TW201103563A - Drug delivery nanodevice, its preparation method and uses thereof - Google Patents

Abstract

Nanodevice and method for in vivo monitoring and release of drugs are provided. The disclosed nanodevice is characterized in having a drug-loaded nanosphere that is capable of releasing the encapsulated drugs upon magnetically stimulation. The nanodevice may also be used as a contrast agent for in vivo imaging and monitoring the concentration and distribution of the released drugs and/or active compounds injected separately into a target site of a subject.

Description

201103563 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a nanometer drug delivery device, a preparation method and use thereof. [Prior Art] There are many ways to deliver drugs to patients, including oral, nasal inhalation, transmucosal diffusion, subcutaneous and intramuscular injection, parenteral and implantation. Oral has always been the most common way. However, current oral medications, including capsules and suspicions, have some shortcomings, such as poor efficacy and non-controlled release resulting in too fast absorption of the drug or incomplete absorption, gastrointestinal discomfort and other side effects. In addition, these drugs may not provide a local therapeutic effect and/or may not be able to monitor the release of the drug in real time. Therefore, there is a need for an improved drug delivery system and/or device for more efficient delivery of drugs into a patient, reducing side effects while allowing for the tracking of drug release at a target location within the patient in vivo. A variety of imaging techniques are available to track metallic nanoparticles, such as nanogold particles, in vivo. The images produced by these imaging techniques reflect the differences in tissue and structural density within an individual's body. The most commonly used imaging techniques include X-ray photography, c〇mputed tomography (CT), and nuclear magnetic resonance imaging (MRI). The invention designs, manufactures and adopts a novel nano device as a drug delivery carrier' to stimulate a specific part of an individual's body, and can actively release the drug from the distal end of 201103563, and can utilize the above Know the contrast technique to track the release of the drug in vivo, including its concentration and distribution. SUMMARY OF THE INVENTION The present disclosure is directed to a nanoscale drug delivery device, a method of manufacture and use thereof. This nanoscale drug delivery device comprises a nanosphere characterized by a shell-core structure. The core phase of the nanosphere can be embedded with a drug or a biologically active substance, and the outer shell is made of a magnetic material, and further a quantum dot is bonded on the surface of the shell layer to form a so-called nai. Meter device (nanodevice). When a specific magnetic field is applied to the unique structure of the nano device, the magnetic outer casing is magnetically stimulated to induce deformation of the magnetic outer casing, and the quantum dots are optically changed, so that the drug or biologically active substance embedded in the nuclear phase can Depending on the strength of the applied magnetic field and the length of time, it is released into the specific body part of the subject to be tested in a controlled release form. In addition, other suitable imaging techniques, such as X-ray photography, computed tomography, and magnetic resonance imaging, can be used to track the nanoscale drug delivery device of the present disclosure in vivo with or without the application of an additive. . A first aspect of the present disclosure is to provide a method of making a nanoscale drug delivery device. The method comprises the steps of: (a) providing a first solution that disperses nanospheres in a first solvent comprising a zinc salt; (b) providing a second solution that is capable of at least two quantum dot precursors Mixing in the second solvent; (c) mixing the first solution with the second solution to form a quantum dot on the surface of the nanosphere. The first solvent is usually composed of two solvents selected from the group consisting of trioctylphosphine (TOP), tetrahydrofuran (THF), tetrahydrofuran (THF), C6-18 olefins and dimethylsulfoxidase. , DMSO); the second solvent is an alkylamine such as oleylamine and hexadecylamine. The quantum dot precursor is at least two materials selected from the group consisting of cuprous chloride (I), indium (III) trichloride, indium (III) iodide, sulfur powder, zinc stearate, Gasification of cadmium and Te powder. The quantum dots themselves are paramagnetic and can be any of the following:

CuInZn, CuInS2, CdS, ZnS or CdTe. According to an example, the above-described nanosphere is formed by a method comprising the steps of: (a) mixing a polymerizable material, an inorganic material or a mixture thereof with a drug into a suspension in a polar solvent, thereby forming a drug-containing nanoparticle; and (b) adding at least two metal oxide precursors to the suspension; wherein the at least two metal oxide precursors may surround the Nai granules of the drug And self-assembled into a metal oxide shell. In one embodiment, the polymeric material is selected from the group consisting of polyethylene 11 pyrrolidone (PVP), polyethylene (PE), polyamine, polyester, polyanhydride, polyether, polyacetal, polysaccharide, and phospholipid In the group of substances composed; and the inorganic material is selected from the group consisting of titanium oxide, cerium oxide, and a composite material composed of calcium and phosphorus. The metal oxide outer shell is a single crystal shell layer, a polycrystalline shell layer or an amorphous shell comprising any of the following materials, including Fe2〇3 Fe304, CoFe204, MnFe204 or Gd203. A second aspect of the present disclosure is to provide a nanodevice. The nanodevice includes a nanosphere and a quantum dot. This nanosphere contains a core made of a polymerizable material, an inorganic material or a combination thereof, and an outer casing made of a metal emulsion. The above quantum dots are deposited on the surface of the outer casing and the quantum dots are selected from the group consisting of CuInZn, 201103563.

CuInS2, CdS, ZnS and CdTe. The drug suitable for embedding in the nucleus may be any of the following: an anti-epileptic agent, an anti-tumor agent, an antibacterial agent, an anti-viral gas, an anti-proliferative agent, an anti-inflammatory agent, an anti-diabetic agent, or a hormone. The third aspect of the present disclosure provides a method of tracking a nanodevice manufactured by the above method in vivo and a method of releasing it by magnetic induction. The method comprises the steps of applying a sufficient amount of the nanodevice of the invention to a body-body part; and magnetically stimulating the body part by about 10 to 180 with a magnetic field having an intensity between about 0.05 kA/m and 2.5 kA/m In seconds, the drug is embedded in the nanodevice. The drug is released to the body part of the individual that is magnetically stimulated. The method further comprises the steps of: tracking the body part of the individual in vivo by means of the present disclosure by means of χ_domain shadow, computerized tomography and nuclear magnetic resonance imaging without the application of a developer. The body of the two JS- / η-port MSLs can be exemplified by the following detailed description and the accompanying claims. Before the narrative, it should be understood that the terms in the specification and the attached words should not be interpreted as the best in the dictionary and the dictionary. The inventor is allowed to define (4) appropriately. It is only for the purpose of the explanation. The following is a detailed description of the preferred embodiment of the present invention with reference to the accompanying drawings. The following describes a novel nanomaterial for use in a live nanodevice, which produces a shadow and/or magnetically induced drug release. It is possible to control this part of the slave in the body, such as the brain of the human body. Moreover, it is possible to use the image technology of the developer to track the nano device in the living body with or without additional addition, monthly/lower. Conventional _ Examples of the agent include a visitor A >knowledge; ilS long-term iodine, iodine-based developer, hydrazine, hydrazine, iron oxide and/or oxidized woven with bell. (a) is a schematic view of the nano drug delivery device 1 of the present invention. This is the combination of the 梦7Γ and the rafter 10, which are formed by the nanosphere 1 and the scorpion point 14 shown in Fig. 1(b). In this example, only one quantum dot 14' is shown in green. However, it is to be understood that the quantum sphere 12 may contain a plurality of quantum dots 14 when necessary. This nanosphere 12 is characterized by a shell/core structure. 4 Xuan 16 may be composed of a polymerizable material, an inorganic material or a combination of the two materials. The outer casing 18 is composed of a metal oxide. Quantum dots 14 are deposited on the surface of the outer casing 18. The nanodevice 1 is designed to embed the drug in the core 16 of the nanosphere 12 composed of a polymeric material, an inorganic material or a combination of the two materials. The drug 20, which is embedded in the core 16, can be released in a controlled manner by magnetically stimulating the outer casing 18 with a magnetic field (MF) to deform and/or collapse the metal oxide outer casing. Making nanospheres The method of making nanospheres has been disclosed in the open literature (see Hu et al., "Core/Single-Crystal-Shell Nanospheres for Conducting 201103563

