亚胺）活化纳米球表面的羧基，再滴加带有末端氨基的靶分子溶液，使活化的羧基与靶分子的氨基共价反应形成稳定的酰胺键；当纳米球的材料含有氨基时（如聚赖氨酸、聚精氨酸、含有赖氨酸和精氨酸的多肽和蛋白质、以及含有氨基的多糖等），可以选择含有羧基的单克隆抗体或叶酸等配体作为靶分子，然后采取以上方法活化靶分子的羧基后使之嫁接于纳米球表面上；对于既不含有羧基、又不含有氨基的可生物降解材料（如聚醚类和聚酯类高分子），可以采用共聚法使之带有一些氨基或者羧基，制作成纳米球之后采用以上相同方法可使靶分子嫁接于纳米球表面上。
When the material of the nanosphere contains a carboxyl group (such as polyglutamic acid, polyaspartic acid, polypeptides and proteins containing glutamic acid and aspartic acid, and polysaccharides containing carboxyl groups), a monoclonal group containing an amino group may be selected. a ligand such as an antibody or galactosamine as a target molecule, and then
EDAC and NHS ( N-
Hydroxyl succinimide) activates the carboxyl group on the surface of the nanosphere, and then drops the target molecule solution with the terminal amino group to covalently react the activated carboxyl group with the amino group of the target molecule to form a stable amide bond; when the nanosphere material is contained For amino groups (such as polylysine, polyarginine, polypeptides and proteins containing lysine and arginine, and amino group-containing polysaccharides, etc.), a monoclonal antibody containing a carboxyl group or a ligand such as folic acid can be selected as a target. Molecules, then adopt the above method to activate the carboxyl group of the target molecule and graft it onto the surface of the nanosphere; for biodegradable materials (such as polyethers and polyester polymers) which contain neither carboxyl groups nor amino groups, The copolymerization method is carried out with some amino groups or carboxyl groups, and after the nanospheres are formed, the target molecules can be grafted on the surface of the nanospheres by the same method as above.
步骤（ 3
）所述的活性自由基聚合技术（又称为可控聚合）是本领域中比较成熟的技术，在本发明中可以按照以下步骤进行： Step (3
The living radical polymerization technique (also referred to as controlled polymerization) is a relatively mature technology in the art, and can be carried out in the following steps in the present invention:
首先，利用 EDAC 的催化在步骤（ 2 ）得到的纳米球表面偶联 4- 氯甲基苯甲酸（ CBA
），然后将二乙基二硫代氨基甲酸钠（ NaDC ）固定至所述的 CBA 上的苄位甲基上，最后通过紫外线引发单体异丙基丙烯酰胺（ NIPAM ）、丙烯酸（ AA
）或甲基丙烯酸（ MAA ）在纳米球表面的活性自由基接枝聚合反应。其中，高分子发生相转变而收缩的 pH 点可以通过 AA （或 MAA ）与 NIPAM
之间的摩尔比控制，当所述的摩尔比在 1 ： 1~50 范围内，可以控制所述的 pH 敏感型高分子在 pH5.0~6.0
范围内发生转变。高分子的嫁接密度可以通过纳米球表面 CBA 的偶联量控制，而纳米球表面 CBA 的偶联量可以通过 CBA
的初始浓度和反应时间来控制；高分子的链长长度（分子量）可以通过合成时单体的浓度和聚合反应时间来控制。 First, the surface of the nanosphere obtained in step (2) is coupled with 4-chloromethylbenzoic acid (CBA) by catalysis of EDAC.
Then, sodium diethyldithiocarbamate (NaDC) is fixed to the benzylic methyl group on the CBA, and finally the monomer is isopropyl acrylamide (NIPAM), acrylic acid (AA).
Or active radical graft polymerization of methacrylic acid (MAA) on the surface of nanospheres. Among them, the pH point at which the polymer undergoes phase transformation and shrinks can pass AA (or MAA) and NIPAM.
The molar ratio between the two, when the molar ratio is in the range of 1: 1~50, the pH-sensitive polymer can be controlled at pH 5.0~6.0.
A change takes place within the scope. The grafting density of the polymer can be controlled by the coupling amount of CBA on the surface of the nanosphere, and the coupling amount of CBA on the surface of the nanosphere can pass CBA.
The initial concentration and reaction time are controlled; the chain length (molecular weight) of the polymer can be controlled by the concentration of the monomer at the time of synthesis and the polymerization time.
步骤（ 3 ）还可以通过共价偶联反应实现，例如，通过羧基官能团与氨基官能团的反应将 pH
敏感型高分子共价偶联至步骤（ 2 ）得到的纳米球表面之上。首先， pH 敏感型高分子的合成方法采用以 AIBN 为引发剂的自由基聚合法，此时采用嵌段共聚法使
pH 敏感型高分子的一端具有数个丙烯胺（或丙烯酸），从而使得热敏型高分子的末端具有数个氨基（羧基）。然后，在 EDAC 的催化下，利用羧基与氨基的反应将 pH
敏感型高分子共价偶联至纳米球表面之上。 Step (3) can also be achieved by a covalent coupling reaction, for example, by reacting a carboxyl functional group with an amino functional group.
The sensitive polymer is covalently coupled to the surface of the nanosphere obtained in step (2). First, the synthesis method of pH-sensitive polymer uses a radical polymerization method using AIBN as an initiator, in which case block copolymerization is used.
The pH-sensitive polymer has a plurality of acrylamines (or acrylic acids) at one end, so that the terminal of the thermosensitive polymer has a plurality of amino groups (carboxy groups). Then, under the catalysis of EDAC, the reaction of the carboxyl group with the amino group is used to pH.
The sensitive polymer is covalently coupled to the surface of the nanosphere.
同现有技术相比，本发明的有益效果体现在： Compared with the prior art, the beneficial effects of the present invention are embodied in:
（ 1 ）通过 pH 敏感型高分子的作用，提高了对造影材料对肿瘤细胞的靶向功能； (1) Enhancing the targeting function of contrast materials on tumor cells by the action of pH-sensitive polymers;
（ 2 ）降低了造影剂的用量，减少了毒副作用和制造成本。 (2) Reduce the amount of contrast agent, reduce toxic side effects and manufacturing costs.
图 1 为本发明所述的肿瘤早期诊断用隐形造影材料特异性靶向癌细胞的机理图； 1 is a schematic diagram of a mechanism for specifically targeting cancer cells by using a stealth contrast material for early diagnosis of tumors according to the present invention;
图 2 为实施例 1 中利用活性自由基接枝聚合技术在可生物降解纳米球表面合成异丙基丙烯酰胺 -
甲基丙烯酸共聚物（ PNIPAM-MAA ）的反应示意图； Figure 2 shows the synthesis of isopropyl acrylamide on the surface of biodegradable nanospheres by living radical graft polymerization in Example 1.
Schematic diagram of the reaction of methacrylic acid copolymer (PNIPAM-MAA);
图 3 为实施例 1 中所制备的白蛋白纳米球的透射电镜照片； Figure 3 is a transmission electron micrograph of the albumin nanosphere prepared in Example 1;
图 4 为实施例 1 中所制备的白蛋白纳米球（ a ）和表面偶联有 pH
敏感型高分子的白蛋白纳米球（ b ）的透射电镜照片对比图； Figure 4 shows the albumin nanospheres (a) prepared in Example 1 and the surface coupled with pH.
Comparison of transmission electron micrographs of sensitive macromolecular albumin nanospheres (b);
图 5 为实施例 6 中所制备的肿瘤早期诊断用隐形造影材料被肝癌细胞 HepG2
摄取的定量分析图； Figure 5 is a view showing the invisible contrast material for early diagnosis of tumors prepared in Example 6 by hepatoma cells HepG2
Quantitative analysis of intake;
图 6 为实施例 11 中所制备的肿瘤早期诊断用隐形造影材料被***细胞 HeLa
摄取的定量分析图。 Figure 6 shows the invisible angiographic material for early diagnosis of tumors prepared in Example 11 by cervical cancer cells HeLa
Quantitative analysis of intake.
实施例 1 Example 1
（ 1 ）具有 MRI 造影功能的超顺磁性氧化铁纳米粒子（ SPION ）的制备 (1) Preparation of superparamagnetic iron oxide nanoparticles (SPION) with MRI contrast
将 FeCl3
.6H2O （
5.4 g , 20 mmol ）和油酸钠（ 18.3 g , 60 mmol ）溶于 40 mL 乙醇、 30 mL 去离子水和 70 mL
正己烷的混合溶剂中，加热至 70oC 反应 4 h ，然后将混合溶液转移至分液漏斗中，除去下层水相，上层油相用 30 mL
去离子水洗涤三次，将正己烷蒸发之后获得油酸铁复合物的固体。将油酸铁复合物（ 18 g , 20 mmol ）和油酸（ 2.8 g , 10 mmol ）溶于
1- 十八烷烯（ 30 g ）之中，再将混合物加热至 320 oC （升温速率为 3.3 oC/min
），在氩气保护下反应 1 h 之后，室温冷却溶液，再加入乙醇（ 250 mL ），离心（ 6000 rpm ）十分钟即可获得粒径约为 14 nm 的单分散的
SPION ，最后将所得 SPION 真空干燥，低温保存（ 0 - 4 oC ）。 Dissolve FeCl 3 . 6H 2 O ( 5.4 g , 20 mmol ) and sodium oleate ( 18.3 g , 60 mmol ) in a mixture of 40 mL ethanol, 30 mL deionized water and 70 mL of n-hexane and heat to 70 o C was reacted for 4 h, then the mixed solution was transferred to a separatory funnel, the lower aqueous phase was removed, and the upper oil phase was washed three times with 30 mL of deionized water, and n-hexane was evaporated to obtain a solid of the iron oleate complex. The iron oleate complex (18 g, 20 mmol) and oleic acid (2.8 g, 10 mmol) were dissolved in 1-octadecene (30 g) and the mixture was heated to 320 o C (the rate of temperature increase was 3.3 o C/min), after reacting for 1 h under argon protection, cool the solution at room temperature, add ethanol (250 mL), and centrifuge (6000 rpm) for 10 minutes to obtain a monodisperse SPION with a particle size of about 14 nm. Finally, the resulting SPION is vacuum dried and stored at a low temperature (0 - 4 o C).
（ 2 ）可生物降解的白蛋白纳米球的制备及其对 MRI 造影剂 SPION 的包埋 (2) Preparation of biodegradable albumin nanospheres and their embedding of MRI contrast agent SPION
配制 pH 10.8 的 10 mM NaCl 水溶液，再用该溶液配制浓度为 20 mg/mL 的
牛血清白蛋白（ BSA ） 水溶液，然后向 2.0 mL BSA 水溶液中加入 2.0 mL 无水乙醇，磁力搅拌 10 min 后以 2.0 mL/min
的滴加速度添加 4.0 mL 乙醇（总乙醇添加量与 BSA 水溶液的体积比为 3.0 ），滴加过程持续磁力搅拌，乙醇滴加结束后立即加入 8%
的戊二醛水溶液（戊二醛 -BSA 质量比为 0.24 ）交联固化 24 h ，然后加入 1.0 mL 甘氨酸（ 40 mg/mL ）来中和过量的戊二醛，反应
2.0 h 后，对样品进行离心（ 20,000×g, 20min ），所得样品用 10mM NaCl 水溶液洗涤两次，最后冷冻干燥 48 h 即可获得
可生物降解的白蛋白纳米球。将第一步制得的 MRI 造影剂 SPION 分散至 20 mg/mL 的 BSA 水溶液中，采用上述同样方法即可制得包埋有 造影剂
SPION 的白蛋白纳米球。 Prepare a 10 mM NaCl solution at pH 10.8 and use this solution to prepare a concentration of 20 mg/mL.
