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WO2018193278A1 - Agent de contraste nanoparticulaire pour le diagnostic précoce de la maladie d'alzheimer par imagerie par résonance magnétique (irm) - Google Patents

Agent de contraste nanoparticulaire pour le diagnostic précoce de la maladie d'alzheimer par imagerie par résonance magnétique (irm) Download PDF

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WO2018193278A1
WO2018193278A1 PCT/IB2017/000517 IB2017000517W WO2018193278A1 WO 2018193278 A1 WO2018193278 A1 WO 2018193278A1 IB 2017000517 W IB2017000517 W IB 2017000517W WO 2018193278 A1 WO2018193278 A1 WO 2018193278A1
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composition
group
disease
nanoparticle
peg
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PCT/IB2017/000517
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English (en)
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Lawrence William BAUM
Hee Lum Albert CHOW
Kwok Kin CHENG
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The Chinese University Of Hong Kong
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Priority to PCT/IB2017/000517 priority Critical patent/WO2018193278A1/fr
Publication of WO2018193278A1 publication Critical patent/WO2018193278A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1833—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
    • A61K49/1857—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
    • A61K49/1857—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA
    • A61K49/186—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA the organic macromolecular compound being polyethyleneglycol [PEG]

Definitions

  • AD Alzheimer's disease
  • Current AD drugs only provide partial symptomatic relief and do not slow degeneration.
  • many drug candidates are being tested and some of these may prove effective in delaying disease progression. Therefore, it is increasingly important to identify patients as early as possible in the disease course in order to initiate treatment before irreversible brain injury takes place.
  • the disclosure herein is directed to a novel nanoparticle that can enter the brain and specifically bind to amyloid plaques or deposits and is therefore useful for their detection by magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • A-beta which, as a toxic ingredient, may limit the maximum safe dosage that can be administered to a patient and accordingly may limit the sensitivity of the method.
  • the invention uses non-toxic and natural materials that have well established safety profiles and do not require further toxicological testing for securing regulatory approval.
  • amyloid plaques are indicative for AD, the ability to find these plaques earlier, which the present invention provides, will allow the possibility to slow the progression or even prevent the onset of AD.
  • U.S. Patent No. 8,060,179 was directed to the use of a super quantum interference device (SQUID) and not MRI for diagnosis. Additional methods of diagnosis are described in the following: NASAdsson EM, Wadghiri YZ, Mosconi L, Blind JA, Knudsen E, Asuni A, et al. A non-toxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice.
  • SQUID super quantum interference device
  • the present invention provides solutions to challenges outlined above as well as to many others.
  • the present invention provides a magnetic resonance imaging (MRI) diagnostic agent composition, including: a superparamagnetic nanoparticle, a polymer, and at least one binder of an amyloid plaque; wherein the binder is attached to the surface of the nanoparticle; and wherein the polymer coats the nanoparticle having a binder attached to the surface of the nanoparticle.
  • MRI magnetic resonance imaging
  • the present invention provides a method of labeling amyloid plaques for MRI detection, including contacting the composition of claim 1 with an amyloid plaque, thereby labeling amyloid plaques for MRI detection.
  • the present invention provides a method of diagnosing a disease or condition in a patient, including administering a composition set forth herein to a patient; labeling an amyloid plaque in the patient with the composition; acquiring MRI images of the patient having the composition administered; analyzing the images to detect amyloid plaque in the patient; and diagnosing a disease or condition in a patient.
  • the present invention provides a method of administering a composition set forth herein, including contacting the composition with the blood stream of a patient.
  • the present invention provides a method of preparing a composition set forth herein, including preparing an alkaline solution, a polymer solution, and a metal-halide solution; mixing the alkaline solution, polymer solution, and metal-halide solution to form a mixture; contacting the mixture with an oxidizing agent.
  • Figure 1 shows a transmission electron micrograph (TEM) image of PEG-supported iron oxide (mean particle size ⁇ 30nm).
  • Figure 2 shows an adsorption isotherm of curcumin and iron oxide (at room temperature).
  • Figure 3 shows the experimental data fit on Langmuir isotherm model and that curcumin binds on a homogenous site and forms a monolayer on the iron oxide surface.