Drug Release via a Magnetically Triggered Rupturing

The mechanism, Adv. Mater., 2008 20, 2690-2695), the entire disclosure of which is hereby incorporated by reference in its entirety in its entirety in its entirety in the the the the the In a polar solvent such as water or a Cw alcohol, 1-10% by weight of a polymerizable material, an inorganic material or a mixture thereof is mixed with each other to form a suspension, thereby forming a polymer type, an inorganic type or a polymer. /inorganic nanoparticle; and adding at least two metal oxide precursors to the suspension; wherein the at least two metal oxide precursors self-assemble into a metal oxide shell around the inner nanoparticle A suitable polymerizable material that can be used to form the core phase of the nanosphere, including but not limited to 'polyacetone ketone (pvp), polymethylene (four), polyamine, poly, poly, Jujun, polycondensation, vinegar and vegetable fat. The above polysaccharide may be starch, sputum, ma ^, β cellulose, pectin, chitin or chitin; and the above mt phospholipid choline (pc ), phospholipid lysine (ps), phospholipid B is PVP. In an example, the polymer material is composed of, but not limited to, titanium dioxide, oxidized granules and a boat, and the inorganic material is a di-acid salt. Composite material. In one example, it is a dioxide oxidizer. ~1 cut; and in another, the inorganic material can self-assemble around the metal oxide y or inorganic nano particles, chlorination Ferrous (11), metal oxide precursors include 'but not limited (II), iron acetate (In), g ^ iron (111), cobaltated cobalt (11), ferrous nitrate Extrusion; face (11), barium chloride (antimony) and manganese acetate (11). Double may be a single crystal shell 201103563 layer, polycrystalline shell layer or amorphous shell layer containing any of the following materials, including Fe2 〇3, Fe3〇4, c〇Fe2Q4, MnFe2〇4 or Gd203. 4 In one example, the metal oxide outer shell is a single crystal type iron oxide shell formed by a method comprising the following steps: Or a polar solvent of an A 6 alcohol, containing a molar ratio of about 2:] [to about 5: !, which will contain ferrous chloride (II) and gas. At least two metal oxide precursors, including iron (111), are mixed and form a suspension; the pH is adjusted to between 7 and 2; and the formed iron oxide is self-assembled into a metal around the nanoparticle. Oxide shell. Suitable Cw alcohols may be selected from the group consisting of decyl alcohol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, isoamyl alcohol, hexanol, etc. Suitable metals may also be used. An oxide precursor according to the above steps to form a metal oxide shell composed of other metal halides. For example, CoCl2 and FeCl3 may be used to form a c〇Fe204 shell; MnCl2 and FeCl3 may be used to form a MnFe2〇4 shell; Barium acetate or Gd(〇H)2 is formed to form a Gd203 shell. If a drug-loaded nanosphere is to be produced, the biologically active substance may be added to the above suspension and mixed uniformly so that the drug may be embedded in the structure of the polymerizable material or the inorganic material; In the above manner, the metal oxide is surrounded by the drug-containing nanoparticle, and assembled into a metal oxide outer shell to form a desired drug-loaded nanosphere. The amount of drug that can be embedded in the core phase of the nanoparticle is generally determined by experimentation, and this depends on the type of drug to be embedded. In this context, the terms "drug (dmg)" or "biologically active substance" are used interchangeably and refer to conditions that can be used to treat and/or prevent a variety of pharmaceutical fields and can be A compound or composition that is administered to a living organism, such as 201103563, a mammal, particularly a human. Drugs useful herein include, but are not limited to, nucleic acids such as DNA or small interfering RNA (siRNA); peptides; proteins such as bovine serum albumin, glycoproteins or collagen; antibiotics; antioxidants such as vitamin E Or vitamin C (ie, ascorbic acid); immunogenic preparations, such as vaccines; anti-epileptic agents, such as acetazolamide, carbamazepine, clobazam, sulphate Clonazepam, diazepam, ethosuximide, ethotoin, felbamate, fosphenytoin, gabapentin, Lamotrigine, levetiracetam, mephenytoin, metharbital, methsuximide, methazolamide, epilepsy Oxcarbazepine), Phenobarbital, phenytoin, phensuximide, pregabalin, primidone, sodium valproate Substitute Alcohol (stiripentol), 0 tiagabine, topiramate, trimethadione, valproic acid, vigabatrin or salnifloxacin (zonisamide); anti-tumor agents, such as taxol, camptothecin (CPT), topotecan (TPT) or irinotecan (CPT-11); antibacterial agents such as zinc oxide or a quaternary amine compound; an antiviral agent such as acyclovir, ribavirin, zanamivir, oseltamivir, zidovudine or Lamivudine; anti-proliferative drug 201103563 'such as actinomycin, doxorubicin, daunorubicin, valrubicine, idarubicin, Epirubicin, bleomycin, plicamycin or mitomycin; anti-inflammatory agents such as corticosteroids, ibuprofen, cancer removal Ingot (methotrexate), aspirin, aspirin, Salicyclic acid, diphenyhydramine, naproxen, phenylbutazone. Bow j indomethacin or ketoprofen; anti-diabetic agents, including sulfonylureas, such as tolbutamide, acetohexamide, Tolazamide, chlorpropamide, glipizide, glyburide, glimepiride or gliclazide, amphetamine An acid derivative (eg, gliglelinide or nateglinide); a biguanides such as metformin, phenformin or buformin; Selling thiazolidinediones such as rosiglitazone, pioglitazone or troglitazone; alpha-glucosidase inhibitors such as rice Migitol or acarbose; peptide analogs, such as exenatide, liraglutide, taspoglutide, weige Column '' vildagliptin, Sugar vitamins (sitagliptin or pramlintide); and hormones, such as insulin, epidermal growth factor (EPF) and sterols, such as yellow 201103563 f apricot estrogen 1 glandular skin #_ 醇明In one embodiment, the 荜=素 contained in the nanosphere. According to this hair; 〇,), for example, about. ^ 2,5,8,1〇,19 1 c υ·2, 〇·5, 1, 35:3δ, Art: Should; 2 2 5 Need: Sound or Reality: %. In any medical field, there is a general magnetic field induction _===::, = the drug is two such as ethosylamine;