An aqueous solution of bovine serum albumin (BSA) was added to 2.0 mL of BSA aqueous solution, 2.0 mL of absolute ethanol, and magnetically stirred for 10 min to 2.0 mL/min.
The dropping rate was added with 4.0 mL of ethanol (the volume ratio of total ethanol added to BSA aqueous solution was 3.0), the magnetic stirring was continued during the dropping process, and 8% was added immediately after the completion of the ethanol addition.
An aqueous solution of glutaraldehyde (glutaraldehyde-BSA mass ratio of 0.24) was cross-linked and cured for 24 h, then 1.0 mL of glycine (40 mg/mL) was added to neutralize excess glutaraldehyde.
After 2.0 h, the sample was centrifuged (20,000 × g, 20 min), and the obtained sample was washed twice with 10 mM NaCl aqueous solution, and finally freeze-dried for 48 h.
Biodegradable albumin nanospheres. The MRI contrast agent SPION prepared in the first step was dispersed into a 20 mg/mL aqueous solution of BSA, and the contrast agent was prepared by the same method as described above.
SPION's albumin nanospheres.
（ 4 ）白蛋白纳米球表面 pH 敏感型高分子 的合成 (4) Synthesis of pH-sensitive polymer on the surface of albumin nanospheres
采用活性自由基接枝聚合技术（可控聚合）在白蛋白纳米球（包埋有 SPION
、且表面偶联有配体叶酸）的表面合成一种 pH 敏感型高分子 ，即异丙基丙烯酰胺 - 甲基丙烯酸共聚物（ PNIPAM-MAA ），如图 2 所示。 配制 5
mg/mL 的 CBA 溶液，将 50 mg EDAC 溶于 10 mL CBA 溶液（冰浴），然后加入 90 mL 白蛋白纳米球 悬浊液（ 5.0
mg/mL ），将混合液置于室温下磁力搅拌，反应 24 小时，对样品进行离心（ 20,000×g, 20min ），将所得样品分散于 100 mL
超纯水中，加入 3.0 g NIPAM 和 200 mg MAA ，在 400W 紫外灯（紫外光波长 300-500 nm ，峰值 350 nm ）下照射
1-5 小时，将所得复合纳米粒子离心、洗涤、冻干，从而制得一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤 早期诊断用隐形造影材料，可用作
T2 加权的 MRI 造影剂。 A pH-sensitive polymer, isopropyl acrylamide, was synthesized on the surface of albumin nanospheres (SPION embedded with ligand folic acid) by living radical graft polymerization (controlled polymerization). - Methacrylic acid copolymer (PNIPAM-MAA), as shown in Figure 2. Prepare a 5 mg/mL CBA solution, dissolve 50 mg EDAC in 10 mL CBA solution (ice bath), then add 90 mL albumin nanosphere suspension (5.0 mg/mL) and place the mixture at room temperature. Stir and react for 24 hours. Centrifuge the sample (20,000 × g, 20 min), disperse the sample in 100 mL of ultrapure water, add 3.0 g of NIPAM and 200 mg of MAA, and use a 400 W UV lamp (UV wavelength 300-500). After irradiation for 1-5 hours at nm and peak value of 350 nm, the obtained composite nanoparticles are centrifuged, washed, and lyophilized to prepare a brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer, and the like. early diagnosis of cancer in invisible contrast material, may be used as T 2 weighted MRI contrast agent.
图 3 为实施例 1 中所制备的白蛋白纳米球的透射电镜照片； Figure 3 is a transmission electron micrograph of the albumin nanosphere prepared in Example 1;
图 4 为实施例 1 中所制备的白蛋白纳米球（ a ）和表面偶联有 pH 敏感型高分子的白蛋白纳米球（
b ）的透射电镜照片对比图，（ b ）中纳米球表面的印迹圈是纳米球表面成功偶联 pH 敏感型高分子的证据。 Figure 4 is an albumin nanosphere (a) prepared in Example 1 and an albumin nanosphere having a pH-sensitive polymer coupled to it (
b) TEM photo comparison chart, (b) The imprinting circle on the surface of the nanosphere is evidence of successful coupling of pH-sensitive polymer on the surface of the nanosphere.
实施例2Example 2
（ 1 ） 具有 MRI 造影功能的顺磁性 Gd-DTPA 配合物的制备 (1) Preparation of paramagnetic Gd-DTPA complex with MRI contrast
取 3 g Gd2O3 和 7.3 g DTPA 混合，加水
40 mL ，加热并搅拌回流 16 h ，待反应物全部溶解后温度降至室温，用滤膜滤去杂质后，加入 120mL 丙酮，析出白色凝胶状沉淀，以丙酮洗涤 3
次，烘干至恒重，收率为 80% 。在配合物的合成中，选择金属氧化物为原料，分离时可以将未反应的 Gd2O3
过滤除去。 Mix 3 g of Gd 2 O 3 and 7.3 g of DTPA, add 40 mL of water, heat and stir to reflux for 16 h. After the reactants are all dissolved, the temperature is lowered to room temperature. After filtering impurities with a filter, 120 mL of acetone is added to precipitate white coagulation. The gelatinous precipitate was washed 3 times with acetone and dried to constant weight in a yield of 80%. In the synthesis of the complex, a metal oxide is selected as a raw material, and unreacted Gd 2 O 3 can be removed by filtration during separation.
（ 2 ） 可生物降解的白蛋白纳米球的制备及其对 MRI 造影剂 Gd-DTPA
配合物的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 1
相同，即可制得一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 T1 加权的 MRI 造影剂。
(2) Preparation of biodegradable albumin nanospheres and embedding of MRI contrast agent Gd-DTPA complex, coupling of albumin nanosphere surface ligand folic acid, albumin nanosphere surface pH sensitive polymer The synthesis of the same method as in Example 1 can produce a stealth contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer, etc., which can be used as T 1 -weighted MRI. Contrast agent.
实施例 3 Example 3
（ 1 ） 具有 CT 造影功能的金纳米颗粒的制备 (1) Preparation of gold nanoparticles with CT imaging function
第一步，配制 10 mM 的 NaBH4 水溶液、 10 mM 的
HAuCl4•3H2O 水溶液和 75 mM 的 CTAB 水溶液，将 0.125 mL 的
HAuCl4•3H2O 水溶液加入 4.375 mL 的 CTAB 水溶液混合均匀，然后加入 0.500 mL
冰浴的 NaBH4 水溶液，倒置混合 2 h 制成 5 mL 金种子液。第二步，配制 6.258 mM 的 L- 抗坏血酸水溶液，取
9.587 mL 的 L- 抗坏血酸水溶液加入 0.213 mL 的 75 mM 的 CTAB 水溶液，然后再加入 0.2 mL 的 10 mM 的
HAuCl4•3H2O 水溶液，温和搅拌，制成 10 mL 的生长液，当生长液的颜色从橙色变为无色，立即加入 5
μ L 的金种子液，倒置混合直至混合液颜色慢慢变红。最后，将混合液静置 24 h 。 In the first step, 10 mM NaBH 4 aqueous solution, 10 mM HAuCl 4 •3H 2 O aqueous solution and 75 mM CTAB aqueous solution were prepared, and 0.125 mL of HAuCl 4 •3H 2 O aqueous solution was added to 4.375 mL of CTAB aqueous solution and mixed uniformly. Add 0.500 mL of ice bath of NaBH 4 solution and mix for 2 h to make 5 mL of gold seed solution. In the second step, prepare 6.258 mM L-ascorbic acid aqueous solution, add 9.587 mL of L-ascorbic acid aqueous solution to 0.213 mL of 75 mM CTAB aqueous solution, then add 0.2 mL of 10 mM HAuCl 4 •3H 2 O aqueous solution, gently stir. Make 10 mL of growth solution. When the color of the growth solution changes from orange to colorless, immediately add 5 μL of gold seed solution and mix by inversion until the color of the mixture slowly turns red. Finally, the mixture was allowed to stand for 24 h.
（ 2 ） 可生物降解的白蛋白纳米球的制备及其对 CT
造影剂金纳米颗粒的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 1
相同，即可制得一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 CT 造影剂。 (2) Preparation of biodegradable albumin nanospheres and their correlation to CT
Embedding of contrast agent gold nanoparticles, coupling of folic acid on the surface of albumin nanospheres, synthesis of pH-sensitive polymer on albumin nanospheres and examples 1
Similarly, a stealth angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained and used as a CT contrast agent.
实施例4Example 4
将实施例 1 步骤（ 1 ）中 MRI 造影剂 SPION 改为 PET 造影剂，选
18 F -FDG 作为医学造影剂，可生物降解的白蛋白纳米球的制备及其对 PET 造影剂 18 F -FDG
的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 1
相同，即可制得一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 In step 1 (1), MRI contrast agent SPION was changed to PET contrast agent, 18 F -FDG was selected as medical contrast agent, preparation of biodegradable albumin nanosphere and its effect on PET contrast agent 18 F -FDG Embedding, coupling of folic acid on the surface of the albumin nanospheres, and synthesis of the pH-sensitive polymer on the surface of the albumin nanospheres are the same as in the first embodiment, and a brain cancer, kidney cancer, breast cancer, lung cancer, and ovary can be obtained. Invisible contrast materials for early diagnosis of cancer, uterine cancer, nasopharyngeal cancer, etc., can be used as PET contrast agents.
实施例 5 Example 5
将实施例 1 步骤（ 1 ）中 MRI 造影剂 SPION
改为荧光素造影剂，选含四吡咯基团的近红外荧光染料酞菁作为医学造影剂，可生物降解的白蛋白纳米球的制备及其对荧光素造影剂酞菁的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面
pH 敏感型高分子的合成与实施例 1 相同，即可制得一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作荧光素造影剂
。 Example 1 Step (1) MRI contrast agent SPION
Changed to fluorescein contrast agent, selected near-infrared fluorescent dye phthalocyanine containing tetrapyrrolyl group as medical contrast agent, preparation of biodegradable albumin nanosphere and embedding of fluorescein contrast agent phthalocyanine, albumin Coupling of folic acid on the surface of nanospheres, surface of albumin nanospheres
The synthesis of the pH-sensitive polymer is the same as in the first embodiment, and a stealth angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained. Fluorescein contrast agent
.
实施例 6 Example 6
将实施例 1 步骤（ 3 ）中白蛋白纳米球表面偶联的靶分子改为半乳糖胺，在 EDAC
的催化下，利用半乳糖胺的氨基与白蛋白纳米球表面的羧基之间的化学反应，在白蛋白纳米球表面偶联能够特异性靶向作用于肝癌的配体半乳糖胺。具体制备方法简述如下：用
PBS 作溶剂配制 500 µg/mL 的半乳糖胺溶液，将 50 mg EDAC 溶于 10 mL 半乳糖胺溶液（冰浴），然后加入 90 mL 溶于 PBS
的包埋有医学造影剂的白蛋白纳米球悬浊液（ 5.0 mg/mL ），将混合液置于室温下磁力搅拌，反应 24 小时，对样品进行离心（ 20,000×g,
20min ），所得样品用 PBS 洗涤两次，最后冷冻干燥 48 h 即可获得表面偶联有配体半乳糖胺、且内部包埋有医学造影剂的白蛋白纳米球。其他步骤与实施例
1 相同，即可制得一种肝癌早期诊断用隐形造影材料，可用作 T2 加权的 MRI 造影剂。 The target molecule coupled to the surface of the albumin nanosphere in the step (3) of Example 1 was changed to galactosamine, and the chemical reaction between the amino group of the galactosamine and the carboxyl group on the surface of the albumin nanosphere was catalyzed by EDAC. The ligand galactosamine capable of specifically targeting the liver cancer is coupled to the surface of the albumin nanosphere. The specific preparation method is as follows: prepare 500 μg/mL galactosamine solution with PBS as solvent, dissolve 50 mg EDAC in 10 mL galactosamine solution (ice bath), and then add 90 mL of PBS-embedded solution. The albumin nanosphere suspension (5.0 mg/mL) of the medical contrast agent was magnetically stirred at room temperature for 24 hours, and the sample was centrifuged (20,000×g, 20 min), and the obtained sample was washed with PBS. Then, finally freeze-drying for 48 h can obtain albumin nanospheres with a surface coupled with ligand galactosamine and embedded with a medical contrast agent. Other steps are same as in Example 1, to prepare an early diagnosis of liver cancer in invisible contrast material, it may be used as T 2 weighted MRI contrast agent.
