WO2017054750A1 - 纳米粒子及其制备方法 - Google Patents

纳米粒子及其制备方法 Download PDF

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WO2017054750A1
WO2017054750A1 PCT/CN2016/100782 CN2016100782W WO2017054750A1 WO 2017054750 A1 WO2017054750 A1 WO 2017054750A1 CN 2016100782 W CN2016100782 W CN 2016100782W WO 2017054750 A1 WO2017054750 A1 WO 2017054750A1
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nanoparticle
magnetic
nanoparticles
monomer
core
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French (fr)
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孙颖浩
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Shanghai Clinical Engine Technology Development Co ltd
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Shanghai Clinical Engine Technology Development Co ltd
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Priority to RU2018115691A priority Critical patent/RU2723259C1/ru
Priority to JP2018535225A priority patent/JP2018532526A/ja
Priority to EP16850374.6A priority patent/EP3357521A4/en
Priority to KR1020187012108A priority patent/KR102169606B1/ko
Priority to CN201680044568.0A priority patent/CN108025115B/zh
Priority to US15/763,625 priority patent/US20180289866A1/en
Publication of WO2017054750A1 publication Critical patent/WO2017054750A1/zh
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Definitions

  • the present invention relates to nanoparticles and methods for their preparation. Further, the present invention also relates to a stone extraction device comprising nanoparticles and an application thereof.
  • urinary calculi is as high as 5%-10%, which can be found in any part of the kidney, bladder, ureter and urethra. Renal and ureteral stones are common. Clinical observations have found that calcium-containing stones are the most common type of stone in urinary stones. It accounts for 70%-80% of all urinary stones. At present, only a few cases of calcium-containing stones can confirm the pathological cause, and the cause of most calcium-containing stones is not fully understood. According to the chemical composition of stones, it can be divided into four types: calcium-containing stones, infected stones, uric acid stones, and cystine stones.
  • Calcium-containing stones can be divided into: simple calcium oxalate, calcium oxalate and calcium phosphate, and calcium oxalate and a small amount of uric acid; the main components of infected stones are magnesium ammonium phosphate and hydroxyapatite; uric acid stone components can be divided into: uric acid The uric acid amine or a small amount of calcium oxalate in addition to the above components; cystine stones can be classified into pure cystine or a small amount of calcium oxalate.
  • Ureteral soft/hard laparoscopic lithotripsy through the natural cavity of the human body for gravel has the advantage of small trauma and gravel effect, is the main treatment of most ureteral stones and kidney stones.
  • current ureteral soft/hard laparoscopic lithotripsy also has certain disadvantages: 1. The ureteral middle and upper calculi and stone fragments are easily rushed back into the kidney by the recoil of the perfusion water or gravel tool; 2. The ureteral lumen and the kidney The residual stone debris in each crucible lacks a quick, safe and effective method of removal. Blocking the ureteral calculi with tools is an important means to prevent ureteral stones from being recoiled back to the kidney.
  • the set of stone baskets (such as the various stone-removing baskets described in the patent publications JP2009536081A, DE19904569A1, WO2004056275A1, WO2011123274A1, all of which are designed in the shape of a net) are the most commonly used stone intercepting and removing tools, which are supported above the stone. It is meshed to prevent the upward movement of stone debris. At the same time, the stone basket is used as a stone removing tool to mesh and take out small stone debris.
  • the amount of stone taken each time is limited, and it is often necessary to enter the mirror multiple times. Repeated water injection into the mirror increases the risk of residual debris drift.
  • the stone basket does not completely seal the ureteral lumen. The probability of stones leaking nets; in addition, the stone ribs in the set of stone baskets are easy to squeeze out of the basket hole, and it is easy to scratch the ureteral wall when dragging the stone, and serious complications are caused.
  • CN105283140A describes a kit for cross-linking gels that encapsulate urethral stones and/or urethral stone fragments.
  • a gel-containing magnetic reagent stimulation
  • the cationic polymer is substantially dispersed in the form of a solvent rather than being aggregated to the periphery of the stone due to the principle of similar compatibility, which is insufficient. Magnetized stones and guided stones are removed.
  • a first object of the present invention is to provide a nanoparticle capable of safely and efficiently extracting urinary calculi located at a kidney, a ureter or the like, the nanoparticle having excellent dispersibility; and a second object of the present invention is to provide The preparation method of the nano particles having different morphological structures; the third object of the present invention is to provide the application of the nanoparticles together with a self-made magnetic probe system in the urinary stone surgery; the fourth object of the present invention is to The nanoparticles are prepared as a product for urinary stone removal.
  • a nanoparticle comprising a nanoparticle core composed of a magnetic material; and a surface modifier monomer coupled to the nanoparticle core by an initiator and/or a crosslinking agent Nanoparticle shell.
  • the nanoparticles comprise: a nanoparticle core composed of a magnetic material; and in situ modification of a surface modifier monomer to the surface of the nanoparticle core by an initiator and/or a crosslinking agent a nanoparticle shell formed; wherein, after surface modification, the surface of the nanoparticle contains an amide bond or a carboxyl group, and the shell accounts for 0.5-45% by weight of the nanoparticle (excluding the end point), preferably 1-40 %, more preferably 2-40%, still more preferably 1-15% or 2-15%, most preferably 1%, 2%, 15% or 40%.
  • the nanoparticles comprise: a nanoparticle core composed of a magnetic material; and in situ modification of a surface modifier monomer to the surface of the nanoparticle core by an initiator and/or a crosslinking agent a nanoparticle shell formed; wherein the surface of the nanoparticle contains an amide bond or a carboxyl group after surface modification functionalization, and the magnetic nanoparticle core preparation method is a coprecipitation method, wherein the magnetic material solution and the catalyst are added by electrons The pump assists continuous dripping.
  • the nanoparticles comprise: a nanoparticle core composed of a magnetic material; and in situ modification of a surface modifier monomer to the surface of the nanoparticle core by an initiator and/or a crosslinking agent Nanoparticle a sub-shell; wherein, after surface modification, the surface of the nanoparticle contains an amide bond or a carboxyl group, and the magnetic nanoparticle core preparation method is a coprecipitation method, wherein the surface modifier monomer is added by an electronic pump Auxiliary continuous drop.
  • the nanoparticles encapsulate the stone by physical adsorption, chemical bonding, and photosensitization, temperature sensitivity, and pH-sensitive crosslinking, specifically, the effect of binding between the nanoparticles and the stone.
  • Forces include: van der Waals forces, hydrophobic interactions, adsorption and surface deposition that form interacting envelopes; covalent bonds between carboxyl-stones, including hydrogen bonds, ester bonds, amide bonds, and other covalent bonds; Winding and chemical crosslinking.
  • the nanoparticles of 2-50 nm diameter core, the overall weight percentage by weight of nanoparticles is 30% to 95%
  • constituting the core of magnetic material comprises Fe 3+, Fe 2+, Mn 2+ , Ni 2+ compound, and one or both of different iron, nickel, copper, cobalt, platinum, gold, rhodium, ruthenium, osmium, iridium metal complexes or complexes and oxides of the above metals
  • the combination of the above is preferably one of Fe 3+ , Fe 2+ , Mn 2+ , Ni 2+ or a combination of any two or more thereof, and more preferably the ratio of Fe 3+ to Fe 2+ is from 15% to 85%, preferably 1:2.5 to 1.5:1.
  • the nanoparticle preparation method used in the present invention can well control the size and size of the magnetic nanoparticle core, especially the nanoparticles prepared by the method, and the relationship among the parameters of the nanoparticle obtained by the invention.
  • the dispersion of nanoparticles into biomedical applications is very good, less than 1.1.
  • the surface modifying agent comprises a hydrophilic, hydrophobic, photosensitivity, temperature sensitive or pH sensitive functional responsive surface modifying agent
  • the hydrophilic surface modifying agent comprises acrylic acid, Methacrylic acid, isobutyl acrylamide or poly N-substituted isopropyl acrylamide
  • the hydrophobic surface modifier comprises olefins, preferably polystyrene, polyethylene or oleic acid
  • the photosensitive surface modifier is selected From the group of azo and quinoline and benzophenone (PVBP), preferably ethylene benzophenone
  • said temperature sensitive surface modifier is selected from amphiphilic polymers bearing an amide bond, preferably polyacrylamide Or a poly-N-substituted isopropyl acrylamide
  • the pH-sensitive surface modifier is selected from the group consisting of a polymer having a carboxyl group and a quaternary ammonium salt, preferably polyacrylic acid, dimethylamine ethyl
  • the crosslinking agent comprises 3-(methacryloyloxy)propyltriethoxysilane, divinylbenzene, diisocyanate or N,N-methylenebispropene An amide, and the initiator includes 3-chloropropionic acid, CuCl, 4,4'-dimercapto-2,2-bipyridine or potassium persulfate.
  • a second aspect of the invention provides a method of preparing the nanoparticles, comprising the steps of: a) preparing the nanoparticle core with the magnetic material; and b) using the initiator and/or crosslinker Surface modifier A monomer is attached in situ to the nanoparticle core to form a nanoparticle shell to form the nanoparticle.
  • in situ as used herein is meant that the surface modifying agent is attached directly to the surface of the nanoparticle core.
  • the obtained modified nanoparticles have a particle diameter of 50 to 5000 nm, which varies depending on various conditions.
  • the nanoparticle core is composed of Fe 3 O 4 , MnFe 2 O 4 , ⁇ -Fe 2 O 3 or other nano-sized ferrite particles, and the ferrite is prepared by the following steps Body particles:
  • the catalyst is added at a normal temperature of 20-30 ° C to adjust the pH of 8-12, preferably 10;
  • the magnetic nanoparticle core can be obtained by separating and drying with a magnet at 50-100 ° C, preferably 70 ° C in a water bath, after 20-40 minutes of reaction.
  • the above oxygen-containing metal salt is FeCl 3 ⁇ 6 H 2 O and FeCl 2 ⁇ 4H 2 O, dissolved in a molar ratio of 15% to 85%, preferably 1:2.5 to 1.5:1.
  • the catalyst is aqueous ammonia. According to the above steps, Fe 3 O 4 nanoparticles can be obtained.
  • the above step b comprises: dispersing the prepared nanoparticles into an aqueous solution, and adding 3-chloropropionic acid, polystyrene, CuCl, and 4,4'-dimercapto-2, a 2-dipyridine solution in xylene, a molar ratio between the iron particle solution and the reaction liquid is 1:1; and the mixture is reacted at 130 ° C for 15 to 30 hours, preferably 24 hours; and the nanometer is collected by a magnet The particles were washed repeatedly with toluene to obtain magnetic iron oxide nanoparticles coated with hydrophobic polystyrene.
  • the above step b comprises: dissolving and dispersing the obtained nanoparticle core into xylene, and adding a silane coupling agent, wherein the silane coupling agent, wherein the nanoparticles, xylene and silane are coupled
  • a silane coupling agent wherein the silane coupling agent, wherein the nanoparticles, xylene and silane are coupled
  • the agent is added in a ratio of 95:5; under nitrogen protection, 20-100 ° C, preferably 80 ° C for 2-5 h, preferably 3 hours; washed with an alcohol solvent (preferably anhydrous ethanol) for 12 h, dispersed by ultrasound
  • an alcohol solvent preferably anhydrous ethanol
  • potassium persulfate is added; under nitrogen protection, the reaction is carried out at 40-80 ° C for 10 minutes, then the acrylic acid is added to continue the reaction at 40-80 ° C for 1 h, preferably the reaction temperature is 70 °; and the magnetic separation is washed and dried to prepare.
  • the above step b comprises: dissolving and dissolving Fe 3 O 4 nanoparticles in xylene, and adding a silane coupling agent, wherein the silane coupling agent (Fe 3 O 4 nanoparticles and silane The coupling agent is added in a ratio of 95:5); under a nitrogen atmosphere, the reaction is carried out at 80 ° C for 2-5 h, preferably 3 hours; and washed with an alcohol solvent (preferably anhydrous ethanol) for 12 h, and ultrasonically dispersed into an aqueous solution.
  • an alcohol solvent preferably anhydrous ethanol
  • the photosensitive monomer modification on the hydrophilic surface modification comprises: dissolving the polyacrylic acid modified magnetic nanoparticles in an alcohol solvent, dispersing by ultrasonication for 5-30 minutes, and then adding
  • the initiator and the photosensitive monomer polyethylene benzophenone can be prepared by isolating the oxygen at 130 ° C for 24 hours, and then preparing the photosensitive monomer-modified magnetic nanoparticles.
  • the method of dropping the ammonia water is an electronic pump assisted continuous dropping at a speed of 20-100 drops/min, preferably 40-60 drops/min;
  • the magnetic material is a simple material
  • the liquid monomer is added by an electronic pump to assist continuous dropping, and the reaction stirring speed is 100-1000 rpm, preferably 500-700 rpm.
  • the particle size, distribution and morphology (such as sphere, rod shape and diamond shape) of the obtained magnetic nanoparticle core can be relatively easily controlled;
  • the particle size and distribution of the surface-modified magnetic nanoparticles prepared by the above method are superior to those of the conventional preparation method, and the dispersion coefficient (PD.I.) of the obtained nanoparticles is basically as shown in the following table. Close to 1.0, it is clearly indicated that the particle size distribution of the obtained particles is narrow. This is very important because for in vivo biomedical applications, the size and dispersion of nanoparticles determines the breadth of their medical applications.
  • the PD.I. method described herein describing the dispersibility of nanoparticles is as follows:
  • Rh represents the hydrodynamic radius of the particle.
  • Magnetic nanoparticle core Surface modification Diameter / nm 40-50 80-100 PD.I./a.u. 0.005 0.0055
  • the structure of the nanoparticles obtained by the present invention is clear.
  • a magnetic probe rod system in which magnetic nanoparticles are combined with stones, It can be used in stone extraction devices for the urinary system.
  • the stone removing device comprises the above-mentioned nano particles and the magnetic rod removing system of the auxiliary stone taken out, and the stone removing device can be used for taking out urinary stones such as kidney stones, ureteral stones and bladder stones, and the system can be applied to the human body. Removal of biliary system stones and other particulate matter in other organs.
  • the stone extraction magnetic probe system includes a handle, a flexible rod, a magnetic field source, a magnetic conductive material segment, etc., and the handle may be provided with an AC or DC power supply, a power switch, a DC battery compartment and an AC plug;
  • the flexible probe is made of polymer material, such as PU, TPU, PE, PVC, NYLON, PEBAX and silicone rubber, and modified materials of the above materials.
  • the flexible probe can be embedded with a magnetic field made of permanent magnet or electromagnet.
  • the configuration is more conducive to the treatment of intrarenal stones under the ureteroscope, avoiding the rigid structure of the permanent magnet or the electromagnet itself, resulting in the inflexibility of the magnetic probe tip, so that the magnetic probe can be smoothly inserted into the ureteroscope In the working channel, driven by the ureteroscope, it can be inserted into the upper, middle and lower jaws of the kidney for stone removal.