  • Figure 4 shows cur cumin-conjugated iron oxide nanoparticles
  • Figure 5 shows confocal microscopy of fluorescent (left) and phase-contrast images (right) of amyloid plaques in consecutive APP (amyloid precursor protein) transgenic mouse brain sections. From top to bottom: Thioflavin T, curcumin, and curcumin-conjugated iron oxide.
  • Figure 6 shows Prussian blue stained iron oxide particles found in APP transgenic mouse brain section 5 hours after intravenous injection of curcumin-iron oxide nanoparticles.
  • Figure 7 shows bright light view of iron oxide in APP transgenic mouse brain (left). Figure 7 also shows a fluorescent microscopy view of curcumin found on the same particle (right).
  • Figure 8 shows, in the top image, a magnetic resonance image of an AD mouse brain. Black spots are iron oxide nanoparticles retained inside the brain 5 hours after injection.
  • Figure 8 shows, in the bottom image, a non-transgenic littermate control mouse treated and imaged under the same conditions.
  • Figure 9 shows a bright view of histochemically labeled brain sections from a transgenic mouse injected with curcumin-conjugated magnetic nanoparticles.
  • Figure 10 shows matches among black dots visualized by MRI, plaques labeled immunohistochemically, and plaques labeled by curcumin-conjugated magnetic nanoparticles.
  • Figure 11 shows brain sections from a control mouse assayed by MRI and histochemical labeling.
  • Figure 12 shows immunohistochemically labeled amyloid plaques in a transgenic mouse brain section, along with co-localization of curcumin and iron.
  • Figure 13 shows the correlation between plaque density identified with immunochemistry and dark spot density identified with in vivo MRI, for transgenic mice injected with curcumin-conjugated magnetic nanoparticles.
  • the present invention provides compositions and methods for use with MRI for diagnosing diseases involving amyloid plaques such as Alzheimer's disease, dementia, Parkinson's disease, and Lewy body disease.
  • the disclosure herein is directed to a novel nanoparticle that can cross the blood-brain barrier and bind with amyloid plaques and other similar protein aggregates such that they can be detected by magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • the compositions, techniques, and methods set forth herein also provide a non-invasive means to diagnosing Alzheimer's disease at an early stage.
  • the term "superparamagnetic” refers to a form of magnetism, which appears, for example, in small ferromagnetic or ferrimagnetic nanoparticles.
  • magnetization can randomly flip direction under the influence of temperature.
  • the typical time between two flips is called the Neel relaxation time.
  • Neel relaxation time In the absence of external magnetic field, when the time used to measure the magnetization of the nanoparticles is much longer than the Neel relaxation time, their magnetization appears to be in average zero. As such, they are said to be in the superparamagnetic state. In this state, an external magnetic field is able to magnetize the nanoparticles, similarly to a paramagnet. However, their magnetic susceptibility is much larger than that of paramagnets.
  • nanoparticle refers to a particle having physical dimensions less than about 100 nanometers and greater than about 0.1 nanometers.
  • binding refers to an agent, composition, or compound that is capable of binding or associating or complexing to an amyloid plaque.
  • amyloid plaques refers to insoluble fibrous protein aggregates sharing specific structural traits. Plaques may also be referred to as deposits. These misfolded structures alter their proper configuration such that they erroneously interact with one another or other cell components to form insoluble fibrils. They have been associated with the pathology of more than 20 serious human diseases. Abnormal accumulation of amyloid fibrils in organs may lead to
  • amyloidosis and may play a role in various neurodegenerative disorders.
  • protein aggregate refers to the product of protein aggregation, which is a biological phenomenon where misfolded proteins aggregate, accumulate, and/or, clump together either intracellularly or extracellularly. These protein aggregates are often toxic and have been implicated in a wide variety of diseases known as amyloidoses, including Alzheimer's, Parkinson's and prion disease.
  • the term "indicative" means to have the characteristics of a certain disease or to suggest the presence of status of a certain disease.
  • amyloid plaques are indicative of Alzheimer's disease because they are commonly associated with this disease.
  • a patient having amyloid plaques may have Alzheimer's disease, and therefore such plaques may indicate, e.g., to a doctor, the status as to whether or not the patient has Alzheimer's disease.
  • hydrophilic refers to a chemical group having a tendency to repel non-polar or uncharged chemical groups, e.g., hexane, and to attract polar or charged chemical groups, e.g. , water. "Hydrophilic” also refers to a chemical that tends to dissolve in, mix with, or be wetted by water.
