WO2018033165A1 - 一种高分子-金属氧化物复合物及其制备方法与应用 - Google Patents

一种高分子-金属氧化物复合物及其制备方法与应用 Download PDF

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WO2018033165A1
WO2018033165A1 PCT/CN2017/106676 CN2017106676W WO2018033165A1 WO 2018033165 A1 WO2018033165 A1 WO 2018033165A1 CN 2017106676 W CN2017106676 W CN 2017106676W WO 2018033165 A1 WO2018033165 A1 WO 2018033165A1
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polymer
metal oxide
iron
polyacrylic acid
oxide composite
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PCT/CN2017/106676
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English (en)
French (fr)
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侯丽英
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上海迈景纳米科技有限公司
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Priority to GB1903731.6A priority Critical patent/GB2568434A/en
Priority to US16/325,604 priority patent/US20190247524A1/en
Publication of WO2018033165A1 publication Critical patent/WO2018033165A1/zh

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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F292/00—Macromolecular compounds obtained by polymerising monomers on to inorganic materials
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the invention relates to the field of nanotechnology and biomedical engineering technology, in particular to a polymer-metal oxide composite.
  • superparamagnetic nanoparticles represented by iron oxide have been widely used in various fields of biomedical science due to their unique physical and chemical properties, such as biomagnetic separation, targeted drug delivery, gene transfection, immunodiagnosis, and deficiency.
  • Iron anemia treatment enhanced magnetic resonance imaging and other fields.
  • nanometer-sized iron oxide particles have been widely studied and applied in the treatment of superparamagnetic magnetic resonance contrast agents and iron deficiency anemia.
  • the molecular structure of iron oxide nanoparticles in the above applications is mainly a polymer complex of triiron tetroxide or ferric oxide, and commercial superparamagnetic iron oxide complex molecular contrast agents mainly include Combidex, Resovist and Feridex.
  • the molecular structure of these three types of iron oxide complexes is: the center is a triiron tetroxide crystal particle, and the surface is chelated by a hydroxyl group-coordinated iron atom on a hydrophilic polymer (such as dextran), thereby making this
  • the iron oxide-like complex can be dispersed in an aqueous solution;
  • the commercial iron oxide nanoparticle as a iron deficiency anemia iron-containing agent mainly has Ferumoxtol, and adopts a molecular structure in which a carboxylated modified glucan is chelated with an iron atom.
  • the final particle size is 60-150 nm.
  • the preparation method has the advantages of simple method, simple operation and easy mass production.
  • the coprecipitation method has a faster reaction rate, and the nucleation and crystallization processes are difficult to separate, resulting in poor monodispersity of the particles and wide particle size distribution, which requires further sorting to obtain a desired particle size.
  • the reaction medium of the coprecipitation method is an aqueous phase
  • the reaction temperature is lower than 100 ° C, and the lower reaction temperature makes the crystallinity of the central iron oxide crystals lower, resulting in weak magnetization and poor actual contrast effect.
  • the high-temperature thermal decomposition method can reach nano-particles with narrow particle size distribution and higher crystallinity due to high reaction temperature.
  • the nano-particles obtained by the traditional high-temperature thermal decomposition method are generally oil-soluble, which is not conducive to further biological applications.
  • the aqueous phase nanoparticles using polyol as a stabilizer have a small amount of surface modification, and are prone to poor agglomeration stability when applied to in vivo angiography, which seriously affects the blood circulation cycle, and the imaging effect is not satisfactory.
  • US Patent No. 6,599,498 B1 discloses a molecular structure of a modified superparamagnetic iron oxide complex using carboxydextran as a coordination polymer, which uses carboxydextran as a surface modifying polymer to The coordination capacity of the central iron atom is enhanced, and at the same time, the free iron ion oozing is reduced during application, which alleviates the hypersensitivity reaction in clinical use [VS Balakrishnan et al, Eur. J. Clin. Invest. 39 (2009) 489.].
  • the molecular structure still does not achieve complete chelation of iron atoms on the surface of iron oxide, and there is still a problem of hypersensitivity reaction of dispersion stability and free iron ion exudation in clinical application.
  • CN 103347543 A discloses a molecular structure of an iron oxide composite coated with a hydrophilic material centered on high crystallinity iron oxide particles, the surface of which is coupled with carboxymethyldextran by ligand exchange.
  • the nanoparticle is a hydrophobic surface and cannot be used for biological applications, further ligand exchange is required, that is, the hydrophilic polymer ligand is used to convert the nanoparticles into hydrophilic nanoparticles.
  • This method has a long cycle, and due to the use of ligand exchange, the chelation between the surface ligand and the iron ion is weak, and it is easy to fall off and release free iron ions to cause a hypersensitivity reaction.
  • CN101002951A discloses a method for preparing hydrophilic iron oxide complex molecules by a polyol method, which can prepare hydrophilic, monodisperse and high crystallinity iron oxide complex molecules relatively easily, but the surface organic matter content is small. Therefore, its physiological stability is poor, and its blood circulation characteristics in the living body cannot be guaranteed.
  • the molecular structure design of the complex and its key problems in vivo application are related to the application effect of iron oxide complex as a magnetic resonance contrast agent and iron deficiency iron supplement in vivo, and also whether it will release freely in the body. Iron ions and the resolution of safety issues such as hypersensitivity reactions.
  • the present invention provides a polymer-metal oxide composite comprising metal oxide particles at the core and modified in the metal oxide a polymer on the surface of the particle, the polymer having a functional group capable of bonding to a metal in the metal oxide, and a density of a surface binding site of the polymer and the metal oxide particle is higher than 2 sites/ Square nanometer;
  • the polymer-metal oxide composite contains one or more metal elements such as iron, cobalt, nickel, iron cobalt, iron nickel, and the like.
  • the polymer is selected from one or more of polyacrylic acid, polyacrylic acid salt, methyl polyacrylic acid, methyl polyacrylate, polylactic acid, polylactic acid salt, and polyphosphate.
  • the polymer has a weight average molecular weight of 500 to 500,000 Da.
  • the polymer has a weight average molecular weight of 500 to 3000 Da.
  • the lower molecular weight polymer-metal oxide composite is less toxic to organisms and has better biocompatibility when used as an injection.
  • the total mass of the polymer accounts for 25% to 70% of the polymer-metal oxide composite.
  • the total mass of the polymer accounts for 40% to 70% of the polymer-metal oxide composite.
  • the metal oxide is selected from one or more of the group consisting of iron oxide, manganese oxide, cobalt oxide, chromium oxide, and nickel oxide.
  • the metal oxide is iron oxide.
  • the polymer-metal oxide composite is a polyacrylic acid-iron oxide complex, and a density of surface binding sites of the polyacrylic acid and the iron oxide particles is higher than 2 sites/square nanometer;
  • the central iron oxide particles have a particle diameter of 1 to 30 nm under a transmission electron microscope.
  • the surface-coupled polymer is a low molecular weight polyacrylic acid
  • the polyacrylic acid has a weight average molecular weight of 1000-10000
  • the total mass of the polyacrylic acid accounts for 25%-70% of the complex molecule.
  • the polyacrylic acid-iron oxide complex consists of a high crystallinity iron oxide center and a high proportion of surface carboxyl polymer, and the novel molecular structure gives the polyacrylic acid-iron oxide complex a high degree of hydrophilicity and physiology.
  • High dispersion stability in saline solution, good chelating properties with free and surface iron ions, excellent magnetic resonance relaxation enhancement properties and iron metabolism properties, these properties make these new polyacrylic acid-iron oxide complexes applicable Magnetic resonance imaging contrast agents in tissues or cells such as blood vessels, liver, spleen, lymph, and heart, and iron deficiency anemia iron supplements.
  • the invention also provides a preparation method of the above polymer-metal oxide composite, the preparation method comprising the following steps:
  • Step 1 the precipitating agent is dissolved in a reducing solvent to form a solution B;
  • Step 2 dissolving the polymer in the reducing solvent
  • Step 3 weigh the metal salt, the metal salt is dissolved in the mixed solution obtained in step 2, formulated into solution A;
  • Step 4 the solution A and the solution B are reacted under microwave conditions; cooling to obtain a polymer-metal oxide complex molecular colloid;
  • Step 5 separating and removing the polymer-metal oxide complex molecular colloid obtained in the step 4 to remove impurities (excluding impurities mainly means removing a solvent, a heavy metal or an unreacted polymer, etc.) to obtain the polymer- Metal oxide composite.
  • impurities excluding impurities mainly means removing a solvent, a heavy metal or an unreacted polymer, etc.
  • the reducing solvent is a hydrophilic high boiling point solvent, and the reducing solvent has a boiling point of 180 ° C or higher.
  • the reducing solvent is selected from one or more of diethylene glycol, ethylene glycol, propylene glycol, glycerin, propylene glycol, and diethylene glycol.
  • the precipitating agent is sodium hydroxide, sodium acetate or sodium borohydride.
  • the polymer is selected from one or more of polyacrylic acid, polyacrylic acid salt, methyl polyacrylic acid, methyl polyacrylate, polylactic acid, polylactic acid salt, and polyphosphate.
  • the metal salt is one or more selected from the group consisting of ferric chloride, iron sulfate, iron hydroxide, iron acetylacetonate, and iron cobalt acetylacetonate.
  • reaction temperature under the microwave conditions is from 180 ° C to 280 ° C.
  • reaction time under the microwave conditions is from 5 min to 30 min.
  • the method for preparing the polyacrylic acid-iron oxide composite comprises the following steps:
  • Step 1 the precipitating agent is dissolved in a reducing solvent to form a solution B;
  • Step 2 dissolving polyacrylic acid in the reducing solvent
  • Step 3 the iron salt is dissolved in the mixed solution obtained in step 2, formulated into solution A;
  • Step 4 the solution A and the solution B are reacted under microwave conditions; cooling to obtain a polyacrylic acid-iron oxide complex molecular colloid;
  • Step 5 separating and separating the polyacrylic acid-iron oxide complex molecular colloid obtained in the step 4 to obtain a polyacrylic acid-iron oxide complex.
  • the present invention also provides a nuclear magnetic resonance contrast agent comprising the above-described polymer-metal oxide composite containing iron element.
  • the nuclear magnetic resonance contrast agent can perform enhanced T1, T2 and T2* magnetic resonance imaging on normal or diseased blood vessels, liver, spleen, lymph, heart and other organs or tissues.
  • the nuclear magnetic resonance contrast agent is an injection or an oral preparation.
  • the invention also provides the use of the above nuclear magnetic resonance contrast agent in tissue or nuclear magnetic development.
  • tissue or cell is a blood vessel, a liver, a spleen lymph or a heart.
  • the present invention also provides a iron-reinforcing agent comprising the above-mentioned polymer-metal oxide composite containing iron element.
  • the iron supplement can rapidly increase the levels of hemoglobin and transferrin in the blood.
  • iron supplement is an injection or an oral preparation.
  • Oral formulations include capsules, tablets and the like.
  • the invention also provides the application of the above iron supplement in the preparation of a medicament for treating iron deficiency anemia.