  • a nanoparticle product comprising the invention, the nanoparticles being prepared in the form of a solution or a powder.
  • the invention provides a new preparation process for synthesizing hydrophilic, hydrophobic, temperature sensitive and pH sensitive and light sensitive magnetic nanoparticles, which makes the preparation process simple and reproducible, and is convenient for popularization and use.
  • the hydrophobic nanoparticles interacted with the stones through hydrophobic interaction, the hydrophilic nanoparticles interact with the stones through chemical bonds, the photosensitive nanoparticles in the light, the photopolymer encapsulates the stones, the temperature sensitive and pH sensitive nanoparticles
  • the stones in the ureter can be wrapped by the physical wrapping, and then under the action of the external magnetic field, the small stones remaining in the body can be quickly taken out of the body without damage, and the ureteral wall is not damaged when the stones are dragged, and it is convenient and difficult to place at the same time.
  • Fig. 1 is a TEM image of a core transmission electron microscope and a particle size distribution diagram under dynamic light scattering of different morphological structures obtained in Example 1 of the present invention.
  • Example 2 is a dynamic light scattering particle size distribution diagram of the monomer-modified nanoparticles obtained in Example 4 of the present invention; and a transmission electron microscope TEM image of the monomer-modified nanoparticles obtained in Example 3 of the present invention.
  • Figure 3 is a nanoparticle obtained in Example 3 of the present invention in the synthesis of the monomer to modify various Fe 3 + / Fe 2 + ratio nanoparticle core hysteresis regression line.
  • Example 4 is a diagram showing the separation of the stone of the photosensitive monomer-modified nanoparticle core obtained in Example 4 of the present invention, and the separation effect of the core of the different functional Fe 3+ /Fe 2+ nanoparticles by the functional monomer modification.
  • Figure 5 is a graph showing the biocompatibility of functional magnetic nanoparticles obtained by Example 4 of the present invention on 293t cells.
  • Fig. 6 is a graph showing the effect of in vitro assisted stone separation of nanoparticles obtained in Example 6 of the present invention.
  • Fig. 7 is a graph showing the evaluation of animal in vivo safety of the nanoparticles in the present invention.
  • Fig. 8 is a schematic overall view of a magnetic probe system for taking out auxiliary stones in the present invention.
  • Figure 9 is a schematic view of the handle portion of the magnetic probe system with the auxiliary stones removed in the present invention.
  • FIG. 10 is a schematic diagram of an AC power supply scheme for a magnetic probe system with an auxiliary stone taken out according to the present invention.
  • Figure 11 is a schematic view showing the internal structure of the magnetic probe system of the present invention using an electromagnet as a magnetic field source.
  • FIG. 12 is a schematic view showing a scheme of using a magnet as a magnetic field source and configuring a magnetically permeable material at a distal end in the magnetic probe system of the present invention.
  • Figure 13 is a schematic view showing a scheme of using a permanent magnet as a magnetic field source and a magnetically permeable material segment at a distal end in the magnetic probe system of the present invention.
  • Figure 14 is a schematic view of the magnetic probe system of the present invention using a permanent magnet as a magnetic field source without a magnetically conductive material.
  • Figure 15 shows the principle of interaction between magnetic particles and stones.
  • Figure 16 shows the stirring of the reaction system in steps 2-4) of the method for producing nanoparticles of the present invention, which is magnetic stirring at a speed of 100-1000 rpm, preferably 500-700 rpm.
  • FIG. 17 shows the method of adding ammonia water and liquid monomer in steps 1-4) of the method for preparing nanoparticles of the present invention, wherein the electron pump is continuously and uniformly dropped, and the dropping speed is between 20 and 100 drops/min, preferably 40-60 drops / minute.
  • Figure 18 shows the effect of the surface modifier monomer addition method on particle dispersibility.
  • 19 and 20 show transmission electron micrographs of the particles after continuous addition and dropping.
  • Figure 21 shows the effect of the nanoparticle shell on the dispersibility of the nanoparticles as a percentage of the weight of the nanoparticles.
  • an excellent dispersibility for safely and efficiently removing a urinary system Magnetic nanoparticles of the stone provides a functional magnetic nano particle, which comprises magnetic nanoparticles such as hydrophilicity, hydrophobicity, photoresponse, temperature response and pH response, and has a spherical shape, a rod shape, etc., and the structure is a core-shell structure, and is composed of a magnetic core.
  • hydrophilic surface modifier forming a hydrophilic outer shell by polymerization to enclose a magnetic core
  • the nanoparticle comprises a positively, negatively and electrically neutral hydrophilic material; the hydrophobic surface modification is modified by a poorly water soluble polymer and an inorganic material; and the other functional materials such as photosensitization, temperature sensitivity and pH
  • the sensitive monomer modifier can be polymerized by a crosslinking agent and embedded in a hydrophobic outer shell, or these monomer modifiers can be directly attached to the surface of the core in situ by an initiator and/or a crosslinking agent.
  • materials for synthesizing magnetic nanoparticle cores include Fe 3+ , Fe 2+ and Mn 2+ , Ni 2+ compounds. And iron (Fe), nickel (Ni), copper (Cu), cobalt (Co), platinum (Pt), gold (Au), bismuth (Eu), strontium (Gd), strontium (Dy), strontium (Tb) Or a metal complex or a composite of the above metals and an oxide such as Fe 3 O 4 or MnFe 2 O 4 , preferably iron, manganese or a compound thereof; one of them may be used alone or a combination of any two or more thereof may be used.
  • the size of the core is between 2-50 nm.
  • the magnetic nanoparticle core is prepared by a coprecipitation method, an emulsion method, a redox reaction or a high temperature and high pressure method, and the weight of the magnetic nanoparticle core accounts for 30% to 95% by weight of the entire functional magnetic nanoparticle.
  • the ratio of Fe 3+ to Fe 2+ is 15% to 85%, preferably 1:2.5 to 1.5:1 of Fe 3+ and Fe 2+ .
  • the surface of the magnetic nanoparticles can be functionalized, such as hydrophilic modification, hydrophobic modification, and modification with light, temperature, pH sensitive materials, and the like.
  • a hydrophilic modifying functional particle wherein a core size of 2 to 50 nm, the magnetic nanocore weight accounts for 30 to 95% of the entire nanoparticle; and the hydrophilic surface modifier is A polycation or an anionic polymer or the like, such as acrylic acid, methacrylic acid, isobutyl acrylamide or the like; and the weight percentage of the entire hydrophobic magnetic nanoparticle is 2-8%.
  • the magnetic core particles are coated with an initiator such as 3-chloropropionic acid or the like on the surface thereof, and then subjected to a chemical reaction such as a radical, a ring-opening party, and an atom transfer radical polymerization (ATRP) to give acrylic acid or methacrylic acid.
  • a chemical reaction such as a radical, a ring-opening party, and an atom transfer radical polymerization (ATRP) to give acrylic acid or methacrylic acid.
  • ATRP atom transfer radical polymerization
  • isobutylacrylamide-based polymer is modified to the surface of the particles by a crosslinking agent; the particles may be in the form of spheres, rods and layers, preferably spherical particles.
  • the crosslinking agent is 3-(Methacryloxy)propyl triethoxysilane (MPS), divinylbenzene and diisocyanate or N,N-methylene Bis-acrylamide (MBA) and the like.
  • a hydrophobic modifying functional particle wherein the core size is 2-50 nm, the magnetic nano core weight accounts for 30-95% of the entire nanoparticle; the hydrophobic surface modifier is insoluble A monomer of water, such as an olefin such as polystyrene; the weight is 2-8% by weight of the entire hydrophobic magnetic nanoparticle.
  • the magnetic core particles are hydrophobically polymerized with styrene by an initiator such as 3-chloropropionic acid or the like on the surface thereof, followed by a chemical reaction such as a radical, a ring-opening party, and an atom transfer radical polymerization (ATRP).
  • the particles are modified to the surface of the particles by a crosslinking agent; the particles may be in the form of spheres, rods and layers, preferably spherical particles.
  • the crosslinking agent is 3-(methacryloyloxy)propyltriethoxysilane (MPS), divinylbenzene and diisocyanate or N,N-methylenebisacrylamide (MBA) or the like.
  • a photosensitive surface-modifying functional particle wherein the core size is 2 to 50 nm, the magnetic nano-core weight is 30 to 95% of the entire nanoparticle; and the photosensitive modifier is selected from the group Nitrogen and quinoline and benzophenone (PVBP), etc.; weight accounts for 2-8% by weight of the entire hydrophobic magnetic nanoparticles.
  • the magnetic core particles are benzophenone by attaching an initiator such as 3-chloropropionic acid or the like to the surface thereof, and then by a chemical reaction such as a radical, a ring-opening party, and an atom transfer radical polymerization (ATRP).
  • the PVBP)-based photopolymer is modified to the surface of the particles by a crosslinking agent; the particles may be in the form of spheres, rods, and layers, preferably spherical particles.
  • the crosslinking agent is 3-(methacryloyloxy)propyltriethoxysilane (MPS), divinylbenzene and diisocyanate or N,N-methylenebisacrylamide (MBA) or the like.
  • a temperature-sensitive surface-modifying functional particle wherein a core size of 2 to 50 nm, the magnetic nano-core weight accounts for 30 to 95% of the entire nanoparticle; and the temperature-sensitive surface modifier is selected
  • An amphiphilic polymer having an amide bond such as polyacrylamide, poly N-substituted isopropyl acrylamide or the like; weight percentage of 2-8% by weight of the entire hydrophobic magnetic nanoparticle.
  • the magnetic core particles are poly(N-substituted) by attaching an initiator such as 3-chloropropionic acid or the like to the surface thereof, and then by a chemical reaction such as a radical, an open-loop gathering, and an atom transfer radical polymerization (ATRP).
  • the propyl acrylamide temperature-sensitive polymer is modified to the surface of the particles by a crosslinking agent; the particles may be in the form of spheres, rods and layers, preferably spherical particles.
  • the crosslinking agent is 3-(methacryloyloxy)propyltriethoxysilane (MPS), divinylbenzene and diisocyanate or N,N-methylenebisacrylamide (MBA) or the like.
  • a pH-sensitive surface-modifying functional particle wherein 2-50 nm, the magnetic nano-core weight accounts for 30-95% of the entire nano-particle; the pH-sensitive surface modifier is selected from the group consisting of There are carboxyl and quaternary ammonium salts such as polyacrylic acid, dimethylamine ethyl ester and dimethylaminopropyl methacrylate; and the weight percentage of the entire hydrophobic magnetic nanoparticles is 2-8%.
  • the magnetic core particles are triggered by being attached to the surface thereof A reagent such as 3-chloropropionic acid or the like, and then dimethylaminoethyl methacrylate and dimethylaminopropyl methacrylate are subjected to a chemical reaction such as a radical, a ring-opening party, and an atom transfer radical polymerization (ATRP).
  • a reagent such as 3-chloropropionic acid or the like
  • dimethylaminoethyl methacrylate and dimethylaminopropyl methacrylate are subjected to a chemical reaction such as a radical, a ring-opening party, and an atom transfer radical polymerization (ATRP).
  • a chemical reaction such as a radical, a ring-opening party, and an atom transfer radical polymerization (ATRP).
  • the pH-sensitive polymer is modified to the surface of the particles by a crosslinking agent; the particles may be in the form of spheres, rods and layers
  • an initiator and/or a crosslinking agent are further included.
  • the initiator includes an initiator such as thermal initiation, such as potassium persulfate, ammonium persulfate, and an oleogen initiator;
  • the crosslinking agent includes 3-(methacryloyloxy)propyltriethoxysilane (MPS), Divinylbenzene and diisocyanate or N,N-methylenebisacrylamide (MBA), molecular weight of 100,000 and oleic acid.
  • a method of preparing nanoparticles is provided.
  • the preparation method generally includes the synthesis of a magnetic nanoparticle core and its two major steps based on the different surface modifications of the magnetic nanoparticle core (hydrophilic, hydrophobic and temperature sensitive, photosensitive and pH sensitive).
  • the two steps of the preparation method are described in detail below by taking magnetic Fe 3 O 4 nanoparticles as an example.
  • FeCl 3 ⁇ 6 H 2 O and FeCl 2 ⁇ 4H 2 O are in a certain molar ratio (FeCl 3 ⁇ 6H 2 O and FeCl 2 ⁇ 4H 2 O molar ratio is 15% to 85%, preferably 1:2.5 to 1.5: 1) Dissolve in 100mL of water, discharge oxygen in the solution by nitrogen, add ammonia water at normal temperature 20-30 °C to adjust the pH value of 8-12, preferably 10, continue to stir the reaction for 20-40 minutes; then at 50-100 After reacting at 70 ° C for 30-40 minutes in a water bath at 70 ° C, the Fe 3 O 4 nanoparticles can be obtained by separating and drying with a magnet; the nanoparticle cores have different preparation methods such as coprecipitation, thermal decomposition, and water. Thermal synthesis method, microemulsion method (reverse micelle method), and the like.
  • the core of the Fe 3 O 4 nanoparticle prepared in the step 1) is dispersed in an aqueous solution, and after the initiator 3-chloropropionic acid is added for 12 hours, the hydrophobic surface-modified monomer polystyrene and the active initiator CuCl are added.
  • a xylene solution of 4,4'-dimercapto-2,2-bipyridine (the molar ratio between the above iron particle solution and the reaction liquid is 1:1), and the mixture is reacted at 130 ° C under continuous stirring. -30 h, preferably 24 hours; the nanoparticles were collected with a magnet and repeatedly washed with toluene to obtain hydrophobic polystyrene-coated magnetic iron oxide nanoparticles.
  • the reaction time is preferably 18 to 30 h, preferably 24 hours.
  • the solvent is toluene or xylene in an amount of 1/2 to 1 by volume of the monomer, and the surface-modified polystyrene magnetic nanoparticles, the mass ratio of the initiator to the monomer is 95. : 0.5:4.5.
  • the core of the Fe 3 O 4 nanoparticles prepared in the above step 1) is dissolved and dispersed in xylene, and a silane coupling agent (addition ratio of Fe 3 O 4 nanoparticles and silane coupling agent is 95:5) is added to the nitrogen gas protection.
  • the alcohol solvent preferably anhydrous ethanol
  • the alcohol solvent preferably anhydrous ethanol
  • the alcohol solvent preferably anhydrous ethanol
  • the alcohol solvent is washed and dried for 12h, ultrasonically dispersed into the aqueous solution, added potassium persulfate; under nitrogen protection, 40-80 ° C reaction
  • acrylic acid is added to continue the reaction at 40-80 ° C for 1 h, preferably at a reaction temperature of 70 °C; magnetic separation washing and drying to prepare polyacrylic acid-modified hydrophilic surface-modified magnetic nanoparticles.
  • the silane coupling agent is 3-(methacryloyloxy)propyltriethoxysilane (MPS) in an amount of 8 to 16 times the mass of the acrylic acid; the solvent is benzene or 2-toluene; potassium persulfate is used as The initiator; the reaction is preferably carried out for a period of from 20 minutes to 80 minutes.