  • hydrophobic refers to a chemical group having a tendency to attract non-polar or uncharged chemical groups, e.g. , hexane, and to repel polar or charged chemical groups, e.g. , water.
  • Hydrodrophobic also refers to a chemical that tends not to dissolve in, mix with, or be wetted by water.
  • hydrodynamic particle size refers to the smallest diameter of a hypothetical three-dimensional sphere into which a particle of the present invention could be encapsulated.
  • biodegradable refers to the ability of a composition to be broken down, particularly into innocuous products by the action of living organisms.
  • amphiphilic is used to describe a chemical compound as possessing both hydrophilic and lipophilic hydrophobic properties.
  • copolymer refers to a polymer derived from two (or more) monomeric species, as opposed to a homopolymer where only one monomer is used.
  • an alternating copolymer may have the form of -A-B-A-B-A-B-A-B-A-B.
  • a random copolymer may have the form of -A-A-B-A- B-B-A-B-A-A-A-B-B-B-B-A.
  • a block copolymer may have the form of -(A-A-A)-(B-B-B)-(A-A-A)- (B-B-B)-(A-A- A)-.
  • the present invention provides a magnetic resonance imaging (MRI) diagnostic agent composition, which includes a superparamagnetic nanoparticle, a polymer, and at least one binder of an amyloid plaque.
  • MRI magnetic resonance imaging
  • the binder is attached to the surface of the nanoparticle.
  • the polymer coats the nanoparticle having a binder attached to the surface of the nanoparticle.
  • the nanoparticles described herein have a first layer that includes a polymer that adheres to and coats the surface of the nanoparticle. In some embodiments, the nanoparticles described herein have a second layer that includes at least one binder of an amyloid plaque. In some embodiments, the binder of an amyloid plaque is attached to the surface of the nanoparticle. In some embodiments, the binder of an amyloid plaque is attached to the surface of the nanoparticle which is not already bonded to the polymer. In some embodiments, the binder of an amyloid plaque which is attached to the surface of the nanoparticle is capable of binding to an amyloid plaque. In certain embodiments, the nanoparticle includes a core which includes the superparamagnetic material. In some
  • the polymer and the binder of the amyloid plaque are adhered or bonded to the surface of the superparamagnetic nanoparticle.
  • the polymer and the binder of the amyloid plaque may be closely associated on the surface of the nanoparticle.
  • the binder of the amyloid plaque extends beyond the surface of the polymer even though both the polymer and the binder of the amyloid plaque are attached to the surface of the nanoparticle.
  • both the polymer and the binder of an amyloid plaque are bonded to the surface of the nanoparticle and the binder of the amyloid plaque is sufficiently exposed to be capable of binding to an amyloid plaque.
  • the present invention provides a magnetic resonance imaging (MRI) diagnostic agent composition, including: a superparamagnetic nanoparticle, a polymer, and at least one binder of an amyloid plaque; wherein the binder is attached to the surface of the nanoparticle; and wherein the polymer coats the nanoparticle having a binder attached to the surface of the nanoparticle.
  • the polymer and the binder are both attached to the surface of the nanoparticle.
  • the polymer and the binder are intimately associated on the surface of the nanoparticle.
  • the polymer coats both the binder and the surface of the nanoparticle.
  • the polymer coats the surface of the a nanoparticle but does not prevent the binder, which is attached to the surface of the nanoparticle, from binding to an amyloid plaque.
  • the present invention provides that the binder is of an amyloid plaque. In other embodiments, the present invention provides that the binder is of an amyloid deposit. In certain embodiments, the amyloid plaque is selected from the group consisting of protein aggregates, A-beta aggregates, and synuclein. In some embodiments, the amyloid plaque is indicative of a disease selected from the group consisting of Alzheimer's disease, dementia, Parkinson's disease, and Lewy body disease. [0040] In some embodiments, the present invention provides that the amyloid plaque is capable of forming a chemical bond with curcumin.
  • the present invention provides that the nanoparticle includes iron. In certain embodiments, the present invention provides that the nanoparticle includes magnetite. In other embodiments, the present invention provides that the nanoparticle includes a metal selected from the group consisting of iron, gold, platinum, silver, and cobalt. In yet other embodiments, the present invention provides that the nanoparticle includes a semiconductor selected from the group consisting of cadmium selenide, cadmium sulfide, lead selenide, lead sulfide, zinc selenide, zinc sulfide, and combinations thereof. In some embodiments, the nanoparticle includes iron oxide.