所制肿瘤早期诊断用隐形造影材料被肝癌细胞 HepG2 摄取的定量分析见图 5 ，其中，
SPION-AN-GAL-PM 代表内部包埋有造影剂 SPION 、表面偶联有靶分子 GAL 和 pH 敏感型高分子 PNIPAM-MAA （ PM
）的白蛋白纳米球（ AN ）； SPION-AN 代表仅包埋有造影剂 SPION 的白蛋白纳米球（ AN ）。如图 5 所示， HepG2 细胞在 pH5.5
时摄取 SPION-AN-GAL-PM 的量比 pH7.4 时摄取 SPION-AN-GAL-PM 的量要明显高得多、也明显高于 pH5.5 时摄取
SPION-AN 的量。该结果表明， SPION-AN-GAL-PM 在 pH5.5 时能被肝癌细胞大量特异性摄取，而在 pH7.4
时由于靶分子隐藏于高分子之中而只能被肝癌细胞少量摄取，这就说明 pH 敏感型高分子能防止靶分子被正常细胞非特异性摄取。 Quantitative analysis of the ingestion of the invisible contrast material by the hepatoma cell HepG2 by the early diagnosis of the tumor is shown in Fig. 5 , wherein
SPION-AN-GAL-PM stands for internal embedding of contrast agent SPION, surface coupled with target molecule GAL and pH sensitive polymer PNIPAM-MAA (PM
Albumin nanospheres (AN); SPION-AN represents albumin nanospheres (AN) encapsulating only the contrast agent SPION. As shown in Figure 5, HepG2 cells are at pH 5.5.
The amount of SPION-AN-GAL-PM ingested was significantly higher than that of SPION-AN-GAL-PM at pH 7.4, and significantly higher than that at pH 5.5.
The amount of SPION-AN. This result indicates that SPION-AN-GAL-PM can be specifically taken up by liver cancer cells at pH 5.5, and at pH 7.4.
Since the target molecule is hidden in the polymer and can only be taken up by a small amount of liver cancer cells, this indicates that the pH-sensitive polymer can prevent the target molecule from being non-specifically taken up by normal cells.
实施例 7 Example 7
将实施例 2 中白蛋白纳米球表面偶联的靶分子改为半乳糖胺，具体制备方法与实施例 6
相同，其他步骤与实施例 2 相同，即可制得一种肝癌早期诊断用隐形造影材料，可用作 T1 加权的 MRI 造影剂。 The target molecule coupled to the surface of the albumin nanosphere in Example 2 was changed to galactosamine, and the preparation method was the same as that in Example 6. The other steps were the same as in Example 2, and a stealth angiography for early diagnosis of liver cancer was prepared. material, may be used as T 1 weighted MRI contrast agent.
实施例 8 Example 8
将实施例 3 中白蛋白纳米球表面偶联的靶分子改为半乳糖胺，具体制备方法与实施例 6
相同，其他步骤与实施例 3 相同，即可制得一种肝癌早期诊断用隐形造影材料，可用作 CT 造影剂。 The target molecule coupled to the surface of the albumin nanosphere in Example 3 was changed to galactosamine, and the specific preparation method and the embodiment 6
Similarly, the other steps are the same as in the third embodiment, and a stealth contrast material for early diagnosis of liver cancer can be obtained, which can be used as a CT contrast agent.
实施例9Example 9
将实施例 4 中白蛋白纳米球表面偶联的靶分子改为半乳糖胺，具体制备方法与实施例 6
相同，其他步骤与实施例 4 相同，即可制得一种肝癌早期诊断用隐形造影材料，可用作 PET 造影剂。 The target molecule coupled to the surface of the albumin nanosphere in Example 4 was changed to galactosamine, and the specific preparation method and Example 6
Similarly, the other steps are the same as in the fourth embodiment, and a stealth contrast material for early diagnosis of liver cancer can be obtained, which can be used as a PET contrast agent.
实施例10Example 10
将实施例 5 中白蛋白纳米球表面偶联的靶分子改为半乳糖胺，具体制备方法与实施例 6
相同，其他步骤与实施例 5 相同，即可制得一种肝癌早期诊断用隐形造影材料，可用作荧光素造影剂。 The target molecule coupled to the surface of the albumin nanosphere in Example 5 was changed to galactosamine, and the specific preparation method and Example 6
Similarly, the other steps are the same as in the case of Example 5, and a stealth contrast material for early diagnosis of liver cancer can be obtained, which can be used as a fluorescein contrast agent.
实施例11Example 11
将实施例 1 步骤（ 5 ）中 pH 敏感型高分子合成时的单体甲基丙烯酸（ MAA ）改为丙烯酸（ AA
），从而在白蛋白纳米球表面合成一种 pH 敏感型高分子异丙基丙烯酰胺 - 丙烯酸共聚物（ PNIPAM-AA ），其他实验方法与条件均与实施例 1
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 T2 加权的 MRI 造影剂。
The monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer in the step (5) of Example 1 was changed to acrylic acid (AA) to synthesize a pH-sensitive polymer isopropyl group on the surface of the albumin nanosphere. Acrylamide-acrylic acid copolymer (PNIPAM-AA), other experimental methods and conditions are the same as in Example 1, to obtain another brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal carcinoma stealth early diagnosis of cancer and other contrast material, may be used as T 2 weighted MRI contrast agent.
所制肿瘤早期诊断用隐形造影材料被***细胞 HeLa 摄取的定量分析见图 6 ，其中，
SPION-AN-FA-PA 代表内部包埋有造影剂 SPION 、表面偶联有靶分子 FA 和 pH 敏感型高分子 PNIPAM-AA （ PA
）的白蛋白纳米球（ AN ）， SPION-AN 代表内部包埋有造影剂 SPION 的白蛋白纳米球（ AN ）。如图 6 所示， HeLa 细胞在 pH5.5
时摄取 SPION-AN-FA-PA 的量比 pH7.4 时摄取 SPION-AN-FA-PA 的量要明显高得多、也明显高于 pH5.5 时摄取
SPION-AN 的量。该结果表明， SPION-AN-FA-PA 在 pH5.5 时能被***细胞大量特异性摄取，而在 pH7.4
时由于靶分子隐藏于高分子之中而只能被***细胞少量摄取，这就说明 pH 敏感型高分子能防止靶分子被正常细胞非特异性摄取。 Quantitative analysis of the ingestion of invisible contrast material by cervical cancer cells HeLa for early diagnosis of tumors is shown in Fig. 6, wherein
SPION-AN-FA-PA stands for internal embedding of contrast agent SPION, surface coupled with target molecule FA and pH sensitive polymer PNIPAM-AA (PA
Albumin nanospheres (AN), SPION-AN represent albumin nanospheres (AN) with a contrast agent SPION embedded therein. As shown in Figure 6, HeLa cells are at pH 5.5.
The amount of SPION-AN-FA-PA taken was significantly higher than that of SPION-AN-FA-PA at pH 7.4, and significantly higher than that at pH 5.5.
The amount of SPION-AN. This result indicates that SPION-AN-FA-PA can be specifically taken up by cervical cancer cells at pH 5.5, and at pH 7.4.
Since the target molecule is hidden in the polymer and can only be taken up by a small amount of cervical cancer cells, this indicates that the pH-sensitive polymer can prevent the target molecule from being non-specifically taken up by normal cells.
实施例12Example 12
将实施例 2 中 pH 敏感型高分子合成时的单体甲基丙烯酸（ MAA ）改为丙烯酸（ AA
），从而在白蛋白纳米球表面合成一种 pH 敏感型高分子异丙基丙烯酰胺 - 丙烯酸共聚物（ PNIPAM-AA ），其他实验方法与条件均与实施例 2
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 T1 加权的 MRI 造影剂。
The monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 2 was changed to acrylic acid (AA) to synthesize a pH-sensitive polymer isopropylacrylamide-acrylic acid on the surface of albumin nanospheres. Copolymer (PNIPAM-AA), other experimental methods and conditions are the same as in Example 2, and another tumor diagnosis such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal carcinoma, etc. can be obtained. stealth contrast material can be used as T 1 weighted MRI contrast agent.
实施例 13 Example 13
将实施例 3 中 pH 敏感型高分子合成时的单体甲基丙烯酸（ MAA ）改为丙烯酸（ AA
），从而在白蛋白纳米球表面合成一种 pH 敏感型高分子异丙基丙烯酰胺 - 丙烯酸共聚物（ PNIPAM-AA ），其他实验方法与条件均与实施例 3
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 CT 造影剂。 The monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 3 was changed to acrylic acid (AA).
), thereby synthesizing a pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer (PNIPAM-AA) on the surface of albumin nanospheres, and other experimental methods and conditions are the same as in Example 3
In the same way, another kind of stealth contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer and nasopharyngeal cancer can be obtained, which can be used as a CT contrast agent.
实施例 14 Example 14
将实施例 4 中 pH 敏感型高分子合成时的单体甲基丙烯酸（ MAA ）改为丙烯酸（ AA
），从而在白蛋白纳米球表面合成一种 pH 敏感型高分子异丙基丙烯酰胺 - 丙烯酸共聚物（ PNIPAM-AA ），其他实验方法与条件均与实施例 4
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 The monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 4 was changed to acrylic acid (AA).
), thereby synthesizing a pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer (PNIPAM-AA) on the surface of albumin nanospheres, and other experimental methods and conditions are the same as in Example 4
Similarly, another type of brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer and other invisible contrast materials for early diagnosis can be obtained, which can be used as a PET contrast agent.
实施例 15 Example 15
将实施例 5 中 pH 敏感型高分子合成时的单体甲基丙烯酸（ MAA ）改为丙烯酸（ AA
），从而在白蛋白纳米球表面合成一种 pH 敏感型高分子异丙基丙烯酰胺 - 丙烯酸共聚物（ PNIPAM-AA ），其他实验方法与条件均与实施例 5
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作荧光素造影剂。 The monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer in Example 5 was changed to acrylic acid (AA).
), thereby synthesizing a pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer (PNIPAM-AA) on the surface of albumin nanospheres, and other experimental methods and conditions are the same as in Example 5
In the same way, another kind of stealth contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer and nasopharyngeal cancer can be obtained, which can be used as a fluorescein contrast agent.
实施例16Example 16
将实施例 6 中 pH 敏感型高分子合成时的单体甲基丙烯酸（ MAA ）改为丙烯酸（ AA
），从而在白蛋白纳米球表面合成一种 pH 敏感型高分子异丙基丙烯酰胺 - 丙烯酸共聚物（ PNIPAM-AA ），其他实验方法与条件均与实施例 6
相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作 T2 加权的 MRI 造影剂 。The monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 6 was changed to acrylic acid (AA) to synthesize a pH-sensitive polymer isopropylacrylamide-acrylic acid on the surface of albumin nanospheres. , are the same copolymer (PNIPAM-AA) and other experimental methods and conditions of Example 6, to obtain another early diagnosis of liver cancer in invisible contrast material, it may be used as T 2 weighted MRI contrast agent.