  • the mass ratio of the surface-modified magnetic ferroferric oxide nanoparticles, potassium persulfate and acrylic acid monomer is from 25 to 100:1:100.
  • the alcohol solvent herein is methanol, ethanol or butanol, preferably ethanol
  • the reaction temperature is preferably from 100 ° C to 150 ° C
  • the reaction time is preferably from 18 h to 24 h
  • the photosensitive monomer-modified magnetic nanoparticles are used.
  • the mass ratio of potassium sulfate to ethylene benzophenone monomer is from 25 to 100:1:100.
  • the core of the Fe 3 O 4 nanoparticles prepared in the above step 1) is dissolved and dispersed in xylene, and a silane coupling agent (addition ratio of Fe 3 O 4 nanoparticles and silane coupling agent is 95:5) is added to the nitrogen gas protection.
  • the alcohol solvent preferably anhydrous ethanol
  • the photosensitive monomer ethylene benzophenone, or the temperature sensitive monomer N-substituted isopropyl acrylamide, or the pH sensitive monomer dimethylaminoethyl methacrylate was added and reacted at 40-80 ° C for 1 h.
  • the reaction temperature is 70 degrees; the magnetic separation is washed and dried, and the magnetic nanoparticles having photosensitive, temperature sensitive or pH sensitive surface modification can be separately prepared.
  • the functionally modified nanoparticles herein may also be cross-reacted with steps 2.1 and 2.2) and step 3) after the surface modification of the nanoparticles described in steps 2.1 and 2.2). That is, after the 3-chloropropionic acid is modified in step 2.1 (or the silicone coupling agent in step 2.2), the hydrophobic monomer styrene (or hydrophilic monomer acrylic acid) and the functional sheet are simultaneously added.
  • the silane coupling agent is 3-(methacryloyloxy)propyltriethoxysilane (MPS) in an amount of 8 to 16 times the mass of the acrylic acid; the solvent is benzene or 2-toluene; 8 to 16 times; potassium persulfate is used as an initiator; the reaction is preferably carried out for 20 minutes to 80 minutes.
  • the mass ratio of the surface-modified magnetic ferroferric oxide nanoparticles, potassium persulfate and acrylic acid monomer is from 25 to 100:1:100.
  • the alcohol solvent herein is methanol, ethanol or butanol, preferably ethanol, and the reaction temperature is preferably 100 ° C to 150 ° C, and the reaction time is preferably 18 h to 24 h, functional monomer-modified magnetic nanoparticles,
  • the mass ratio of potassium persulfate to functional monomer is from 25 to 100:1:100.
  • the Fe 3 O 4 nanoparticles are nano-ferric oxide particles (Fe 3 O 4 ), MnFe 2 O 4 , and nano-iron oxide particles ( ⁇ -Fe 2 O 3 ) or other nano-sized ferrite particles
  • the ammonia water is a catalyst
  • the reaction pH is preferably 9-10
  • the reaction time is preferably 20-30 minutes
  • the reaction temperature is between 50-100 °C.
  • the ratio of Fe 3+ :Fe 2+ is from 15% to 85%, preferably from 1.5:1 to 1:2.5.
  • the nanoparticle core is nano-iron tetraoxide particles (Fe 3 O 4 ).
  • Fe 3 O 4 nano-iron tetraoxide particles
  • the catalyst is aqueous ammonia
  • the pH of the reaction is preferably It is 9 to 10
  • the reaction time is preferably 20 to 30 minutes
  • the reaction temperature is between 50 and 100 ° C, preferably 70 to 80 ° C
  • the preferred Fe 3+ :Fe 2+ ratio is 15% to 85%, preferably 1: 2.5 to 1.5:1.
  • the stirring in the above reaction system is magnetic stirring at a speed of from 100 to 1,000 rpm, preferably from 500 to 700 rpm.
  • the ammonia water and the liquid monomer are added in such a manner that the electron pump is continuously and continuously dropped, and the dropping speed is between 20 and 100 drops/min, preferably 40 to 60 drops/min.
  • a magnetic probe system for assisting urinary stone removal comprising a handle 1, a flexible rod 2, a magnetic field source 3 and a selectively configurable magnetic material section 4,
  • the handle side is defined as the proximal end of the instrument, and one end of the magnetic field source is defined as the distal end.
  • the switch 11 can be integrated on the handle 1, and the magnetic field power supply can be selectively powered by a DC battery, and the corresponding handle Battery compartment 12a and the battery compartment cover 13a, the alternating current can also be selected as the magnetic field power supply, and the corresponding handle is provided with the AC power plug 12b;
  • the magnetic field source is selected from the electromagnet, the magnetic field source 3 is composed of the electromagnet core 32a and the electromagnetic coil 33a, and the external
  • the magnetic field source encapsulating film 31a is made of a biocompatible material; when the magnetic field source 3 is a permanent magnet, the magnetic field source 3 is composed of a permanent magnet 32b and a magnetic field source encapsulating film 31b on the surface; in order to ensure the present invention is accessible to the human body.
  • the magnetic material section 4 can be disposed at the distal end of the magnetic field source 3, and when the electromagnet is selected as the magnetic field source, the magnetic material section 4a can be disposed at the distal end of the electromagnet 3a, and the magnetic conductive material section is efficiently
  • the magnetic conductive material 42a is composed of a magnetic conductive material encapsulating film 41a, and the high-efficiency magnetic conductive material 42a may be made of an iron-based magnetic conductive material, preferably a pure iron material, and the magnetic conductive material encapsulating film 41a is the same material as the magnetic field source encapsulating film 31a;
  • the magnetic conductive material segment 4b may be disposed at the distal end of the permanent magnet 3b, and is composed of the high-efficiency magnetic conductive material 42b and the magnetic conductive material encapsulating film 41b.
  • the magnetic conductive material encapsulating film 41b and the magnetic field source encapsulating film 31b The material is the same; when the magnetic field source does not need to be provided with a magnetic material segment at the distal end, the present invention will be composed of the handle 1, the flexible rod 2 and the magnetic field source 3, for example, when the permanent magnet is selected as the magnetic field source, the distal magnetic field source of the present invention It will be composed of a permanent magnet 32c and a magnetic field source encapsulating film 31c outside thereof; the flexible rod 2 in the above scheme may be made of a polymer material such as selected from the group consisting of PU, TPU, PE, PVC, NYLON, PEBAX, and silicone rubber, and the like.
  • the modified material or the like, the corresponding magnetic field source encapsulating films 31a, 31b, 31c and the magnetic conductive material encapsulating films 41a, 41b are all made of the same material as the flexible rod.
  • the present invention provides a product comprising magnetic nanoparticles, which is further processed to obtain a stone removal solution (physiological saline, a buffer is a solvent) or a stone powder, preferably a stone removal solution.
  • a stone removal solution physiological saline, a buffer is a solvent
  • a stone powder preferably a stone removal solution.
  • the product is a product for medical use.
  • the basic principle of the high-efficiency extraction system of the urinary system stone composed of the magnetic nano-particles combined with the magnetic probe is shown in the following steps: 1. smashing of the stone in the body; 2. injection of functional magnetic nanoparticles, the magnetic nano-particle has excellent Dispersion (dispersion is related to dispersion coefficient, the smaller the dispersion coefficient, the better the dispersion); 3. The interaction between functional magnetic nanoparticles and stones; 4.
  • the functional magnetic nanoparticles coated with stones Closely related to the dispersibility of magnetic particles, the better the dispersibility, the better the effect of coating the stone); 5, the physical or chemical cross-linking of the magnetic nanoparticles on the surface of the stone; 6, the magnetized stone is taken out under the guidance of an external magnetic field (The effect of the stone being guided and taken out is closely related to the effect of coating the stone, and the better the effect of coating the stone, the more excellent the effective removal of the stone).
  • the magnetic nanoparticles encapsulate the magnetized stone by physical adsorption, chemical bonding or the like.
  • the physical adsorption mainly refers to the attraction of the hydrophobic magnetic particles-particles and the particles-stones through the van der Waals force and the hydrophobic interaction in the range of action, so that the magnetic particles are adsorbed and wrapped on the surface of the stone;
  • Chemical bonding mainly refers to hydrophilic magnetic nanoparticles - between particles and between particles - stones Mainly by the formation of chemical bonds (carboxy-particles on the surface of the particles - chemical bonds between the stones such as hydrogen bonds, covalent bonds, etc.), so that the magnetic particles are wrapped around the surface of the stone;
  • the chemical bonding includes functional magnetic nanoparticles (such as photosensitive, The temperature-sensitive nanoparticles, etc.) firstly coat the stones by physical adsorption, and then further enhance the force between the particles-particles and the particles-stones by means of photosensitive crosslinking, temperature-sensitive physical winding (cross-linking) and the like.
  • the solution is placed in a 70 ° C water bath for 20 minutes, vigorously stirred to remove excess ammonia water;
  • the flask was naturally cooled to room temperature while stirring vigorously;
  • the synthetic Fe 3 O 4 magnetic particle suspension was poured into a 50 ml centrifuge tube, the magnetic particles were attracted by a strong magnet, the waste liquid was discarded, deionized water was added, and the magnetic particles were ultrasonically resuspended.
  • the MnFe 2 O 4 nanoparticles having an average particle diameter of 9 nm were added to a solution of an initiator aqueous solution of 3-chloropropionic acid at a concentration of 1.0 mol/L, and the pH of the solution was adjusted to 4 with hydrochloric acid, and stirred overnight; the nanoparticles were collected by a magnet.
  • Example 1 1 g of Fe 3 O 4 obtained in Example 1 (for example, 10 nm Fe 3 O 4 obtained by a coprecipitation method), 5 ml of a silane coupling agent (methacryloxypropyltrimethoxysilane, KH570) It was mixed with 50 ml of xylene in a reaction flask. The reaction was stirred at 80 ° C for 3 h under a nitrogen atmosphere.
  • a silane coupling agent methacryloxypropyltrimethoxysilane, KH570
  • the mixture was centrifuged, and washed with ethanol for 3 times to remove the silane coupling agent adsorbed on the surface of Fe 3 O 4 , and dried under vacuum for 12 hours; the above-mentioned siloxane coupling agent-activated Fe 3 O 4 , 40 mg of potassium persulfate, 30 ml of deionized water was placed in the flask, and the reaction was stirred at 40 ° C for 10 minutes under a nitrogen atmosphere. Then, 4 ml of acrylic acid was slowly dropped into the flask, and the reaction was stirred at 40 ° C for 1 h under a nitrogen atmosphere. The nanoparticles were magnetically separated, washed 3 times with deionized water, and finally vacuum dried.
  • Photosensitive monomer synthesis method with photocrosslinking property direct polymerization of 4-vinylbenzophenone (4VBP) and styrene monomer by atom transfer radical polymerization (ATRP) copolymerization to obtain polystyrene with photosensitive properties
  • ATRP atom transfer radical polymerization
  • PS-PVBP Polyvinyl benzophenone copolymer
  • Polystyrene 75 - co-polyvinyl benzophenone 25 Polyacrylic acid 100 , ie (PS 75 -co-PVBP 25 ) 115 -b-PAA 100 , selected as the polymerization of micelles formed in aqueous solution Things. 5 mg (PS 75 -co-PVBP 25 ) 115 -b-PAA 100 and 10 mg of Fe 3 O 4 obtained in Example 1 (for example, 10 nm Fe 3 O 4 obtained by a coprecipitation method) were dissolved in 10 ml of dimethyl group.
  • a formamide (DMF) solution In a formamide (DMF) solution; then, with vigorous stirring, gradually add double distilled water (0.1 ml / min); when the volume of water reaches 60%, the resulting solution is added to the dialysis membrane with a molecular weight cut off 12K-14K After dialysis for 24 h with water to remove DMF; then, the micelle solution was transferred into a quartz tube and irradiated with a laser (emission wavelength of 315-400 nm) at different time periods to form photosensitive monomer-coated nanoparticles.
  • DMF formamide
  • Example 1 1 g of Fe 3 O 4 obtained in Example 1 (for example, 10 nm Fe 3 O 4 obtained by a coprecipitation method), 5 ml of a silane coupling agent (methacryloxypropyltrimethoxysilane, KH570) It was mixed with 50 ml of xylene in a reaction flask. The reaction was stirred at 80 ° C for 3 h under a nitrogen atmosphere.
  • a silane coupling agent methacryloxypropyltrimethoxysilane, KH570
  • the mixture was centrifuged and washed with ethanol for 3 times to remove the silane coupling agent adsorbed on the surface of Fe 3 O 4 , and dried under vacuum for 12 hours; the above-mentioned siloxane coupling agent-activated Fe 3 O 4 , 40 mg of potassium persulfate, 30 ml of deionized water was placed in the flask, and the reaction was stirred at 40 ° C for 10 minutes under a nitrogen atmosphere. Then, 4 ml of an aqueous solution of N-isopropylacrylamide was slowly dropped into the flask, and the reaction was stirred at 40 ° C for 1 h under a nitrogen atmosphere. The nanoparticles were magnetically separated, washed 3 times with deionized water, and finally vacuum dried.
  • Example 1 1 g of Fe 3 O 4 obtained in Example 1 (for example, 10 nm Fe 3 O 4 obtained by a coprecipitation method), 5 ml of a silane coupling agent (methacryloxypropyltrimethoxysilane, KH570) It was mixed with 50 ml of xylene in a reaction flask. The reaction was stirred at 80 ° C for 3 h under a nitrogen atmosphere.
  • a silane coupling agent methacryloxypropyltrimethoxysilane, KH570
  • the mixture was centrifuged and washed with ethanol for 3 times to remove the silane coupling agent adsorbed on the surface of Fe 3 O 4 , and dried under vacuum for 12 hours; the above-mentioned siloxane coupling agent-activated Fe 3 O 4 , 40 mg of potassium persulfate, 30 ml of deionized water was placed in the flask, and the reaction was stirred at 40 ° C for 10 minutes under a nitrogen atmosphere. Then, 4 ml of an aqueous solution of dimethylaminoethyl methacrylate was slowly dropped into the flask, and the reaction was stirred at 40 ° C for 1 h under a nitrogen atmosphere. The nanoparticles were magnetically separated, washed 3 times with deionized water, and finally vacuum dried.
  • Cell plating 293t cells in logarithmic growth phase were digested and counted after centrifugation. The cell density was 5.0 ⁇ 10 4 /well in 96-well plates, 100 ⁇ l of serum-containing medium was added to each well, and a blank cell hole was placed around each circle. They were all supplemented with 100 ⁇ l of serum-containing medium and placed in a 7% CO 2 , 37 ° C cell culture incubator overnight.
  • the hydrophilic modified magnetic nanoparticles of Example 3 were added to the cell wells, and incubated with N87 cells, 100 ⁇ l per well, wherein the magnetic nanoparticles obtained in Example 3 were at concentrations of 0.1, 0.2, 0.4, and 0.8, respectively.