  • the polymer-metal oxide composite provided by the invention contains a large amount of polyelectrolyte polymer, has good dispersion stability, uniform particle size distribution, high crystallinity of the central metal oxide, good contrast effect and long cycle function. .
  • the uniformity of microwave heating is good, the heating efficiency is high, the synthesis process is greatly shortened, and the preparation cost is reduced.
  • the invention provides a novel molecular structure of a polymer-metal oxide, especially a polyacrylic acid-iron oxide complex, and a preparation thereof for the problem that the surface iron atom has low chelation density and weak bonding strength in the prior iron oxide composite.
  • Methods, and such complexes are prepared in a variety of dosage forms for use in magnetic resonance contrast agents and iron supplements for the treatment of iron deficiency anemia. It greatly extends the polyacrylic acid-iron oxide complex in vivo The time of the ring effectively overcomes the shortcomings of the existing iron oxide complex injection with hypersensitivity reaction, plus the superparamagnetism of the complex itself and the function of participating in iron metabolism, enabling it to be applied to magnetic resonance imaging contrast agents. And iron supplements for the treatment of iron deficiency anemia.
  • Figure 1 is a graph showing thermogravimetric analysis of four polyacrylic acid-iron oxide complex molecules in a preferred embodiment of the present invention
  • Figures 1a to 1d respectively show polyacrylic acid-oxidation in Examples 1-4.
  • FIG. 2 is a transmission electron microscope (TEM) photograph particle size distribution diagram of four polyacrylic acid-iron oxide complex molecules in a preferred embodiment of the present invention
  • FIGS. 2a to 2d respectively show examples 1-4.
  • Figure 3 shows the saturation magnetization curves of four polyacrylic acid-iron oxide complex molecules in a preferred embodiment of the invention
  • Figure 3a shows the four polyacrylic acid-iron oxide complexes of Examples 1-4.
  • the saturation magnetization curve of the molecule Figure 3b shows an enlarged view of the curve near zero;
  • Figure 4 shows the relaxation time curves of four polyacrylic acid-iron oxide complex molecules in a preferred embodiment of the invention
  • Figures 4a, 4b show the polyacrylic acid-iron oxide complexes of Examples 1-4.
  • Figure 5 is a graph showing the sterilization stability curves of four polyacrylic acid-iron oxide complex molecular injection agents in a preferred embodiment of the present invention.
  • Figure 6 is a graph showing the stability curves of four polyacrylic acid-iron oxide complex molecular injection agents in a preferred embodiment of the present invention.
  • Figure 7 is a diagram showing normal liver magnetic resonance imaging of different concentrations of polyacrylic acid-iron oxide complex molecular injection in a preferred embodiment of the present invention.
  • Figure 8 is a graph showing a contrast-enhanced magnetic resonance imaging of a polyacrylic acid-iron oxide complex molecular injection agent and a commercial sputum contrast agent in a normal blood vessel in a preferred embodiment of the present invention
  • Figure 9 is a view showing a magnetic resonance image of a diseased liver tissue (liver cancer) of a polyacrylic acid-iron oxide complex molecular injection in a preferred embodiment of the present invention.
  • Figure 10 is a magnetic resonance imaging diagram of a diseased blood vessel (aneurysm) of a polyacrylic acid-iron oxide complex molecular injection in a preferred embodiment of the present invention
  • Figure 10a Aneurysm model rabbit left common carotid artery bridging hemangioma (shown at the head of the arrow) clearly shows that the aneurysm model has a positive view of the middle part of the common carotid artery in the left common carotid artery.
  • the diameter of the hemangioma is significantly larger than that of the common carotid artery, which is significantly different from the contralateral normal carotid artery.
  • Figure 10b removes the rest. After the blood vessels, the aneurysm is more obvious;
  • the lateral view of the aneurysm in Fig. 10c and Fig. 10d is highly consistent with the gross pathological morphology of the aneurysm taken during surgery;
  • Figure 11 is a view showing the magnetic resonance image of the coronary artery of the polyacrylic acid-iron oxide complex molecular injection in the preferred embodiment of the present invention
  • Figure 11a shows the imaging result of the 15 minute coronary artery (shown by the dotted line), coronary artery Can be clearly displayed
  • Figure 11b shows the results of coronary artery (shown in dashed lines) after 180 minutes, the coronary artery information has almost disappeared
  • Figure 11c shows the imaging results of the 15min coronary anterior descending artery (shown by the dotted line), the anterior descending coronary artery can be obvious
  • Figure 11d shows the results of a 15-minute coronary circumflex artery (shown in phantom), and the coronary circumflex can be clearly displayed;
  • Figure 12 is a schematic view showing the possible structure of a polyacrylic acid-iron oxide complex molecule in a preferred embodiment of the present invention.
  • a solution A (the solution is brown); finally, the solution A is placed in a three-necked flask at a constant temperature of 220 ° C for 10 min in a microwave reactor, and then rapidly added to the hot solution B. The reaction is carried out instantaneously and the temperature is kept for 10 minutes. After cooling, a polyacrylic acid-iron oxide complex molecular colloid is obtained, and then 4 L of ultrapure water is added for ultrafiltration washing, and the composite is spray-dried to obtain a polyacrylic acid-ferric oxide complex molecule.
  • the measuring tube is used to measure 100 ml of propylene glycol, and then 15 g of sodium borohydride is weighed by a precision balance, dissolved in propylene glycol by ultrasonication, heating and stirring to prepare a solution B, and the solution B is placed in a 70 ° C oven for constant temperature;
  • solution A is prepared (the solution is brown); finally, solution A is placed in a three-necked flask at a constant temperature of 240 ° C for 20 min in a microwave reactor, and then hot solution B is quickly added, and the reaction is instantaneously carried out. Constant temperature for 30min. Thereafter, cooling was carried out to obtain a polyacrylic acid-iron oxide complex molecular colloid, followed by precipitation with ethyl acetate and ethanol, and the precipitated complex was washed three times, and finally dispersed in water to freeze-dry to obtain a polyacrylic acid-ferric oxide complex molecule.
  • a solution A (the solution is brown); finally, the solution A is placed in a three-necked flask at a constant temperature of 200 ° C for 20 min in a microwave reactor. Then, the hot solution B was quickly added, and the reaction was carried out instantaneously, and the temperature was kept for 30 minutes. Thereafter, cooling was carried out to obtain a sodium colloid-iron oxide complex molecular colloid, followed by precipitation with ethyl acetate, and the precipitated complex was washed three times to obtain a black sodium polyacrylate-ferric oxide complex solution. The obtained sodium polyacrylate-ferric oxide complex solution was heated to 80 ° C, and air was introduced into the system for 4 hours to obtain a reddish brown sodium polyacrylate-ferric oxide complex solution to make the composite. more stable.
  • Constant temperature secondly, weighed 6 g of sodium polyacrylate solution (45%) with a weight average molecular weight of 1200 Da in a beaker, weighed 300 ml of glycerin in a beaker, stirred and sonicated to dissolve the two; quickly weighed iron acetylacetonate 2g and 1g of acetylacetone iron manganese, dissolved in a mixture of glycerol and sodium polyacrylate by heating, sonication, stirring, to form solution A (the solution is brown); finally, solution A is placed in a three-necked flask in the microwave The reactor was thermostated at 220 ° C for 20 min, then the hot solution B was quickly added, and the reaction was carried out instantaneously, and the temperature was kept for 30 min.
  • Constant temperature Secondly, weigh the weight 5.6g of polylactic acid with a molecular weight of 10000Da was placed in a beaker, then weighed 300ml of diethylene glycol in a beaker, stirred and sonicated to dissolve the two; quickly weigh 2g of anhydrous ferric chloride, and heated, sonicated and stirred Dissolved in a mixture of diethylene glycol and polylactic acid, formulated into solution A (the solution is brown); finally, the solution A is placed in a three-necked flask at 200 ° C for 20 min in a microwave reactor, and then rapidly added to the hot solution B, the reaction Instantly, at a constant temperature of 30 minutes.
  • Constant temperature secondly, weighed 4.2g of polyphosphate with a weight average molecular weight of 30,000 Da in a beaker, weighed 300 ml of diethylene glycol in a beaker, stirred and sonicated to dissolve the two; quickly weighed anhydrous ferric chloride 2g It is dissolved in a mixture of diethylene glycol and polyphosphate by heating, sonicating, stirring to prepare solution A (the solution is brown); finally, solution A is placed in a three-necked flask at a constant temperature of 200 ° C for 20 min in a microwave reactor. Then, the hot solution B is quickly added, and the reaction is carried out instantaneously, and the temperature is kept for 30 minutes.
  • each particle-modified polyacrylic acid contains 3339.60 carboxyl groups
  • the free carboxyl group content of the polyacrylic acid-iron oxide complex molecule is 18.681 mmol per g Fe 3 O 4 , that is, it is required to chelate 11 carboxyl groups per 1.322 nm 2 , so the chelation density of the carboxyl group is 8 /nm 2 .
  • the content of free carboxyl group in the molecule of iron oxide complex by conductometric titration is 18.681mmol per g Fe 3 O 4
  • a particle-modified polyacrylic acid contains 3339.60 carboxyl groups, of which 2784 are free carboxyl groups, and about 80% are Sodium is saturated, so the number of molecules of Na is 2227 to 2784.
  • the polyacrylic acid-iron oxide complex molecular solution obtained in Example 1-4 was dropped on the copper mesh of the carbon support film, and after being naturally air-dried, the morphology and size of the composite were observed under a transmission electron microscope (TEM).
  • the original TEM image of the four batches of samples is shown in the left figure of Fig. 2.
  • the particle size distribution of the composite molecular size in the figure is shown in the right figure of Fig. 2. It can be seen from Fig. 2 that the molecular weight of the composite molecule is good, and it is a single crystal nanoparticle molecule, and the interplanar spacing is 0.251 nm, corresponding to the crystal plane of triiron tetroxide (311). From the statistical particle size diagram, it is shown that the molecular size distribution of these nanocomposites is uniform, the crystallinity is high, and no agglomeration occurs between the particles.
  • Example 1 the percentage of surface polyacrylic acid in the polyacrylic acid-iron oxide complex molecule in Example 1 is 27.5%, and the mass of acrylic acid in a polyacrylic acid-iron oxide complex is: 5.92 ⁇ 10 -19 g.
  • the number of molecules of acrylic acid (C 3 H 4 O 2 ) contained was 5.92 ⁇ 10 -19 ⁇ 6.02 ⁇ 10 23 ⁇ 72 4950.
  • the polyacrylic acid-iron oxide complex in Example 1 has an average molecular formula of Fe 12144 O 26092 C 14850 H 19800 ;
  • Example 2 the average molecular formula of the polyacrylic acid-iron oxide complex in Example 2 was Fe 6960 O 39632 C 45528 H 60704 ;
  • the polyacrylic acid-iron oxide complex in Example 3 has an average molecular formula of Fe 3339 O 19016 C 21846 H 29128 ;
  • the polyacrylic acid-iron oxide complex of Example 4 had an average molecular formula of Fe 2064 O 10702 C 11925 H 15900 .
  • Figure 12 shows a possible structural schematic of a polyacrylic acid-iron oxide complex molecule.