  • the present invention provides nanoparticles wherein the nanoparticle' s dimensions are less than 30 nm. In certain embodiments, the composition's hydrodynamic particle size is less than 300 nm. In some embodiments, the hydrodynamic particle size of about 10 nm to about 300 nm.
  • the present invention provides compositions wherein the binder is a bioflavonoid or a dye.
  • the binder is a dye selected from the group consisting of curcumin, Congo red, Thioflavin T/S, quercetin, epicatechin, hesperidin, rutin, and tangeritin.
  • the dye is curcumin.
  • the present invention provides compositions the polymer is hydrophilic.
  • the hydrophilic polymer is selected from the group consisting of polyethylene glycol (PEG), dextran,
  • polyvinylpyrrolidone PVP
  • fatty acids polyvinyl alcohol (PVA)
  • polyacrylic acid polypeptides, phosphorylcholine, poly(D, L- lactide), poly(N-isopropylacrylamide) (PolyNIPAAM), chitosan, gelatin, polylactic-co-glycolic acid (PLGA), poly caprolactone (PCL), and poly(butyl)cyanoacrylate (PBCA).
  • PVP polyvinylpyrrolidone
  • PVA polyvinyl alcohol
  • Polyacrylic acid polypeptides
  • phosphorylcholine poly(D, L- lactide)
  • PolyNIPAAM poly(N-isopropylacrylamide)
  • chitosan gelatin
  • PLGA polylactic-co-glycolic acid
  • PCL poly caprolactone
  • PBCA poly(butyl)cyanoacrylate
  • the hydrophilic polymer is polyethylene glycol (PEG).
  • the present invention provides compositions further including a biodegradable amphiphilic copolymer.
  • the biodegradable amphiphilic copolymer is selected from the group consisting of polylactic-co-glycolic acid (PLGA), poly caprolactone (PCL), polylactic acid (PLA), polyethylene glycol (PEG), methoxypolyethylene glycol (MePEG), polyethylene oxide (PEO), poly butadiene (PBD), d-a-tocopheryl polyethylene glycol 1000 succinate, PEG-PLA, PEG-PCL, PEG-PLGA, MePEG-PLA, MePEG-PCL, MePEG- PLGA, PEO-PBD, and Vitamin E TPGS.
  • the present invention provides compositions further including a hydrophilic polymer stabilizer.
  • the hydrophilic polymer stabilizer is selected from the group consisting of polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycols (PEG), hydroxypropyl methylcellulose (HPMC), and Poloxamer, polylactic-co-gly colic acid (PLGA), poly caprolactone (PCL), polylactic acid (PLA), poly(butyl)cyanoacrylate (PBCA), and chitosan.
  • compositions further including a cationic surfactant selected from the group consisting of benzalkonium chloride, benzethonium chloride, and cetrimide.
  • compositions further including an anionic surfactant selected from the group consisting of docusate sodium and sodium lauryl sulfate.
  • the present invention provides compositions further including a non-ionic surfactant selected from the group consisting of glyceryl monooleate, sorbitan esters, polyoxyethylene sorbitan fatty acid esters, and polyoxyethylene alkyl ethers.
  • the non-ionic surfactant is a sorbitan ester selected from the group consisting of sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan sesquioleate, and sorbitan trioleate.
  • the non-ionic surfactant is a polyoxyethylene sorbitan fatty acid ester selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and polysorbate 85.
  • the non-ionic surfactant is a polyoxyethylene alkyl ether selected from the group consisting of polyethylene glycol monocetyl ether, polyethylene glycol monolauryl ether, polyethylene glycol monooleyl ether, and polyethylene glycol monostearyl ether.
  • the poloxamer is selected from the group consisting of P124, P188, P237, P338, and P407.
  • the present invention provides compositions wherein the nanoparticle is iron oxide and the dye is curcumin. In some embodiments, the present invention provides compositions having a calculated maximum loading of 75 milligrams of curcumin per gram of iron oxide. In some embodiments, the present invention provides compositions having a calculated minimum loading of 5 milligrams of curcumin per gram of iron oxide.