实施例 17 Example 17
将实施例 7 中 pH 敏感型高分子合成时的单体甲基丙烯酸（ MAA ）改为丙烯酸（ AA
），从而在白蛋白纳米球表面合成一种 pH 敏感型高分子异丙基丙烯酰胺 - 丙烯酸共聚物（ PNIPAM-AA ），其他实验方法与条件均与实施例 7
相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作 T1 加权的 MRI 造影剂。 The monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 7 was changed to acrylic acid (AA) to synthesize a pH-sensitive polymer isopropylacrylamide-acrylic acid on the surface of albumin nanospheres. , are the same copolymer (PNIPAM-AA) and other experimental methods and conditions of Example 7, to obtain another early diagnosis of liver cancer in invisible contrast material can be used as T 1 weighted MRI contrast agent.
实施例 18 Example 18
将实施例 8 中 pH 敏感型高分子合成时的单体甲基丙烯酸（ MAA ）改为丙烯酸（ AA
），从而在白蛋白纳米球表面合成一种 pH 敏感型高分子异丙基丙烯酰胺 - 丙烯酸共聚物（ PNIPAM-AA ），其他实验方法与条件均与实施例 8
相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作 CT 造影剂。 The monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 8 was changed to acrylic acid (AA).
), thereby synthesizing a pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer (PNIPAM-AA) on the surface of albumin nanospheres, and other experimental methods and conditions are the same as in Example 8
In the same way, another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
实施例 19 Example 19
将实施例 9 中 pH 敏感型高分子合成时的单体甲基丙烯酸（ MAA ）改为丙烯酸（ AA
），从而在白蛋白纳米球表面合成一种 pH 敏感型高分子异丙基丙烯酰胺 - 丙烯酸共聚物（ PNIPAM-AA ），其他实验方法与条件均与实施例 9
相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作 PET 造影剂。 The monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 9 was changed to acrylic acid (AA).
), a pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer (PNIPAM-AA) was synthesized on the surface of albumin nanospheres, and other experimental methods and conditions were the same as in Example 9
In the same way, another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a PET contrast agent.
实施例20Example 20
将实施例 10 中 pH 敏感型高分子合成时的单体甲基丙烯酸（ MAA ）改为丙烯酸（ AA
），从而在白蛋白纳米球表面合成一种 pH 敏感型高分子异丙基丙烯酰胺 - 丙烯酸共聚物（ PNIPAM-AA ），其他实验方法与条件均与实施例 10
相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作荧光素造影剂。 The monomeric methacrylic acid (MAA) in the synthesis of the pH-sensitive polymer of Example 10 was changed to acrylic acid (AA).
), thereby synthesizing a pH-sensitive polymer isopropylacrylamide-acrylic acid copolymer (PNIPAM-AA) on the surface of albumin nanospheres, and other experimental methods and conditions are the same as in Example 10
In the same way, another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a fluorescein contrast agent.
实施例 21 Example 21
将实施例 1 中可生物降解的白蛋白纳米球改为壳聚糖纳米球，其制备以及对医学造影剂的包埋方法如下：配制
0.2% （ w/v ）的壳聚糖溶液，溶剂为 1% （ w/v ）的醋酸，将医学造影剂（与实施例 1 相同）分散至壳聚糖溶液中，用氢氧化钠将该溶液的 pH
值调至 4.7-4.8 ；配制 0.3% （ w/v ）的三聚磷酸钠（ TPP ）水溶液；在磁力搅拌下，向 0.5mL 的上述壳聚糖溶液中加入 0.1mL 的
TPP 溶液，从而制得离子交联的包埋了医学造影剂的壳聚糖纳米球。其他实验方法与条件与实施例 1
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 T2 加权的 MRI 造影剂。
The biodegradable albumin nanospheres in Example 1 were changed to chitosan nanospheres, and the preparation thereof and the embedding method for the medical contrast agent were as follows: 0.2% (w/v) chitosan solution was prepared, and the solvent was 1% (w/v) acetic acid, the medical contrast agent (same as in Example 1) was dispersed into the chitosan solution, and the pH of the solution was adjusted to 4.7-4.8 with sodium hydroxide; 0.3% (w) was prepared. /v) aqueous solution of sodium tripolyphosphate (TPP); 0.1 mL of TPP solution was added to 0.5 mL of the above chitosan solution under magnetic stirring to prepare an ion-crosslinked shell embedded with a medical contrast agent. Glycan nanospheres. Other experimental methods and conditions are the same as in the first embodiment, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained, which can be used as T. 2 weighted MRI contrast agents.
实施例 22 Example 22
将实施例 2 中可生物降解的白蛋白纳米球改为壳聚糖纳米球，其制备以及对医学造影剂（与实施例 2
相同）的包埋方法与实施例 21 相同，其他实验方法与条件与实施例 2
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 T1 加权的 MRI 造影剂。
The biodegradable albumin nanospheres of Example 2 were changed to chitosan nanospheres, and the preparation thereof and the embedding method for the medical contrast agent (same as in Example 2) were the same as in Example 21, and other experimental methods and conditions. As in Example 2, can be prepared another early diagnosis of cancer, brain cancer, renal cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal stealth contrast material can be used as MRI contrast T 1 weighted Agent.
实施例 23 Example 23
将实施例 3 中可生物降解的白蛋白纳米球改为壳聚糖纳米球，其制备以及对医学造影剂（与实施例 3
相同）的包埋方法与实施例 21 相同，其他实验方法与条件与实施例 3
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 CT 造影剂。 The biodegradable albumin nanospheres of Example 3 were changed to chitosan nanospheres, and their preparation and medical contrast agents (with Example 3)
The same method of embedding is the same as in Example 21, other experimental methods and conditions and Example 3
In the same way, another kind of stealth contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer and nasopharyngeal cancer can be obtained, which can be used as a CT contrast agent.
实施例 24 Example 24
将实施例 4 中可生物降解的白蛋白纳米球改为壳聚糖纳米球，其制备以及对医学造影剂（与实施例 4
相同）的包埋方法与实施例 21 相同，其他实验方法与条件与实施例 4
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 The biodegradable albumin nanospheres of Example 4 were changed to chitosan nanospheres, and their preparation and medical contrast agents (with Example 4)
The same method of embedding is the same as in Example 21, other experimental methods and conditions and Example 4
Similarly, another type of brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer and other invisible contrast materials for early diagnosis can be obtained, which can be used as a PET contrast agent.
实施例25Example 25
将实施例 5 中可生物降解的白蛋白纳米球改为壳聚糖纳米球，其制备以及对医学造影剂（与实施例 5
相同）的包埋方法与实施例 21 相同，其他实验方法与条件与实施例 5
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作荧光素造影剂。 The biodegradable albumin nanospheres of Example 5 were changed to chitosan nanospheres, and their preparation and medical contrast agents (with Example 5)
The same method of embedding is the same as in Example 21, other experimental methods and conditions and Example 5
In the same way, another kind of stealth contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer and nasopharyngeal cancer can be obtained, which can be used as a fluorescein contrast agent.
实施例 26 Example 26
将实施例 11 中可生物降解的白蛋白纳米球改为壳聚糖纳米球，其制备以及对医学造影剂（与实施例 11
相同）的包埋方法与实施例 21 相同，其他实验方法与条件与实施例 11
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 T2 加权的 MRI 造影剂。
The biodegradable albumin nanospheres of Example 11 were changed to chitosan nanospheres, and the preparation thereof and the embedding method for the medical contrast agent (same as in Example 11) were the same as in Example 21, and other experimental methods and conditions. As in Example 11, to obtain another early diagnosis of cancer, brain cancer, renal cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal invisible with contrast material, it may be used as T 2 weighted MRI contrast Agent.
实施例27Example 27
将实施例 12 中可生物降解的白蛋白纳米球改为壳聚糖纳米球，其制备以及对医学造影剂（与实施例 12
相同）的包埋方法与实施例 21 相同，其他实验方法与条件与实施例 12
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 T1 加权的 MRI 造影剂。
The biodegradable albumin nanospheres of Example 12 were changed to chitosan nanospheres, and the preparation thereof and the embedding method for the medical contrast agent (same as in Example 12) were the same as in Example 21, and other experimental methods and conditions. As in Example 12, to obtain another early diagnosis of cancer, brain cancer, renal cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal stealth contrast material can be used as MRI contrast T 1 weighted Agent.
实施例 28 Example 28
将实施例 13 中可生物降解的白蛋白纳米球改为壳聚糖纳米球，其制备以及对医学造影剂（与实施例 13
相同）的包埋方法与实施例 21 相同，其他实验方法与条件与实施例 13
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 CT 造影剂。 The biodegradable albumin nanospheres of Example 13 were changed to chitosan nanospheres, and their preparation and medical contrast agents (and Example 13)
The same method of embedding is the same as in Example 21, other experimental methods and conditions and Example 13
In the same way, another kind of stealth contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer and nasopharyngeal cancer can be obtained, which can be used as a CT contrast agent.
实施例 29 Example 29
将实施例 14 中可生物降解的白蛋白纳米球改为壳聚糖纳米球，其制备以及对医学造影剂（与实施例 14
相同）的包埋方法与实施例 21 相同，其他实验方法与条件与实施例 14
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 The biodegradable albumin nanospheres of Example 14 were changed to chitosan nanospheres, their preparation and for medical contrast agents (and Example 14)
The same method of embedding is the same as in Example 21, and other experimental methods and conditions and examples 14
Similarly, another type of brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer and other invisible contrast materials for early diagnosis can be obtained, which can be used as a PET contrast agent.
实施例30Example 30
将实施例 15 中可生物降解的白蛋白纳米球改为壳聚糖纳米球，其制备以及对医学造影剂（与实施例 15
相同）的包埋方法与实施例 21 相同，其他实验方法与条件与实施例 15
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作荧光素造影剂。 The biodegradable albumin nanospheres of Example 15 were changed to chitosan nanospheres, and their preparation and medical contrast agents (with Example 15)
The same method of embedding is the same as in Example 21, and other experimental methods and conditions and examples 15
In the same way, another kind of stealth contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer and nasopharyngeal cancer can be obtained, which can be used as a fluorescein contrast agent.
实施例31Example 31
将实施例 2 中的 MRI 造影剂 Gd-DTPA 配合物改成已经商业化的 Gd-DOTA
配合物，可生物降解的白蛋白纳米球的制备及其对 MRI 造影剂 Gd-DOTA 配合物的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 2 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作
T1 加权的 MRI 造影剂。 The MRI contrast agent Gd-DTPA complex in Example 2 was changed to a commercially available Gd-DOTA complex, the preparation of biodegradable albumin nanospheres and the embedding of the MRI contrast agent Gd-DOTA complex The coupling of folic acid on the surface of the albumin nanospheres and the synthesis of the pH-sensitive polymer on the surface of the albumin nanospheres are the same as in the second embodiment, and another brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer can be obtained. , uterine cancer, nasopharyngeal cancer early diagnosis invisible contrast material can be used as T 1 weighted MRI contrast agent.
实施例 32 Example 32
将实施例 7 中的 MRI 造影剂 Gd-DTPA 配合物改成已经商业化的 Gd-DOTA
配合物，可生物降解的白蛋白纳米球的制备及其对 MRI 造影剂 Gd-DOTA 配合物的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 7 相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作 T1 加权的 MRI 造影剂。 The MRI contrast agent Gd-DTPA complex in Example 7 was changed to a commercially available Gd-DOTA complex, the preparation of biodegradable albumin nanospheres and its embedding of MRI contrast agent Gd-DOTA complex The coupling of the galactosamine on the surface of the albumin nanospheres and the pH-sensitive polymer on the surface of the albumin nanospheres are the same as in the case of Example 7, and another invisible angiographic material for early diagnosis of liver cancer can be obtained. T 1 MRI contrast agent for weighting.