  • the center is the grain of iron oxide nanoparticles, and the surface is a high-density polyacrylic acid polymer chain.
  • Some carboxyl groups on the molecular chain are bonded to iron atoms in the iron oxide nanoparticles by chemical coordination bonds, and the remaining unchelated The carboxyl chain segment is extended and distributed in the particle The outer surface.
  • the main feature of the molecular structure of the composite is that the density of iron atoms on the surface of the iron oxide is chelated by the carboxyl group to 2/square nanometer or more. This dense chelation makes the surface of the iron oxide have an ultra-high polyacrylic acid modification amount, which is reduced.
  • the amount of modification also allows the outer surface of the composite to have a high density of extended carboxyl chains, imparting excellent hydrophilicity to the composite and a high negative potential in aqueous solution, greatly improving the dispersion stability of the particles.
  • the particle size of the iron oxide nanoparticles in the composite is 1 to 10 nm under transmission electron microscopy, and the mass of the surface-coupled polymer polyacrylic acid accounts for 25% to 70% of the total mass of the composite molecules.
  • the polyacrylic acid-iron oxide complex molecules of Examples 1-4 are in aqueous solution by surface zeta potential test.
  • the surface potentials were: -41.3 mV, -42.8 mV, -45.1 mV, and -40.9 mV, respectively, indicating that the complex molecules carry a large amount of negative charge, and these excess negative charges allow the particles to be stably dispersed in the aqueous solution.
  • the polyacrylic acid-iron oxide complex of Example 1-4 was dispersed in physiological saline, and as shown in the figure, the polyacrylic acid-iron oxide complex molecule was visually observed to be stably dispersed in physiological saline, and the solution color was uniform and absent.
  • the sedimentation phenomenon indicates that the negative charge on the surface of the complex molecule enables the molecule to maintain good dispersibility in physiological saline.
  • Example 1-4 Take about 5 mL of the polyacrylic acid-iron oxide complex molecular solution obtained in Example 1-4, freeze-dry, and weigh about 10-15 mg of solid powder before testing. The sample is wrapped in a weighing paper and wrapped into a flat rectangular shape. The vibrating sample magnetometer was tested at room temperature and the results are shown in Figure 3, where the inserted thumbnail is an enlarged view of the curve near zero.
  • the saturation magnetizations of the polyacrylic acid-iron oxide complex molecules obtained in Examples 1-4 were: 62.6, 69.4, 49.6, and 49.1 emu/g, respectively. It can be seen by inserting a small figure that the magnetization curve passes through the origin, that is, there is no remanence, which proves that the novel polyacrylic acid-iron oxide complex molecules have superparamagnetism.
  • the polyacrylic acid-iron oxide complex molecules obtained in Examples 1-4 were tested for Fe content, and then the samples were diluted to 4, 5, 6, 7, 8 ⁇ 10 -4 mol/L, and 200 uL of the diluted sample was added to the test.
  • the relaxed tubes are numbered 4, 5, 6, 7, and 8, respectively.
  • the tube was placed in a constant temperature water bath at 37 ° C. Open the test software and first calibrate and test the relaxation time of the sample.
  • the relaxation time of the polyacrylic acid-iron oxide complex molecule in Examples 1-4 is shown in Figure 4.
  • the r 1 relaxation rate is 5.61-17.5
  • the r 2 relaxation rate is 20.3-72.7, where r 2 /r 1
  • the values are between 3.2 and 4.2.
  • the polyacrylic acid-iron oxide complex molecular solution prepared in any of the embodiments 1-4 is dried by freeze
  • the polyacrylic acid-iron oxide complex molecules are obtained by drying or spray drying, and the content of iron elements therein is determined by atomic absorption spectrometry. According to the iron content obtained by the above measurement, a corresponding volume of water or physiological saline is added according to the final concentration of iron element (umol Fe/L).
  • the final concentration of iron element is 5-1000 umol Fe/L, preferably 50-200 umol Fe/L.
  • the above polyacrylic acid-iron oxide complex molecular solution which has been configured according to the final concentration requirement of the iron element is ultrasonically dispersed to prepare a stable polyacrylic acid-iron oxide complex molecular injection.
  • the prepared polyacrylic acid-iron oxide complex injection was sterilized by autoclaving at 121 ° C for 30 minutes. After cooling, the stability of the injection was observed. The injection had no obvious sedimentation phenomenon, and the color of the solution did not change significantly.
  • the sample was subjected to dynamic light scattering (DLS) to test the hydraulic preparation of the injection complex molecule after sterilization. As shown in Fig. 5, the particle size and particle size distribution of the polyacrylic acid-iron oxide complex before and after sterilization were not obvious. The change. It shows that the prepared polyacrylic acid-iron oxide complex injection can be sterilized by high temperature, which effectively improves the safety of the injection.
  • DLS dynamic light scattering
  • the polyacrylic acid-iron oxide complex molecular solution prepared by any one of the examples 1-4 is obtained by freeze drying or spray drying to obtain a polyacrylic acid-iron oxide complex molecule, and the content of iron element is determined by atomic absorption spectrometry. .
  • the final concentration of iron element (umol Fe / L), the pharmaceutical auxiliary lactose (10% - 30%), starch (5% - 25%), ethyl cellulose (10) %-25%, dissolved in anhydrous ethanol), and anhydrous ethanol to make suitable wet granules, passed through 80 mesh stainless steel mesh, dried at room temperature, passed through 20 mesh stainless steel mesh, and added talcum powder (1%- 10%), stearic acid (0.2%-5%), evenly mixed, flat stamping.
  • the final concentration of iron in the tablet is from 5 to 1000 umol Fe/kg, preferably from 50 to 200 umol Fe/kg.
  • the polyacrylic acid-iron oxide complex molecular solution prepared by any one of the examples 1-4 is obtained by freeze drying or spray drying to obtain a polyacrylic acid-iron oxide complex molecule, and the content of iron element is determined by atomic absorption spectrometry. .
  • the content of iron element is determined by atomic absorption spectrometry.
  • the final concentration of iron umol Fe / L
  • the final concentration of iron in the capsule is 5-1000 umol Fe/kg, preferably the final concentration of iron in the capsule is 50-200 umol Fe/kg.
  • the polyacrylic acid-iron oxide complex molecular injection prepared in Example 16 was placed for three days to one year, and its stability was observed. The color of the injection solution did not change significantly, and the solution did not precipitate uniformly. Samples were taken to test the hydraulic diameter of the injection complex molecules by dynamic light scattering (DLS), as shown in Figure 6, with no significant changes. This indicates that the polyacrylic acid-iron oxide complex molecular injection agent has a high proportion of polyacrylic acid modification on its surface, and a high proportion of polyacrylic acid has excellent stability of the polyacrylic acid-iron oxide complex molecule due to its strong electrostatic repulsion force. Suitable for intravenous injection Injectable use.
  • DLS dynamic light scattering
  • the polyacrylic acid-iron oxide complex molecular injection obtained in Example 16 was used, and the supernatant was filtered using a 3KDa ultrafiltration centrifuge tube, and the free iron ions in the supernatant were determined by atomic absorption. concentration. A certain amount of free iron ions was also added to the injection, and after half an hour, the concentration of free iron ions in the supernatant was measured by atomic absorption, and the test results are shown in Table 1. The results showed that the injection did not release free iron ions even for 120 days. After the addition of free iron ions, the injection can simultaneously reduce the concentration of free iron ions, effectively reducing the hypersensitivity caused by imaging in vivo.
  • the injection preparation of the novel iron oxide complex molecule can effectively reduce the release of free iron ions and reduce the hypersensitivity reaction, and is suitable for clinical use as a contrast agent and iron supplement.
  • the polyacrylic acid-iron oxide complex molecular injection prepared in Example 16 was configured as a contrast agent having a concentration of 40, 85, and 135 umol Fe/L, and was injected into the model rabbit via the ear vein at a dose of 1 ml/kg, respectively, in the injection.
  • T 1 weighted imaging of the rabbit liver was performed before, at 0 min, 3 min, 5 min, 10 min, 20 min, and 30 min after injection.
  • the results of magnetic resonance imaging are shown in Figure 7: the liver signals of rabbits were decreased in different injection concentration models; the small hepatic vein branches in the liver of rabbits showed clear (40 arrow) in the 40umol/L injection concentration model; 85umol/L injection concentration model rabbits The trunk of the liver vein (shown by the arrow) in the liver showed clear, and the small branches were slightly blurred; the 135umol/L injection concentration model showed the main hepatic vein trunk and small branches in the liver of the rabbit, but the results were slightly lower than 85umol/L and 40umol/ respectively. L injection concentration model rabbit. This new type of iron oxide complex molecular injection can be used for magnetic resonance imaging of normal liver tissue.
  • the aorta and vena cava were not ideal, the vascular signal was reduced, and the contour was blurred.
  • the Fe contrast agent clearly showed the aorta, vena cava and portal vein for at least 30 min, and the effect was similar at each time point and prolonged with time.
  • the finer spinal cord arteries and veins (shown by thick arrows) showed a slight increase in the range, while Gd-DTPA showed a small amount of spinal cord arteries only at 30 s. It shows that iron contrast agent can obtain vascular images with higher contrast, and has obvious long-circulation characteristics. After 30 minutes, it still has clear blood vessel imaging effect.
  • the utility model overcomes the short development time of the commercial bismuth contrast agent, the unclear signal and the blurred outline. It is indicated that the novel iron oxide complex molecular contrast agent is capable of being applied to long-term vascular imaging in vivo due to its surface coupled with high-density polyacrylic acid, and the effect is far superior to the existing commercial sputum contrast agent.
  • the tumor model rabbit liver was injected with the stabilized polyacrylic acid-iron oxide complex molecular injection prepared in Example 16 before and after (concentration: 135 umol/L; dose: 1 ml/kg), and respectively subjected to T 1 weighted imaging (T 1 WI). And T 2 weighted imaging (T 2 WI).
  • T 1 WI and T 2 WI showed better results on tumors (shown by the arrow head) than before injection, and liver signals were significantly lower than before injection, and the lesions were prominent.
  • the normal liver tissue with a significantly reduced signal after the contrast agent was injected showed a relatively high-signal tumor lesion, which made the contrast more intense.
  • This new type of iron oxide complex molecular injection can be used for magnetic resonance imaging of diseased liver tissue (such as liver cancer), and both T 1 weighted imaging (T 1 WI) and T 2 weighted imaging (T 2 WI) can effectively Increasing the contrast between the diseased liver tissue and normal liver tissue is conducive to clinical diagnostic research and has a high potential for clinical application.
  • the rabbit liver of the vascular aneurysm model was injected with the stabilized polyacrylic acid-iron oxide complex molecular injection prepared in Example 16 before and after (concentration: 135 umol/L; dose: 1 ml/kg).
  • the results of magnetic resonance imaging are shown in Figure 10: a.
  • Aneurysm model Rabbit left common carotid artery bridging aneurysm (shown in the head of the arrow) clearly shows the aortic model of the left common carotid artery in the left common carotid artery The diameter of the tumor is obviously larger than that of the common carotid artery, which is obviously different from the contralateral normal common carotid artery; b.