  • Fig. 6 weigh a certain amount of stone, use a crowbar to form a powder, (particle size 0.5-2mm), pour into a transparent glass bottle, add PBS solution to the stone solution to obtain the stone solution, and mix it.
  • the hydrophilic modified magnetic particle separation liquid of Example 3 at a concentration of 1 mg/ml was added and gently shaken. After standing for five minutes, it was separated by a magnet. During the standing process, it was observed that the color of the mixed solution gradually became light, and after five minutes, it was observed that black magnetic particles were adsorbed on the surface of the stone. Under the guidance of the magnetic field, the stones on which the magnetic particles are adsorbed move in the direction of the magnet.
  • the hydrophilic modified magnetic nanoparticles of Example 3 were placed at a concentration of 0.5 mg/ml, 200 ⁇ L, for two consecutive days. Timely (such as one week, two weeks, etc.) to observe the living state of the mice.
  • the results showed that after intravenous injection of 200 ⁇ L of magnetic nanoparticle solution, no obvious toxicity was observed in nude mice and mice within 1 week; intraperitoneal injection of the same concentration of particle solution 3 times, observed within 3 months of mice and rats The state of survival is good. It is indicated that the prepared magnetic nanoparticles have good biocompatibility, and it is initially evaluated that they have substantially no acute toxicity and chronic toxicity.
  • the ureteroscope In the treatment of kidney stone disease, the ureteroscope is performed with renal calculus and laser lithotripsy. After the calcane laser is used to complete the step of crushing the kidney stone, the hydrophilic magnetic nanoparticle prepared in the third embodiment of the present invention is taken. 200ml of the solution was injected into the kidney through the working channel of the ureteroscope, so that the hydrophilic magnetic nanoparticle solution was thoroughly mixed with the stone debris. After about 3 minutes, the nanoparticles in the solution completely adhered to the stone debris. The surface magnetizes the stone debris.
  • the magnetic probe system is taken out, and the working channel of the ureteroscope is placed in the kidney, and the magnetized stone is under the magnetic field of the distal end of the magnetic probe system.
  • the debris will be brought closer to the end of the magnetic probe and adsorbed on the magnetic probe.
  • the magnetic probe system with the end of the stone debris is removed from the ureteroscope sheath together with the ureteroscope to the outside of the body, the stone debris at the end of the magnetic probe is removed, and the endoscope is taken again for stone operation. , all the stone debris in the kidney was taken out of the body.
  • the stone has a diameter of about 20 mm and is located in the lower jaw of the kidney.
  • the hydrophilic magnetic nanoparticle material of the present invention is combined with the stone to take out the magnetic probe system, so that all the stones (100%) are taken out of the body.
  • the stoneware basket is used to remove stones and the patient is allowed to row stones by powdered gravel.
  • the technical solution of the invention achieves simple and efficient complete stone discharge, which greatly improves the efficiency and safety of stone removal surgery.
  • Example 1 1 g of Fe 3 O 4 obtained in Example 1 (for example, 10 nm Fe 3 O 4 obtained by a coprecipitation method), 5 ml of a silane coupling agent (methacryloxypropyltrimethoxysilane, KH570) It was mixed with 50 ml of xylene in a reaction flask. The reaction was stirred at 80 ° C for 3 h under a nitrogen atmosphere.
  • a silane coupling agent methacryloxypropyltrimethoxysilane, KH570
  • the mixture was centrifuged and washed with ethanol for 3 times to remove the silane coupling agent adsorbed on the surface of Fe 3 O 4 , and dried under vacuum for 12 hours; the above-mentioned siloxane coupling agent-activated Fe 3 O 4 , 40 mg of potassium persulfate, 30 ml of deionized water was placed in the flask, and the reaction was stirred at 40 ° C for 10 minutes under a nitrogen atmosphere.
  • the monodispersity coefficient of magnetic nanoparticles was determined using a German ALV-CGS3 dynamic and static laser light scattering instrument. See Figure 18 for specific experimental results. As can be seen from Fig. 18, the particle monodispersity coefficient (0.0043 ⁇ 0.0016) of the continuously added magnetic nanoparticles is much lower than that of the magnetic nanoparticles of the dropping group (0.478 ⁇ 0.075). Thus, the magnetic nanoparticles obtained by continuously adding the groups have more excellent dispersibility.
  • the dispersibility of the continuously added magnetic nanoparticles is more excellent than the dispersibility of the magnetic nanoparticles of the dropping group.
  • Example 1 1 g of Fe 3 O 4 obtained in Example 1 (for example, 10 nm Fe 3 O 4 obtained by a coprecipitation method), 5 ml of a silane coupling agent (methacryloxypropyltrimethoxysilane, KH570) It was mixed with 50 ml of xylene in a reaction flask. The reaction was stirred at 80 ° C for 3 h under a nitrogen atmosphere.
  • a silane coupling agent methacryloxypropyltrimethoxysilane, KH570
  • the mixture was centrifuged and washed with ethanol for 3 times to remove the silane coupling agent adsorbed on the surface of Fe 3 O 4 , and dried under vacuum for 12 hours; the above-mentioned siloxane coupling agent-activated Fe 3 O 4 , 40 mg of potassium persulfate, 30 ml of deionized water was placed in the flask, and the reaction was stirred at 40 ° C for 10 minutes under a nitrogen atmosphere.
  • the nanoparticle dispersion of the nanoparticles in the following six groups was systematically compared.
  • the monodispersity coefficient of magnetic nanoparticles was determined using a German ALV-CGS3 dynamic and static laser light scattering instrument. The specific experimental results are as follows: the monodispersity coefficient of the first group of nanoparticles is 0.5 ⁇ 0.04; the second group of nanoparticles The monodispersity coefficient is 0.026 ⁇ 0.0026; the monodispersity coefficient of the third group of nanoparticles is 0.036 ⁇ 0.003; the monodispersity coefficient of the fourth group of nanoparticles is 0.022 ⁇ 0.002; the fifth group of nanoparticles is single The coefficient of dispersion was 0.031 ⁇ 0.0028; the monodispersity coefficient of the nanoparticles of Group 6 was 0.58 ⁇ 0.05.