实施例 33 Example 33
将实施例 12 中的 MRI 造影剂 Gd-DTPA 配合物改成已经商业化的 Gd-DOTA
配合物，可生物降解的白蛋白纳米球的制备及其对 MRI 造影剂 Gd-DOTA 配合物的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 12 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作
T1 加权的 MRI 造影剂。 The MRI contrast agent Gd-DTPA complex in Example 12 was changed to a commercially available Gd-DOTA complex, the preparation of biodegradable albumin nanospheres and the embedding of the MRI contrast agent Gd-DOTA complex The coupling of folic acid on the surface of the albumin nanospheres and the pH-sensitive polymer on the surface of the albumin nanospheres are the same as in the case of Example 12, and another brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer can be obtained. , uterine cancer, nasopharyngeal cancer early diagnosis invisible contrast material can be used as T 1 weighted MRI contrast agent.
实施例34Example 34
将实施例 17 中的 MRI 造影剂 Gd-DTPA 配合物改成已经商业化的 Gd-DOTA
配合物，可生物降解的白蛋白纳米球的制备及其对 MRI 造影剂 Gd-DOTA 配合物的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 17 相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作 T1 加权的 MRI 造影剂。 The MRI contrast agent Gd-DTPA complex in Example 17 was changed to a commercially available Gd-DOTA complex, the preparation of biodegradable albumin nanospheres and the embedding of the MRI contrast agent Gd-DOTA complex The coupling of galactosamine on the surface of the albumin nanospheres and the pH-sensitive polymer on the surface of the albumin nanospheres are the same as in Example 17, and another invisible angiographic material for early diagnosis of liver cancer can be obtained. T 1 MRI contrast agent for weighting.
实施例35Example 35
将实施例 22 中的 MRI 造影剂 Gd-DTPA 配合物改成已经商业化的 Gd-DOTA
配合物，可生物降解的壳聚糖纳米球的制备及其对 MRI 造影剂 Gd-DOTA 配合物的包埋、壳聚糖纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 22 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作
T1 加权的 MRI 造影剂。 The MRI contrast agent Gd-DTPA complex in Example 22 was changed to a commercially available Gd-DOTA complex, and the preparation of the biodegradable chitosan nanosphere and its package for the MRI contrast agent Gd-DOTA complex The coupling of the surface ligand of the chitosan nanospheres and the synthesis of the pH-sensitive polymer on the surface of the albumin nanospheres are the same as in the case of Example 22, and another brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer early diagnosis invisible contrast material can be used as T 1 weighted MRI contrast agent.
实施例 36 Example 36
将实施例 27 中的 MRI 造影剂 Gd-DTPA 配合物改成已经商业化的 Gd-DOTA
配合物，可生物降解的壳聚糖纳米球的制备及其对 MRI 造影剂 Gd-DOTA 配合物的包埋、壳聚糖纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 27 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作
T1 加权的 MRI 造影剂。 The MRI contrast agent Gd-DTPA complex in Example 27 was changed to a commercially available Gd-DOTA complex, and the preparation of the biodegradable chitosan nanosphere and its package for the MRI contrast agent Gd-DOTA complex The coupling of the surface ligand of the chitosan nanospheres and the synthesis of the pH-sensitive polymer on the surface of the albumin nanospheres are the same as in the case of Example 27, and another brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer early diagnosis invisible contrast material can be used as T 1 weighted MRI contrast agent.
实施例37Example 37
将实施例 2 中的 MRI 造影剂 Gd-DTPA 配合物改成
Gd2O3 纳米粒子，具体制备方法如下：将 6.0 mmol
GdCl3.6H2O 加入 30 mL 的 DEG 中，持续磁力搅拌，在硅油油浴中 140-160 ℃加热1 h
，然后加入 30 mL 含有 7.5 mmol NaOH 的 DEG 溶液，在反应物完全溶解后，将油浴温度升温至 180 ℃ ，在快速搅拌下反应 4 h 。
The MRI contrast agent Gd-DTPA complex in Example 2 was changed to Gd 2 O 3 nanoparticles, and the specific preparation method was as follows: 6.0 mmol GdCl 3 .6H 2 O was added to 30 mL of DEG, and magnetic stirring was continued for the silicone oil. Heat in the oil bath at 140-160 °C for 1 h, then add 30 mL of DEG solution containing 7.5 mmol NaOH. After the reaction is completely dissolved, the temperature of the oil bath is raised to 180 °C and reacted for 4 h with rapid stirring.
可生物降解的白蛋白纳米球的制备及其对 MRI 造影剂
Gd2O3 纳米粒子的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 2
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 T1 加权的 MRI 造影剂。
Preparation of biodegradable albumin nanospheres and its application to MRI contrast agent Gd 2 O 3 nanoparticles, coupling of albumin nanosphere surface ligand folic acid, synthesis of albumin nanosphere surface pH sensitive polymer As in Example 2, can be prepared another early diagnosis of cancer, brain cancer, renal cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal stealth contrast material can be used as MRI contrast T 1 weighted Agent.
实施例38Example 38
将实施例 7 中的 MRI 造影剂 Gd-DTPA 配合物改成
Gd2O3 纳米粒子，具体制备方法与实施例 37 相同。可生物降解的白蛋白纳米球的制备及其对 MRI 造影剂
Gd2O3 纳米粒子的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例
7 相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作 T1 加权的 MRI 造影剂。 The MRI contrast agent Gd-DTPA complex in Example 7 was changed to Gd 2 O 3 nanoparticles, and the specific preparation method was the same as in Example 37. Preparation of Biodegradable Albumin Nanospheres and Encapsulation of MRI Contrast Agent Gd 2 O 3 Nanoparticles, Coupling of Albumin Nanosphere Surface Ligand Galactosamine, Albumin Nanosphere Surface pH Sensitive Polymer The synthesis of the same as in Example 7 can be used to obtain another invisible contrast material for early diagnosis of liver cancer, which can be used as a T1-weighted MRI contrast agent.
实施例 39 Example 39
将实施例 12 中的 MRI 造影剂 Gd-DTPA 配合物改成
Gd2O3 纳米粒子，具体制备方法与实施例 37 相同。可生物降解的白蛋白纳米球的制备及其对 MRI 造影剂
Gd2O3 纳米粒子的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例
12 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 T1 加权的 MRI
造影剂。 The MRI contrast agent Gd-DTPA complex in Example 12 was changed to Gd 2 O 3 nanoparticles, and the specific preparation method was the same as in Example 37. Preparation of biodegradable albumin nanospheres and its application to MRI contrast agent Gd 2 O 3 nanoparticles, coupling of albumin nanosphere surface ligand folic acid, synthesis of albumin nanosphere surface pH sensitive polymer As in Example 12, to obtain another early diagnosis of cancer, brain cancer, renal cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal stealth contrast material can be used as MRI contrast T 1 weighted Agent.
实施例 40 Example 40
将实施例 17 中的 MRI 造影剂 Gd-DTPA 配合物改成
Gd2O3 纳米粒子，具体制备方法与实施例 37 相同。可生物降解的白蛋白纳米球的制备及其对 MRI 造影剂
Gd2O3 纳米粒子的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例
17 相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作 T1 加权的 MRI 造影剂。 The MRI contrast agent Gd-DTPA complex in Example 17 was changed to Gd 2 O 3 nanoparticles, and the specific preparation method was the same as in Example 37. Preparation of Biodegradable Albumin Nanospheres and Encapsulation of MRI Contrast Agent Gd 2 O 3 Nanoparticles, Coupling of Albumin Nanosphere Surface Ligand Galactosamine, Albumin Nanosphere Surface pH Sensitive Polymer synthesis same as in Example 17, to obtain another early diagnosis of liver cancer in invisible contrast material can be used as T 1 weighted MRI contrast agent.
实施例 41 Example 41
将实施例 22 中的 MRI 造影剂 Gd-DTPA 配合物改成
Gd2O3 纳米粒子，具体制备方法与实施例 37 相同。可生物降解的壳聚糖纳米球的制备及其对 MRI 造影剂
Gd2O3 纳米粒子的包埋、壳聚糖纳米球表面配体叶酸的偶联、壳聚糖纳米球表面 pH 敏感型高分子的合成与实施例
22 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 T1 加权的 MRI
造影剂。 The MRI contrast agent Gd-DTPA complex in Example 22 was changed to Gd 2 O 3 nanoparticles, and the specific preparation method was the same as in Example 37. Preparation of biodegradable chitosan nanospheres and its embedding of MRI contrast agent Gd 2 O 3 nanoparticles, coupling of surface ligands of chitosan nanospheres, and pH sensitivity of chitosan nanospheres The synthesis of the molecule is the same as in Example 22, and another invisible contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained, which can be used as T 1 weighting. MRI contrast agent.
实施例 42 Example 42
将实施例 27 中的 MRI 造影剂 Gd-DTPA 配合物改成
Gd2O3 纳米粒子，具体制备方法与实施例 37 相同。可生物降解的壳聚糖纳米球的制备及其对 MRI 造影剂
Gd2O3 纳米粒子的包埋、壳聚糖纳米球表面配体叶酸的偶联、壳聚糖纳米球表面 pH 敏感型高分子的合成与实施例
27 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 T1 加权的 MRI
造影剂。 The MRI contrast agent Gd-DTPA complex in Example 27 was changed to Gd 2 O 3 nanoparticles, and the specific preparation method was the same as in Example 37. Preparation of biodegradable chitosan nanospheres and its embedding of MRI contrast agent Gd 2 O 3 nanoparticles, coupling of surface ligands of chitosan nanospheres, and pH sensitivity of chitosan nanospheres The synthesis of the molecule is the same as in Example 27, and another invisible contrast material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained, which can be used as T 1 weighting. MRI contrast agent.
实施例 43 Example 43
将实施例 3 中制备金纳米颗粒的还原剂 NaBH4
改为柠檬酸钠，具体制备方法如下：在 100 mL 的圆底烧瓶中加入 50 mL 超纯水，在快速磁力搅拌下加入 2.5 mL 的 5 mM
HAuCl4 溶液，在沸水裕中加热，然后加入 0.5 、 0.625 、 1.0 或 2.0 mL 的柠檬酸钠溶液（ 1%
），反应在沸水浴中持续 10 min ，最后在室温下搅拌降温，即可获得粒径分别为 38 、 35 、 16 、 14 nm 的金纳米颗粒。更大的金纳米颗粒（
100 nm ）可以 14 nm 的金纳米颗粒为种子进行合成，具体制备方法如下：取 0.75 mL 的 14 nm 的金纳米颗粒加入 97.25 mL
超纯水中，然后加入 1.0 mL 的 1% (w/v) 的 HAuCl4•3H2O 溶液，在室温下快速搅拌，加入
0.22 mL 的 1% 柠檬酸钠，再加入 1.0 mL 的 0.03 M 对苯二酚，搅拌过夜，从而制得 100 nm 的金纳米颗粒。 The reducing agent NaBH 4 for preparing the gold nanoparticles in Example 3 was changed to sodium citrate, and the specific preparation method was as follows: 50 mL of ultrapure water was added to a 100 mL round bottom flask, and 2.5 mL of 5 was added under rapid magnetic stirring. mM HAuCl 4 solution, heated in boiling water, then add 0.5, 0.625, 1.0 or 2.0 mL of sodium citrate solution (1%), the reaction is continued in a boiling water bath for 10 min, and finally stirred at room temperature to cool down, you can get Gold nanoparticles with particle sizes of 38, 35, 16, and 14 nm, respectively. Larger gold nanoparticles (100 nm) can be synthesized from 14 nm gold nanoparticles. The specific preparation method is as follows: 0.75 mL of 14 nm gold nanoparticles are added to 97.25 mL of ultrapure water, then 1.0 mL is added. 1% (w/v) of HAuCl 4 •3H 2 O solution, stir rapidly at room temperature, add 0.22 mL of 1% sodium citrate, add 1.0 mL of 0.03 M hydroquinone, and stir overnight. 100 nm gold nanoparticles.