The prescription=drug is two J_ to 100, such as Xi Shuqing-(1), and the prepared nanospheres have an average diameter of about 10 to 100 nm, for example, about 1 〇, u, 17 Wide ". ,, 4. , 5. 60, 7. ,8. , 9 = eight amorphous shell and single crystal core also suggests that oxygen will surround the PVP core and self-assembled into an iron oxide shell. Iron bismuth Manufacture of nanodevices One of the present disclosures relates to a method for making a nanodevice. The disclosed method is characterized by the steps of: (4) providing a first solution 'the remaining nanospheres dispersed in the first solvent' and the zinc salt and the nanosphere in the first solvent are about 1-40 Mg/ml and 0.02-0.2 millimoles/ml; / (8) provides a second solution 'which mixes at least two quantum dot precursors in the agent' in which each quantum dot precursor is in the second solvent The concentration is about 0.003-0.03 millimoles/ml; 12 201103563 (c) at a temperature of about inert gas and about lot: ~300t: the liquid is mixed with the second solution to form a quantum on the surface of the nanosphere ...ΐStep (8) Let 'the first solution be formed in the presence of a zinc salt, too η in the first solvent. The nanosphere can be obtained by the above method; two: or no therapeutic agent or drug at its core can be loaded into the two phases according to the method disclosed above: In another example, the nanosphere can be Used as a developer, so there is no need to embed the drug in its core phase. The first solvent is usually composed of two solvents selected from the group consisting of trioctylphosphine (TOP), tetradium (10) rahydrofuran, THF. ), Q i8 hydrocarbons and di- to bases: ethy^xid, DMS0). In the examples, the first solvent is = and hexan. Suitable salts for use in the present invention include, but 1 'diethyl a thioaminyl-f-acid zinc salt. The concentration of the non-spherical dispersion in the first solution is between about gram/μl, for example, about 5, 1 〇, Gu Guang ^ 18 2 〇, 22, 25, 28, 30, 32, 35, 38 or 40 liters. The concentration of zinc salt dispersed in the first solution is between (4) 2 〇 2 mM/ml, for example about (10), G 〇 3, 〇〇 5, 〇 〇6, 〇〇7, 0.08 ' 0.1 > 0.11 s 0 12 > 〇^ * U.12 0.13, 0.14, 0.15, 〇.16, 0.17, 0.18, 0.19 or 〇·2 毫In step (b), the second solution is prepared by mixing at least two quantum dot precursors in a second solvent. In one example, the second solution is deleted. 'For example, oleylamine (ο- or heXadeCylamine). But 'other types of solvents can be used as long as 13 201103563. The solvent can dissolve the quantum dot precursor. The quantum dot type on the surface of the nanosphere shell is used to select an appropriate quantum dot precursor, and quantum dots suitable for use in the present invention include, but are not limited to, CuInZn, CuInS2, CdS, ZnS or CdTe. If the desired quantum dot is CdS, then cadmium chloride (strontium) and sulfur powder can be selected as quantum dot precursors. In one example, the desired quantum dot is CuInZn, so the selected quantum dot precursor includes cuprous chloride (I), Indium trioxide (III), indium(III) oxide and zinc stearate. When the quantum dot sought is CuInS2, cuprous chloride (I), indium trichloride (III), or Indium (III) and sulfur powder are used as quantum dot precursors. In another example, zinc stearate is used. Sulfur powder is used as a precursor to deposit ZnS quantum dots, and cadmium chloride and Te powder are used to deposit CdTe quantum dots. The concentration of each quantum dot precursor in the second solution is between 0.003-0.03 mmol/ml. For example, about 0.003, 0.005, 0.007, 0.009, 0.0, 0.012, 0.014, 0.016, 0.018, 0, 02, 0,022, 0.024, 0.026, 0.028, and 0.03 millimoles per milliliter. Finally, in step (c), the first solution and the second solution are in an inert gas atmosphere such as nitrogen, helium, neon, argon or a combination thereof, and at a temperature of from about 10 ° C to 300 ° C. The solutions are mixed with one another to form quantum dots on the surface of the nanospheres. In one example, the operating temperature is set at about 140 °C. The nano device manufactured according to the above manner can be used as a drug carrier for delivering the drug to any target position in a subject, such as the brain or any other organ of the human body; The manufactured nanodevice acts as a tool to illuminate and track the pharmacokinetics of the drug at the location of the subject's internal standard. 14 201103563 In vivo angiography and magnetically induced drug release A further aspect of the present disclosure is to provide a method of in vivo angiography and magnetic evoked drug release from a nanodevice made in the manner described above. The disclosed method comprises the steps of: (a) applying a sufficient amount of the nanodevice of the invention to a body part of the subject to be tested; and (b) applying a sputum at the body part between about 〇·〇5 kA/m to 2.5 The magnetic field of kA/m is magnetically induced for a period of about 1 〇 to 180 seconds to magnetically induce the nanodevice, so that the drug embedded in the nanodevice can be released into the body part of the subject to be tested. The disclosed method further includes the steps of: tracking the body part of the subject to be tested, including electron spin resonance (ESR) angiography, using an imaging method selected from the group consisting of: X-ray angiography, computed tolnography (CT) angiography and nuclear magnetic resonance (MRI) angiography. The subject to be tested referred to herein is a human or non-human animal. Examples of non-human animals include all vertebrates, such as mammals, such as primates, dogs, caries (eg, mice and rats), cats, sheep, horses, or pigs; and non-mammals, such as birds, Amphibians, reptiles, etc. In one example, the subject is a human. The nanodevice of the present disclosure may be administered systemically to the subject to be tested by inhalation or injection; or may be administered to a localized area by intravenous or topical application, eg, to the gastrointestinal, liver or renal system, or It is applied to the specific, treatment site of the subject or the body surface by intravenous or topical application to areas such as the abdomen, lumbar spine, arms or legs. These and other possible methods and methods of application are well known and readily understood by those skilled in the art and should therefore be included in the materials of this disclosure. Suitable body parts for 201103563 can be selected according to the following conditions, such as the type of active agent, individual physical condition including gender, age, body, and/or current and past medical history. An experienced physician can decide on a body part that is suitable for injection without a _. In the second part, the body part is the upper arm part of the human. In another example, 'the brain is located in the human. The nanodevice according to the present disclosure will not be inhaled or injected immediately: two people: there is any safety threat to health', ie, this nanometer is set, according to an embodiment of the present disclosure, Using injection, oral, perfusion d::', the drug-loaded nanodevice is introduced into the body of the subject to be tested, and the nanodevice is placed in the body part of interest/that is, the drug is expected to be released. The location of the brain (for example, the brain has more than six concentrations. In this case, the nanodevice itself remains almost intact, and the electron spin resonance (ESR) = technique can be used to trace the nanodevice in the body. The concentration in the deep body part is: a nuclear magnetic resonance imaging technique, which generates an image by magnetic resonance enhanced by dynamic nuclear polarization in the usual 〜 〜 显影 显影 显影 显影 显影 显影 显影 显影 显影 显影 显影 显影 显影 显影 显影The specific body part comes into the future. In the disclosure, the developer is the iron oxide device of the nano device: it can also be combined with the nano device and other photographic agent of the present disclosure to provide high-quality images. .appropriate And =: limited, sulfuric acid lock a dose, -, iron oxide 201103563 = (d) after the initial (four) image, using the magnetic field induced to make the nanodevice   housing shell completely or partially disintegrated, and will be embedded in the nano device drug release The position of the target. In particular, the body part is irradiated with a magnetic field for a period of time, for example, about 1 second to 18 seconds, to release the embedded drug into the body part, thereby producing a specific therapeutic effect, such as a transcription gene. Or treating cancer. The intensity of the magnetic field (magnetie fidd, na) is from about 〇.〇5kA/m to about 2.5kA/m, for example about 〇5, 〇卜〇2 〇3, 〇.4, 0.5, 0.6, 0.7. , 0.8, 0.9, L0, 】. 12, 13, 14, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2", 2.2, 2.3, 2.m5kA/m. The period during which MF is applied is from about 10 seconds to About 18 〇 seconds, for example about 1 〇, 2 〇, 3 〇, 4 〇, 50, 60, 7 〇, 80, 9 〇, 1 〇〇, 11 〇, 12 〇 13 (), 14 (), =, 160, 170 or 180 seconds. Once magnetically stimulated, the quantum dots deposited on the surface of the outer shell absorb magnetic energy, deforming the metal oxide shell of the nanodevice, thereby The drug buried in the core phase can be released to the target position. In the most extreme case, the entire metal oxide shell will completely disintegrate after the magnetic field stimulation, so that the drug is quickly released. Therefore, it can be applied by control. The strength and time of the magnetic field to control the release = the amount of drug is multiplied. In other words, the intensity and/or time of the magnetic field applied to a specific part of the body can be controlled to be embedded in the present disclosure. The amount of drug in the content of the nano-device. Once the drug embedded in the core phase is released, the subsequent measurement can be carried out using engineering techniques to map the pharmacokinetic relationship of the drug, and therefore, the MRI can be utilized. The NMR signal is used to monitor/measure the concentration and/or distribution of the released drug. For example, the ^^^ rule signal is used to monitor the kinetics of the released drug or to produce a three-dimensional image showing the distribution of the developer (ie, the nanometer set 201103563 of the present disclosure, and to predict the conformity of the drug of interest). Pharmacokinetic properties. According to another embodiment of the present disclosure, an empty device of the present disclosure can be used as a developer to track or contrast another active drug (eg, 'amphetamine'), which can be applied to the present disclosure. After the nano device of the content, it is injected or aggregated to one of the individual targets. Hereinafter, the content of the present invention will be further explained through specific embodiments and accompanying drawings. It is to be understood that 'unless otherwise stated' The same element symbols represent the same elements. EXAMPLES The following examples are provided to illustrate specific aspects of the invention, and the scope of the invention is not intended to be the same. Example 1 Manufacturing and analysis of a nanodevice embedded with a model drug 1.1 Manufacturing pvP-Fe304 core-shell nanospheres Dissolve polyvinylpyrrolidone (PVP) in distilled water to a concentration of 4% by weight, and then this PVP solution Heat to 80 ° C. In this PVP solution, add 1 mg of fluorene-fluorescein isothiocyanate (TITC) to stir and mix for about 6 hours. PVP in the solution will automatically Assembled into nanospheres and embedded in FITC to form PVP nanoparticles loaded with FITC. Under nitrogen filling,