  • compositions of the present invention encompass compositions made by admixing a compound, nanoparticle, or composition of the present invention and a pharmaceutically acceptable carrier and/or excipient or diluent. Such compositions are suitable for pharmaceutical use in an animal or human.
  • compositions of the present invention include a compound, nanoparticle, or composition described herein, or a pharmaceutically acceptable salt thereof, as an active ingredient and a pharmaceutically acceptable carrier and/or excipient or diluent.
  • a pharmaceutical composition may optionally contain other therapeutic ingredients.
  • the compounds of the present invention can be combined as the active ingredient in intimate admixture with a suitable pharmaceutical carrier and/or excipient according to conventional pharmaceutical compounding techniques. Any carrier and/or excipient suitable for the form of preparation desired for administration is contemplated for use with the compounds disclosed herein.
  • the compositions may be prepared by any of the methods well-known in the art of pharmacy.
  • compositions include compositions suitable for topical, parenteral, pulmonary, nasal, rectal or oral administration.
  • compositions suitable for systemic (enteral or parenteral) administration include oral, rectal, sublingual, or sublabial administration.
  • the compositions may be administered by injection, e.g., via a syringe, subcutaneously, intravenously, intramuscularly, or intraperitoneally.
  • Compositions for pulmonary administration include, but are not limited to, dry powder compositions consisting of the powder of a compound described herein, or a salt thereof, and the powder of a suitable carrier and/or lubricant.
  • the compositions for pulmonary administration can be inhaled from any suitable dry powder inhaler device known to a person skilled in the art.
  • compositions for systemic administration include, but are not limited to, dry powder compositions consisting of the composition as set forth herein and the powder of a suitable carrier and/or excipient.
  • the compositions for systemic administration can be represented by, but not limited to, tablets, capsules, pills, syrups, solutions, and suspensions.
  • the present invention provides compositions further including a pharmaceutical surfactant.
  • the present invention provides compositions further including a cryoprotectant.
  • the cryoprotectant is selected from the group consisting of glucose, sucrose, trehalose, lactose, sodium glutamate, PVP, HP CD, CD, glycerol, maltose, mannitol, and saccharose.
  • the present invention provides a pharmaceutical composition including the composition of claim 1 and a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient includes a salt or a diluent.
  • the present invention provides compositions including an effective amount of the composition of claim 1.
  • the composition is formulated for oral administration or intravenous administration and includes the composition of claim 1 and at least one member selected from the group consisting of an aqueous solution and a buffer solution.
  • the nanoparticles of the present invention may be prepared by the methods set forth herein.
  • curcumin conjugated iron oxide nanoparticle can be prepared by the following procedure.
  • iron oxide nanoparticles can be prepared by the oxidation-precipitation principle, e.g. , Tada M, Hatanaka S, Sanbonsugi H,
  • a mixture of an alkaline solution e.g. , KOH (1 mol/L) with 2% polyethylene glycol (PEG)
  • a metal halide e.g., FeC solution
  • pH 7.8
  • hydrogen peroxide is added to yield a dark black precipitate.
  • the products are purified, washed by de-ionized water and then acetone, and dried.
  • iron oxide nanoparticles can be synthesized by the reverse co-precipitation method described in, for example, Aono H, Hirazawa H, Naohara T, Maehara T, Kikkawa H, Watanabe Y. Synthesis of fine magnetite powder using reverse coprecipitation method and its heating properties by applying AC magnetic field. Materials Research Bulletin 2005; 40(7): 1126-1135.
  • a base solution e.g. , NaOH dissolved in deoxygenated purified water
  • an iron solution e.g.
  • nanoparticles that are approximately 10 to 30 nm in size.
  • the methods set forth herein are useful for preparing nanoparticles that are loaded with curcumin at a maximum loading of about 75 mg per gram of iron oxide.
  • the maximum loading is defined herein as the loading for which curcumin forms a monolayer surface on the nanoparticle.
  • the maximum loading of curcumin is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75 mg per gram of iron oxide.
  • other elements of curcumin is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,
  • the maximum loading of curcumin is 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg per gram of iron oxide.
  • the loading of curcumin on the nanoparticles can also be defined in terms of the mole ratio of curcumin to iron oxide.
  • nanoparticles are loaded with curcumin in a range from about 0.05: 1 to about 1 : 1 mole ratio of curcumin to iron oxide.