可生物降解的白蛋白纳米球的制备及其对上述五种不同粒径的金纳米颗粒的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 3
相同，即可制得另外四种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 CT 造影剂。
Preparation of biodegradable albumin nanospheres and embedding of the above five different particle size gold nanoparticles, coupling of albumin nanosphere surface ligand folic acid, albumin nanosphere surface pH sensitive polymer Synthesis and Example 3
In the same way, another four kinds of brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer and other invisible contrast materials for early diagnosis can be obtained, which can be used as a CT contrast agent.
实施例 44 Example 44
将实施例 8 中制备金纳米颗粒的还原剂 NaBH4
改为柠檬酸钠，具体制备方法与实施例 43
相同。可生物降解的白蛋白纳米球的制备及其对所制五种不同粒径的金纳米颗粒的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 8 相同，即可制得另外四种肝癌早期诊断用隐形造影材料，可用作 CT 造影剂。 The reducing agent NaBH 4 for preparing gold nanoparticles in Example 8 was changed to sodium citrate, and the specific preparation method was the same as in Example 43. Preparation of Biodegradable Albumin Nanospheres and Encapsulation of Five Different Particle Size Gold Nanoparticles, Coupling of Albumin Nanosphere Surface Ligand Galactosamine, Albumin Nanosphere Surface pH Sensitive The synthesis of the polymer is the same as in Example 8, and another four kinds of invisible contrast materials for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
实施例 45 Example 45
将实施例 3 中 CT 造影剂金纳米颗粒换为已经商业化的 CT
造影剂碘海醇，可生物降解的白蛋白纳米球的制备及其对 CT 造影剂碘海醇的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 3 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 CT 造影剂。
Replace the CT contrast agent gold nanoparticles in Example 3 with a commercially available CT
Preparation of contrast agent iohexol, biodegradable albumin nanospheres and its encapsulation of CT contrast agent iohexol, coupling of folic acid on the surface of albumin nanospheres, pH of albumin nanospheres
The synthesis of the sensitive polymer is the same as in Example 3, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained. CT contrast agent.
实施例 46 Example 46
将实施例 8 中 CT 造影剂金纳米颗粒换为已经商业化的 CT
造影剂碘海醇，可生物降解的白蛋白纳米球的制备及其对 CT 造影剂碘海醇的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 8 相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作 CT 造影剂。 Replace the CT contrast agent gold nanoparticles in Example 8 with a commercially available CT
Preparation of contrast agent iohexol, biodegradable albumin nanospheres and its encapsulation of CT contrast agent iohexol, coupling of galactosamine on the surface of albumin nanospheres, pH of albumin nanospheres
The synthesis of the sensitive polymer is the same as in the case of Example 8, and another stealth contrast material for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
实施例 47 Example 47
将实施例 13 中 CT 造影剂金纳米颗粒换为已经商业化的 CT
造影剂碘海醇，可生物降解的白蛋白纳米球的制备及其对 CT 造影剂碘海醇的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 13 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 CT 造影剂。
Replace the CT contrast agent gold nanoparticles in Example 13 with a commercially available CT
Preparation of contrast agent iohexol, biodegradable albumin nanospheres and its encapsulation of CT contrast agent iohexol, coupling of folic acid on the surface of albumin nanospheres, pH of albumin nanospheres
The synthesis of the sensitive polymer is the same as in Example 13, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained. CT contrast agent.
实施例 48 Example 48
将实施例 18 中 CT 造影剂金纳米颗粒换为已经商业化的 CT
造影剂碘海醇，可生物降解的白蛋白纳米球的制备及其对 CT 造影剂碘海醇的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 18 相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作 CT 造影剂。 Replace the CT contrast agent gold nanoparticles in Example 18 with a commercially available CT
Preparation of contrast agent iohexol, biodegradable albumin nanospheres and its encapsulation of CT contrast agent iohexol, coupling of galactosamine on the surface of albumin nanospheres, pH of albumin nanospheres
The synthesis of the sensitive polymer is the same as in Example 18, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
实施例 49 Example 49
将实施例 23 中 CT 造影剂金纳米颗粒换为已经商业化的 CT
造影剂碘海醇，可生物降解的壳聚糖纳米球的制备及其对 CT 造影剂碘海醇的包埋、壳聚糖纳米球表面配体叶酸的偶联、壳聚糖纳米球表面 pH
敏感型高分子的合成与实施例 23 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 CT 造影剂。
Replace the CT contrast agent gold nanoparticles in Example 23 with a commercially available CT
Preparation of contrast agent iohexol, biodegradable chitosan nanospheres and its encapsulation of CT contrast agent iohexol, coupling of surface ligands of chitosan nanospheres, pH of chitosan nanospheres
The synthesis of the sensitive polymer is the same as in Example 23, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained. CT contrast agent.
实施例 50 Example 50
将实施例 28 中 CT 造影剂金纳米颗粒换为已经商业化的 CT
造影剂碘海醇，可生物降解的壳聚糖纳米球的制备及其对 CT 造影剂碘海醇的包埋、壳聚糖纳米球表面配体叶酸的偶联、壳聚糖纳米球表面 pH
敏感型高分子的合成与实施例 28 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 CT 造影剂。
Replace the CT contrast agent gold nanoparticles in Example 28 with a commercially available CT
Preparation of contrast agent iohexol, biodegradable chitosan nanospheres and its encapsulation of CT contrast agent iohexol, coupling of surface ligands of chitosan nanospheres, pH of chitosan nanospheres
The synthesis of the sensitive polymer is the same as in Example 28, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained. CT contrast agent.
实施例 51 Example 51
将实施例 3 中 CT 造影剂金纳米颗粒换为已经商业化的 CT
造影剂硫酸钡混悬剂，可生物降解的白蛋白纳米球的制备及其对 CT 造影剂硫酸钡的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 3 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 CT 造影剂。
Replace the CT contrast agent gold nanoparticles in Example 3 with a commercially available CT
Contrast agent barium sulfate suspension, preparation of biodegradable albumin nanospheres and its encapsulation of CT contrast agent barium sulfate, folic acid coupling of albumin nanosphere surface ligand, albumin nanosphere surface pH
The synthesis of the sensitive polymer is the same as in Example 3, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained. CT contrast agent.
实施例 52 Example 52
将实施例 8 中 CT 造影剂金纳米颗粒换为已经商业化的 CT
造影剂硫酸钡混悬剂，可生物降解的白蛋白纳米球的制备及其对 CT 造影剂硫酸钡的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 8 相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作 CT 造影剂。 Replace the CT contrast agent gold nanoparticles in Example 8 with a commercially available CT
Contrast agent barium sulfate suspension, preparation of biodegradable albumin nanospheres and its encapsulation of CT contrast agent barium sulfate, coupling of galactosamine on the surface of albumin nanospheres, surface pH of albumin nanospheres
The synthesis of the sensitive polymer is the same as in the case of Example 8, and another stealth contrast material for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
实施例 53 Example 53
将实施例 13 中 CT 造影剂金纳米颗粒换为已经商业化的 CT
造影剂硫酸钡混悬剂，可生物降解的白蛋白纳米球的制备及其对 CT 造影剂硫酸钡的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 13 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 CT 造影剂。
Replace the CT contrast agent gold nanoparticles in Example 13 with a commercially available CT
Contrast agent barium sulfate suspension, preparation of biodegradable albumin nanospheres and its encapsulation of CT contrast agent barium sulfate, folic acid coupling of albumin nanosphere surface ligand, albumin nanosphere surface pH
The synthesis of the sensitive polymer is the same as in Example 13, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained. CT contrast agent.
实施例 54 Example 54
将实施例 18 中 CT 造影剂金纳米颗粒换为已经商业化的 CT
造影剂硫酸钡混悬剂，可生物降解的白蛋白纳米球的制备及其对 CT 造影剂硫酸钡的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH
敏感型高分子的合成与实施例 18 相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作 CT 造影剂。 Replace the CT contrast agent gold nanoparticles in Example 18 with a commercially available CT
Contrast agent barium sulfate suspension, preparation of biodegradable albumin nanospheres and its encapsulation of CT contrast agent barium sulfate, coupling of galactosamine on the surface of albumin nanospheres, surface pH of albumin nanospheres
The synthesis of the sensitive polymer is the same as in Example 18, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
实施例 55 Example 55
将实施例 23 中 CT 造影剂金纳米颗粒换为已经商业化的 CT
造影剂硫酸钡混悬剂，可生物降解的壳聚糖纳米球的制备及其对 CT 造影剂硫酸钡的包埋、壳聚糖纳米球表面配体叶酸的偶联、壳聚糖纳米球表面 pH
敏感型高分子的合成与实施例 23 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 CT 造影剂。
Replace the CT contrast agent gold nanoparticles in Example 23 with a commercially available CT
Contrast agent barium sulfate suspension, preparation of biodegradable chitosan nanospheres and its encapsulation of CT contrast agent barium sulfate, coupling of surface ligands of chitosan nanospheres, and surface of chitosan nanospheres pH
The synthesis of the sensitive polymer is the same as in Example 23, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained. CT contrast agent.
实施例 56 Example 56
将实施例 28 中 CT 造影剂金纳米颗粒换为已经商业化的 CT
造影剂硫酸钡混悬剂，可生物降解的壳聚糖纳米球的制备及其对 CT 造影剂硫酸钡的包埋、壳聚糖纳米球表面配体叶酸的偶联、壳聚糖纳米球表面 pH
敏感型高分子的合成与实施例 28 相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 CT 造影剂。
Replace the CT contrast agent gold nanoparticles in Example 28 with a commercially available CT
Contrast agent barium sulfate suspension, preparation of biodegradable chitosan nanospheres and its encapsulation of CT contrast agent barium sulfate, coupling of surface ligands of chitosan nanospheres, and surface of chitosan nanospheres pH
The synthesis of the sensitive polymer is the same as in Example 28, and another invisible angiographic material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained. CT contrast agent.
实施例 57 Example 57
将实施例 4 中 PET 造影剂 18 F -FDG 换为
64 Cu ，可生物降解的白蛋白纳米球的制备及其对 PET 造影剂 64 Cu
的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 4
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 The PET contrast agent 18 F -FDG in Example 4 was changed to 64 Cu, the preparation of biodegradable albumin nanospheres and the entrapment of PET contrast agent 64 Cu and the coupling of folic acid on the surface of albumin nanospheres. The synthesis of the pH-sensitive polymer on the surface of albumin nanospheres is the same as in the case of Example 4, and an early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained. Invisible contrast material can be used as a PET contrast agent.
实施例 58 Example 58
将实施例 9 中 PET 造影剂 18 F -FDG 换为
64 Cu ，可生物降解的白蛋白纳米球的制备及其对 PET 造影剂 64 Cu
的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 9 相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作
PET 造影剂。 The preparation of the PET contrast agent 18 F -FDG in Example 9 was changed to 64 Cu, the preparation of biodegradable albumin nanospheres and the entrapment of the PET contrast agent 64 Cu, the surface ligand of the albumin nanospheres, galactosamine The synthesis of the pH-sensitive polymer on the surface of the coupled and albumin nanospheres is the same as in Example 9, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a PET contrast agent.