  • the above experimental results show that the groups 2, 3, 4 and 5, ie, the outer shell, are compared with the first and sixth groups, that is, the monodispersity coefficient of the nanoparticles in the shells in the 0.5% and 45% by weight of the particles.
  • the monodispersity coefficients of the nanoparticles in the 1%, 2%, 15%, and 40% by weight groups are much lower (see Figure 21), and thus the nanoparticles of Groups 2, 3, 4, and 5 Has more excellent dispersion.

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Abstract

一种纳米粒子及其制备方法、包含纳米粒子的结石取出装置及应用。所述纳米粒子包括由磁性材料构成的纳米粒子内核，以及通过引发剂和/或交联剂将表面修饰剂单体连接到所述纳米粒子内核形成的纳米粒子外壳。所制得纳米粒子能够将输尿管中的结石包裹，然后在外加磁场的作用下，无损伤快速将体内残存的细小的结石取出体外，拖移结石时不损伤输尿管壁、同时放置方便且不易造成结石移位。

Description

纳米粒子及其制备方法 技术领域
本发明涉及纳米粒子及其制备方法。进一步地，本发明还涉及包含纳米粒子的结石取出装置及其应用。
背景技术
泌尿系结石发病率高达5％-10％，可见于肾、膀胱、输尿管和尿道的任何部位，以肾与输尿管结石为常见。经临床观测发现，含钙结石是泌尿系结石中最常见的结石类型。约占全部泌尿系结石的70％-80％。目前，仅有少数含钙结石病例能明确其病理病因，而大多数含钙结石的病因尚不十分清楚。按结石化学成分可分为含钙结石、感染结石、尿酸结石、胱氨酸结石四类。含钙结石可分为：单纯的草酸钙、草酸钙和磷酸钙、以及除草酸钙还有少量的尿酸；感染结石主要成分是磷酸镁铵和羟磷灰石；尿酸结石成分可分为：尿酸、尿酸胺或除上述成分外还含有少量的草酸钙；胱氨酸结石可分为：纯胱氨酸或含有少量草酸钙成分。
输尿管软/硬镜碎石术经过人体自然腔道进行碎石，具有对病人创伤小和碎石效果确切的优点，是目前绝大多数输尿管结石和肾脏结石的主要治疗手段。然而，目前输尿管软/硬镜碎石术也存在一定不足：1.输尿管中、上段结石及结石碎片容易被灌注水流或碎石工具的反冲力冲回肾内；2.输尿管管腔内以及肾脏各盏内的残留结石碎屑缺乏快捷、安全、有效的取出方法。通过工具封阻在输尿管结石上方是防止输尿管结石被反冲回肾脏的重要手段，目前临床上也有一些输尿管封堵器，通常情况下此类结石阻截工具还兼具取出结石的功能。然而这些输尿管封堵器在实际使用中仍存在一定的缺点。套石篮(如专利公开号JP2009536081A、DE19904569A1、WO2004056275A1、WO2011123274A1中所述的各种取石网篮，均是采用网兜状设计)是目前最常用的结石阻截取出工具，其在跨越结石的上方后撑开成网状从而起到防止结石碎屑向上漂移的作用，同时，套石篮作为取石工具，将小的结石碎屑网住并取出。但是套石篮每次取石的量有限，往往需要多次进镜，而反复注水进镜则会增加残留碎屑漂移的风险；另外，套石篮并不能将输尿管管腔完全封住，仍存在结石漏网的机率；再者，套石篮中的结石凸棱容易从篮孔中挤出，拖移取石时容易划伤输尿管壁，严重者引起并发症。
另外，CN105283140A描述了一种包封尿道结石和/或尿道结石碎片的经交联的凝胶的试剂盒。但是，当含有凝胶的磁性试剂(模拟)添加到含有结石的水溶液中时，由于相似相溶原理，阳离子聚合物基本以溶解在溶剂的形式分散开，而不是聚集到结石周边，这不足以磁化结石及引导结石取出。
综上所述，亟需一种具有优良的分散性、可收集结石、取石便捷、拖移结石时不损伤输尿管壁、同时放置方便且不易造成结石移位的泌尿系统取石的材料及方法。
发明内容
本发明的目的在于解决现有的输尿管软/硬镜碎石手术中存在的结石碎屑残留及不易取出的问题。为此，本发明第一目的在于提供一种能够安全高效地用于取出位于肾脏、输尿管等位置的泌尿系统结石的纳米粒子，该纳米粒子具有优良的分散性；本发明的第二目的在于提供所述具有不同形态结构的纳米粒子的制备方法；本发明的第三目的在于提供所述纳米粒子配合自制磁探杆系统在泌尿系统结石手术过程中的应用；本发明的第四个目的是将所述纳米粒子制备成用于泌尿系统结石取出的产品。
本发明的第一方面，提供纳米粒子，所述纳米粒子包括由磁性材料构成的纳米粒子内核；以及通过引发剂和/或交联剂将表面修饰剂单体连接到所述纳米粒子内核形成的纳米粒子外壳。
根据本发明的某些实施方案，所述纳米粒子包括：由磁性材料构成的纳米粒子内核；以及通过引发剂和/或交联剂将表面修饰剂单体原位修饰到所述纳米粒子内核表面形成的纳米粒子外壳；其中，经过表面修饰功能化后所述纳米粒子表面含有酰胺键或者羧基，且所述外壳占纳米粒子重量百分比为0.5-45％(不包括端点)，优选为1-40％，更优选为2-40％，还更优选为1-15％或2-15％，最优选为1％、2％、15％或40％。
根据本发明的某些实施方案，所述纳米粒子包括：由磁性材料构成的纳米粒子内核；以及通过引发剂和/或交联剂将表面修饰剂单体原位修饰到所述纳米粒子内核表面形成的纳米粒子外壳；其中，经过表面修饰功能化后所述纳米粒子表面含有酰胺键或者羧基，且所述磁性纳米粒子内核制备方法为共沉淀法，其中磁性材料溶液和催化剂的添加方式为电子泵辅助连续滴加。
在另一实施方案中，所述纳米粒子包括：由磁性材料构成的纳米粒子内核；以及通过引发剂和/或交联剂将表面修饰剂单体原位修饰到所述纳米粒子内核表面形成的纳米粒 子外壳；其中，经过表面修饰功能化后所述纳米粒子表面含有酰胺键或者羧基，且所述磁性纳米粒子内核制备方法为共沉淀法，其中所述表面修饰剂单体的添加方式为电子泵辅助连续滴加。
根据本发明的某些实施方案，所述纳米粒子通过物理吸附、化学键合及光敏、温敏和pH值敏感交联作用来包裹结石，具体来说，所述纳米粒子与结石之间结合包裹的作用力包括：形成相互作用包裹的范德华力、疏水相互作用、吸附及表面沉积；羧基-结石之间形成共价键，包括氢键、酯键、酰胺键及其他共价键；链间的相互物理缠绕和化学交联。
根据本发明的某些实施方案，所述纳米粒子内核直径为2-50nm，重量占整个纳米粒子的重量百分比为30％～95％，构成内核的磁性材料包括Fe3+、Fe2+、Mn2+、Ni2+化合物，及由不同的铁、镍、铜、钴、铂、金、铕、钆、镝、铽金属单质、或上述金属的复合物及氧化物的一种或任意两种以上的组合，优选Fe3+、Fe2+、Mn2+、Ni2+的一种或任意两种以上的组合，更优选Fe3+和Fe2+的比例为15％到85％，优选1∶2.5到1.5∶1。需要说明的是，本发明所采用的纳米粒子制备方法能够很好的控制磁性纳米粒子内核的大小和尺寸，尤其是相比其他方法制备的纳米粒子，本发明所获的纳米粒子的参数中关系到生物医学应用的纳米粒子的分散性非常好，小于1.1。
根据本发明的某些实施方案，其中所述表面修饰剂包括亲水性、疏水性、光敏性、温敏性或pH敏感性功能响应性表面修饰剂，其中亲水性表面修饰剂包括丙烯酸、甲基丙烯酸、异丁基丙烯酰胺或聚N-取代异丙基丙烯酰胺；所述疏水性表面修饰剂包括烯烃类，优选聚苯乙烯、聚乙烯或油酸；所述光敏性表面修饰剂选自偶氮类和喹啉类及二苯甲酮(PVBP)类，优选乙烯二苯甲酮；所述温敏性表面修饰剂选自带有酰胺键的两亲性聚合物，优选聚丙烯酰胺或聚N-取代异丙基丙烯酰胺；所述pH敏感性表面修饰剂选自带有羧基和季铵盐类聚合物，优选聚丙烯酸、二甲胺乙酯及甲基丙烯酸二甲胺丙酯。
根据本发明的某些实施方案，所述交联剂包括3-(甲基丙烯酰氧基)丙基三乙氧基硅烷、二乙烯基苯、二异氰酸酯或N，N-亚甲基双丙烯酰胺，而所述引发剂包括3-氯丙酸、CuCl、4，4′-二壬基-2，2-联吡啶或过硫酸钾。
本发明的第二方面，提供制备所述纳米粒子的方法，包括步骤：a)利用所述磁性材料制备所述纳米粒子内核；并且b)通过所述引发剂和/或交联剂将所述表面修饰剂 单体原位连接到所述纳米粒子内核以形成纳米粒子外壳，从而形成所述纳米粒子。此处所述“原位”是指表面修饰剂直接连接到纳米粒子内核的表面上。所获得的修饰好的纳米粒子的粒径在50-5000纳米之间，根据不同的条件有所不同。
根据本发明的某些实施方案，所述纳米粒子内核由Fe3O4、MnFe2O4、γ-Fe2O3或其他纳米级尺寸的铁氧体粒子构成，通过如下步骤制备这些铁氧体粒子：
将一定比例的含金属盐材料溶解于水中；
通入氮气将溶液中的氧气排出；
在常温20-30℃下加入催化剂来调节pH值为8-12，优选10；
继续搅拌反应20-40分钟；并且
在50-100℃下，优选70℃水浴下，反应20-40分钟后，用磁铁分离干燥即可得到磁性纳米粒子内核。
在本发明一个具体实施方案中，上述含氧金属盐为FeCl3·6H2O和FeCl2·4H2O，按照摩尔比15％到85％，优选1∶2.5到1.5∶1，溶解于水中，其中所述催化剂为氨水。按上述步骤即可得到Fe3O4纳米粒子。
根据本发明的某些实施方案，上述步骤b包括：将所制备的纳米粒子分散到水溶液中，并且加入3-氯丙酸、聚苯乙烯、CuCl和4，4′-二壬基-2，2-联吡啶的二甲苯溶液，上述铁粒子溶液与反应液之间摩尔比例为1∶1；将上述混合液在130℃，持续搅拌下反应15-30h，优选24小时；并且用磁铁收集纳米粒子并用甲苯反复洗涤，得到疏水聚苯乙烯包裹的磁性氧化铁纳米粒子。
根据本发明的某些实施方案，上述步骤b包括：将所得纳米粒子内核溶解分散到二甲苯中，并且加入硅烷偶联剂，其中该硅烷偶联剂，其中纳米粒子、二甲苯和硅烷偶联剂的加入比例为95∶5；在氮气保护下，20-100℃，优选80℃下反应2-5h，优选3小时；用醇类溶剂(优选无水乙醇)洗涤干燥12h，经超声分散到水溶液中，加入过硫酸钾；在氮气保护下，40-80℃下反应10分钟后加入丙烯酸继续在40-80℃下反应1h，优选反应温度70度；并且磁分离洗涤干燥，即可制备得到聚丙烯酸修饰的亲水性纳米粒子。
根据本发明的某些实施方案，上述步骤b包括：将Fe3O4纳米粒子溶解分散到二甲苯中，并且加入硅烷偶联剂，其中该硅烷偶联剂(Fe3O4纳米粒子和硅烷偶联剂的加入比例为95∶5)；在氮气保护下，80℃下反应2-5h，优选3小时；用醇类溶剂(优选 无水乙醇)洗涤干燥12h，经超声分散到水溶液中，加入过硫酸钾；在氮气保护下，40-80℃下反应10分钟后加入将光敏单体如乙烯二苯甲酮，温敏单体如N-异丙基丙烯酰胺，或pH敏感单体如甲基丙烯酸二甲胺丙酯等(或丙烯酸及苯乙烯的共混单体)，继续在40-80℃下反应1h，优选反应温度70度；并且磁分离洗涤干燥，即可分别制备得到光敏性、温敏性或pH敏感性功能性单体修饰的磁性纳米粒子。
在本发明某些实施方案中，在亲水性表面修饰上进行光敏单体修饰包括：将聚丙烯酸修饰的磁性纳米粒子溶解分散于醇类溶剂中，经超声分散5-30分钟后，然后加入引发剂和光敏单体聚乙烯二苯甲酮，在130℃下隔绝氧气搅拌回流反应24h后，即可制备得到所述光敏单体修饰的磁性纳米粒子。
上述实施方案中，当将氨水作为催化剂来制备纳米粒子时，所述氨水的滴加方法为电子泵辅助连续滴加，速度在20-100滴/分钟，优选40-60滴/分钟；并且当所述磁性材料为单质材料时，所述液体单体的添加方式为电子泵辅助连续滴加，反应搅拌速度在100-1000转/分钟，优选500-700转/分钟。
此处需要说明的是，在上述我们设计的合成方法和制备工艺条件下，能够比较容易的控制所获得的磁纳米粒子内核的粒径、分布及形貌(如球形、棒状及菱形等)；而且，上述方法制备的表面修饰的磁纳米粒子的粒径和分布优于传统的制备方法获得的磁纳米粒子，如下表所示，所获得的纳米粒子的分散性系数(PD.I.)基本接近于1.0，清楚表示所获得的粒子的粒径分布窄。这一点非常重要，因为对于体内生物医学应用而言，纳米粒子的大小和分散性决定了其医学应用的广泛性。此处所述的描述纳米粒子的分散性的PD.I.定义方法如下：
PD.I.＝<Rh2>/<Rh>2
这里，Rh表示的是粒子的流体力学半径。
所述纳米粒子内核及经表面修饰后的磁性纳米粒子的分布PD.I.如下表所示：
  磁纳米粒子内核 表面修饰后
直径/nm 40-50 80-100
PD.I./a.u. 0.005 0.0055
另外，如图例2所示，本发明所获得纳米粒子的结构清晰。
根据本发明的第三方面，提供由磁性纳米粒子结合结石取出磁探杆系统组成的、 可以用于泌尿系统的结石取出装置。该结石取出装置包括本发明的上述纳米粒子和辅助结石取出的磁探杆系统，该结石取出装置可用于肾脏结石、输尿管结石及膀胱结石等泌尿系统结石的取出，也可将该系统应用于人体胆道系统结石及其他脏器内结石性颗粒物的取出。
具体来说，所述的结石取出磁探杆系统包括手柄、柔性杆、磁场源、导磁材料段等，手柄上可以设有交流或直流电源，电源开关，直流电池仓及交流电插头等结构；柔性探杆由高分子材料制成，如包括PU、TPU、PE、PVC、NYLON、PEBAX和硅橡胶以及上述材料的改性材料等，柔性探杆中可以嵌入永磁铁或电磁铁制成的磁场源，并可选择性的利用高效导磁材料与磁场源相连，形成不同结构配置的柔性磁探杆，例如将永磁铁放置于柔性杆的中后端，而将导磁材料置于磁探杆末端，该配置更利于应用在输尿管软镜下处理肾脏内结石，避免了永磁铁或电磁铁本身的刚性结构导致磁探杆末端非柔性的情况，从而使得磁探杆能够顺利地插入输尿管软镜的工作通道内，在输尿管软镜的驱动下，可以伸入肾脏的上、中、下盏内进行取石操作。
本发明的第四方面，提供包含本发明的纳米粒子产品，所述纳米粒子被制备成溶液或粉剂形式。