  • nanoparticles are loaded with curcumin in a range from about 0.05: 1 to about 0.5: 1, in a range from about 0.3: 1 to about 0.75: 1, in a range from about 0.55: 1 to about 1 : 1, in a range from about 0.05 to about 0.25, in range from about 0.2: 1 to about 0.4: 1, from about 0.35: 1 to about 0.55: 1, from about 0.5: 1 to about 0.7: 1, from about 0.65: 1 to about 0.85: 1, or from about 0.8: 1 to about 1 : 1 mole ratio of curcumin to iron oxide.
  • nanoparticles loaded with curcumin at about 0.4: 1 mole ratio of curcumin to iron oxide maintained their size during subsequent removal of solvent through dialysis.
  • the nanoparticles are prepared using high power sonication. In some embodiments, the nanoparticles are dispersed in
  • the suspension is further dried by vacuum concentrator.
  • the nanoparticles are encapsulated in a polymeric micelle.
  • a PEG-PLA co-block polymer is dissolved in an organic phase while nanoparticles are dispersed in an aqueous phase.
  • nanoparticles are both provided in an organic phase while an aqueous phase is also provided. In certain embodiments, both phases are co-injected into a multi-inlet vortex mixer. In some embodiments, the nanoparticles are subjected to high energy generation during rapid mixing. In certain embodiments, the nanoparticles are separated and prevented from aggregation. In some embodiments, polyvinyl pyrrolidone (PVP) or polyvinyl alcohol (PVA) is added into the solution. In some embodiments, the PVP or PVA are dissolved in an aqueous layer that is co-injected with the organic phase into a vortex mixer. [0068] In some embodiments, the solvent remaining in the nanoparticle suspension is eliminated by dialysis or centrifugal filtration.
  • PVP polyvinyl pyrrolidone
  • PVA polyvinyl alcohol
  • drying is achieved by adding cryogenic protectant such as sucrose, mannitol, beta cyclodextrin, or glucose, and then co-freezing with the nanosuspension for freeze drying.
  • cryogenic protectant such as sucrose, mannitol, beta cyclodextrin, or glucose
  • the methods include storing the dried nanoparticles.
  • polysorbate 80 or mannitol is added to a solution of the nanoparticles in order to reconstitute them.
  • the present invention provides a method of labeling amyloid plaques for MRI detection, including contacting a composition, described herein, with an amyloid plaque, thereby labeling amyloid plaques for MRI detection.
  • the amyloid plaque is selected from the group consisting of protein aggregates, A-beta aggregates, and synuclein.
  • the amyloid plaque is indicative of a disease selected from the group consisting of Alzheimer's disease, dementia, Parkinson's disease, and Lewy body disease.
  • the present invention provides a method of diagnosing a disease or condition in a patient, including administering a composition, described herein, to the patient; labeling an amyloid plaque in the patient with the composition; acquiring MRI images of the patient having the composition administered; analyzing the images to detect amyloid plaque in the patient; and thereby diagnosing a disease or condition in a patient.
  • the present invention provides a method of administering the composition, described herein, including contacting the composition with the blood stream of a patient.
  • the present invention provides a method of preparing a composition described herein, including preparing an alkaline solution, a polymer solution, and a metal-halide solution; mixing the alkaline solution, polymer solution, and metal-halide solution to form a mixture; and contacting the mixture with an oxidizing agent.
  • the methods include using a confined impinging jet mixer or multi-inlet vortex mixer to prepare the composition by flash nanoprecipitation.
  • the methods include drying the composition by freeze drying, spray drying or vacuum concentration.
  • the present invention provides methods of assisting the diagnosis of a disease where amyloid plaques are present, such as Alzheimer's disease, dementia, Parkinson's disease, and Lewy body disease.
  • a disease where amyloid plaques are present such as Alzheimer's disease, dementia, Parkinson's disease, and Lewy body disease.
  • the methods include administering a composition of the present invention to a patient. In some embodiments, the methods further include allowing the composition of the present invention to bind or complex with an amyloid plaque. In some embodiments, the methods further include using MRI to image the amyloid plaque that is bound to a composition of the present invention. In some embodiments, the methods further include diagnosing a patient as having, or as likely to have, a disease where amyloid plaques are present, such as Alzheimer's disease, dementia, Parkinson's disease, and Lewy body disease. In some embodiments, the diagnosing involves analyzing an MRI image for contrast that indicates the presence of amyloid plaques. In some embodiments, the contrast is induced in the MRI image by the composition of the present invention. In certain embodiments, the diagnosing is for an early stage of a disease recited herein.