实施例 59 Example 59
将实施例 14 中 PET 造影剂 18 F -FDG 换为
64 Cu ，可生物降解的白蛋白纳米球的制备及其对 PET 造影剂 64 Cu
的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 14
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 The PET contrast agent 18 F -FDG in Example 14 was changed to 64 Cu, the preparation of biodegradable albumin nanospheres and the entrapment of PET contrast agent 64 Cu and the coupling of folic acid on the surface of albumin nanospheres. The synthesis of the pH-sensitive polymer on the surface of albumin nanospheres is the same as in Example 14, and another tumor for brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer, etc. can be prepared for early diagnosis. Invisible contrast material can be used as a PET contrast agent.
实施例 60 Example 60
将实施例 19 中 PET 造影剂 18 F -FDG 换为
64 Cu ，可生物降解的白蛋白纳米球的制备及其对 PET 造影剂 64 Cu
的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 19 相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作
PET 造影剂。 The PET contrast agent 18 F -FDG in Example 19 was changed to 64 Cu, the preparation of biodegradable albumin nanospheres and its encapsulation of PET contrast agent 64 Cu, albumin nanosphere surface ligand galactosamine The synthesis of the pH-sensitive polymer on the surface of the coupled and albumin nanospheres is the same as in Example 19, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a PET contrast agent.
实施例 61 Example 61
将实施例 24 中 PET 造影剂 18 F -FDG 换为
64 Cu ，可生物降解的壳聚糖纳米球的制备及其对 PET 造影剂 64 Cu
的包埋、壳聚糖纳米球表面配体叶酸的偶联、壳聚糖纳米球表面 pH 敏感型高分子的合成与实施例 24
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 Preparation of PET contrast agent 18 F -FDG in Example 24 to 64 Cu, preparation of biodegradable chitosan nanospheres and encapsulation of PET contrast agent 64 Cu, surface ligand of folic acid nanospheres folic acid The synthesis of the pH-sensitive polymer on the surface of the coupled chitosan nanosphere is the same as in Example 24, and another tumor of brain, kidney, breast, lung, ovarian, uterine, nasopharyngeal, etc. can be obtained. Invisible contrast materials for early diagnosis can be used as PET contrast agents.
实施例 62 Example 62
将实施例 29 中 PET 造影剂 18 F -FDG 换为
64 Cu ，可生物降解的壳聚糖纳米球的制备及其对 PET 造影剂 64 Cu
的包埋、壳聚糖纳米球表面配体叶酸的偶联、壳聚糖纳米球表面 pH 敏感型高分子的合成与实施例 29
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 The PET contrast agent 18 F -FDG in Example 29 was changed to 64 Cu, the preparation of biodegradable chitosan nanospheres and the encapsulation of PET contrast agent 64 Cu and the surface ligand of chitosan nanospheres. The synthesis of the pH-sensitive polymer on the surface of the coupled chitosan nanospheres is the same as in Example 29, and another tumor such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal carcinoma, etc. can be obtained. Invisible contrast materials for early diagnosis can be used as PET contrast agents.
实施例 63 Example 63
将实施例 4 中 PET 造影剂 18 F -FDG 换为
124 I ，可生物降解的白蛋白纳米球的制备及其对 PET 造影剂 124 I
的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 4
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 The PET contrast agent 18 F -FDG in Example 4 was changed to 124 I , the preparation of biodegradable albumin nanospheres and the entrapment of PET contrast agent 124 I and the coupling of albumin nanosphere surface ligand folic acid The synthesis of the pH-sensitive polymer on the surface of albumin nanospheres is the same as in the case of Example 4, and an early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained. Invisible contrast material can be used as a PET contrast agent.
实施例 64 Example 64
将实施例 9 中 PET 造影剂 18 F -FDG 换为
124 I ，可生物降解的白蛋白纳米球的制备及其对 PET 造影剂 124 I
的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 9 相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作
PET 造影剂。 The PET contrast agent 18 F -FDG in Example 9 was changed to 124 I , the preparation of biodegradable albumin nanospheres and its encapsulation of PET contrast agent 124 I , albumin nanosphere surface ligand galactosamine The synthesis of the pH-sensitive polymer on the surface of the coupled and albumin nanospheres is the same as in Example 9, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a PET contrast agent.
实施例 65 Example 65
将实施例 14 中 PET 造影剂 18 F -FDG 换为
124 I ，可生物降解的白蛋白纳米球的制备及其对 PET 造影剂 124 I
的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 14
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 The PET contrast agent 18 F -FDG in Example 14 was changed to 124 I , the preparation of biodegradable albumin nanospheres and the entrapment of PET contrast agent 124 I and the coupling of albumin nanosphere surface ligand folic acid The synthesis of the pH-sensitive polymer on the surface of albumin nanospheres is the same as in Example 14, and another tumor for brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer, etc. can be prepared for early diagnosis. Invisible contrast material can be used as a PET contrast agent.
实施例 66 Example 66
将实施例 19 中 PET 造影剂 18 F -FDG 换为
124 I ，可生物降解的白蛋白纳米球的制备及其对 PET 造影剂 124 I
的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 19 相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作
PET 造影剂。 The PET contrast agent 18 F -FDG in Example 19 was changed to 124 I , the preparation of biodegradable albumin nanospheres and its encapsulation of PET contrast agent 124 I , albumin nanosphere surface ligand galactosamine The synthesis of the pH-sensitive polymer on the surface of the coupled and albumin nanospheres is the same as in Example 19, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a PET contrast agent.
实施例 67 Example 67
将实施例 24 中 PET 造影剂 18 F -FDG 换为
124 I ，可生物降解的壳聚糖纳米球的制备及其对 PET 造影剂 124 I
的包埋、壳聚糖纳米球表面配体叶酸的偶联、壳聚糖纳米球表面 pH 敏感型高分子的合成与实施例 24
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 The PET contrast agent 18 F -FDG in Example 24 was changed to 124 I , the preparation of biodegradable chitosan nanospheres and the entrapment of PET contrast agent 124 I , the surface ligand of folic acid nanospheres folic acid The synthesis of the pH-sensitive polymer on the surface of the coupled chitosan nanosphere is the same as in Example 24, and another tumor of brain, kidney, breast, lung, ovarian, uterine, nasopharyngeal, etc. can be obtained. Invisible contrast materials for early diagnosis can be used as PET contrast agents.
实施例 68 Example 68
将实施例 29 中 PET 造影剂 18 F -FDG 换为
124 I ，可生物降解的壳聚糖纳米球的制备及其对 PET 造影剂 124 I
的包埋、壳聚糖纳米球表面配体叶酸的偶联、壳聚糖纳米球表面 pH 敏感型高分子的合成与实施例 29
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 The PET contrast agent 18 F -FDG in Example 29 was changed to 124 I , the preparation of biodegradable chitosan nanospheres and the entrapment of PET contrast agent 124 I , the surface ligand of folic acid nanospheres folic acid The synthesis of the pH-sensitive polymer on the surface of the coupled chitosan nanospheres is the same as in Example 29, and another tumor such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal carcinoma, etc. can be obtained. Invisible contrast materials for early diagnosis can be used as PET contrast agents.
实施例 69 Example 69
将实施例 4 中 PET 造影剂 18 F -FDG 换为
94 Tc ，可生物降解的白蛋白纳米球的制备及其对 PET 造影剂 94 Tc
的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 4
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 The PET contrast agent 18 F -FDG in Example 4 was changed to 94 Tc , the preparation of biodegradable albumin nanospheres and the entrapment of PET contrast agent 94 Tc and the coupling of folic acid on the surface of albumin nanospheres. The synthesis of the pH-sensitive polymer on the surface of albumin nanospheres is the same as in the case of Example 4, and an early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained. Invisible contrast material can be used as a PET contrast agent.
实施例 70 Example 70
将实施例 9 中 PET 造影剂 18 F -FDG 换为
94 Tc ，可生物降解的白蛋白纳米球的制备及其对 PET 造影剂 94 Tc
的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 9 相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作
PET 造影剂。 The PET contrast agent 18 F -FDG in Example 9 was changed to 94 Tc , the preparation of biodegradable albumin nanospheres and its encapsulation of PET contrast agent 94 Tc , albumin nanosphere surface ligand galactosamine The synthesis of the pH-sensitive polymer on the surface of the coupled and albumin nanospheres is the same as in Example 9, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a PET contrast agent.
实施例 71 Example 71
将实施例 14 中 PET 造影剂 18 F -FDG 换为
94 Tc ，可生物降解的白蛋白纳米球的制备及其对 PET 造影剂 94 Tc
的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 14
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 The PET contrast agent 18 F -FDG in Example 14 was changed to 94 Tc , the preparation of biodegradable albumin nanospheres and the entrapment of PET contrast agent 94 Tc and the coupling of albumin nanosphere surface ligand folic acid The synthesis of the pH-sensitive polymer on the surface of albumin nanospheres is the same as in Example 14, and another tumor for brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal cancer, etc. can be prepared for early diagnosis. Invisible contrast material can be used as a PET contrast agent.
实施例 72 Example 72
将实施例 19 中 PET 造影剂 18 F -FDG 换为
94 Tc ，可生物降解的白蛋白纳米球的制备及其对 PET 造影剂 94 Tc
的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 19 相同，即可制得另一种肝癌早期诊断用隐形造影材料，可用作
PET 造影剂。 The PET contrast agent 18 F -FDG in Example 19 was changed to 94 Tc , the preparation of biodegradable albumin nanospheres and its encapsulation of PET contrast agent 94 Tc , albumin nanosphere surface ligand galactosamine The synthesis of the pH-sensitive polymer on the surface of the coupled and albumin nanospheres is the same as in Example 19, and another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a PET contrast agent.
实施例 73 Example 73
将实施例 24 中 PET 造影剂 18 F -FDG 换为
94 Tc ，可生物降解的壳聚糖纳米球的制备及其对 PET 造影剂 94 Tc
的包埋、壳聚糖纳米球表面配体叶酸的偶联、壳聚糖纳米球表面 pH 敏感型高分子的合成与实施例 24
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 The PET contrast agent 18 F -FDG in Example 24 was changed to 94 Tc , the preparation of biodegradable chitosan nanospheres and its encapsulation of PET contrast agent 94 Tc , the surface ligand of folic acid nanospheres folic acid The synthesis of the pH-sensitive polymer on the surface of the coupled chitosan nanosphere is the same as in Example 24, and another tumor of brain, kidney, breast, lung, ovarian, uterine, nasopharyngeal, etc. can be obtained. Invisible contrast materials for early diagnosis can be used as PET contrast agents.
实施例 74 Example 74
将实施例 29 中 PET 造影剂 18 F -FDG 换为
94 Tc ，可生物降解的壳聚糖纳米球的制备及其对 PET 造影剂 94 Tc
的包埋、壳聚糖纳米球表面配体叶酸的偶联、壳聚糖纳米球表面 pH 敏感型高分子的合成与实施例 29
相同，即可制得另一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作 PET 造影剂。 The PET contrast agent 18 F -FDG in Example 29 was changed to 94 Tc , the preparation of biodegradable chitosan nanospheres and its encapsulation of PET contrast agent 94 Tc , the surface ligand of folic acid nanospheres folic acid The synthesis of the pH-sensitive polymer on the surface of the coupled chitosan nanospheres is the same as in Example 29, and another tumor such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, nasopharyngeal carcinoma, etc. can be obtained. Invisible contrast materials for early diagnosis can be used as PET contrast agents.