FeCl3 · 6H20 and FeCl2 · 4H20 (wherein the molar ratio of FeCl2/FeCl3 is about 2:1) were dissolved in water and vigorously stirred at 80 C with the above-mentioned FITC-loaded PVP nanoparticles. After 4 hours, 2 ml of aqueous ammonia (NH40H, 33%) was slowly added to make the iron oxide shell deposited on the surface of the pvp nanosphere. Next, the solution was centrifuged at 6000 rpm, the supernatant was removed and the collection was collected. The precipitate was washed 4 times with distilled water. The pVPee3〇4 core-shell nanosphere was isolated by centrifugation. Fig. 20) is a view showing the operation of the nanodevice for forming a transportable drug according to the procedure of the present embodiment. Figs. 2(b) and 2(c) are a transmission electron microscope (TEM) photograph and a high-resolution transmission electron microscope (HRTEM) photograph of the nanospheres produced in accordance with the present embodiment, respectively. From the results of Figures 2(b) and 2(c), it can be confirmed that each nanosphere is a sphere with a diameter of 10-15 nm and has an amorphous core and a single crystal shell structure, showing iron oxide. The precursors self-assemble into a shell around the PVP core after nucleation. 1,2 Depositing Zn-Cu-In-S (ZCIS) quantum dots on the surface of the nanosphere of Example 1.1 In order to grow ZCIS quantum dots on the surface of the nanosphere, the nanosphere of Example 1.1 was resuspended in the containing三.M millimolar diethyldithiocarbamate zinc salt ([(C2H5)2NCSS]2Zn) in trioctylphosphine (TOP, 90%, technical grade). The above solution was further diluted with octadecene (ODE, 90%, technical grade) to form a first solution. Then, at 5 〇. (: CuCl and InCl3 were dissolved in the oleylamine to form a second solution. Then, the two solutions were mixed under nitrogen and heated to 14 (TC) to deposit quantum dots on the surface of the nanosphere of Example 1.1. Figure 2(d) is a HRTEM photograph of a nanosphere doped with ZCIS, in which a solid particle of ZCIS quantum dots is deposited on the annular shell of the nanosphere and the suspension produces a fluorescent light under UV light. Light (see the illustration in Fig. 2(d)) ' indicates that the nanodevice of the present embodiment can be used not only as a carrier for delivering a drug' but also as a nanocarbon needle for contrast. Energy dispersive X-ray spectrometer ( Energy dispersive X-ray spectrometer (EDS) analysis confirmed that this ring 19 201103563 region is mainly composed of Fe and the solid particles are mainly composed of Cii and S (data not shown). Further superconducting quantum interference device (super The quantum interference device, SQUID) (MPMS, XL7) was analyzed at 298 K and the magnetic field strength was between -10000 and + 10000 G to analyze the nanodevice of Example 1.2 and the nanosphere of Example 1.1 (ie, There is no quantum dot deposition on the outer shell of the nanosphere) Magnetic. The results are shown in Fig. 3. Both the nanodevice of Example 1, 2 and the nanosphere of Example 1.1 exhibited supermagnetic behavior, and the nanodevice of Example 1-2 was used due to the dilution effect. Compared with the nanosphere of Example 1.1, it has a smaller saturation magnetization (Ms). 1.3 Controlling the release of the model drug embedded therein from the nanodevice of Example 1.2. The nano device is placed in a high frequency magnetic field (HFMF) with an intensity between 50 and 100 kHz, so that the embedded model drug (ie, 'green fluoresce' FITC) can be released from the nano device. Power, function generators, amplifiers, and cooling water are used to create this HFMF. Similar equipment is revealed in the PNAS article (vol 103, 3540-3545 (2006)). The magnetic % intensity depends on the coil used. The coil consists of 8 loops. The frequency is set at 50 kHz and the magnetic field strength (H) is approximately 2.5 kA/m ° with circulating water to control the temperature of the HFMF generator to 25. (: in 20 ml phosphate buffer Discharge of 5% (% by weight) of magnetic nanodevices in liquid (131^7.4) The model is based on a PL spectrometer (PL fluorescence spectrometer F-4500 'Hitachi' Japan) to measure the release mode of the dye molecule after applying a 5 kHz high frequency magnetic field (HFMF) and the fluorescence intensity of the nanodevice. ° / ° (% by weight) concentration, the nano device of Example 1 was dispersed in water 20 201103563 - segment at different times ' χ _ photoelectron spectroscopy (xps) is equipped at the anode