  • the aneurysm is more obvious after removing the remaining blood vessels; c. and d.
  • the lateral view of the aneurysm and the gross pathology of the aneurysm taken during the operation The form is highly consistent.
  • This new type of iron oxide complex molecular injection can be used for magnetic resonance imaging of diseased blood vessels (such as aneurysms). Magnetic resonance imaging can effectively increase the contrast between diseased blood vessels and normal blood vessels.
  • Clinical diagnostic research has the potential for extremely high clinical applications.
  • Example 16 After microbes ( ⁇ 30 kg) were anesthetized with sodium pentobarbital, the polyacrylic acid-iron oxide complex molecular injection prepared in Example 16 (concentration: 135 umol/L; dose: 1 ml/kg) was intravenously administered to pigs. 3T GE Magnetic Resonance Imaging (Signa HDxt, 3T) imaging.
  • Figure 11 The results of magnetic resonance imaging are shown in Figure 11:
  • Figure a shows the imaging results of the 15-minute coronary artery (shown by the dotted line), and the coronary artery can be clearly displayed;
  • b is the imaging result of the coronary artery (shown by the dotted line) after 180 minutes, and the coronary artery information Almost disappeared;
  • c picture is the 15min coronary anterior descending artery (shown in dotted line) imaging results, the anterior descending coronary artery can be clearly displayed;
  • d picture is the 15min coronary circumflex artery (shown in dotted line) imaging results, coronary circumflex Can be clearly displayed.
  • This new type of iron oxide complex molecular injection can be used for magnetic resonance imaging of coronary arteries, which is beneficial to clinical diagnosis and has great potential for clinical application.
  • Eighteen SD male rats about 200 g, were used and divided into three groups of 6 rats each.
  • the first group normal control group: normal feeding; the second group (iron deficiency anemia control group): low-iron feeding; the third group (iron deficiency anemia treatment experimental group): low-iron feeding, blood sampling at week 4
  • the polyacrylic acid-iron oxide complex injection prepared in Example 16 was injected afterwards; the food intake of each group was approximately the same during the experiment.
  • Hgb Hemoglobin

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Abstract

一种高分子-金属氧化物复合物，其包括位于核心的金属氧化物颗粒和修饰在金属氧化物颗粒表面的高分子，该高分子具有能与金属氧化物中的金属键合的官能团，高分子与金属氧化物颗粒表面结合位点的密度高于2个位点/平方纳米。上述高分子-金属氧化物复合物的制备方法及其作为核磁共振造影剂和补铁剂的应用。所述高分子-金属氧化物复合物大幅度延长了其在体内循环的时间，有效克服了已有的造影剂导致超敏反应的缺点，加上复合物本身所具有的超顺磁性和参与铁代谢的功能，使其能够应用于磁共振成像造影剂和治疗缺铁性贫血症的补铁剂。

Description

一种高分子-金属氧化物复合物及其制备方法与应用
本申请要求申请日为2016年8月19日的中国专利申请CN201610695196.X的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及纳米技术和生物医学工程技术领域，尤其涉及一种高分子-金属氧化物复合物。
背景技术
近年来，以氧化铁为代表的超顺磁性纳米颗粒以其独特的理化特性，被广泛应用于生物医学的各个领域，如：生物磁分离、靶向给药、基因转染、免疫诊断、缺铁性贫血治疗、增强核磁共振成像等多个领域。在上述领域中，尤其以基于纳米尺寸的氧化铁颗粒在超顺磁性磁共振造影剂和缺铁性贫血治疗上得到了广泛的研究和应用。
目前，上述应用中的氧化铁纳米颗粒的分子结构主要是四氧化三铁或三氧化二铁的高分子复合物，商业的超顺磁氧化铁复合物分子造影剂主要有Combidex、Resovist和Feridex。这三类氧化铁复合物的分子结构为：中心为四氧化三铁晶体颗粒，表面采用亲水性的聚合物(如葡聚糖)上的羟基配位铁原子的方式螯合，从而使这类氧化铁复合物能够分散于水溶液中；作为缺铁性贫血补铁剂的商业化氧化铁纳米颗粒主要有Ferumoxtol，采用的是羧基化改性的葡聚糖与铁原子螯合的分子结构。由于上述氧化铁表面修饰的亲水聚合物与中心的铁原子之间的配位能力较弱且配位密度较低，在加工处理或储存过程中，特别是在高温蒸汽灭菌的过程中，容易出现表面聚合物脱落引起颗粒失去分散稳定性的问题，同时也会出现因游离铁离子的释放而引起的超敏反应现象[Juan Gallo,Nicholas J.Long,Eric O.Aboagye.Chem.Soc.Rev 42(2013)7816]。目前商业化的
Figure PCTCN2017106676-appb-000001
造影剂其主要的制备工艺为共沉淀法，中心氧化铁颗粒的粒径为5nm左右，表面使用葡聚糖包覆来降低其表面生物毒性和增加颗粒的分散稳定性，最终颗粒的粒径为60-150nm。该制备方法具有方法简单、操作简单、易大规模生产的优点。但是共沉淀方法反应速率较快，成核与结晶过程难以分离，导致颗粒单分散性差，颗粒粒径分布较广，需要进一步的分选得到符合要求的粒径。同时由于共沉淀方法的反应介质为水相，所以反应温度低于100℃，较低的反应温度使中心氧化铁晶体的结晶度较低，从而导致磁化强度较弱，实际造影效果较差。而高温热分解法由于反应温度高，可以到粒径分布较窄和结晶度更高的纳米颗粒，传统的高温热分解法得到的纳米颗粒一般为油溶性的，不利于进一步的生物应用，而使用多元醇作为稳定剂的水相纳米颗粒由于表面修饰量较少，在应用于体内造影时易出现团聚稳定性差等现象，严重影响其血液循环周期， 成像效果不理想。
美国专利US6599498B1公开了一种使用羧基葡聚糖为配位聚合物的修饰超顺磁氧化铁复合物分子结构，这类氧化铁复合物由于使用羧基葡聚糖作为表面修饰聚合物，使其与中心铁原子的配位能力增强，同时使其在应用时自由的铁离子渗出减少，缓解了临床使用时的超敏反应[V.S.Balakrishnan et al,Eur.J.Clin.Invest.39(2009)489.]。但是该分子结构仍然没有实现氧化铁表面铁原子的完全螯合，临床应用时仍然存在分散稳定性和游离铁离子渗出的超敏反应问题。
CN 103347543A公开了一种涂覆有亲水材料的氧化铁复合物的分子结构，这类复合物中心为高结晶度的氧化铁颗粒，表面采用配体交换的方式耦合羧甲基葡聚糖。但是由于该纳米颗粒为疏水性表面，不能进行生物应用，需要进行进一步的配体交换，即用亲水性的聚合物配体将纳米颗粒转为亲水性纳米颗粒。这种方法周期较长，同时由于使用配体交换的方式，表面配体与铁离子之间的螯合作用较弱，容易脱落而释放出自由的铁离子引起超敏反应。
CN101002951A公开了一种多元醇方法制备亲水氧化铁复合物分子的方法，该方法能够较为简便地制备亲水性、单分散、结晶度高的氧化铁复合物分子，但是由于表面有机物含量较少，故其生理稳定性较差，不能保证其在生物体内的血液循环特性。