本发明为合成亲水、疏水、温敏和pH敏感性及光敏感的磁性纳米粒子的制备提供了新的制备工艺，使得制备过程简单且重复性好，便于推广使用。所制得的疏水纳米粒子与结石之间通过疏水相互作用，亲水纳米粒子与结石之间通过化学键相互作用，光敏纳米粒子在光照下，光敏聚合物包裹结石，温敏及pH值敏感纳米粒子与结石之间通过物理包裹能够将输尿管中的结石包裹，然后在外加磁场的作用下，无损伤快速将体内残存的细小的结石取出体外，拖移结石时不损伤输尿管壁、同时放置方便且不易造成结石移位。
以下结合附图更好地说明本发明。
附图说明
图1是本发明实施例1中获得的不同形态结构的内核透射电镜TEM图及动态光散射下的粒径分布图。
图2是本发明实施例4获得的单体修饰的纳米粒子的动态光散射粒径分布图；及本发明实施例3获得的单体修饰的纳米粒子的透射电镜TEM图。
图3是本发明实施例3获得的纳米粒子在合成时单体修饰不同Fe3+/Fe2+比例纳米粒子内核的磁滞回归线。
图4是本发明实施例4获得的光敏单体修饰纳米粒子内核的结石分离图，合成功能单体修饰不同Fe3+/Fe2+比例纳米粒子内核的分离效果图。
图5是本发明实施例4获得的功能磁性纳米粒子对293t细胞生物相容性图。
图6是本发明实施例6获得的纳米粒子体外辅助结石分离效果图。
图7是本发明中的纳米粒子的动物体内安全性评价图。
图8是本发明中辅助结石取出的磁探杆系统整体示意图。
图9是本发明中辅助结石取出的磁探杆系统手柄部示意图。
图10是本发明辅助结石取出的磁探杆系统采用交流供电方案示意图。
图11是本发明磁探杆系统采用电磁铁作为磁场源的内部结构示意图。
图12是本发明磁探杆系统选用电磁铁作为磁场源并远端配置导磁材料段方案示意图。
图13是本发明磁探杆系统选用永磁铁作为磁场源并远端配置导磁材料段方案示意图。
图14是本发明磁探杆系统选用永磁铁作为磁场源远端不配置导磁材料段示意图。
图15示了磁性粒子与结石的相互作用原理。
图16示出了本发明纳米粒子制备方法的步骤2-4)中的反应体系的搅拌，为磁力搅拌，速度在100-1000转/分钟，优选500-700转/分钟。
图17示出了本发明纳米粒子制备方法的步骤1-4)中氨水及液体单体的添加方式为电子泵连续匀速滴加，其滴加的速度在20-100滴/分钟之间，优选40-60滴/分钟。
图18示出了表面修饰剂单体滴加方式对粒子分散性的影响。
图19和图20示出了连续加和滴加后粒子的透射电镜照片。
图21示出了纳米粒子外壳占纳米粒子的重量百分比对纳米粒子分散性的影响。
具体实施方案
以下结合附图和具体实施例，对本发明作进一步说明。应理解，以下实施例仅用于说明本发明而非用于限定本发明的范围。
根据本发明的第一方面，提供一种具有优良的分散性，能够安全高效取出泌尿系 统结石的磁性纳米粒子。本发明提供的是一种功能磁性纳米粒子，包括亲水性、疏水性、光响应、温度响应、pH响应等磁性纳米粒子，形态有球形、棒状等，结构为核壳结构，由磁性内核，亲水性、疏水性、温敏、pH敏感或光敏性表面修饰剂和少量引发剂等单体修饰剂组成，所述亲水性表面修饰剂通过聚合反应形成亲水性外壳包裹着磁性内核的纳米粒子，包括带正电、负电及电中性的亲水材料；所述疏水表面修饰是由水溶性较差的高分子及无机材料修饰；所述另外其他功能材料如光敏、温敏及pH敏感单体修饰剂可以通过交联剂聚合并嵌于疏水性外壳上，或者这些单体修饰剂可以通过引发剂和/或交联剂原位直接连接于内核表面。
在所述亲水、疏水、温敏、pH敏感及光敏等各种响应磁性纳米粒子中，用于合成磁性纳米粒子内核的材料包括Fe3+、Fe2+和Mn2+、Ni2+化合物，及铁(Fe)、镍(Ni)、铜(Cu)、钴(Co)、铂(Pt)、金(Au)、铕(Eu)、钆(Gd)、镝(Dy)、铽(Tb)等金属单质、或上述金属的复合物及氧化物如Fe3O4或MnFe2O4等，优选铁、锰或其化合物；也可选用其中的一种或是任意两种以上的组合，内核的尺寸在2-50nm之间。
所述磁性纳米粒子内核的制备方法有共沉淀法、乳液法、氧化还原反应或高温高压等方法，所述的磁性纳米粒子内核的重量占整个功能磁性纳米粒子的重量百分比为30％～95％，以合成Fe3O4为例，Fe3+和Fe2+的比例为15％到85％，优选Fe3+和Fe2+的1∶2.5到1.5∶1。
所述磁性纳米粒子的表面能够经功能化修饰，如亲水修饰、疏水修饰、及具有光、温度、pH敏感材料修饰等。
根据本发明的第一实施方案，提供亲水性修饰功能粒子，其中内核尺寸为2-50nm，所述磁纳米内核重量占整个纳米粒子的30-95％；所述亲水性表面修饰剂为聚阳离子或阴离子聚合物等，如丙烯酸、甲基丙烯酸及异丁基丙烯酰胺类等；重量占整个疏水性磁性纳米粒子重量百分比为2-8％。所述磁性核粒子通过在其表面接上引发剂如3-氯丙酸等，然后通过化学反应，如自由基、开环聚会及原子转移自由基聚合反应(ATRP)等将丙烯酸、甲基丙烯酸及异丁基丙烯酰胺类聚合物通过交联剂修饰到粒子表面；所述粒子的形态可以是球形、棒状及层状，优选球形粒子。所述交联剂为3-(甲基丙烯酰氧基)丙基三乙氧基硅烷(3-(Methacryloxy)propyl triethoxysilane)(MPS)、二乙烯基苯和二异氰酸酯或N，N-亚甲基双丙烯酰胺(MBA)等。
根据本发明的第二实施方案，提供疏水性修饰功能粒子，其中内核尺寸为2-50nm，所述磁纳米内核重量占整个纳米粒子的30-95％；所述疏水性表面修饰剂为不溶于水的单体，如烯烃类，如聚苯乙烯等；重量占整个疏水性磁性纳米粒子重量百分比为2-8％。所述磁性核粒子通过在其表面接上引发剂如3-氯丙酸等，然后通过化学反应，如自由基、开环聚会及原子转移自由基聚合反应(ATRP)等将苯乙烯类疏水聚合物通过交联剂修饰到粒子表面；所述粒子的形态可以是球形、棒状及层状，优选球形粒子。所述交联剂为3-(甲基丙烯酰氧基)丙基三乙氧基硅烷(MPS)、二乙烯基苯和二异氰酸酯或N，N-亚甲基双丙烯酰胺(MBA)等。
根据本发明的第三实施方案，提供光敏性表面修饰功能粒子，其中内核尺寸为2-50nm，所述磁纳米内核重量占整个纳米粒子的30-95％；所述光敏性修饰剂选自偶氮类和喹啉类及二苯甲酮(PVBP)类等；重量占整个疏水性磁性纳米粒子重量百分比为2-8％。所述磁性核粒子通过在其表面接上引发剂如3-氯丙酸等，然后通过化学反应，如自由基、开环聚会及原子转移自由基聚合反应(ATRP)等将二苯甲酮(PVBP)类光敏聚合物通过交联剂修饰到粒子表面；所述粒子的形态可以是球形、棒状及层状，优选球形粒子。所述交联剂为3-(甲基丙烯酰氧基)丙基三乙氧基硅烷(MPS)、二乙烯基苯和二异氰酸酯或N，N-亚甲基双丙烯酰胺(MBA)等。
根据本发明的第四实施方案，提供温敏性表面修饰功能粒子，其中内核尺寸2-50nm，所述磁纳米内核重量占整个纳米粒子的30-95％；所述温敏性表面修饰剂选自带有酰胺键的两亲性聚合物如聚丙烯酰胺、聚N-取代异丙基丙烯酰胺等；重量占整个疏水性磁性纳米粒子重量百分比为2-8％。所述磁性核粒子通过在其表面接上引发剂如3-氯丙酸等，然后通过化学反应，如自由基、开环聚会及原子转移自由基聚合反应(ATRP)等将聚N-取代异丙基丙烯酰胺温敏类聚合物通过交联剂修饰到粒子表面；所述粒子的形态可以是球形、棒状及层状，优选球形粒子。所述交联剂为3-(甲基丙烯酰氧基)丙基三乙氧基硅烷(MPS)、二乙烯基苯和二异氰酸酯或N，N-亚甲基双丙烯酰胺(MBA)等。
根据本发明的第五实施方案，提供pH敏感性表面修饰功能粒子，其中2-50nm，所述磁纳米内核重量占整个纳米粒子的30-95％；所述pH敏感性表面修饰剂选自带有羧基和季铵盐类聚合物如聚丙烯酸、二甲胺乙酯及甲基丙烯酸二甲胺丙酯等；重量占整个疏水性磁性纳米粒子重量百分比为2-8％。所述磁性核粒子通过在其表面接上引发 剂如3-氯丙酸等，然后通过化学反应，如自由基、开环聚会及原子转移自由基聚合反应(ATRP)等将甲基丙烯酸二甲胺乙酯及甲基丙烯酸二甲胺丙酯等pH值敏感类聚合物通过交联剂修饰到粒子表面；所述粒子的形态可以是球形、棒状及层状，优选球形粒子。所述交联剂为3-(甲基丙烯酰氧基)丙基三乙氧基硅烷(MPS)、二乙烯基苯和二异氰酸酯或N，N-亚甲基双丙烯酰胺(MBA)等。
本发明上述各实施方案中，还进一步包括引发剂和/或交联剂。所述引发剂包括热引发等引发剂如过硫酸钾、过硫酸铵及偶蛋类引发剂；交联剂包括3-(甲基丙烯酰氧基)丙基三乙氧基硅烷(MPS)、二乙烯基苯和二异氰酸酯或N，N-亚甲基双丙烯酰胺(MBA)、分子量为10万及油酸等。
根据本发明的第二方面，提供一种纳米粒子的制备方法。该制备方法总地来说包括磁性纳米粒子内核的合成，及其基于该磁性纳米粒子内核的不同表面修饰(亲水、疏水及温敏、光敏和pH敏感)两个主要步骤。以下以制备磁性Fe3O4纳米粒子为例，分别对该制备方法的两个步骤进行详细描述。
1)制备磁性Fe3O4纳米粒子的内核
将FeCl3·6H2O和FeCl2·4H2O按照一定的摩尔比(FeCl3·6H2O和FeCl2·4H2O摩尔比为15％到85％，优选1∶2.5到1.5∶1)溶解于100mL水中，通入氮气将溶液中的氧气排出，在常温20-30℃下加入氨水调节pH值为8-12，优选10，继续搅拌反应20-40分钟；然后在50-100℃下，优选70℃水浴下反应20-40分钟后，用磁铁分离干燥即可得到Fe3O4纳米粒子；所述纳米粒子内核有不同种的制备方法如共沉淀法、热分解法、水热合成法、微乳液法(反相胶束法)等。
2)对合成的Fe3O4纳米粒子内核的表面修饰
2.1)对合成的Fe3O4纳米粒子内核表面疏水性修饰
将步骤1)所制备的Fe3O4纳米粒子内核分散到水溶液中，加入引发剂3-氯丙酸预处理12小时后，添加疏水性表面修饰单体聚苯乙烯、及活性引发剂CuCl和4，4′-二壬基-2，2-联吡啶的二甲苯溶液(上述铁粒子溶液与反应液之间摩尔比例为1∶1)，将上述混合液在130℃，持续搅拌下反应15-30h，优选24小时；用磁铁收集纳米粒子并用甲苯反复洗涤，得到疏水聚苯乙烯包裹的磁性氧化铁纳米粒子。
这里，3-氯丙酸作为引发剂，CuCl和4，4′-二壬基-2，2-联吡啶作为引发剂。此外，根据本发明的一种实施方案，反应时间优选18～30h，优选24小时。此外，根据 本发明的一种实施方案，所述溶剂为甲苯或二甲苯，用量为单体体积的1/2～1，表面被修饰的聚苯乙烯磁性纳米粒子、引发剂和单体的质量比为95∶0.5∶4.5。
2.2)对合成的Fe3O4纳米粒子内核的表面亲水性修饰
取上述步骤1)制备得到的Fe3O4纳米粒子内核溶解分散到二甲苯中，加入硅烷偶联剂(Fe3O4纳米粒子和硅烷偶联剂的加入比例为95∶5)在氮气保护下，80℃下反应2-5h，优选3小时，醇类溶剂(优选无水乙醇)洗涤干燥12h，经超声分散到水溶液中，加入过硫酸钾；在氮气保护下，40-80℃下反应10分钟后加入丙烯酸继续在40-80℃下反应1h，优选反应温度70度；磁分离洗涤干燥，即可制备得到聚丙烯酸修饰的亲水性表面修饰的磁性纳米粒子。
这里，硅烷偶联剂为3-(甲基丙烯酰氧基)丙基三乙氧基硅烷(MPS)，用量为丙烯酸质量的8～16倍；溶剂为苯或2-甲苯；过硫酸钾作为引发剂；反应优选时间20分钟～80分钟。根据本发明的一种实施方案，表面被修饰的磁性四氧化三铁纳米粒子、过硫酸钾和丙烯酸单体的质量比为25～100∶1∶100。
此外，此处的醇类溶剂为甲醇、乙醇或是丁醇，优选乙醇，所述反应温度优选为100℃～150℃，反应时间优选为18h～24h，光敏单体修饰的磁性纳米粒子、过硫酸钾和乙烯二苯甲酮单体的质量比为25～100∶1∶100。
2.3)对合成的Fe3O4纳米粒子内核的表面功能性修饰
取上述步骤1)制备得到的Fe3O4纳米粒子内核溶解分散到二甲苯中，加入硅烷偶联剂(Fe3O4纳米粒子和硅烷偶联剂的加入比例为95∶5)在氮气保护下，80℃下反应2-5h，优选3小时，醇类溶剂(优选无水乙醇)洗涤干燥12h，经超声分散到水溶液中，加入过硫酸钾；在氮气保护下，40-80℃下反应10分钟后，加入光敏单体乙烯二苯甲酮，或温敏单体N-取代异丙基丙烯酰胺，或pH敏感单体甲基丙烯酸二甲胺乙酯，在40-80℃下反应1h，优选反应温度70度；磁分离洗涤干燥，即可分别制备得到具有光敏、温度敏感或pH敏感性表面修饰的磁性纳米粒子。
此外，此处的功能性修饰的纳米粒子也可以是在步骤2.1及2.2)中所述纳米粒子表面预修饰后，与步骤2.1及2.2)与步骤3)的交叉反应。也就是在步骤2.1中所述3-氯丙酸作修饰后(或步骤2.2)中的硅氧烷偶联剂修饰)，同时添加疏水单体苯乙烯(或亲水单体丙烯酸)和功能单体如乙烯二苯甲酮、N-取代异丙基丙烯酰胺或甲基丙烯酸二甲胺乙，等在40-80℃下反应1h，优选反应温度70度；磁分离洗涤干燥，即可 制备得到具有光、温度或pH值敏感性表面修饰的磁性纳米粒子。共同反应得到相应聚苯乙烯(或聚丙烯酸)与功能单体共修饰的功能性纳米粒子。
这里，硅烷偶联剂为3-(甲基丙烯酰氧基)丙基三乙氧基硅烷(MPS)，用量为丙烯酸质量的8～16倍；溶剂为苯或2-甲苯；为丙烯酸质量的8～16倍；过硫酸钾作为引发剂；反应优选时间20分钟～80分钟。根据本发明的一种实施方案，表面被修饰的磁性四氧化三铁纳米粒子、过硫酸钾和丙烯酸单体的质量比为25～100∶1∶100。
此外，此处的醇类溶剂为甲醇、乙醇或是丁醇，优选乙醇，所述反应温度优选为100℃～150℃，反应时间优选为18h～24h，功能性单体修饰的磁性纳米粒子、过硫酸钾和功能单体的质量比为25～100∶1∶100。
在所述制备纳米氧化铁的过程中(步骤1中)，所述Fe3O4纳米粒子为纳米四氧化三铁粒子(Fe3O4)、MnFe2O4，纳米三氧化二铁粒子(γ-Fe2O3)或其他纳米级尺寸的铁氧体粒子，所述氨水为催化剂，反应pH值优选为9～10，反应时间优选20～30分钟，反应温度在50-100℃之间，优选70～80℃，所述优选Fe3+∶Fe2+比例为15％到85％，优选为1.5∶1到1∶2.5。
另外，在上述制备纳米氧化铁的过程(即步骤1)中)，所述纳米粒子内核为纳米四氧化三铁粒子(Fe3O4)。本领域技术人员可以理解，还可以使用MnFe2O4，纳米三氧化二铁粒子(γ-Fe2O3)或其他纳米级尺寸的铁氧体粒子，所述氨水为催化剂，反应pH值优选为9～10，反应时间优选20～30分钟，反应温度在50-100℃之间，优选70～80℃，所述优选Fe3+∶Fe2+比例为15％到85％，优选1∶2.5到1.5∶1。
此外，在本发明上述各实施方案中，上述反应体系中的搅拌为磁力搅拌，速度在100-1000转/分钟，优选500-700转/分钟。
此外，在本发明上述各实施方案中，氨水及液体单体的添加方式为电子泵连续匀速滴加，其滴加的速度在20-100滴/分钟之间，优选40-60滴/分钟。通过利用电子泵连续匀速滴加，可以简单实现规模化生产，并且可以很好地控制纳米粒子的分散性\均匀性。