1253.6 electron volts of Mg "ESCALAB 25 〇 (10) sound vG

Executed in Scientific, West Sussex, υκ). The chemical shift of the XPS peak is normalized to the peak of 284 6 ev, c i seconds. The results are shown in Figure 4. Before the application of the magnetic field, when the FITC-loaded nanosphere was stored under the chamber for 24 hours, no drug was released. This observation was confirmed by the PL spectrometer and observed to indicate that the dye could be It is buried in the core ~ phase for a long time without leaking out. However, as shown in the 4th (&) figure, once the HFME is applied for different times, the intensity of the green fluorescence emitted by the model drug released from the nanosphere at 517 nm will vary with the applied magnetic field strength. Increasing and increasing, conversely, the red fluorescence intensity of a quantum dot decreases as the applied magnetic field time increases. The effect of varying degrees of HFME on the release of the drug from the nanodevice of Example 1 was also tested and the results are shown in Figure 4(b). For the three different strengths of HFME applied, the fluorescence intensity has a linear relationship with the length of time of the applied HFME, which means that the HFME of a predetermined intensity can be applied for a predetermined period of time, and the package is controlled in a controlled manner. The buried model drug is released, and the ZCIS quantum dots of the nanodevice can be used to monitor the release of the model drug. 1.4 In vitro monitoring The release of the model drug from the nanodevice of Example 1 maintains human cervical cancer cell line (Hela cells) in penicillin supplemented with 10% fetal calf serum, 100 units/ml and 1 μμ§ / ηι1 of streptomycin in DMEM medium. The cells were then incubated at 37 ° C in an environment containing 5% C 〇 2 . The medium device of Example 1 was added to the medium, and the cells were incubated with the cells for 12 hours. Next, the cells were treated with HFMF for 0, 90 and 180 seconds, and the cells were observed with a PL microscope (Nikon TE-2000U, Japan). The digital analysis software (Nikon, transcript) was used to analyze the fluorescence intensity of the model drug and the nanodevice, and the exposure conditions were the same for each color channel. The Nikon C1 software was used for analysis, which splits the fluorescence intensity from 1 to 255. The range of fluorescence intensity is as follows: blue channel (60-255), green channel (40-255), red channel (30-255). The results are shown in Figures 5 and 6. As shown in Figure 5, the application of the magnetic field from 0 seconds to 180 seconds allows the model drug or fluorescent substance (green channel) to be quickly released from the cell while simultaneously detecting the fluorescence intensity of the ZCIS quantum dot. (Red channel) is followed by a drop. The fluorescence of the model drug and the ZCIS quantum dot was analyzed by a digital analysis software (Nikon, Japan). Bsum, Gsum, and Rsum represent the total fluorescence intensity in the blue, green, and red channels in the image, respectively. Blue fluorescence is due to the nucleus stained with DAPI and it is expected that this fluorescence intensity should not be too close in each cell. Therefore, the intensity of the blue channel is used as a standard in each image. Gsum and Rsum represent the total fluorescence intensity from the released drug and the quantum point, respectively. Gsum/Bsum represents the ratio of the fluorescence intensity of the green channel to the fluorescence intensity of the blue channel and also represents the relative intensity of the nanodevice in each cell. The results are shown in Figure 6. Gsum/Bsum and Rsum/Rsum produce two curves respectively with the length of the magnetic field in the cell. These curves show that the relative drug concentration in cells (expressed as Gsum/Bsum) increases with increasing stimulation period. Conversely, at the same time, the fluorescence intensity of the nanodevice (ie, the firefly from the ZCIS quantum dot) The light intensity, expressed as Rsum/Rsum, decreases proportionally. 22 201103563 Example 2 Using a Nanodevice embedded with an anticancer agent to perform a live sputum treatment 2.1 Let the cells inhale the mouth of the nanodevice of Example 1 Before performing the in vitro treatment, evaluate according to the following procedure using an eschar microscope The ability of the cells to inhale the nanodevice of Example 1] Briefly, human lung adenocarcinoma Α549 cell line was maintained in DMEM medium containing 10% fetal calf serum, 1% penicillin/streptomycin. Then, the cells were cultured in an environment containing 5% C〇2 at 37 ° C. The A549 cell line was grown in a 6-well plate. The medium device containing the FITC model drug was added to the medium in the example. The cells were incubated with the cells for different times and then washed 3 times with phosphate buffer (PBS, pH 7.4) to remove excess nanodevices that were not inhaled into the cells. The cells were fixed with 3% formic acid, stained with DAPI and rhodamine solution, and then observed under a conjugated focus microscope. It can be found that these nanodevices have accumulated in the cells after 2 hours of incubation with the nanodevice (see Figure 7), demonstrating that the cells can be inhaled quickly and efficiently by inhaling these nanodevices. 