因此，如何设计氧化铁复合物的分子结构，实现氧化铁纳米颗粒表面的铁原子被完全稳定地螯合，且使配合物外部具有高密度的亲水性基团，成为解决超顺磁性氧化铁复合物分子结构设计及其在体内应用的关键问题，关系到氧化铁复合物在体内作为磁共振造影剂和缺铁性补铁剂的应用效果，也关系到其应用于体内是否会释放出自由铁离子和引起超敏反应等安全问题的解决。
发明内容
有鉴于现有技术的上述缺陷，本发明提供了一种高分子-金属氧化物复合物，所述高分子-金属氧化物复合物包括位于核心的金属氧化物颗粒和修饰在所述金属氧化物颗粒表面的高分子，所述高分子具有能与所述金属氧化物中的金属键合的官能团，所述高分子与所述金属氧化物颗粒表面结合位点的密度高于2个位点/平方纳米；所述高分子-金属氧化物复合物的平均分子通式为：MnNpOmCaHbNac，其中M代表金属元素，N为N、P或S，n为500-20000，p为0-20000，a为1000-50000，c为500-20000，m＝(3/2～4/3)n+(2/3)a，b＝(4/3)a。
进一步地，所述高分子-金属氧化物复合物包含一种以上的金属元素，例如铁、钴、镍、铁钴、铁镍等。
进一步地，所述高分子选自聚丙烯酸、聚丙烯酸盐、甲基聚丙烯酸、甲基聚丙烯酸盐、聚乳酸、聚乳酸盐和聚磷酸酯中的一种或几种。
进一步地，所述高分子的重均分子量为500-500000Da。
更进一步地，所述高分子的重均分子量为500-3000Da。较低分子量的高分子-金属氧化物复合物在作为注射剂应用时，对生物体毒性较小，生物相容性较好。
进一步地，所述高分子的总质量占所述高分子-金属氧化物复合物的25％-70％。
进一步地，所述高分子的总质量占所述高分子-金属氧化物复合物的40％-70％。
进一步地，所述金属氧化物选自氧化铁，氧化锰、氧化钴、氧化铬和氧化镍中的一种或几种。
进一步地，所述金属氧化物为氧化铁。
进一步地，所述高分子-金属氧化物复合物为聚丙烯酸-氧化铁复合物，所述聚丙烯酸与所述氧化铁颗粒表面结合位点的密度高于2个位点/平方纳米；所述聚丙烯酸-氧化铁复合物的平均分子通式为：FenOmCaHbNac，其中n为500-20000，a为1000-50000，c为500-20000，m＝(3/2～4/3)n+(2/3)a，b＝(4/3)a。
进一步地，中心氧化铁颗粒在透射电镜下的粒径为1～30nm。
进一步地，表面偶联的高分子为低分子量的聚丙烯酸，聚丙烯酸的重均分子量为1000-10000，聚丙烯酸的总质量占复合物分子的25％-70％。
这类聚丙烯酸-氧化铁复合物由高结晶度的氧化铁中心和高比例的表面羧基聚合物组成，所形成的新型分子结构赋予了聚丙烯酸-氧化铁复合物具有高度的亲水性、生理盐水溶液中的高分散稳定性、与自由及表面铁离子的良好螯合性、优异的磁共振弛豫增强性能和铁代谢特性，上述特性使这类新型的聚丙烯酸-氧化铁复合物可应用于血管、肝脏、脾脏、淋巴、心脏等组织或细胞的磁共振成像造影剂以及缺铁性贫血补铁剂等领域。
本发明还提供了上述高分子-金属氧化物复合物的制备方法，所述制备方法包括以下步骤：
步骤1、将沉淀剂溶解在还原性溶剂中，配成溶液B；
步骤2、将所述高分子溶解在所述还原性溶剂中；
步骤3、称量金属盐，将所述金属盐溶解在步骤2中得到的混合溶液中，配成溶液A；
步骤4、将所述溶液A与所述溶液B在微波条件下进行反应；冷却，得到高分子-金属氧化物复合物分子胶体；
步骤5、将步骤4中得到的所述高分子-金属氧化物复合物分子胶体分离洗涤除杂(除杂主要是指除去溶剂、重金属或未反应的高分子等)，得到所述高分子-金属氧化物复合物。
进一步地，所述还原性溶剂为亲水性高沸点溶剂，所述还原性溶剂的沸点在180℃以上。
进一步地，所述还原性溶剂选自一缩二乙二醇、乙二醇、丙二醇、丙三醇、异丙二醇、二甘醇中的一种或几种。
进一步地，所述沉淀剂为氢氧化钠、醋酸钠或硼氢化钠。
进一步地，所述高分子选自聚丙烯酸、聚丙烯酸盐、甲基聚丙烯酸、甲基聚丙烯酸盐、聚乳酸、聚乳酸盐和聚磷酸酯中的一种或几种。
进一步地，所述金属盐选自三氯化铁、硫酸铁、氢氧化铁、乙酰丙酮铁、乙酰丙酮铁钴中的一种或几种。
进一步地，在所述微波条件下的反应温度为180℃-280℃。
进一步地，在所述微波条件下的反应时间为5min-30min。
进一步地，所述聚丙烯酸-氧化铁复合物的制备方法包括以下步骤：
步骤1、将沉淀剂溶解在还原性溶剂中，配成溶液B；
步骤2、将聚丙烯酸溶解在所述还原性溶剂中；
步骤3、将铁盐溶解在步骤2中得到的混合溶液中，配成溶液A；
步骤4、将所述溶液A与所述溶液B在微波条件下进行反应；冷却，得到聚丙烯酸-氧化铁复合物分子胶体；
步骤5、将步骤4中得到的所述聚丙烯酸-氧化铁复合物分子胶体分离洗涤除杂，得到聚丙烯酸-氧化铁复合物。
本发明还提供了一种核磁共振造影剂，所述核磁共振造影剂包含上述含有铁元素的高分子-金属氧化物复合物。该核磁共振造影剂可以对正常或者病变的血管、肝脏、脾脏、淋巴、心脏等脏器或组织，进行增强的T1、T2以及T2*核磁共振成像。
进一步地，所述核磁共振造影剂为注射剂或口服制剂。
本发明还提供了上述核磁共振造影剂在组织或细胞核磁显影中的应用。
进一步地，所述组织或细胞为血管、肝脏、脾脏淋巴或心脏。
本发明还提供了一种补铁剂，所述补铁剂包含上述含有铁元素的高分子-金属氧化物复合物。该补铁剂能够迅速提高血液中的血红蛋白、转铁蛋白的水平。
进一步地，所述补铁剂为注射剂或口服制剂。口服制剂包括胶囊剂、片剂等。
本发明还提供了上述补铁剂在制备治疗缺铁性贫血药物中的应用。
本发明提供的高分子-金属氧化物复合物表面含有大量聚电解质聚合物，具有良好的分散稳定性，颗粒粒径分布均一，中心金属氧化物结晶度高，造影效果良好，具有长循环的功能。同时由于采用微波的合成工艺，由于微波加热的均匀性良好，加热效率高，极大的缩短了合成的工艺，降低了制备成本。本发明针对以往氧化铁复合物存在的表面铁原子螯合密度低、结合强度弱的问题，提供了一种新型分子结构的高分子-金属氧化物尤其是聚丙烯酸-氧化铁复合物及其制备方法，并将这类复合物制备成多种剂型，应用于磁共振造影剂和治疗缺铁性贫血的补铁剂。其大幅度延长了聚丙烯酸-氧化铁复合物在体内循 环的时间，有效克服了已有的氧化铁复合物注射剂具有超敏反应的缺点，加上复合物本身所具有的超顺磁性和参与铁代谢的功能，使其能够应用于磁共振成像造影剂和治疗缺铁性贫血症的补铁剂。
以下将结合附图对本发明作进一步说明，以充分说明本发明的目的、技术特征和技术效果。
附图说明
根据结合所附附图给出的优选实施方案的描述，本发明的以上和其他目的、特点和优势将变得显而易见，其中：
图1示出了本发明较优实施例中的四种聚丙烯酸-氧化铁复合物分子的热重分析曲线图；图1a至图1d分别示出了实施例1-4中的聚丙烯酸-氧化铁复合物分子的热重分析曲线图；
图2示出了本发明较优实施例中的四种聚丙烯酸-氧化铁复合物分子的透射电镜(TEM)照片粒径分布图；图2a至图2d分别示出了实施例1-4中的聚丙烯酸-氧化铁复合物分子的透射电镜(TEM)照片粒径分布图；
图3示出了本发明较优实施例中的四种聚丙烯酸-氧化铁复合物分子的饱和磁化强度曲线；图3a示出了实施例1-4中的四种聚丙烯酸-氧化铁复合物分子的饱和磁化强度曲线，图3b示出了零附近的曲线放大图；
图4示出了本发明较优实施例中的四种聚丙烯酸-氧化铁复合物分子的弛豫时间曲线；图4a、图4b示出了实施例1-4中的聚丙烯酸-氧化铁复合物分子的弛豫时间曲线；
图5示出了本发明较优实施例中的四种聚丙烯酸-氧化铁复合物分子注射剂灭菌稳定性曲线；
图6示出了本发明较优实施例中的四种聚丙烯酸-氧化铁复合物分子注射剂稳定性曲线；
图7示出了本发明较优实施例中的不同浓度聚丙烯酸-氧化铁复合物分子注射剂的正常肝脏磁共振造成像图；
图8示出了本发明较优实施例中的聚丙烯酸-氧化铁复合物分子注射剂与商用钆造影剂在正常血管中磁共振对比成像图；
图9示出了本发明较优实施例中的聚丙烯酸-氧化铁复合物分子注射剂的病变肝脏组织(肝癌)的磁共振造成像图；
图10示出了本发明较优实施例中的聚丙烯酸-氧化铁复合物分子注射剂的病变血管(动脉瘤)的磁共振造成像图；图10a动脉瘤模型兔左侧颈总动脉桥接血管瘤(箭头头部所示)清晰显示，动脉瘤模型兔左侧颈总动脉中段血管瘤正面观，血管瘤管径明显较颈总动脉粗大，明显区别于对侧正常颈总动脉；图10b去除其余血管后，动脉瘤更加明显； 图10c和图10d动脉瘤侧面观与手术中所拍摄动脉瘤大体病理形态高度一致；
图11示出了本发明较优实施例中的聚丙烯酸-氧化铁复合物分子注射剂的冠状动脉的磁共振造成像图；图11a所示为15min冠状动脉(虚线所示)成像结果，冠状动脉能够明显显示；图11b为180min后冠状动脉(虚线所示)成像结果，冠状动脉信息已几乎消失；图11c为15min冠状动脉前降支(虚线所示)成像结果，冠状动脉前降支能够明显显示；图11d为15min冠状动脉回旋支(虚线所示)成像结果，冠状动脉回旋支能够明显显示；
图12示出了本发明较优实施例中的聚丙烯酸-氧化铁复合物分子可能的结构示意图。
具体实施方式
为更好地说明本发明，便于理解本发明的技术方案，本发明的典型但非限制性的实施例如下：
实施例1
合成步骤：
首先，用量筒量取一缩二乙二醇20ml，再用精密天平称量2g氢氧化钠，通过超声、加热、搅拌使其溶解在一缩二乙二醇中，配成溶液B，溶液B放入70℃烘箱中恒温；其次，称取重均分子量为1000Da的聚丙烯酸6g于烧杯中，再称量500ml一缩二乙二醇于烧杯中，搅拌、超声使二者溶解；快速称量无水三氯化铁2g，通过加热、超声、搅拌使其溶解在一缩二乙二醇和聚丙烯酸的混合液中，配成溶液A(溶液呈棕色)；最后，溶液A置于三口烧瓶中在微波反应器中200℃恒温20min，然后快速加入热的溶液B，反应瞬间进行，恒温30min。之后进行冷却，得到聚丙烯酸-氧化铁复合物分子胶体，之后用乙酸乙酯沉淀，沉淀复合物洗涤三次得到聚丙烯酸-四氧化三铁复合物分子。
实施例2
合成步骤：