  • compositions and nanoparticles described herein are useful for diagnosing a variety of diseases.
  • the compositions and nanoparticles that are described herein are useful for diagnosis in a person that is at least 40 years old; or that is at least 45 years old; or that is at least 50 years old; or that is at least 55 years old; or that is at least 60 years old; or that is at least 65 years old; or that is at least 70 years old; or that is at least 75 years old; or that is at least 80 years old; or that is at least 85 years old; or that is at least 90 years old; or that is at least 95 years old; or that is at least 100 years old.
  • compositions, agents, and nanoparticles described herein may also be administered parenterally.
  • Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • polyol e.g. glycerol, propylene glycol and liquid polyethylene glycol
  • suitable mixtures thereof e.g. glycerol, propylene glycol and liquid polyethylene glycol
  • dosages of the compositions of the present invention range from about 0.5 to about 2 g, in a single administration. In some embodiments for adult humans, greater or lesser dosages may be used, and multiple administrations may be used. The exact dosage will depend upon the mode of administration, the composition involved, on the diagnosis desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • compositions of the present invention can be dispensed in unit dosage form including preferably from about 1 to 500 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
  • these preparations preferably contain a preservative to prevent the growth of microorganisms.
  • Kits providing a unit dosage of the compositions set forth herein are contemplated as within the present invention.
  • Kits providing many unit dosages of the compositions set forth herein are contemplated as within the present invention.
  • kits providing several unit dosages of the compositions set forth herein are contemplated as within the present invention.
  • the kits of the present invention include a unit dosage of a pharmaceutical compositions set forth herein.
  • the kits of the present invention include many unit dosages of a pharmaceutical compositions set forth herein.
  • the kits of the present invention include a unit dosage of a
  • Administration of an appropriate amount the candidate compound may be by any means known in the art such as, for example, oral or rectal, parenteral, intraperitoneal, intravenous, subcutaneous, subdermal, intranasal, or intramuscular.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the packaged nucleic acid suspended in diluents, such as water, saline or PEG 400; (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; and (d) suitable emulsions.
  • liquid solutions such as an effective amount of the packaged nucleic acid suspended in diluents, such as water, saline or PEG 400
  • capsules, sachets or tablets each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin
  • suspensions in an appropriate liquid such as water, saline or PEG 400
  • Tablet forms can include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible carriers.
  • Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • Formulations suitable for parenteral administration such as, for example, by intraarticular (in the joints), intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • compositions of the invention may be used in combination with other drugs that may also be useful in the treatment, prevention, suppression of a neurological or psychological disorder.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the invention.
  • a compound of the invention is used
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound is preferred.
  • the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • the active principle in the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, local or rectal administration, can be administered to animals and humans in unit forms of administration mixed with conventional pharmaceutical carriers.
  • the appropriate unit forms of administration include oral forms such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, sublingual and buccal forms of administration, aerosols, implants, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.
  • Iron oxide nanoparticles were fabricated by the oxidation-precipitation principle. Techniques from the following were also employed: Tada M, Hatanaka S, Sanbonsugi H, Matsushita N, Abe M. Method for synthesizing ferrite nanoparticles ⁇ 30 nm in diameter on neutral pH condition for biomedical applications, J. Appl. Phys. 2003;93(10):7566-7568; and Konwarh R, Saikia JP, Karak N, Konwar BK.
  • curcumin preferentially binds the iron oxide surface, with a calculated maximum loading of 75 mg of curcumin per gram of iron oxide.
  • Figures 2 & 3 show the adsorption isotherm and Langmuir model, which indicate that Curcumin is forming a monolayer and binds at a homogeneous site on the iron oxide surface.
  • Curcumin-conjugated iron oxide was made under high power sonication using, in part, techniques from the above references and also Zhang G, Guo B, Wu H, Tang T, Zhang BT, Zheng L, He Y, Yang Z, Pan X, Chow H, To K, Li Y, Li D, Wang X, Wang Y, Lee K, Hou Z, Dong N, Li G, Leung K, Hung L, He F, Zhang L, Qin L, A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy, Nat Med 2012;18(2):307-314.