2.2 Toxicity analysis of the nanodevice in the cell and its effect on cell viability The in vitro toxicity test of the nanoparticle of Example 1; 1 and the nanodevice of Example 1.2 in A549 cells was analyzed by MTT assay. Briefly, 'A549 cells were first cultured in a % well plate (104 cells/pan)' and then exposed to a series of different concentrations of Nanoparticles of Example 1.1 or Example 1.2 at 37 °C. Under the nano device. After the end, 20 μM of MTT solution was added to the medium and incubation was continued for 4 hours. Next, 23 201103563 replaced the medium with 200 μM DMSO and monitored the absorbance at 570 nm and 650 nm with a Sunrise absorption plate reader. Fig. 8 shows the cytotoxic effect of the nanoparticle of Example 1.1 and the nanodevice of Example 1.2 on A549 cells, and Fig. 9 shows the results of cell survival. The experiment found that cells treated with nanoparticle or nanodevices at concentrations up to 200 μg/ml for 48 hours did not cause any toxic effects on the cells (Fig. 8). The cell survival rate is 85% (Fig. 9). These results show that the nanoparticle or nano device of Example 1 is biocompatible with living cells. 2.3 In vitro treatment with a nanosphere or nanodevice embedded with an anticancer agent, except that the green fluorescent substance-FITC was replaced by camptothecin (CPT), it was prepared in the same manner as in Example 1. A nano device embedded with an anticancer agent. The MTT assay was used to evaluate the anticancer effect of a CPT-loaded nanodevice on cancer cells. Briefly, A549 cells were treated with a CPT-loaded nanodevice for about 6 hours, followed by stimulation of cells with different intensities of HFMF for a period of time to release CPT from the core phase of the nanodevice into the cells. The cells were then incubated for approximately 18 hours and then the MTT assay was used to determine cell viability. Figure 10 shows the survival rate of cells after treatment of A549 cells with a CPT-loaded nanodevice and magnetically induced release of CPT. The survival rate of cancer cells treated with a CPT-loaded nanodevice is greatly reduced, which is generally considered to be the result of both heat and drugs. The results of this example demonstrate that the CPT-loaded nanodevice made in the manner described in the present invention is an excellent drug delivery system having good biocompatibility, high cell absorption rate, and good bioactivity. Magnetic sensitivity and controlled release of the drug at hfmf. Example 3 In vivo treatment with a nanodevice embedding an anti-epileptic agent 3.1 Manufacturing a nano-device containing ethosylamine (ESM) in addition to replacing the green fluorescent substance with an anti-epileptic drug, ethylamine (ESM) - In addition to FITC, a nanodevice embedding ethosylamine was prepared in substantially the manner described in Example 1, and the biotherapy was carried out using this nanodevice. 3.2 In vivo treatment of epilepsy In this trial, Long-Evans and Wistar male rats were used, all of which were housed at room temperature, soundproofed and 12 hours each day and night (lighting time from 7 am to 7 pm) and Free to use food and water in the environment. The entire experimental procedure was performed after approval by the Animal Care and Use Committee. Briefly, animals were numb with barbiturate (60 mg/ml, injection) and implanted with a recording electrode. Next, the mice were placed in a standard stereotaxic instrument. A total of 6 stainless steel screws were locked in the frontal bone (relative to the bregma, A + 2.0, L 2.0) and the occipital region (A-6.0, L 2.0) from both sides of the skull to record the field potential of the cortex. The ground electrode is implanted approximately 2 mm from the tail to the 11th lambda. Secure the socket to the skull surface with a dental cement. The suture was then sutured with a surgical line and the animal was administered antibiotic (chlorotetracycline) and housed separately in a cage until it was restored. The reason for using Long-Evans mice in this experiment is that such mice often exhibit spontaneous spoke-wave discharges (SWDs), which are known to be associated with epilepsy based on evidence in many respects. To confirm that SWDs were controlled via cortex, another model of epilepsy on Pharmacy 25 201103563 was used, i.e., a low dose of sputum was administered to Wistar mice (20 mg/kg 'intravenous injection). In this preliminary animal test, physiological saline, ethosuxamine (ESM), ESM-containing nanospheres (nanosphere-ESM), and ESM-containing nanodevices (nano devices-ESM) were compared. Effect on spontaneous swDs in Long-Evans mice. A wafer having a size of 5 mm x 5 mm x 0.02 mm was prepared and then implanted into the abdominal cavity of a mouse. Other doses were administered via intravenous injection. The results are shown in Figures u and 12. Figure 11 depicts the application of physiological saline, ethosylamine (ESM), ESM-containing nanospheres (nanosphere-ESM), and a NEM-containing nanodevice to the experimental animals. The impact of ESM, device-ESM) on SWDs. There are no significant changes in SWDs. In this experiment, brain wave activity was recorded 1 hour before the treatment (basic line) and 30 minutes after the treatment. The average of the two-hour baseline is used as an index. When the nanospheres ^gSM and the nanodevice-ESM were applied, the mice were fixed in a plastic box and placed in the center of the coil' and then excited by a magnetic field (2.5 kA/m) to enable the ESM to be prepared from the nanometer. Released in a ball or nano device. Although it is difficult to quantify the amount of ESM released into mice, it is certain that compared to ESM alone (Fig. 11(b)), whether it is from nanosphere-ESM (11th ( C_) or the amount of esm released from the nanodevice-ESM (Fig. 11(d)) into the mouse, significantly reducing the number of spontaneous SWDs and their duration. Figure 12 depicts the physiological application The number of SWDs in mice before or after saline, ESM, nanosphere _ESM and nanodevice-ESM, and their total duration. The results of the different forms of ESM can significantly reduce the number of spontaneous SWDs and their total Continuing period. 26 201103563 These in vivo data, although still very preliminary results, show that nanoparticles and wafers with ESM can successfully release the drug through external magnetic field stimulation, as observed in in vitro experiments. At the same time, the released ESM has a therapeutic effect that significantly inhibits SWDs.