本发明的第三方面，提供一种辅助泌尿系统结石取出磁探杆系统，所述磁探杆系统包括手柄1，柔性杆2，磁场源3及可以选择配置的导磁材料段4组成，(本发明中定义手柄侧为器械近端，磁场源一端定义为远端)当选择电磁铁作为磁场源3时，其手柄1上可集成开关11，磁场电源可选择使用直流电池供电，相应的手柄上设有电池仓 12a和电池仓盖13a，也可选择交流电作为磁场电源，相应的手柄上设有交流电源插头12b；当磁场源选用电磁铁时，磁场源3由电磁铁芯32a和电磁线圈33a组成，外部由具有生物相容性材料制成磁场源封装膜31a；当磁场源3选用永磁铁时，磁场源3由永磁铁32b及表面的磁场源封装膜31b组成；为了保证本发明在人体内的可及性，可选择性在磁场源3远端配置导磁材料段4，既当选择电磁铁作为磁场源时，可选择在电磁铁3a远端配置导磁材料段4a，该导磁材料段由高效导磁材料42a和导磁材料封装膜41a组成，高效导磁材料42a可选择铁基导磁材料制成，优选为纯铁材料，导磁材料封装膜41a与磁场源封装膜31a材料相同；当选择永磁铁作为磁场源时，同样可选择在永磁铁3b远端配置导磁材料段4b，由高效导磁材料42b和导磁材料封装膜41b组成，导磁材料封装膜41b与磁场源封装膜31b材料相同；当磁场源远端不需要配置导磁材料段时，本发明将由手柄1，柔性杆2和磁场源3三部分组成，例如当选择永磁铁作为磁场源时，本发明远端磁场源将由永磁铁32c和其外部的磁场源封装膜31c组成；上述方案中的柔性杆2可由高分子材料制成，如选自PU、TPU、PE、PVC、NYLON、PEBAX和硅橡胶以及上述材料的改性材料等，相应的上述磁场源封装膜31a，31b，31c以及导磁材料封装膜41a，41b均选用与柔性杆相同的材料制成。
进一步地，本发明提供了一种包含磁性纳米粒子的产品，该磁性纳米粒子经进一步加工制成的取石溶液(生理盐水，缓冲液为溶剂)或取石粉剂，优选为取石溶液。所述产品是作为用于医学临床的产品。
所示的功能磁性纳米粒子结合磁探杆组成的泌尿系统结石高效取出系统的基本原理通过以下几步实现：1，体内结石的粉碎；2，功能磁性纳米粒子的注入，该磁性纳米粒子具有优良的分散性(分散性与分散系数相关联，分散系数越小，分散性越好)；3，功能磁性纳米粒子与结石的相互作用；4，功能磁性纳米粒子包覆结石(其中，包覆结石与磁性粒子的分散性密切相关，分散性越好，包覆结石的效果越优良)；5，结石表面的磁性纳米粒子的物理或化学交联；6，磁化后的结石在外加磁场引导下取出(其中结石经引导取出的效果与包覆结石的效果密切相关，包覆结石的效果越优良，结石有效取出的效果越优异)。所述的磁性纳米粒子是通过物理吸附、化学键合等作用包裹磁化结石。所述的物理吸附主要是指疏水性磁性粒子-粒子之间及粒子-结石在作用范围内通过范德华力及疏水相互作用而产生的吸引作用，使得磁性粒子吸附并包裹于结石表面；所述的化学键合作用主要是指亲水性磁性纳米粒子-粒子之间及粒子-结石之间 主要通过形成化学键(粒子表面的羧基-结石间的化学键如氢键、共价键等)的方式作用在一起，使得磁性粒子包裹于结石表面；所述化学键合包括功能磁性纳米粒子(如光敏、温敏纳米粒子等)首先通过物理吸附作用于结石，然后通过光敏交联、温敏物理缠绕(交联)等方式进一步增强粒子-粒子之间及粒子-结石之间的作用力来包裹结石。上述作用的原理如图15所示。另外，在纳米粒子经表面修饰单体修饰过程中，表面修饰剂单体的滴加方式或表面修饰剂单体所形成的外壳占纳米粒子的重量百分比散性有显著的影响，如图18-21所示。
以下列举本发明的磁性纳米粒子的结构、制备及其使用的详细示例。
实施例1磁性纳米粒子内核的制备
1.10nmFe3O4的制备-共沉淀法
用50ml去离子水溶解3.05g FeCl3.6H2O和2.08g FeCl2.4H2O(摩尔比1∶1)于三口烧瓶中，实验全程通氮气；用注射器逐滴加入氨水，室温下剧烈搅拌，将pH调至9，溶液由黄色逐渐变成棕色最后变成黑色，反应20分钟；反应结束后，将溶液置于70℃水浴孵育20分钟，剧烈搅拌，以除去多余的氨水；取出三口烧瓶，自然冷却至室温，同时剧烈搅拌；将合成的Fe3O4磁粒子悬液倒入50ml离心管中，用强力磁铁吸引磁粒子，弃废液，加入去离子水，超声重悬磁粒子，如此反复几次洗去多余的氨水至pH中性；将收集的磁粒子置于65℃烘箱中干燥除水；称量合成的磁粒子重量，并配制1.0ml0.02mg/ml磁粒子悬液，用于测量粒径；将0.02M油酸钠溶液逐滴加入到1.0ml 0.2mg/ml磁粒子悬液中，共滴加了1.5ml，在70℃、氮气保护并剧烈搅拌下反应30分钟，然后冷却至室温；过量的油酸钠使用12KD的透析膜透析除去；配制1.0ml 0.02mg/ml油酸钠包裹的Fe3O4溶液，测量其粒径。
2.Fe3O4磁性纳米粒子内核的制备
2.1热分解法
2.1.1合成4nm Fe3O4种子：
5mmol三乙酰丙酮化铁、5mmol 1，2-二羟基十六烷、3mmol油酸、1mmol油胺溶解在20ml的二苯醚中，在氮气保护下磁力搅拌；上述混合液在200℃下加热30分钟后，在氮气保护作用下，265℃加热回流30分钟；停止加热，让反应得到的黑褐色混合液冷却至室温；在大气环境下，加入400ml乙醇，所得黑色的材料通过超速离心 的方法进行分离；离心得到的黑色产物重新溶解在溶有50μL油酸和50μL油胺的正己烷中，600转/10分钟离心除去不溶的残留物；得到的4nm Fe3O4产物用乙醇沉淀，600转/离心10分钟除去溶剂后重新分散到正己烷中。分别以以下不同的方法合成不同大小的表面功能化的纳米粒子。
2.1.2利用4nm Fe3O4种子合成6nm Fe3O4纳米粒子内核
20mmol三乙酰丙酮化铁、10mmol 1，2-二羟基十六烷、6mmol油酸、6mmol油胺溶解在20ml的二苯醚中，在氮气保护下磁力搅拌；上述混合液在200℃下加热2h后，在氮气保护作用下，300℃加热回流1h；停止加热，让反应得到的黑褐色混合液冷却至室温；按前述4nm Fe3O4粒子合成的操作步骤，得到正己烷分散的黑褐色6nm Fe3O4粒子悬液。
2.1.3利用6nm Fe3O4种子合成8nm Fe3O4纳米粒子内核
2mmol三乙酰丙酮化铁、10mmol 1，2-二羟基十六烷、2mmol油酸、2mmol油胺溶解在20ml的乙醚中，在氮气保护下磁力搅拌；称量84mg 6nm Fe3O4粒子，溶于4ml正己烷中，后将其加入上述混合液中；上述混合液首先在100℃下加热30分钟，以除去正己烷，然后在200℃加热1h，接着在氮气保护作用下，300℃加热回流30分钟；停止加热，让反应得到的黑色混合液冷却至室温；按前述4nm Fe3O4粒子合成的操作步骤，得到正己烷分散的黑褐色8nm Fe3O4粒子悬液。类似的，80mg 8nm Fe3O4种子与2mmol三乙酰丙酮化铁和10mmol 1，2-二羟基十六烷反应，可生成10nm Fe3O4纳米粒子。使用这种Fe3O4种子介导的生长方法，可以合成更大粒径的Fe3O4纳米粒子(可达到20nm)。
2.1.4.Fe3O4纳米粒子内核的表面进一步修饰
在大气环境下，将200μl分散有20mg疏水性Fe3O4纳米粒子内核的正己烷溶剂加入2ml溶有20mg 11-氨基十一烷酸四甲基铵盐的二氯甲烷悬液中；震荡该混合液20分钟，期间使用磁铁分离沉降下来的Fe3O4纳米粒子；轻轻倒出溶剂和非磁性的悬浮物，得到的沉淀物用二氯甲烷洗涤一次后用磁铁再次进行分离以除去过量的表面活性剂；在通氮气的条件下干燥得到的产物，后分散到去离子水或pH中性的PBS中即可。
2.2水热合成法
1.35g，5mmol的六水合三氯化铁(FeCl3·6H2O)溶解在40mL乙二醇溶液中形 成澄清的溶液；向上述溶液中加入3.6g醋酸钠和1.0g聚乙二醇，剧烈搅拌30分钟；然后转到50ml密封的不锈钢制高压反应釜中，在200℃下反应8-72h，然后冷却到室温；反应得到的黑色产物用乙醇洗涤几次后在60℃下干燥6h即可；得到粒径在10nm以下的磁性纳米粒子内核。
2.3微乳液法(反相胶束法)
5mmol的Mn(NO3)3和10mmol的Fe(NO3)3溶解在25mL的去离子水中形成澄清透明的溶液；25mL 0.4M的NaDBS([CH3(CH2)11(C6H4)SO3]Na)加入到上述的铁离子溶液中，接着加入大量体积的甲苯，得到的MnFe2O4纳米粒子的粒径取决于水和甲苯的体积比；例如要得到8nm的纳米粒子，水和甲苯的体积比为5∶100；将上述混合液搅拌过夜后，变成含有反向胶束的澄清的单相溶液。
为在反相胶束中形成胶体，在剧烈搅拌下逐滴加入40mL 1M的NaOH溶液，继续搅拌2h即可；通过蒸馏的方法除去溶液中的水和大部分甲苯，使溶液的体积缩小；将上述浓缩后含有悬浮胶体的溶液用水和乙醇清洗以除去溶液中多余的表面活性剂，通过超速离心得到初步磁性纳米粒子内核，在350℃，氮气环境下加热12h即可得到纳米晶体。
实施例2疏水聚苯乙烯表面修饰
(在实施例1得到的磁性纳米粒子内核(MnFe2O4)上进行修饰)
将平均粒径为9nm的MnFe2O4纳米粒子加入浓度为1.0mol/L的引发剂水溶液-3-氯丙酸溶液中，用盐酸将溶液pH调至4，搅拌过夜；用磁铁收集纳米粒子，用水多次洗涤以去除多余的3-氯丙酸；将0.22g干燥的纳米粒子加入持续通氮气的8mL聚苯乙烯溶液中，然后加入4mL溶有0.3mmol CuCl和1.1mmol 4，4′-二壬基-2，2-联吡啶的二甲苯溶液；将上述混合液在130℃，持续搅拌下反应24h；用磁铁收集纳米粒子并用甲苯反复洗涤，得到聚苯乙烯包裹的磁性氧化铁纳米粒子。
实施例3亲水性聚丙烯酸修饰
取1g实施例1中得到的Fe3O4(例如，通过共沉淀法获得的10nm Fe3O4)，5ml的硅烷偶联剂(甲基丙烯酰氧基丙基三甲氧基硅烷，KH570)，与50ml的二甲苯混合于反应瓶中。在氮气保护下，80℃搅拌反应3h。反应完成后离心，并用乙醇洗3遍， 去除吸附在Fe3O4表面的硅烷偶联剂，真空干燥12h；取上述硅氧烷偶联剂活化的Fe3O4，40mg的过硫酸钾，30ml的去离子水于烧瓶中，在氮气保护下，40℃搅拌反应10分钟。然后将4ml的丙烯酸缓慢滴入烧瓶中，在氮气保护下，40℃搅拌反应1h。通过磁性分离纳米粒子，用去离子水洗3次，最后真空干燥。
实施例4纳米粒子的光敏功能修饰
1.光敏功能单体的合成
具有光交联特性的光敏单体合成方法，4-乙烯基二苯甲酮(4VBP)和苯乙烯单体直接聚合通过原子转移自由基聚合反应(ATRP)共聚，获得具有光敏特性的聚苯乙烯-聚乙烯二苯甲酮共聚物(PS-PVBP)共聚物，具体步骤如下：在连接有回流冷凝管的干燥史兰克管中，加入(0.695mg，4.8umol)的Cu(I)Br，(1.0g，4.8mmol)的4VBP，(2u，20umol)的苯乙烯和(1μL，4.8umol)的4-乙烯基二苯甲酮，上述混合物通过冰冻-抽空-解冻循环三次脱气；在-78℃，正氮气压条件下，往上述混合物中加入(5.35μL，48umol)的丙溴酸甲酯，以上混合物被再次通过冰冻-抽空-解冻循环三次除气。负压下加热混合物至85℃，即可发生聚合，反应维持4h；把上述史兰克管浸入液氮中，并加入10ml二氯甲烷以溶解聚合物；所得溶液用甲醇沉淀两次(2×300mL)，得到淡黄色固体PSx-PVBPy，x：y～(60％-90％)，较佳的组成为PS75-PVBP25。同样的方法，通过添加亲水单体丙烯酸，可以获得PS75-PVBP25-PAA100。
2.光敏交联胶束包裹纳米粒子的制备
(聚苯乙烯75-共-聚乙烯二苯甲酮25)-聚丙烯酸100，即(PS75-共-PVBP25)115-b-PAA100，被选作在水溶液中形成胶束的多聚物。将5mg(PS75-共-PVBP25)115-b-PAA100和实施例1中得到的Fe3O410mg(例如，通过共沉淀法获得的10nm Fe3O4)溶于10ml二甲基甲酰胺(DMF)溶液中；随后，在剧烈搅拌下，逐渐加入双蒸水(0.1ml/分钟)；当水的体积达到60％时，将所得溶液加入截断分子量为12K-14K的透析膜中，用水透析24h，以除去DMF；接着，把胶束溶液移入石英管中，分别在不同时间段用激光器辐照(发射波长为315-400nm)，形成光敏单体包裹的纳米粒子。
实施例5纳米粒子的温敏功能修饰
取1g实施例1中得到的Fe3O4(例如，通过共沉淀法获得的10nm Fe3O4)，5ml 的硅烷偶联剂(甲基丙烯酰氧基丙基三甲氧基硅烷，KH570)，与50ml的二甲苯混合于反应瓶中。在氮气保护下，80℃搅拌反应3h。反应完成后离心，并用乙醇洗3遍，去除吸附在Fe3O4表面的硅烷偶联剂，真空干燥12h；取上述硅氧烷偶联剂活化的Fe3O4，40mg的过硫酸钾，30ml的去离子水于烧瓶中，在氮气保护下，40℃搅拌反应10分钟。然后将4ml的N-异丙基丙烯酰胺水溶液缓慢滴入烧瓶中，在氮气保护下，40℃搅拌反应1h。通过磁性分离纳米粒子，用去离子水洗3次，最后真空干燥。
实施例6纳米粒子的pH敏感功能修饰
取1g实施例1中得到的Fe3O4(例如，通过共沉淀法获得的10nm Fe3O4)，5ml的硅烷偶联剂(甲基丙烯酰氧基丙基三甲氧基硅烷，KH570)，与50ml的二甲苯混合于反应瓶中。在氮气保护下，80℃搅拌反应3h。反应完成后离心，并用乙醇洗3遍，去除吸附在Fe3O4表面的硅烷偶联剂，真空干燥12h；取上述硅氧烷偶联剂活化的Fe3O4，40mg的过硫酸钾，30ml的去离子水于烧瓶中，在氮气保护下，40℃搅拌反应10分钟。然后将4ml的甲基丙烯酸二甲胺乙酯水溶液缓慢滴入烧瓶中，在氮气保护下，40℃搅拌反应1h。通过磁性分离纳米粒子，用去离子水洗3次，最后真空干燥。
实施例7生物相容性评价
细胞铺板：取对数生长期的293t细胞消化、离心后计数，在96孔板中铺细胞密度为5.0×104/孔，每孔加入100μl含血清培养液，周围一圈空白细胞孔每个均用100μl含血清培养液补足，放置在7％CO2，37℃的细胞培养箱中过夜。取实施例3的亲水性修饰的磁性纳米粒子加入细胞孔中，与N87细胞进行孵育，每孔加入100μl，其中实施例3所得的磁性纳米粒子的浓度分别为0.1、0.2、0.4、0.8、1.0mg/ml；分别在37℃孵育24h后，用培养基轻轻洗2遍，然后用Cell Counting Kit-8试剂盒检测细胞生存率，其中检测条件为：CCK-8试剂每孔10μl，37℃孵育2h，450nm处用BIO-TEK ELx800全自动酶标仪读出吸光度值，并计算细胞存活率。结果如图5所示，表明合成的亲水性修饰的磁性纳米粒子具有良好的生物相容性，对体内几乎没有毒性，初步证明可以用于体内实验。
实施例8体外纳米粒子辅助结石分离评价
如图6所示，称取一定量的结石，用杵棒撵成粉末，(粒径0.5-2mm)，倒入透明玻璃瓶中，往结石液中添加PBS溶液，获得结石液，混匀后，加入浓度1mg/ml的实施例3的亲水性修饰的磁粒子分离液，轻轻摇晃。静置五分钟后，用磁铁分离。静置过程中能够看到混合液颜色逐渐变淡，五分钟后，能够观察到黑色的磁粒子吸附在结石的表面。在磁场的引导下，表面吸附有磁粒子的结石向磁铁方向移动。