首先，用量筒量取乙二醇100ml，再用精密天平称量8g醋酸钠，通过超声、加热、搅拌使其溶解在乙二醇中，配成溶液B，溶液B放入70℃烘箱中恒温；其次，称取重均分子量为5000Da的聚丙烯酸12g于烧杯中，再称量360ml乙二醇于烧杯中，搅拌、超声使二者溶解；快速称量硫酸铁8g，通过加热、超声、搅拌使其溶解在乙二醇和聚丙烯酸的混合液中，配成溶液A(溶液呈棕色)；最后，溶液A置于三口烧瓶中在微波反应器中220℃恒温10min，然后快速加入热的溶液B，反应瞬间进行，恒温10min。之后进行冷却，得到聚丙烯酸-氧化铁复合物分子胶体，之后加入4L的超纯水进行超滤洗涤，复合物喷雾干燥后得到聚丙烯酸-四氧化三铁复合物分子。
实施例3
合成步骤：
首先，用量筒量取丙二醇100ml，再用精密天平称量15g硼氢化钠，通过超声、加热、搅拌使其溶解在丙二醇中，配成溶液B，溶液B放入70℃烘箱中恒温；其次，称取重均分子量为3000Da的聚丙烯酸30g于烧杯中，再称量1000ml丙二醇于烧杯中，搅拌、超声使二者溶解；快速称量氢氧化铁30g，通过加热、超声、搅拌使其溶解在丙二醇和聚丙烯酸的混合液中，配成溶液A(溶液呈棕色)；最后，溶液A置于三口烧瓶中在微波反应器中240℃恒温20min，然后快速加入热的溶液B，反应瞬间进行，恒温30min。之后进行冷却，得到聚丙烯酸-氧化铁复合物分子胶体，之后用乙酸乙酯和乙醇进行沉淀，沉淀复合物洗涤三次，最后分散在水中进行冷冻干燥得到聚丙烯酸-四氧化三铁复合物分子。
实施例4
合成步骤：
首先，用量筒量取一缩二乙二醇80ml，再用精密天平称量8g氢氧化钠，通过超声、加热、搅拌使其溶解在一缩二乙二醇中，配成溶液B，溶液B放入72℃烘箱中恒温；其次，称取重均分子量为10000Da的聚丙烯酸13.8g于烧杯中，再称量360ml一缩二乙二醇于烧杯中，搅拌、超声使二者溶解；快速称量无水三氯化铁8g，通过加热、超声、搅拌使其溶解在一缩二乙二醇和聚丙烯酸的混合液中，配成溶液A(溶液呈棕色)；最后，溶液A置于三口烧瓶中在微波反应器中220℃恒温5min，然后快速加入热的溶液B，反应瞬间进行，恒温10min。之后进行冷却，得到聚丙烯酸-氧化铁复合物分子胶体，之后用乙酸乙酯沉淀，沉淀复合物洗涤三次得到聚丙烯酸-四氧化三铁复合物分子。
实施例5
合成步骤：
首先，用量筒量取乙二醇20ml，再用精密天平称量2g氢氧化钠，通过超声、加热、搅拌使其溶解在乙二醇中，配成溶液B，溶液B放入70℃烘箱中恒温；其次，称取重均分子量为500Da的聚丙烯酸钠4g于烧杯中，再称量500ml乙二醇于烧杯中，搅拌、超声使二者溶解；快速称量无水三氯化铁2g，通过加热、超声、搅拌使其溶解在乙二醇和聚丙烯酸钠的混合液中，配成溶液A(溶液呈棕色)；最后，溶液A置于三口烧瓶中在微波反应器中200℃恒温20min，然后快速加入热的溶液B，反应瞬间进行，恒温30min。之后进行冷却，得到聚丙烯酸钠-氧化铁复合物分子胶体，之后用乙酸乙酯沉淀，沉淀复合物洗涤三次得到黑色聚丙烯酸钠-四氧化三铁复合物溶液。将所得到的聚丙烯酸钠-四氧化三铁复合物溶液加热至80℃，向体系内通入空气，反应4小时，得到红棕色聚丙烯酸钠-三氧化二铁复合物溶液，以使复合物更加稳定。
实施例6
合成步骤：
首先，用量筒量取丙二醇20ml，再用精密天平称量2g氢氧化钠，通过超声、加热、 搅拌使其溶解在丙二醇中，配成溶液B，溶液B放入70℃烘箱中恒温；其次，称取重均分子量为500000Da的聚丙烯酸钠5.6g于烧杯中，再称量500ml丙二醇于烧杯中，搅拌、超声使二者溶解；快速称量无水三氯化铁2g，通过加热、超声、搅拌使其溶解在丙二醇和聚丙烯酸钠的混合液中，配成溶液A(溶液呈棕色)；最后，溶液A置于三口烧瓶中在微波反应器中200℃恒温20min，然后快速加入热的溶液B，反应瞬间进行，恒温30min。之后进行冷却，得到聚丙烯酸钠-氧化铁复合物分子胶体，之后用乙酸乙酯沉淀，沉淀复合物洗涤三次得到黑色聚丙烯酸钠-四氧化三铁复合物溶液。将所得到的聚丙烯酸钠-四氧化三铁复合物溶液加热至80℃，向体系内通入空气，反应4小时，得到红棕色聚丙烯酸钠-三氧化二铁复合物溶液，以使复合物更加稳定。
实施例7
合成步骤：
首先，用量筒量取丙三醇30ml，再用精密天平称量3g氢氧化钠，通过超声、加热、搅拌使其溶解在丙三醇中，配成溶液B，溶液B放入50℃烘箱中恒温；其次，称取重均分子量为1200Da的聚丙烯酸钠溶液(45％)6g于烧杯中，再称量300ml丙三醇于烧杯中，搅拌、超声使二者溶解；快速称量乙酰丙酮铁2g和乙酰丙酮铁锰1g，通过加热、超声、搅拌使其溶解在丙三醇和聚丙烯酸钠的混合液中，配成溶液A(溶液呈棕色)；最后，溶液A置于三口烧瓶中在微波反应器中220℃恒温20min，然后快速加入热的溶液B，反应瞬间进行，恒温30min。之后进行冷却，得到聚丙烯酸钠-氧化铁锰复合物分子胶体，之后用乙酸乙酯沉淀，沉淀复合物洗涤三次得到黑色聚丙烯酸钠-氧化铁锰复合物溶液。
实施例8
合成步骤：
首先，用量筒量取异丙二醇30ml，再用精密天平称量4g氢氧化钠，通过超声、加热、搅拌使其溶解在异丙二醇中，配成溶液B，溶液B放入50℃烘箱中恒温；其次，称取重均分子量为200000Da的甲基聚丙烯酸钠溶液(40％)4g于烧杯中，再称量300ml异丙二醇于烧杯中，搅拌、超声使二者溶解；快速称量乙酰丙酮铁1.5g和乙酰丙酮铁钴1g，通过加热、超声、搅拌使其溶解在异丙二醇和甲基聚丙烯酸钠的混合液中，配成溶液A(溶液呈棕色)；最后，溶液A置于三口烧瓶中在微波反应器中220℃恒温10min，然后快速加入热的溶液B，反应瞬间进行，恒温30min。之后进行冷却，得到甲基聚丙烯酸钠-氧化铁钴复合物分子胶体，之后用乙酸乙酯沉淀，沉淀复合物洗涤三次得到黑色甲基聚丙烯酸钠-氧化铁钴复合物溶液。
实施例9
合成步骤：
首先，用量筒量取二甘醇30ml，再用精密天平称量4g氢氧化钠，通过超声、加热、搅拌使其溶解在二甘醇中，配成溶液B，溶液B放入50℃烘箱中恒温；其次，称取重均 分子量为10000Da的聚乳酸5.6g于烧杯中，再称量300ml二甘醇于烧杯中，搅拌、超声使二者溶解；快速称量无水三氯化铁2g，通过加热、超声、搅拌使其溶解在二甘醇和聚乳酸的混合液中，配成溶液A(溶液呈棕色)；最后，溶液A置于三口烧瓶中在微波反应器中200℃恒温20min，然后快速加入热的溶液B，反应瞬间进行，恒温30min。之后进行冷却，得到聚乳酸-氧化铁复合物分子胶体，之后用乙酸乙酯沉淀，沉淀复合物洗涤三次得到黑色聚乳酸-四氧化三铁复合物溶液。将所得到的聚乳酸-四氧化三铁复合物溶液加热至80℃，向体系内通入空气，反应4小时，得到红棕色聚乳酸-三氧化二铁复合物溶液，以使复合物更加稳定。
实施例10
合成步骤：
首先，用量筒量取二甘醇30ml，再用精密天平称量4g氢氧化钠，通过超声、加热、搅拌使其溶解在二甘醇中，配成溶液B，溶液B放入50℃烘箱中恒温；其次，称取重均分子量为30000Da的聚磷酸酯4.2g于烧杯中，再称量300ml二甘醇于烧杯中，搅拌、超声使二者溶解；快速称量无水三氯化铁2g，通过加热、超声、搅拌使其溶解在二甘醇和聚磷酸酯的混合液中，配成溶液A(溶液呈棕色)；最后，溶液A置于三口烧瓶中在微波反应器中200℃恒温20min，然后快速加入热的溶液B，反应瞬间进行，恒温30min。之后进行冷却，得到聚磷酸酯-氧化铁复合物分子胶体，之后用乙酸乙酯沉淀，沉淀复合物洗涤三次得到黑色聚磷酸酯-四氧化三铁复合物溶液。将所得到的聚磷酸酯-四氧化三铁复合物溶液加热至80℃，向体系内通入空气，反应4小时，得到红棕色聚磷酸酯-三氧化二铁复合物溶液，以使复合物更加稳定。
实施例11
高分子-金属氧化物复合物的分子结构
对实施例3中的聚丙烯酸-氧化铁复合物分子进行分析：
a.颗粒中聚丙烯酸的含量为：58.261/36.172＝1.611(w/w)，即1g Fe3O4含有的1.611g的聚丙烯酸；
b.一个直径为4.5nm的Fe3O4纳米颗粒的质量：3.14x4.53/6x5.2x10-21＝2.48x10-19g，含有的Fe3O4分子个数为2.48x10-19/232x6.02x1023＝644；
c.1g Fe3O4含有4.5nm颗粒量为：1/(2.48x10-19)/(6.02x1023)＝6.70x10-6mol；
d.颗粒修饰的聚丙烯酸中羧基含量为1.611/72x1000＝22.37(mmol)，即1g Fe3O4含有22.37mmol羧基；
e.每个颗粒修饰的聚丙烯酸中羧基含量为1.611/72/(6.7x10-6)＝3339.60,即一个颗粒表面修饰的聚丙烯酸中含有3339.60个羧基；
f.一个重均分子量为5000Da的聚丙烯酸链含有羧基量为：5000/72＝69.44；
g.一个颗粒表面含有聚丙烯酸链数目为：3339.60/69.44＝48；
h.一根聚丙烯酸链在4.5nm颗粒表面占有的面积为：3.14x4.52/48.09＝1.322nm2；
i.通过电导滴定聚丙烯酸-氧化铁复合物分子中游离的羧基含量为18.681mmol每g Fe3O4，即每1.322nm2上需要螯合11个羧基，故羧基的螯合密度为8个/nm2。
j.通过电导滴定氧化铁复合物分子中游离的羧基含量为18.681mmol每g Fe3O4，一个颗粒表面修饰的聚丙烯酸中含有3339.60个羧基，其中游离羧基为2784个，约80％以上被钠饱和，故Na的分子个数为2227个至2784个。
实施例12
高分子-金属氧化物复合物分子式的计算：
取1-2mL实施例1-4中所得的聚丙烯酸-氧化铁复合物分子溶液进行冷冻干燥，取3-5mg左右的冻干粉样置于加盖的坩埚中，在空气氛围下，以10℃/min的升温速率为加热到1000℃，测试仪器为NETZSCH公司的TG209。测试结束后，以温度为横坐标，热失重含量％为纵坐标，且每个样品测试三次，得出热失重曲线见如图1。
将实施例1-4中所得的聚丙烯酸-氧化铁复合物分子溶液滴加在碳支持膜的铜网上，待其自然风干后，在透射电子显微镜(TEM)下观察复合物的形貌及大小，四批样品的TEM原图如图2左图所示，将图中的复合物分子粒径测量统计后得到粒径分布图如图2右图所示。其中图2中可以看出，复合物分子结晶度较好，为单晶纳米颗粒分子，量出晶面间距为0.251nm，对应为四氧化三铁(311)的晶面。从统计的粒径图上看，说明这类纳米复合物分子粒径分布均一，结晶度高，颗粒间没有发生团聚。
计算复合物的分子式为：
从图2中可以得知实施例1中氧化铁颗粒晶粒直径大小为d＝8.3nm，一个直径为8.3nm的复合物质量
Figure PCTCN2017106676-appb-000002