Example 4 In vivo tracking of nanodevices by magnetic resonance imaging (MRI) 4.1 In vitro MRI except that 0.5% PVP was used as the polymeric material and the final iron concentration was set to not exceed 150 g iron/ml. The procedure described in Example 1 was used to prepare a sample of the nanodevice. For MRI imaging, R1 (spin lattice relaxation rate) and R2 (spin-spin relaxation rate) were measured by 0.47 T nuclear magnetic resonance, respectively. The R1 and R2 of the nanodevice were 63.2 mM^sec-1 and 372.8 mM_1 sec·1, respectively, and were higher than most commercial products.

4.2 In vivo MRI Five Wistar male rats (National Animal Center, Taiwan) were used in this experiment and weighed around 250 to 300 grams. Animals were first anesthetized with 3% isoflurane. A PE-50 catheter was then inserted from the left femoral vein for subsequent administration of an alpha-chloralose anesthetic (70 mg/kg body weight). The anesthetized mice were fixed and maintained in a circulating warm water system. The head of the mouse was fixed with two ear posts and an incisor fixer, and the body was fixed with tape. Images were captured with a Bruker Biospec BMT 47/40 4.7 T system equipped with an active masking gradient system (within 5 〇〇 microseconds, 〇~5.9 G/cm). A 20 cm coil is used as the RF transmitter, and a 2 cm surface coil is placed in the head as a receiver. An image of τ2_ 27 201103563 weights was taken along the median sagittal plane and the anatomical location was found by identifying the prosthesis (pre-basal - 0.8 mm). Figure 13 shows the spin echo sequence (TR = 4000 ms, TE = 8〇ms, f〇V = 4 cm, SLTH = 2 mm, NEX = 2, and the intercept matrix is 256 x 128, and is filled in The matrix after 0 is 256 x 256) The four-cut T2_weighted image is obtained (in the front buff _ 8 mm, _2 8 mm, -4.8 mm and -6.8 mm, respectively). Figure 13 shows that when the injection or nanosphere or nano-sputum is placed in the animal, the analytical ability of the blood vessels and tissues of the brain can be greatly improved. For dynamic perfusion images, a 120-repetition four-cut gradient echo image was taken at the same position (TR = 215 ms, TE = 20 ms, flip angle = 22.5°, F〇V = 4 cm, SLTH = 2 mm, NEX = 1, and the intercept matrix is 256 x 64, and the matrix after filling in 〇 is 256 x 256), and each image takes 13 seconds. Since the half-life in the blood is very long, a nanodevice that is injected into the animal produces a stable and long-lasting MR scan image. The mr signal was observed to be reduced by approximately 45% in the parachymal (Fig. 14). 4, 3 using the nanodevice of Example 1 as a developer for medicinal MRI diagnosis in vivo for performing a medicinal MRI experiment, obtaining a 40-repeated four-cut gradient echo image (other scan images are the same as above), and At the time of the 1st time, the main injection was I〇P (30 mg/kg body weight). After 15 minutes of circulation, 1 〇〇 _ repeated four-cut gradient echo images were obtained and amphetamine (2 mg/kg body weight) was injected at the 2nd time. 28 201103563 Amphetamine is used here as a functional stimulator to reveal different regional cerebral blood volume (rCBV) and activation areas after anesthesia with alpha- gluconate. The experiment found that the activation area included the striatum, brainstem and hypothalamus, as shown in Figure 15, and the signal difference also corresponded to the previous dopamine stimulation experiment. In addition, the use of the nanodevice of Example 1 as a developer also reveals the temporal pattern of brain stimulation after amphetamine stimulation, providing not only a better contrast-to-noise (CIR) but also meaningful meaning. The measurement of neurovascular responses becomes feasible. As described above, the preferred embodiments of the present invention have been described in detail with reference to the accompanying drawings. However, it is to be understood that the preferred embodiments of the invention are intended to It will be apparent that various changes and modifications may be made within the scope and spirit of the invention. BRIEF DESCRIPTION OF THE DRAWINGS The above and other objects, features, advantages and embodiments of the present invention will become more <RTIgt; A schematic diagram of decomposition of a nano-scale drug delivery device and a nanosphere according to an embodiment; FIG. 2(a) is a diagram for manufacturing a polymer core and self-assembling around the polymer core in an embodiment of the invention Schematic diagram of a method for forming a nanodevice of a single crystal iron oxide shell; 29 201103563 Figs. 2(b) and 2(c) are diagrams of a transmission electron microscope (ΓΕΜ) of each sphere according to an embodiment of the present invention. And a high-resolution electron microscope (HRTEM) photograph; FIG. 2(d) is a high-resolution electron microscope (HRTEM) photograph of a nanodevice manufactured according to an embodiment of the present invention, wherein the ring of the nanosphere is The quantum dots of ZC1S are deposited on the peripheral device and the suspension emits fluorescence under the irradiation of υν light (inserted image); FIG. 3 is a view of the nanosphere and the nanodevice prepared according to the embodiment of the present invention, respectively. A graph of the dependence of magnetic field strength; μ Figure 4(a) shows HFMF treatment of the nanoparticle device (30 mg/10 ml 7 fire) embedded with the model drug is about ~1 〇〇 second emission spectrum; Figure 4 (b) shows the model drug FITC under different magnetic field strengths And the spectral intensity emitted by the ZC1S quantum dots; FIG. 5 is a fluorescent photograph taken after 12 hours of processing Hela cells by a device embedded with FITC according to an embodiment of the present invention, wherein Gslm/Bsum represents green fluorescent light. The ratio of the intensity to the intensity of the blue fluorescence and which represents the relative concentration of the model drug FITC in each cell, Rsum/Bsum represents the relative intensity of the nanodevice in each cell; Figure 6 represents the Gsum of the cell in Figure 5. The relationship between Bsum and R_/Bsum with respect to the length of the magnetic field stimulation period; FIG. 7 is a view of the cell inhalation nano device according to an embodiment of the present invention, which was taken after treating the cells for 2 hours by the nano device; The figure shows the cytotoxicity results measured after inhaling cells into a nanosphere or nanodevice for 12, 24 and 48 hours according to an embodiment of the invention; 201103563 Fig. 9 is a treatment with a nanodevice of Weng CPT according to an embodiment of the present invention. Carcinoma Results of cell viability measured after 12, 24 and 48 hours of cells; Figure 00 is a diagram of treatment of cells with a cpt-loaded nanodevice and inhalation of cells into the nanodevice according to an embodiment of the invention, HFMF magnetically stimulates the CPT-loaded nanodevice to release the drug at different times; Figure 11 shows the application of (8) physiological saline to (b) ethosuxamine (ESM) to experimental animals in accordance with an embodiment of the present invention. (28 mg/Kg, ip), (c) nanospheres containing esm (nanospheres Ε8Μ) (48 mg/Kg, ip), and (d) nanodevices containing ESM (nano devices) _ESM, device -ESM) (4〇rng/Kg ip) effect on SWDs; 'Figure 12 depicts the application of physiological sleeping water, ESM (0.5 ml, 28 mg/Kg, in accordance with an embodiment of the invention) Number of SWDs in mice before and after ip), nanosphere-ESM (40 mg/Kg, ip) and nanodevice-ESM (40 mg/Kg, ip) and their total duration: Figure 13 According to an embodiment of the present invention, the nano device is injected into the mouse brain (upper row) and after (lower row), the captured weight image; 2 Figure 14 is the 13th image Dynamic imaging enhanced MRI in the brain region, where (A) is the weighted image taken 3 minutes after the injection of the nanodevice, and (B) and (C) are the signal patterns of the right hemisphere and the left hemisphere, respectively. The red arrow represents the time of injection of the nanodevice; and, 201103563, Fig. 15 is the MRI image of the brain of the mouse after amphetamine stimulation and the activation time map of amphetamine, wherein the correlation degree of the event represented by heat and cold color is +0.5 and -0.5. [Main component symbol description] 10 nanometer drug delivery device 12 nanosphere 14 quantum dot 16 core 18 outer casing 20 drug

32

Claims (1)