实施例 75 Example 75
将实施例 3 中制备金纳米颗粒改为金纳米笼子，具体制备方法如下：将 3 mL 0.75 mM 的
HAuCl4 与 3 mL 0.03 M 的 HMT （六亚甲基四胺）混匀，溶液颜色由浅黄变为透明，然后，加入 3 mL 0.3 M 的
PVP （聚乙烯吡咯烷酮）和 100 μ L 0.01 M 的 AgNO3 ，温和搅拌之后加入 50 μ L 0.08 M 抗坏血酸，将混合溶液搅拌 10 s
，室温静置 12 h 之后离心洗涤，即可得到金纳米笼子。 The gold nanoparticles prepared in Example 3 were changed to gold nano cages, and the preparation method was as follows: 3 mL of 0.75 mM HAuCl 4 and 3 mL of 0.03 M HMT (hexamethylenetetramine) were mixed, and the solution color was light yellow. It became transparent. Then, add 3 mL of 0.3 M PVP (polyvinylpyrrolidone) and 100 μL of 0.01 M AgNO3. After gentle stirring, add 50 μL of 0.08 M ascorbic acid, stir the mixed solution for 10 s, and let stand at room temperature for 12 h. After centrifugation, a gold nanocage is obtained.
可生物降解的白蛋白纳米球的制备及其对上述金纳米笼子的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 3
相同，即可制得另外一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作CT造影剂。
Preparation of Biodegradable Albumin Nanospheres and Its Encapsulation of Gold Nanocage, Coupling of Albumin Nanosphere Surface Ligand, Synthesis of Albumin Nanosphere Surface pH Sensitive Polymer and Example 3
Similarly, another type of stealth angiography material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained and used as a CT contrast agent.
实施例 76 Example 76
将实施例 8 中制备金纳米颗粒改为金纳米笼子，具体制备方法与实施例 75
相同，可生物降解的白蛋白纳米球的制备及其对上述金纳米笼子的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 8
相同，即可制得另外一种肝癌早期诊断用隐形造影材料，可用作CT造影剂。 The gold nanoparticles prepared in Example 8 were changed to gold nano cages, and the specific preparation method and examples 75
The same, the preparation of biodegradable albumin nanospheres and the embedding of the above gold nanocage, the coupling of the albumin nanosphere surface ligand galactosamine, the synthesis of the albumin nanosphere surface pH sensitive polymer and Example 8
In the same way, another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
实施例 77 Example 77
将实施例 3 中制备金纳米颗粒改为金纳米棒，具体制备方法如下：配制 20 mL 含有 0.25 mM
HAuCl4 和 0.25 mM 柠檬酸钠溶液，边搅拌边加入 0.6 mL 冰浴的 0.1 M NaBH4
溶液，加入 NaBH4 后溶液会迅速变为紫色，金纳米粒子形成。在合成该金纳米粒子后 2-5 h 内，该金纳米粒子可作为金纳米种子。配制
10 mL 含有 0.25 mM HAuCl4 和 0.1 M CTAB （十六烷基三甲基溴化铵）的生长溶液，加入 0.05 mL 的
0.1 M 新制抗坏血酸溶液，然后再加入 0.025 mL 的 3.5 nm 金纳米种子，静置反应 48 h ，即可制得金长径比（ aspect ratio
）为 3.0 的金纳米棒。 The gold nanoparticles prepared in Example 3 were changed to gold nanorods, and the preparation method was as follows: 20 mL of a 0.1 M NaBH 4 solution containing 0.25 mM HAuCl 4 and 0.25 mM sodium citrate solution and 0.6 mL ice bath while stirring was prepared. After adding NaBH 4 , the solution will quickly turn purple and gold nanoparticles will form. The gold nanoparticles can be used as gold nano seeds within 2-5 h after synthesizing the gold nanoparticles. Prepare 10 mL of growth solution containing 0.25 mM HAuCl 4 and 0.1 M CTAB (cetyltrimethylammonium bromide), add 0.05 mL of 0.1 M fresh ascorbic acid solution, and then add 0.025 mL of 3.5 nm gold nanoseeds. After standing for 48 h, gold nanorods with an aspect ratio of 3.0 were obtained.
可生物降解的白蛋白纳米球的制备及其对上述金纳米棒的包埋、白蛋白纳米球表面配体叶酸的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 3
相同，即可制得另外一种脑癌、肾癌、乳癌、肺癌、卵巢癌、子宫癌、鼻咽癌等肿瘤早期诊断用隐形造影材料，可用作CT造影剂。
Preparation of Biodegradable Albumin Nanospheres and Its Encapsulation of Gold Nanorods, Coupling of Albumin Nanospheres Surface Folic Acid, Synthesis of Albumin Nanosphere Surface pH Sensitive Polymer and Example 3
Similarly, another type of stealth angiography material for early diagnosis of tumors such as brain cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, and nasopharyngeal cancer can be obtained and used as a CT contrast agent.
实施例 78 Example 78
将实施例 8 中制备金纳米颗粒改为金纳米棒，具体制备方法与实施例 77
相同，可生物降解的白蛋白纳米球的制备及其对上述金纳米棒的包埋、白蛋白纳米球表面配体半乳糖胺的偶联、白蛋白纳米球表面 pH 敏感型高分子的合成与实施例 8
相同，即可制得另外一种肝癌早期诊断用隐形造影材料，可用作CT造影剂。 The gold nanoparticles prepared in Example 8 were changed to gold nanorods, and the specific preparation method and examples 77
The same, the preparation of biodegradable albumin nanospheres and the embedding of the above gold nanorods, the coupling of galactosamine on the surface of albumin nanospheres, and the synthesis of pH-sensitive polymers on the surface of albumin nanospheres Example 8
In the same way, another invisible contrast material for early diagnosis of liver cancer can be obtained and used as a CT contrast agent.
Claims (10)
- 一种肿瘤早期诊断用隐形造影材料，其特征在于，由可生物降解纳米球、包埋于所述的可生物降解纳米球内部的医学造影剂、连接于所述的可生物降解纳米球表面的靶分子和 A stealth contrast material for early diagnosis of a tumor, characterized by comprising: a biodegradable nanosphere, a medical contrast agent embedded inside the biodegradable nanosphere, and a surface of the biodegradable nanosphere attached to the surface Target molecule andpH 敏感型高分子构成。It is composed of a pH-sensitive polymer.
- 根据权利要求 1 所述的 肿瘤早期诊断用隐形造影材料，其特征在于，所述的 pH 敏感型高分子为在 pH5.0~6.0 范围内发生收缩的高分子化合物。The invisible contrast material for early diagnosis of a tumor according to claim 1, wherein the pH-sensitive polymer is at pH 5.0 to 6.0. A polymer compound that shrinks within the range.
- 根据权利要求 1 或 2 所述的 肿瘤早期诊断用隐形造影材料，其特征在于，所述的 pH 敏感型高分子为 异丙基丙烯酰胺 - 丙烯酸共聚物和异丙基丙烯酰胺 - 甲基丙烯酸共聚物中的至少一种 ，分子量范围为 2k-1000k 。The invisible contrast material for early diagnosis of a tumor according to claim 1 or 2, wherein the pH-sensitive polymer is isopropyl acrylamide - at least one of an acrylic copolymer and an isopropylacrylamide-methacrylic acid copolymer having a molecular weight in the range of 2k to 1000k.
- 根据权利要求 1 所述的 肿瘤早期诊断用隐形造影材料，其特征在于，所述的医学造影剂为 MRI 造影剂、 CT 造影剂、 PET造影剂或荧光素造影剂，所述的医学造影剂的粒径为15nm 以下。The invisible contrast material for early diagnosis of a tumor according to claim 1, wherein the medical contrast agent is an MRI contrast agent, a CT contrast agent, A PET contrast agent or a fluorescein contrast agent having a particle diameter of 15 nm or less.
- 根据权利要求 4 所述的 肿瘤早期诊断用隐形造影材料，其特征在于，所述的 MRI 造影剂选自超顺磁性氧化铁纳米粒子、顺磁性 Gd-DTPA 配合物、 Gd-DOTA 配合物和 Gd2O3 纳米粒子中的至少一种；所述的 CT 造影剂选自碘海醇、硫酸钡、金纳米颗粒、金纳米棒和金纳米笼子中的至少一种；所述的 PET 造影剂选自 18 F -FDG 、 64 Cu 、 124 I 和 94 C 中的至少一种；所述的荧光素造影剂为酞菁。The invisible contrast material for early diagnosis of a tumor according to claim 4, wherein the MRI contrast agent is selected from the group consisting of superparamagnetic iron oxide nanoparticles, paramagnetic Gd-DTPA complexes, Gd-DOTA complexes, and Gd. At least one of 2 O 3 nanoparticles;The CT contrast agent is selected from at least one of iohexol, barium sulfate, gold nanoparticles, gold nanorods, and gold nanocage;The PET contrast agent is selected from at least one of 18 F -FDG, 64 Cu , 124 I and 94 C;The fluorescein contrast agent is phthalocyanine.
- 根据权利要求 1 所述的 肿瘤早期诊断用隐形造影材料，其特征在于，所述的可生物降解纳米球的材料选自寡肽、蛋白质、多糖、聚醚类、聚酯类高分子中的至少一种，所述的可生物降解纳米球的粒径为 500nm 以下。According to claim 1 The invisible contrast material for early diagnosis of tumors, wherein the material of the biodegradable nanosphere is at least one selected from the group consisting of oligopeptides, proteins, polysaccharides, polyethers, and polyester polymers. The particle size of the biodegradable nanosphere is Below 500nm.
- 根据权利要求 1 所述的 肿瘤早期诊断用隐形造影材料，其特征在于，所述的靶分子选自单克隆抗体、叶酸或半乳糖胺中至少一种。According to claim 1 A stealth contrast material for early diagnosis of a tumor, characterized in that the target molecule is at least one selected from the group consisting of a monoclonal antibody, folic acid or galactosamine.
- 根据权利要求 1 所述的 肿瘤早期诊断用隐形造影材料，其特征在于，所述的 pH 敏感型 高分子与靶分子的数目比为 0.2-5.0 。The invisible contrast material for early diagnosis of a tumor according to claim 1, wherein the ratio of the pH-sensitive polymer to the target molecule is 0.2-5.0.
- 一种权利要求 1~8 任一所述的肿瘤早期诊断用隐形造影材料的制备方法，其特征在于，包括如下步骤：A claim 1-8 The method for preparing a stealth contrast material for early diagnosis of a tumor according to any of the preceding claims, comprising the steps of:（ 1 ）制备包埋有医学造影剂的可生物降解纳米球；(1) preparing biodegradable nanospheres embedded with a medical contrast agent;（ 2 ）通过共价偶联反应将所述的靶分子连接到步骤（ 1 ）中得到的可生物降解纳米球的表面上，得到中间体； (2) attaching the target molecule to the surface of the biodegradable nanosphere obtained in the step (1) by a covalent coupling reaction to obtain an intermediate;（ 3 ）在步骤（ 2 ）得到的中间体的表面上，采用活性自由基聚合技术合成所述的 pH 敏感型高分子，得到所述的肿瘤早期诊断用隐形材料。(3) synthesizing the pH by living radical polymerization technique on the surface of the intermediate obtained in the step (2) The sensitive polymer obtains the invisible material for early diagnosis of the tumor.
- 根据权利要求 9 所述的肿瘤早期诊断用隐形造影材料的制备方法，其特征在于，步骤（ 3 ）替换为： 将 pH 敏感型高分子通过共价偶联反应连接到步骤（ 2 ）得到的中间体的表面上，得到所述的肿瘤早期诊断用隐形造影材料。 The method for preparing a stealth contrast material for early diagnosis of a tumor according to claim 9, wherein the step (3) is replaced by: The sensitive polymer is attached to the surface of the intermediate obtained in the step (2) by a covalent coupling reaction to obtain the invisible contrast material for early diagnosis of the tumor.
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