含有的Fe3O4分子个数为1.56×10-18×6.02×1023÷232＝4048。
从图1中可以得知实施例1中聚丙烯酸-氧化铁复合物分子中表面聚丙烯酸的百分比为27.5％，一个聚丙烯酸-氧化铁复合物中丙烯酸的质量为：5.92×10-19g，含有的丙烯酸(C3H4O2)分子个数为:5.92×10-19×6.02×1023÷72＝4950。
所以，实施例1中的聚丙烯酸-氧化铁复合物的平均分子式为Fe12144O26092C14850H19800；
同理计算实施例2中的聚丙烯酸-氧化铁复合物的平均分子式为Fe6960O39632C45528H60704；
实施例3中的聚丙烯酸-氧化铁复合物的平均分子式为Fe3339O19016C21846H29128；
实施例4中的聚丙烯酸-氧化铁复合物的平均分子式为Fe2064O10702C11925H15900。
图12示出了聚丙烯酸-氧化铁复合物分子一种可能的结构示意图。中心为氧化铁纳米颗粒的晶粒，表面为高密度的聚丙烯酸高分子链，分子链上的部分羧基与氧化铁纳米颗粒中铁原子以化学配位键的形式键合，剩余的未被螯合的羧基链段则伸展分布在颗粒 的外表面。该复合物分子结构的主要特征在于，氧化铁表面的铁原子被羧基螯合的密度达到2个/平方纳米以上，这种致密的螯合使得氧化铁表面具有超高的聚丙烯酸修饰量，减少了未被螯合而暴露于介质中的表面铁原子的存在，同时也使得该复合物结合的稳定性大大提高，有助于防止螯合的聚丙烯酸从氧化铁表面脱落；超高的聚丙烯酸修饰量还使得该复合物外表面具有高密度伸展的羧基链，赋予了该复合物具有优异的亲水性和在水溶液中很高的负电位，大大提高了颗粒的分散稳定性。该复合物中心氧化铁纳米颗粒在透射电镜下的粒径为1～10nm，表面偶联的高分子聚丙烯酸的质量占复合物分子总质量的25％-70％。
实施例13
高分子-金属氧化物复合物的表面电位和分散稳定性
以聚丙烯酸-氧化铁复合物为例，由于聚丙烯酸-氧化铁复合物表面有大量的游离羧基，通过表面Zeta电位测试，实施例1-4的聚丙烯酸-氧化铁复合物分子在水溶液中的表面电位分别为：-41.3mV、-42.8mV、-45.1mV和-40.9mV，说明复合物分子带有大量负电荷，这些过剩的负电荷使颗粒能够稳定的分散在水溶液。随后，将实施例1-4的聚丙烯酸-氧化铁复合物分散在生理盐水，如图所示，肉眼观察聚丙烯酸-氧化铁复合物分子可以稳定的分散在生理盐水中，溶液颜色均一并且无沉降现象，说明复合物分子表面的负电荷能够使分子在生理盐水中也保持良好的分散性。
实施例14
聚丙烯酸-氧化铁复合物分子的饱和磁化强度：
取5mL左右实施例1-4中所得的聚丙烯酸-氧化铁复合物分子溶液进行冷冻干燥，测试前先要称量约10-15mg的固体粉末，将样品包在称量纸内包成扁平长方形使用振动样品磁强计在室温下进行测试，结果如图3所示，其中插入的小图是零附近的曲线放大图。实施例1-4所得的聚丙烯酸-氧化铁复合物分子的饱和磁化强度分别为：62.6、69.4、49.6、49.1emu/g。通过插入小图可以看出，磁化曲线过原点，即没有剩磁，证明了这类新型的聚丙烯酸-氧化铁复合物分子具有超顺磁性。
实施例15
聚丙烯酸-氧化铁复合物分子的弛豫性能：
取实施例1-4所得的聚丙烯酸-氧化铁复合物分子进行Fe含量测试，随后将样品稀释至4、5、6、7、8×10-4mol/L，取200uL稀释样品加入到测弛豫的管子中，分别编号4，5，6，7，8。将管子放入37℃恒温水浴恒温。打开测试软件，首先进行校正并测试样品的弛豫时间。实施例1-4中聚丙烯酸-氧化铁复合物分子的弛豫时间如图4所示，r1弛豫率为5.61-17.5，r2弛豫率为20.3-72.7，其中r2/r1的值均为3.2-4.2之间。
实施例16
将实施例1-4中任一实施例所制备的聚丙烯酸-氧化铁复合物分子溶液，通过冷冻干 燥或者喷雾干燥得到聚丙烯酸-氧化铁复合物分子，通过原子吸收光谱仪测定其中铁元素的含量。根据上述测量所得的铁元素含量，按照铁元素的最终浓度(umol Fe/L)，加入相应体积的水或者生理盐水。铁元素的最终浓度为5-1000umol Fe/L，优选地，为50-200umol Fe/L。对上述已经按照铁元素的最终浓度要求配置的聚丙烯酸-氧化铁复合物分子溶液进行超声分散，即制备出稳定的聚丙烯酸-氧化铁复合物分子注射剂。并对已配置好的聚丙烯酸-氧化铁复合物注射剂进行121℃，30分钟的高压蒸汽灭菌，冷却后观察注射液的稳定性，注射液没有明显的沉降现象，溶液颜色无明显变化。取样品通过动态光散射仪(DLS)测试灭菌之后的注射剂复合物分子的水力学制剂，如图5所示，灭菌前后聚丙烯酸-氧化铁复合物的粒径和粒径分布均没有明显的变化。说明所配制的聚丙烯酸-氧化铁复合物注射剂能够经过高温灭菌，有效地提高了注射剂的安全性。
实施例17
将实施例1-4中任一实施例所制备的聚丙烯酸-氧化铁复合物分子溶液，通过冷冻干燥或者喷雾干燥得到聚丙烯酸-氧化铁复合物分子，通过原子吸收光谱仪测定其中铁元素的含量。根据上述测量所得的铁元素含量，按照铁元素的最终浓度(umol Fe/L)，加入药用辅料乳糖(10％-30％)、淀粉(5％-25％)、乙基纤维素(10％-25％，无水乙醇溶解)，和无水乙醇制成适宜的湿颗粒，过80目不锈钢筛网，室温下干燥后，过20目不锈钢筛网整粒，加入滑石粉(1％-10％)、硬脂铝酸(0.2％-5％)，混合均匀，平冲压片。片剂中铁元素的最终浓度为5-1000umol Fe/kg，优选地，为50-200umol Fe/kg。
实施例18
将实施例1-4中任一实施例所制备的聚丙烯酸-氧化铁复合物分子溶液，通过冷冻干燥或者喷雾干燥得到聚丙烯酸-氧化铁复合物分子，通过原子吸收光谱仪测定其中铁元素的含量。根据上述测量所得的铁元素含量，按照铁元素的最终浓度(umol Fe/L)，加入药用辅料乳糖(10％-30％)、淀粉(5％-25％)、滑石粉(1％-10％)，聚山梨醇酯80(0.1％-10％)过80目不锈钢筛网，制成混合细粉后，加入1号空胶囊中，将囊身节口处插入药粉反复数次至填满，称重至规定重量，在囊帽口上蘸上40％乙醇套上囊身，擦拭打光得到胶囊。胶囊中铁元素的最终浓度为5-1000umol Fe/kg，优选地，胶囊中铁元素的最终浓度为50-200umol Fe/kg。
实施例19
注射剂的稳定性
将实施例16中制得的聚丙烯酸-氧化铁复合物分子注射剂放置三天至一年，观察其稳定性，注射剂溶液颜色无明显变化，溶液均一没有沉淀。取样品通过动态光散射仪(DLS)测试注射剂复合物分子的水力学直径，如图6所示，无明显变化。这说明聚丙烯酸-氧化铁复合物分子注射剂由于其表面具有高比例的聚丙烯酸修饰，高比例的聚丙烯酸由于其强烈的静电排斥作用力，使聚丙烯酸-氧化铁复合物分子的稳定性优良，适合作为静脉注 射剂使用。
实施例20
聚丙烯酸-氧化铁复合物分子的自由铁离子释放
由于自由铁离子为引起超敏反应的主要成份，取实施例16所得的聚丙烯酸-氧化铁复合物分子注射剂，使用3KDa超滤离心管过滤下清，通过原子吸收测定下清中自由铁离子的浓度。同样向注射剂中添加一定量的自由铁离子，半小时后，通过原子吸收测定下清中自由铁离子的浓度，测试结果如表1所示。结果显示，注射剂即使在120天的时间内没有自由铁离子释放。在添加了自由铁离子之后，注射剂同时能够大幅降低自由铁离子的浓度，有效减少在体内成像时引起的超敏反应。说明这类新型氧化铁复合物分子制备的注射剂，能够有效的降低自由铁离子的释放，减少超敏反应，适合临床作为造影剂和补铁剂使用。
表1
  时间 加入自由铁离子量 下清自由铁离子含量
1 120天 —— 0.24ug/mL
2 2小时 —— 0.30ug/mL
3 2小时 300ug/mL 8.61ug/mL
4 2小时 水 0.09ug/mL
实施例21
不同浓度的聚丙烯酸-氧化铁复合物分子注射剂的正常肝脏成像
将实施例16中制得的聚丙烯酸-氧化铁复合物分子注射剂配置为浓度成40、85、135umol Fe/L的造影剂，按照剂量1ml/kg经耳缘静脉注入模型兔体内，分别在注射前、注射后0min、3min、5min、10min、20min、30min对模型兔肝脏进行T1加权成像。磁共振成像结果如图7所示：不同注射浓度模型兔肝脏信号均降低；40umol/L注射浓度模型兔肝脏内细小肝脏静脉分支显示清晰(箭头头部所示)；85umol/L注射浓度模型兔肝脏内肝脏静脉主干(箭头所示)显示清晰，细小分支稍模糊；135umol/L注射浓度模型兔肝脏内肝内静脉主干及细小分支均显示，但显示效果分别稍逊于85umol/L及40umol/L注射浓度模型兔。说明这类新型氧化铁复合物分子注射剂能够用于正常肝脏组织的磁共振成像。
实施例22
正常血管的磁共振成像
我们选用雄性新西兰白兔作为试验对象进行。所有模型兔均于耳缘静脉注射2.5％戊巴比妥钠(剂量)全麻后，俯卧位固定于动物扫描平板，对腹部加压，以减少呼吸伪影。2S内手动经耳缘静脉推注造影剂后完成扫描，磁共振成像结果如图8所示：
对比剂：
使用商用的钆造影剂作为对比：
Figure PCTCN2017106676-appb-000003
(Gd-DTPA)，Bayer HealthCare  Pharmaceuticals，包装规格：469.01mg/ml×15ml。
分别注射通过实施例16制备的稳定的聚丙烯酸-氧化铁复合物分子注射剂(浓度：135umol/L；剂量：1ml/kg)及Gd-DTPA后30s，铁造影剂及Gd-DTPA均使主动脉(箭头所示)显示；铁造影剂使门静脉(曲线箭头所示)于30s后均显示清晰，而Gd-DTPA于3min时显示门静脉最佳，而后信号强度及范围逐渐缩小，且各时间点对门静脉的显示效果均明显差于铁造影剂的造影效果。Gd-DTPA 3min后对主动脉及腔静脉均不理想，血管信号降低、轮廓模糊；而Fe造影剂对主动脉、腔静脉及门静脉清晰显示至少持续30min，且各时间点效果相似，随时间延长较细小的脊髓动静脉(厚箭头所示)显示范围略有增多，而Gd-DTPA仅在30s时可显示少量的脊髓动脉。说明铁造影剂能够获得对比度更高的血管影像，并且具有明显的长循环特点，在30min后仍然由清晰的血管成像效果。克服了商用钆造影剂显像时间短，信号不清晰且轮廓模糊的特点。说明这类新型氧化铁复合物分子造影剂由于其表面偶联高密度的聚丙烯酸，使其能够应用于体内长时间的血管成像，且效果远优于现有的商用钆造影剂。