201103563 VII. Patent application scope: L A method for manufacturing a nano-scale drug delivery device, comprising the following steps: P-flute, ^~ first solution, which disperses a nanosphere in a quenching agent containing zinc salt , wherein the nanosphere and the zinc salt are in the first solution / □ another: not about 1-4 〇 mg / ml and about 0.02-0.2 mmol / ml; a ^ 仏 first solution, which will At least two quantum dot precursors are mixed in an A solution, wherein the concentration of each quantum dot precursor in the second solution is between about 0.0003_0.03 millimoles per milliliter; in the presence of a gas Next, the one is between 1 〇 ° c and 300. The first solution is mixed with the second solution at a temperature of ruthenium to form a quantum dot on the surface of the nanosphere. 2. The method according to claim 1, wherein the nanosphere is produced by the following steps: 'M0% (% by weight) of one of a polymeric material or an inorganic material in a polar solvent with about 0.01-80 One (% by weight) of one of the drugs is mixed with each other to form a suspension, thereby forming a drug-containing polymerizable or inorganic nanoparticle; and an oxide precursor is added to the suspension (the molar ratio is about 2) : 1 to about 5:1) and vigorously stirred at about 2 (TC to about 120 Torr for about 2-12 hours; wherein the metal oxide precursor can surround the polymer or inorganic nanoparticle itself The method of claim 2, wherein the polar solvent is water or an alcohol of Cu. 4. The method of claim 3, wherein the polymerizable material is selected. Any one of the following: polyvinylpyrrolidone (PVP), polyethylene (PE), polydecylamine, polyethylamine, polyanhydride, polyfluorene, polycondensate, polysaccharide or rouge; and the inorganic material is selected from Any of the following: titanium dioxide, cerium oxide or a composite of calcium and phosphorus 5. The method according to claim 4, wherein the polysaccharide is any one of the following: starch, cellulose, pectin, chitin or quercetin; and the phospholipid is any one of the following: phospholipid The method of claim 3, wherein the metal oxide precursor is selected from any one of the following: chlorine; Ferrous (II), iron (III), cobalt (II) chloride, iron (II) nitrate, iron (III) acetate, acetate (II), chloride (III) and manganese acetate The method of claim 3, wherein the metal oxide outer shell is a single crystal shell layer, a polycrystalline shell layer or an amorphous shell layer comprising any one of the following compounds, including: Fe2〇3 The method of claim 6, wherein the metal oxide precursor comprises iron (II) chloride and iron (III) chloride. And the metal oxide outer shell is a single crystal shell layer formed by the following steps: mixing ferrous chloride in water at a molar ratio of about 2:1 (II) and iron (III) chloride; adjusting the pH to between 7 and 12; and allowing the formed iron oxide to self-assemble into the metal oxide shell around the polymer or inorganic type of nanoparticle. The method of claim 1, wherein the first solvent is composed of two solvents selected from the group consisting of trioctylphosphine (TOP), tetrahydrofuran (THF), C6-18 olefins, and Dimethylsulfoxide (DMS0); and the second solvent is oleylamine or hexadecylamine. 10. The method of claim 1 wherein the zinc salt is zinc diethyldithiocarbamate. The method of claim 1, wherein the quantum dot is any one of the following: CuInZn, CuInS2, CdS, ZnS or CdTe. The method of claim 11, wherein the CuInS2 is formed of at least two quantum dot precursors selected from the group consisting of CuCl, InCl3, Inl3, and sulfur powder. The method of claim 11, wherein the CuInZn is formed of at least two quantum dot precursors selected from the group consisting of CuCl, InCl3, Inl3, and zinc acetate. 14. The method of claim 11, wherein the CdS is formed from at least two quantum dot precursors selected from the group consisting of CdCl2 and sulfur powder. 15. The method of claim 11, wherein the CdTe is formed from at least two quantum dot precursors selected from the group consisting of CdCh and tellurium (Te) powder. 16. The method of claim 11, wherein the ZnS is formed from at least two quantum dot precursors selected from the group consisting of zinc acetate and sulfur powder. 17. The method of claim 1, wherein the temperature is 140 °C. 18. The method of claim 1, wherein the inert gas is any one of the following: N2, He, Ne, Ar, or a combination thereof. 19. A drug delivery device made by the method of claim 1. 20. A nanodevice comprising: 36 201103563 a nanosphere comprising: a core made of a polymeric material or an inorganic material; and an outer shell made of a metal oxide; a quantum dot, Deposited on the outer surface of the outer casing, wherein the quantum dots are any of the following: CuInZn, CuInS2, CdS, ZnS or CdTe. 21. The nanodevice of claim 20, wherein the polymeric material is selected from the group consisting of polyvinylpyrrolidone (PVP), polyethylene (PE), polyamine, polyester, polyanhydride, polyether. a polyacetal, a polysaccharide or a phospholipid; and the inorganic material is selected from the group consisting of titanium dioxide, cerium oxide or a composite material composed of calcium and phosphorus. 22. The nanodevice of claim 2, wherein the metal oxide outer shell is a single crystal shell layer, a polycrystalline shell layer or an amorphous shell layer comprising any one of the following compounds, including: Fe203, Fe304, CoFe204, MnFe204 or Gd2〇3. 23. The nanodevice of claim 2, wherein the nanosphere has a distance between about 10 nm and 1 〇〇 nm. The nanodevice of claim 2, wherein the quantum dot is paramagnetic, and the nanodevice can be tracked and imaged by an imaging technique selected from the group consisting of: electron spin resonance (ESR) Contrast, X-ray photography, computed tomography, and magnetic resonance imaging (MRI). 37 201103563 25. The nanodevice of claim 2, further comprising a drug embedded in the core, and the drug is capable of stimulating the quantum at a magnetic field of from about 0.05 kA/m to about 2.5 kA/m After the point, it is released from the core. 26. The nanodevice of claim 25, wherein the medicament is any one of the following: an anti-epileptic agent, an anti-tumor agent, an antibacterial agent, an antiviral agent, an anti-proliferative agent, an anti-inflammatory agent, an anti-diabetic agent, or Hormones. 27. The nanodevice of claim 26, wherein the anti-inflammatory agent can be any of the following: (corticosteroids), (ibuprofen), (methotrexate), aspirin, salicylic acid (salicyclic acid) ), diphenyhydramine, naproxen, phenylbutazone, indomethacin or ketoprofen. 28. The nanodevice of claim 26, wherein the antiviral agent is any one of the following: acyclovir, ribavirin, zanamivir, ome Oseltamivir, zidovudine or lamivudine. 29. The nanodevice of claim 26, wherein the anti-epileptic agent can be any of the following: acetazolamide, carbamazepine, ci〇bazam , Clonazepam, diazepam, eth〇suximide, 38 201103563 ethotoin, felbamate, fosphenytoin , gabapentin, lamotrigine, levetiracetam, mephenytoin, metharbital, methsuximide, guanidinium Methazolamide, oxcarbazepine, Phenobarbital, phenytoin, phensuximide, pregabalin, deoxyphenobarbital (primid〇) Ne), sodium valproate, stiripentol, tiagabine, topiramate, trimethadione, valproic acid, ammonia Vigabatrin or zonisamide ° 3 The nanodevice of claim 26, wherein the anti-proliferative agent is any one of the following: actinomycin, doxorubicin, daunorubicin, valrubicine ), idarubicin, epirubicin, bleomycin, plicamycin or mitomycin. The nanodevice of claim 20, wherein the antidiabetic agent is any one of the following: sulfonylureas, meglitinides, biguanides, guanidines. Sitting as a thiozolidinediones, alpha-glucosidase inhibitors or a class of peptides. The nano device of claim 20, wherein the sulfonamide can be any of the following: tolbutamide, acetohexamide, tolazamide, Chlorpropamide, η ratio glipizide, glyburide, glimepiride or gliclazide; the amphetamine derivative (meglitinides) Is repaglinide or nateglinide; the biguanides are metformin, phenformin or buformin; The analog (thiazolidinediones) may be rosiglitazone, pioglitazone or troglitazone; the alpha-glucosidase inhibitors are miglitol ( Migiitoi) or acarbose; such peptide analogs are exenatide, liraglutide, taSp〇gjutide, vildagliptin (vildagliptin), sitagiiptin or pulan Peptide (pramlintide). 33. The nanodevice of claim 26, wherein the hormone is any one of the following: an allergic hormone, epidermal growth factor (EGF), lutein, estrogen, adrenocortical steroid or androgen . 34. A method of releasing a magnetically-inducing drug to an individual, comprising: (a) administering a sufficient amount of a nanodevice as claimed in claim 25 to a body part of the 201103563 body; and a body 2 (10) M 2· A magnetic field of 5 kA/m stimulates the body: the device "releases the embedded drug to the body portion of the individual. 35. The method of claim 34, wherein the individual is a human. 36. The method of claim 34, further comprising the step (4) of tracking the nanodevice located in the body part of the individual with an imaging technique selected from the group without additional human-display (4). These include: Electron Spin Resonance (ESR) angiography, X-ray photography, computed tomography, and nuclear magnetic resonance imaging (MRI). VIII. 37. A method of in vivo angiography in a body, comprising: (a) administering a sufficient amount a nanodevice as claimed in claim 2 to a body part of the individual; and (b) in the absence of additional developer, tracking the individual located in the individual with an imaging technique selected from the group consisting of The nanodevice in the body part 'includes: electron spin resonance ( ESR) angiography, photophotography, brain tomography, and magnetic resonance imaging (MRI).