实施例9纳米粒子的动物体内安全性评价
如图7所示，取6周龄裸鼠1只和小鼠3只，分别进行腹腔注射和尾静脉注射。取实施例3的亲水性修饰的磁性纳米粒子浓度为0.5mg/ml，200μL，连续注射两天。定时(如一周，两周等)观察小鼠的生活状态。结果显示，静脉注射200μL磁性纳米粒子溶液后，1周之内，裸鼠及小鼠没有发现明显的毒性；腹腔注射同样浓度的粒子溶液3次，观察发现3个月之内小鼠及大鼠的存活状态良好。说明所制备的磁性纳米粒子具有良好的生物相容性，初步评估其基本没有急性毒性和慢性毒性。
实施例10磁性纳米粒子用于泌尿系结石取出
在肾脏结石疾病治疗过程中，取输尿管软镜行肾脏结石钬激光碎石术，术中利用钬激光完成肾脏结石的破碎步骤后，取本发明实施例3中制备得到的亲水性磁性纳米粒子溶液200ml，通过输尿管软镜的工作通道将该溶液注射到肾脏内，使得亲水性磁性纳米粒子溶液与结石碎屑进行充分混合，约3分钟后，溶液中的纳米粒子完全附着到结石碎屑表面，将结石碎屑磁化。取上述以钕铁硼永磁铁为磁场源3的泌尿系统结石取出磁探杆系统，经输尿管软镜的工作通道置入肾脏内，在磁探杆系统远端的磁场作用下，被磁化的结石碎屑将向磁探杆末端靠拢并吸附在磁探杆上。最后，将末端吸满结石碎屑的磁探杆系统连同输尿管软镜一起从输尿管软镜鞘内退出至体外，取下磁探杆末端的结石碎屑，并再次插入内窥镜行取结石操作，至肾脏内所有结石碎屑被取出体外。本实施例中结石直径约为20mm，位于肾脏下盏内，通过本发明中亲水性磁性纳米粒子材料配合结石取出磁探杆系统的使用，使得结石全部(100％)被取出体外，相比传统利用取石网篮取出结石和通过粉末化碎石让患者自行排石的做法，本发明中的技术方案做到了简单高效的完全排石，大大提高了取石手术效率和安全性。
实施例11表面修饰剂单体滴加方式对磁性纳米粒子分散性的影响
取1g实施例1中得到的Fe3O4(例如，通过共沉淀法获得的10nm Fe3O4)，5ml的硅烷偶联剂(甲基丙烯酰氧基丙基三甲氧基硅烷，KH570)，与50ml的二甲苯混合于反应瓶中。在氮气保护下，80℃搅拌反应3h。反应完成后离心，并用乙醇洗3遍，去除吸附在Fe3O4表面的硅烷偶联剂，真空干燥12h；取上述硅氧烷偶联剂活化的Fe3O4，40mg的过硫酸钾，30ml的去离子水于烧瓶中，在氮气保护下，40℃搅拌反应10分钟。
为了比较表面修饰剂单体(丙烯酸作为代表)的滴加方式对最终磁性纳米粒子的粒子分散性的影响，系统地比较了滴加组(手动逐步滴加丙烯酸表面修饰单体)和连续加组(电子连续滴加丙烯酸表面修饰单体)的实验。在滴加组中，手动逐步滴加4ml的丙烯酸通过注射器，人工逐步(每隔3秒)滴入烧瓶中，在氮气保护下，40℃搅拌反应1h；在连续加组中，电子连续滴加4ml的丙烯酸通过电子泵按照设计的速度不间断的滴加到烧瓶中，在氮气保护下，40℃搅拌反应1h。最后，通过磁性分离纳米粒子，用去离子水洗3次，最后真空干燥。
使用德国ALV-CGS3动静态激光光散射仪，测定磁性纳米粒子的单分散性系数，具体的实验结果请参见图18。由图18可知，相对于滴加组的磁性纳米粒子的粒子单分散性系数(0.478±0.075)而言，连续加组的磁性纳米粒子的粒子单分散性系数(0.0043±0.0016)远远更低，由此连续加组获得的磁性纳米粒子具有更优异的分散性。
进一步地，由图19-20可知，连续加组的磁性纳米粒子的分散性比滴加组的磁性纳米粒子的分散性更加优异。
实施例12纳米粒子外壳占纳米粒子的重量百分比对纳米粒子分散性的影响
取1g实施例1中得到的Fe3O4(例如，通过共沉淀法获得的10nm Fe3O4)，5ml的硅烷偶联剂(甲基丙烯酰氧基丙基三甲氧基硅烷，KH570)，与50ml的二甲苯混合于反应瓶中。在氮气保护下，80℃搅拌反应3h。反应完成后离心，并用乙醇洗3遍，去除吸附在Fe3O4表面的硅烷偶联剂，真空干燥12h；取上述硅氧烷偶联剂活化的Fe3O4，40mg的过硫酸钾，30ml的去离子水于烧瓶中，在氮气保护下，40℃搅拌反应10分钟。
为了比较表面修饰单体(丙烯酸作为代表)在纳米粒子表面形成的外壳的重量百分比对最终粒子分散性的影响，系统地比较了下述六个组中纳米粒子的纳米粒子分散 性：第1组(外壳占粒子重量百分比为0.5％)、第2组(外壳占粒子重量百分比为1％)、第3组(外壳占粒子重量百分比为2％)、第4组(外壳占粒子重量百分比为15％)、第5组(外壳占粒子重量百分比为40％)和第6组(外壳占粒子重量百分比为45％)。在实验中，各重量百分比组的丙烯酸水溶液缓慢滴入烧瓶中，在氮气保护下，40℃搅拌反应1h。通过磁性分离纳米粒子，用去离子水洗3次，最后真空干燥。
使用德国ALV-CGS3动静态激光光散射仪，测定磁性纳米粒子的单分散性系数，具体的实验结果如下：第1组的纳米粒子的单分散性系数为0.5±0.04；第2组的纳米粒子的单分散性系数为0.026±0.0026；第3组的纳米粒子的单分散性系数为0.036±0.003；第4组的纳米粒子的单分散性系数为0.022±0.002；第5组的纳米粒子的单分散性系数为0.031±0.0028；第6组的纳米粒子的单分散性系数为0.58±0.05。
上述实验结果表明，与第1和6组，即，外壳占粒子重量百分比为0.5％和45％组的纳米粒子的单分散性系数相比，第2、3、4和5组，即，外壳占粒子重量百分比为1％、2％、15％和40％组的纳米粒子的单分散性系数远远更低(请参见图21)，由此第2、3、4和5组的纳米粒子具有更优异的分散性。
虽然本发明的许多实施方案已经示于附图和/或在这里讨论，但并不意于将本发明限制于此。可以预料的是本发明的宽度范围将相同于本领域所允许的、以及说明书可以同样的理解。因此，上述描述不应被解释为限制，而仅仅是具体实施方案的例证。本领域技术人员能够在附于此的权利要求书的范围和精神内想象出其他的变型。

Claims (20)

  1. 一种纳米粒子，所述纳米粒子包括：
    由磁性材料构成的纳米粒子内核；以及
    通过引发剂和/或交联剂将表面修饰剂单体原位修饰到所述纳米粒子内核表面形成的纳米粒子外壳；
    其中，经过表面修饰功能化后所述纳米粒子表面含有酰胺键或者羧基，且所述外壳占纳米粒子重量百分比为0.5-45％(不包括端点)。
  2. 如权利要求1所述的纳米粒子，其中所述外壳占纳米粒子重量百分比为1-40％，优选为2-40％，更优选为1-15％，还更优为2-15％，最优选为1％、2％、15％或40％。
  3. 如权利要求1所述的纳米粒子，其中所述纳米粒子内核直径为2-50nm，重量占整个纳米粒子的重量百分比为30％～95％，其磁性材料包括Fe3+、Fe2+、Mn2+、Ni2+化合物，或铁、镍、铜、钴、铂、金、铕、钆、镝、铽金属单质、或上述金属的复合物及氧化物、或上述的一种或任意两种以上的组合，优选Fe3+、Fe2+、Mn2+、Ni2+化合物，更优选Fe3+和Fe2+且比例为15％到85％，优选1∶2.5到1.5∶1。
  4. 如权利要求1-3中任一项所述的纳米粒子，其中所述表面修饰剂包括亲水性、疏水性、光敏性、温敏性或pH敏感性功能响应性表面修饰剂，其中亲水性表面修饰剂包括丙烯酸、甲基丙烯酸、异丁基丙烯酰胺或聚N-取代异丙基丙烯酰胺；所述疏水性表面修饰剂包括烯烃类，优选聚苯乙烯、聚乙烯或油酸；所述光敏性表面修饰剂选自偶氮类和喹啉类及二苯甲酮(PVBP)类，优选乙烯二苯甲酮；所述温敏性表面修饰剂选自带有酰胺键的两亲性聚合物，优选聚丙烯酰胺或聚N-取代异丙基丙烯酰胺；所述pH敏感性表面修饰剂选自带有羧基和季铵盐类聚合物，优选聚丙烯酸、二甲胺乙酯及甲基丙烯酸二甲胺丙酯；所述粒子为球形、棒状或菱形。
  5. 如权利要求1-3中任一项所述的纳米粒子，其中所述交联剂包括3-(甲基丙烯酰氧基)丙基三乙氧基硅烷、二乙烯基苯、二异氰酸酯或N，N-亚甲基双丙烯酰胺， 而所述引发剂包括3-氯丙酸、CuCl、4，4′-二壬基-2，2-联吡啶或过硫酸钾。
  6. 一种纳米粒子，所述纳米粒子包括：
    由磁性材料构成的纳米粒子内核；以及
    通过引发剂和/或交联剂将表面修饰剂单体原位修饰到所述纳米粒子内核表面形成的纳米粒子外壳；
    其中，经过表面修饰功能化后所述纳米粒子表面含有酰胺键或者羧基，且所述磁性纳米粒子内核制备方法为共沉淀法，其中所述表面修饰剂单体的添加方式为电子泵辅助连续滴加。
  7. 如权利要求6所述的纳米粒子，其中所述纳米粒子内核直径为2-50nm，重量占整个纳米粒子的重量百分比为30％～95％，其磁性材料包括Fe3+、Fe2+、Mn2+、Ni2+化合物，或铁、镍、铜、钴、铂、金、铕、钆、镝、铽金属单质、或上述金属的复合物及氧化物、或上述的一种或任意两种以上的组合，优选Fe3+、Fe2+、Mn2+、Ni2+化合物，更优选Fe3+和Fe2+且比例为15％到85％，优选1∶2.5到1.5∶1。
  8. 如权利要求7所述的纳米粒子，其中
    所述纳米粒子与结石包裹交联作用的作用力包括：形成相互作用包裹的范德华力、疏水相互作用、吸附及表面沉积；羧基-结石之间形成化学键，包括氢键、酯键、酰胺键及其他共价键；链间的相互物理及化学链间缠绕和链间的化学交联。
  9. 如权利要求6-8中任一项所述的纳米粒子，其中所述表面修饰剂包括亲水性、疏水性、光敏性、温敏性或pH敏感性功能响应性表面修饰剂，其中亲水性表面修饰剂包括丙烯酸、甲基丙烯酸、异丁基丙烯酰胺或聚N-取代异丙基丙烯酰胺；所述疏水性表面修饰剂包括烯烃类，优选聚苯乙烯、聚乙烯或油酸；所述光敏性表面修饰剂选自偶氮类和喹啉类及二苯甲酮(PVBP)类，优选乙烯二苯甲酮；所述温敏性表面修饰剂选自带有酰胺键的两亲性聚合物，优选聚丙烯酰胺或聚N-取代异丙基丙烯酰胺；所述pH敏感性表面修饰剂选自带有羧基和季铵盐类聚合物，优选聚丙烯酸、二甲胺乙酯及甲基丙烯酸二甲胺丙酯；外壳占纳米粒子重量百分比为0.5-45％(不包括端点)， 优选为1-40％，更优选为2-40％，还更优选为1-15％或2-15％，最优选为1％、2％、15％或40％，优选所述粒子为球形、棒状或菱形。
  10. 如权利要求6-9中任一项所述的纳米粒子，其中所述交联剂包括3-(甲基丙烯酰氧基)丙基三乙氧基硅烷、二乙烯基苯、二异氰酸酯或N，N-亚甲基双丙烯酰胺，而所述引发剂包括3-氯丙酸、CuCl、4，4′-二壬基-2，2-联吡啶或过硫酸钾。
  11. 一种制备权利要求1-10中任一项所述的纳米粒子的方法，包括步骤：
    a)利用磁性材料制备纳米粒子内核；
    b)通过引发剂和/或交联剂将表面修饰剂单体原位连接到所述纳米粒子内核以形成纳米粒子外壳，从而形成所述纳米粒子。
  12. 如权利要求11所述的方法，其中所述磁性材料包括Fe3+、Fe2+、Mn2+、Ni2+化合物、或铁、镍、铜、钴、铂、金、铕、钆、镝、铽金属单质、或上述金属的复合物及氧化物、或上述的一种或任意两种以上的组合，优选Fe3O4、MnFe2O4、γ-Fe2O3或其他纳米级尺寸的铁氧体粒子，更优选FeCl3·6H2O和FeCl2·4H2O，其摩尔比为15％到85％，优选1∶2.5到1.5∶1，通过如下步骤制备：
    将一定比例的含金属盐材料溶解于水中；
    通入氮气将溶液中的氧气排出；
    在常温10-40℃，优选30℃下加入催化剂来调节pH值为7-12，优选10；
    继续搅拌反应10-60分钟；并且
    在40-100℃下，优选70℃水浴下，反应20-40分钟后，用磁铁分离干燥即可得到磁性纳米粒子内核。
  13. 如权利要求12所述的方法，其中当将氨水作为催化剂来制备纳米粒子时，所述氨水的滴加方法为电子泵辅助连续滴加，速度在20-100滴/分钟，优选40-60滴/分钟；并且当所述磁性材料为液态单体材料时，所述液体单体的添加方式为电子泵辅助连续滴加，反应搅拌速度在100-1000转/分钟，优选500-700转/分钟。
  14. 如权利要求11-13任一项所述的方法，进一步包括在所得纳米粒子内核基础上进行疏水性表面修饰，包括步骤：
    将所制备的纳米粒子内核分散到水溶液中，并且加入3-氯丙酸、聚苯乙烯、CuCl和4，4′-二壬基-2，2-联吡啶的二甲苯溶液，上述纳米粒子内核溶液与反应液之间摩尔比例为1∶1；
    将上述混合液在130℃，持续搅拌下反应15-30h，优选24小时；并且
    用磁铁收集纳米粒子并用甲苯反复洗涤，得到疏水聚苯乙烯包裹的磁性纳米粒子。
  15. 如权利要求11-13任一项所述的方法，进一步包括在所得纳米粒子内核基础上进行亲水性表面修饰，包括步骤：
    将纳米粒子内核溶解分散到二甲苯中，并且加入硅烷偶联剂，其中纳米粒子、二甲苯和硅烷偶联剂的加入比例为95∶5；
    在氮气保护下，20-100℃，优选80℃下反应2-5h，优选3小时；
    用醇类溶剂洗涤干燥12h，经超声分散到水溶液中，加入过硫酸钾；
    在氮气保护下，40-80℃下反应10分钟后加入丙烯酸继续在40-80℃下反应1h，优选反应温度70度；并且
    磁分离洗涤干燥，即可制备得到聚丙烯酸修饰的亲水性纳米粒子。
  16. 如权利要求11-13任一项所述的方法，进一步包括在所得纳米粒子内核基础上或在亲水性表面上进行光敏、温敏及pH敏感性表面修饰、或在纳米粒子内核基础上进行亲水性、疏水性、光敏、温敏、pH敏感共修饰，其中在亲水性表面上进行再修饰包括步骤：
    将聚丙烯酸修饰的磁性纳米粒子溶解分散于醇类溶剂中，加入光敏单体如乙烯二苯甲酮，温敏单体如N-异丙基丙烯酰胺，或pH敏感单体如甲基丙烯酸二甲胺丙酯或丙烯酸及苯乙烯的共混单体，继续在40-80℃下反应1h，优选反应温度70度；并且磁分离洗涤干燥，即可分别制备得到光敏性、温敏性或pH敏感性功能性单体修饰的磁性纳米粒子。
  17. 一种结石取出装置，包括如权利要求1-10中任一项所述的纳米粒子和末端柔 性的磁探杆系统，所述磁探杆系统包括手柄、柔性杆、磁场源和导磁材料。
  18. 如权利要求17所述的结石取出装置，其中所述磁探杆系统在手柄上设有交流或直流电源、电源开关、直流电池仓或交流电插头；柔性探杆由高分子材料制成，优选所述柔性探杆中后端包含永磁铁，并任选在柔性探杆末端包含柔性导磁材料。
  19. 一种产品，所述产品包含如权利要求1-10中任一项所述的纳米粒子，其中所述纳米粒子为溶液或粉剂，优选为溶液。
  20. 权利要求1-10任一项所述的纳米粒子制备用于生物体内取石的产品的用途，所述产品优选用于人或动物的泌尿系统取石。
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