实施例23
肝癌模型成像的磁共振成像
对肿瘤模型兔肝脏注入实施例16制备的稳定的聚丙烯酸-氧化铁复合物分子注射剂前、后(浓度：135umol/L；剂量：1ml/kg)，分别进行T1加权成像(T1WI)及T2加权成像(T2WI)。磁共振成像结果如图9所示：T1WI及T2WI对肿瘤(箭头头部所示)的显示效果均优于注射前，肝脏信号均较注射前明显降低，病灶凸显。T1WI上由于注射对比剂前病灶呈低信号，注射对比剂后信号明显降低的正常肝组织衬托出相对呈高信号的肿瘤病灶，使得对比更加强烈。对比肿瘤肝脏的大体病理，肿瘤形态于增强扫描显示肿瘤病灶形态高度一致。说明这类新型氧化铁复合物分子注射剂能够用于病变的肝脏组织(如肝癌)的磁共振成像，且T1加权成像(T1WI)及T2加权成像(T2WI)均能有效地增加病变肝脏组织和正常肝脏组织之间的影响对比度，有利于临床的诊断研究，具有极高的临床应用的潜力。
实施例24
血管动脉瘤模型的磁共振成像
对血管动脉瘤模型兔肝脏注入实施例16制备的稳定的聚丙烯酸-氧化铁复合物分子注射剂前、后(浓度：135umol/L；剂量：1ml/kg)。磁共振成像结果如图10所示：a.动脉瘤模型兔左侧颈总动脉桥接血管瘤(箭头头部所示)清晰显示，动脉瘤模型兔左侧颈总动脉中段血管瘤正面观，血管瘤管径明显较颈总动脉粗大，明显区别于对侧正常颈总动脉；b.去除其余血管后，动脉瘤更加明显；c.和d.动脉瘤侧面观与手术中所拍摄动脉瘤大体病理形态高度一致。说明这类新型氧化铁复合物分子注射剂能够用于病变的血管(如动脉瘤)的磁共振成像，磁共振成像能有效地增加病变血管和正常血管之间的影响对比度，有利 于临床的诊断研究，具有极高的临床应用的潜力。
实施例25
小型猪冠脉的磁共振成像
对小型猪(～30kg)使用戊巴比妥钠麻醉后，向猪体内静脉注射实施例16制备的聚丙烯酸-氧化铁复合物分子注射剂(浓度：135umol/L；剂量：1ml/kg)，使用3T GE磁共振成像仪(Signa HDxt，3T)成像。磁共振成像结果如图11所示：a图所示为15min冠状动脉(虚线所示)成像结果，冠状动脉能够明显显示；b图为180min后冠状动脉(虚线所示)成像结果，冠状动脉信息已几乎消失；c图为15min冠状动脉前降支(虚线所示)成像结果，冠状动脉前降支能够明显显示；d图为15min冠状动脉回旋支(虚线所示)成像结果，冠状动脉回旋支能够明显显示。说明这类新型氧化铁复合物分子注射剂能够用于冠状动脉的磁共振成像，有利于临床的诊断研究，具有极高的临床应用的潜力。
实施例26
聚丙烯酸-氧化铁复合物注射剂的补铁实验
选用18只SD雄性大鼠，约200g，分为三组，每组6只。第一组(正常对照组)：正常喂食；第二组(缺铁性贫血对照组)：低铁喂食；第三组(缺铁性贫血治疗实验组)：低铁喂食，第4周取血后注射实施例16制备的聚丙烯酸-氧化铁复合物注射剂；实验期间各组的进食量大致保持一致。观察指标：分别于实验开始时，第二周，第四周，第五周尾尖取血，测定血常规，统计Hgb(血红蛋白)、Hct(血细胞比容)、RBC(红血球)，T检验统计组间差异，结果如表2所示。实验结果表明缺铁饲料喂养大鼠4周后，成功的建立了缺铁性贫血模型(与空白组相比P<0.01)。静脉一次性注射补铁剂，在给药一周后即可观察到贫血症状的改善(与空白组相比P<0.05)，该制剂具有补铁效果。
表2
血红蛋白(Hgb)测定结果
Figure PCTCN2017106676-appb-000004
Figure PCTCN2017106676-appb-000005
注：*：P<0.05，**：P<0.01
血细胞比容(Hct)测定结果
Figure PCTCN2017106676-appb-000006
Figure PCTCN2017106676-appb-000007
注：*：P<0.05，**：P<0.01
红血球(RBC)测定结果
Figure PCTCN2017106676-appb-000008
Figure PCTCN2017106676-appb-000009
注：*：P<0.05，**：P<0.01
以上详细描述了本发明的较佳具体实施例。应当理解，本领域的普通技术无需创造性劳动就可以根据本发明的构思作出诸多修改和变化。因此，凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验可以得到的技术方案，皆应在由权利要求书所确定的保护范围内。

Claims (26)

  1. 一种高分子-金属氧化物复合物，其特征在于，所述高分子-金属氧化物复合物包括位于核心的金属氧化物颗粒和修饰在所述金属氧化物颗粒表面的高分子，所述高分子具有能与所述金属氧化物中的金属键合的官能团，所述高分子与所述金属氧化物颗粒表面结合位点的密度高于2个位点/平方纳米；所述高分子-金属氧化物复合物的平均分子通式为：MnNpOmCaHbNac，其中M代表金属元素，N为N、P或S，n为500-20000，p为0-20000，a为1000-50000，c为500-20000，m＝(3/2～4/3)n+(2/3)a，b＝(4/3)a。
  2. 根据权利要求1所述的高分子-金属氧化物复合物，其特征在于，所述高分子-金属氧化物复合物包含一种以上的金属元素。
  3. 根据权利要求1所述的高分子-金属氧化物复合物，其特征在于，所述高分子选自聚丙烯酸、聚丙烯酸盐、甲基聚丙烯酸、甲基聚丙烯酸盐、聚乳酸、聚乳酸盐和聚磷酸酯中的一种或几种。
  4. 根据权利要求1所述的高分子-金属氧化物复合物，其特征在于，所述高分子的重均分子量为500-500000Da。
  5. 根据权利要求4所述的高分子-金属氧化物复合物，其特征在于，所述高分子的重均分子量为500-3000Da。
  6. 根据权利要求1所述的高分子-金属氧化物复合物，其特征在于，所述高分子的总质量占所述高分子-金属氧化物复合物的25％-70％。
  7. 根据权利要求1所述的高分子-金属氧化物复合物，其特征在于，所述高分子的总质量占所述高分子-金属氧化物复合物的40％-70％。
  8. 根据权利要求1所述的高分子-金属氧化物复合物，其特征在于，所述金属氧化物选自氧化铁，氧化锰、氧化钴、氧化铬和氧化镍中的一种或几种。
  9. 根据权利要求1-8中任一项所述的高分子-金属氧化物复合物，其特征在于，所述金属氧化物为氧化铁。
  10. 根据权利要求1-8中任一项所述的高分子-金属氧化物复合物，其特征在于，所述高分子-金属氧化物复合物为聚丙烯酸-氧化铁复合物，所述聚丙烯酸与所述氧化铁颗粒表面结合位点的密度高于2个位点/平方纳米；所述聚丙烯酸-氧化铁复合物的平均分子通式为：FenOmCaHbNac，其中n为500-20000，a为1000-50000，c为500-20000，m＝(3/2～4/3)n+(2/3)a，b＝(4/3)a。
  11. 根据权利要求1-8中任一项所述的高分子-金属氧化物复合物的制备方法，其特征在于，所述制备方法包括以下步骤：
    步骤1、将沉淀剂溶解在还原性溶剂中，配成溶液B；
    步骤2、将所述高分子溶解在所述还原性溶剂中；
    步骤3、称量金属盐，将所述金属盐溶解在步骤2中得到的混合溶液中，配成溶液 A；
    步骤4、将所述溶液A与所述溶液B在微波条件下进行反应；冷却，得到高分子-金属氧化物复合物分子胶体；
    步骤5、将步骤4中得到的所述高分子-金属氧化物复合物分子胶体分离洗涤除杂，得到所述高分子-金属氧化物复合物。
  12. 根据权利要求11所述的高分子-金属氧化物复合物的制备方法，其特征在于，所述还原性溶剂为亲水性高沸点溶剂，所述还原性溶剂的沸点在180℃以上。
  13. 根据权利要求11或12所述的高分子-金属氧化物复合物的制备方法，其特征在于，所述还原性溶剂选自一缩二乙二醇、乙二醇、丙二醇、丙三醇、异丙二醇、二甘醇中的一种或几种。
  14. 根据权利要求11所述的高分子-金属氧化物复合物的制备方法，其特征在于，所述沉淀剂为氢氧化钠、醋酸钠或硼氢化钠。
  15. 根据权利要求11所述的高分子-金属氧化物复合物的制备方法，其特征在于，所述高分子选自聚丙烯酸、聚丙烯酸盐、甲基聚丙烯酸、甲基聚丙烯酸盐、聚乳酸、聚乳酸盐和聚磷酸酯中的一种或几种。
  16. 根据权利要求11所述的高分子-金属氧化物复合物的制备方法，其特征在于，所述金属盐选自三氯化铁、硫酸铁、氢氧化铁、乙酰丙酮铁、乙酰丙酮铁钴中的一种或几种。
  17. 根据权利要求11所述的高分子-金属氧化物复合物的制备方法，其特征在于，在所述微波条件下的反应温度为180℃-280℃。
  18. 根据权利要求11所述的高分子-金属氧化物复合物的制备方法，其特征在于，在所述微波条件下的反应时间为5min-30min。
  19. 根据权利要求11所述的高分子-金属氧化物复合物的制备方法，其特征在于，所述制备方法包括以下步骤：
    步骤1、将沉淀剂溶解在还原性溶剂中，配成溶液B；
    步骤2、将聚丙烯酸溶解在所述还原性溶剂中；
    步骤3、将铁盐溶解在步骤2中得到的混合溶液中，配成溶液A；
    步骤4、将所述溶液A与所述溶液B在微波条件下进行反应；冷却，得到聚丙烯酸-氧化铁复合物分子胶体；
    步骤5、将步骤4中得到的所述聚丙烯酸-氧化铁复合物分子胶体分离洗涤除杂，得到聚丙烯酸-氧化铁复合物。
  20. 一种核磁共振造影剂，其特征在于，所述核磁共振造影剂包含根据权利要求9或10所述的高分子-金属氧化物复合物。
  21. 根据权利要求20所述的核磁共振造影剂，其特征在于，所述核磁共振造影剂为 注射剂或口服制剂。
  22. 根据权利要求20或21所述的核磁共振造影剂在组织或细胞核磁显影中的应用。
  23. 根据权利要求22所述的应用，所述组织或细胞为血管、肝脏、脾脏、淋巴或心脏。
  24. 一种补铁剂，其特征在于，所述补铁剂包含根据权利要求9或10所述的高分子-金属氧化物复合物。
  25. 根据权利要求24所述的补铁剂，其特征在于，所述补铁剂为注射剂或口服制剂。
  26. 根据权利要求24或25所述的补铁剂在制备治疗缺铁性贫血药物中的应用。
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