  • the Curcumin solution was mixed with pre-dispersed iron oxide, in dimethylformamide, under ultra-sonication for 8 minutes. The suspension is further dried by vacuum concentrator.
  • Figure 4 shows the Curcumin-conjugated PEG-supported iron oxide nanoparticles.
  • PEG-PLA co-block polymer was dissolved in an organic phase while curcumin-conjugated iron oxide was dispersed in an aqueous phase. Both phases were co-injected into a multi -inlet vortex mixer.
  • the PLA tail of PEG-PLA co-block polymer was favored to adhere to the curcumin-coated surface and form a micelle structure therewith. Due to the high energy generated during the rapid mixing, the nanoparticles are separated and prevented from aggregation.
  • polyvinyl pyrrolidone (PVP) or polyvinyl alcohol (PVA) is added into the solution.
  • the solvent remaining in the nanoparticle suspension was eliminated by dialysis or centrifugal filtration. Drying was achieved by adding cryogenic protectant such as sucrose, mannitol, beta cyclodextrin, or glucose, and then co-freezing with the nanosuspension for freeze drying.
  • cryogenic protectant such as sucrose, mannitol, beta cyclodextrin, or glucose
  • the dried nanoparticles can be stored indefinitely and then re-suspended in aqueous solution.
  • polysorbate 80 or mannitol is added to the reconstituted solution before use. Relevant techniques and materials can be found in the following: Ren T, Xu N, Cao C, Yuan W, Yu X, Chen J, et al.
  • Recent approaches to diagnose AD by detecting amyloid ⁇ plaques include radioactive dye imaged by positron emission tomography (PET) and PET.
  • Curcumin-conjugated magnetic nanoparticles The size of the iron core is ⁇ 30 nm, and the final hydrodynamic particle size is ⁇ 300 nm. These particles have been tested in vitro and in vivo for amyloid plaque binding ability and blood-brain barrier penetration, and in vivo for MRI.
  • Figure 5 shows confocal fluorescent and phase-contrast images of Thioflavin T, curcumin, and curcumin-conjugated iron oxide nanoparticles applied to consecutive sections of an APP (amyloid precursor protein) transgenic mouse brain. All three reagents bind amyloid plaques.
  • Figure 9 shows a typical brain section of an APP transgenic mouse injected with curcumin-conjugated magnetic nanoparticles.
  • the red spots indicate amyloid plaques stained by a mixture of 4G8 and 6E10 monoclonal antibodies to ⁇ peptide, and blue indicates iron oxide.
  • the magnified view demonstrates that iron oxide was in close proximity to an amyloid plaque.
  • Figure 10 shows a matched MRI (left) and double-stained APP transgenic mouse brain section (right). Many of the dark spots found in MRI co-localized with immunolabeled amyloid plaques (red) and iron oxide (blue). The inset is a 40x magnification of the selected area, showing amyloid plaques (red) and iron (blue) in the bright field image (left) and plaques (orange) in the fluorescent image (right). The fluorescence was orange because curcumin emits at 520 nm, while the fluorescent label used for immunolabeling the plaques emits at 570 nm. The combination of these yellow and red emitted signals results in a bright orange color. The images show that circumin-conjugated magnetic nanoparticles are able to bind amyloid and can be visualized by MRI or immunohistochemistry.
  • FIG. 11 shows a section of a non-transgenic control mouse of the same age after injection of curcumin-conjugated magnetic nanoparticles. No iron oxide signal was detected by MRI (left). As expected, no amyloid plaques (red) or iron (blue) was detected on the matched histology section (right).
  • Example 5 Curcumin-conjugated magnetic nanoparticles as a diagnostic agent
  • Curcumin-conjugated magnetic nanoparticles can thus be used clinically for diagnostic imaging of ⁇ plaques.

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Abstract

La présente divulgation concerne une nouvelle nanoparticule qui peut traverser la barrière hémato-encéphalique et former une liaison avec des plaques amyloïdes et autres agrégats protéiques apparentés pour la détection par imagerie par résonance magnétique (IRM). Les compositions, les procédés de fabrication et les procédés d'utilisation ci-décrits fournissent également un moyen non invasif pour diagnostiquer la maladie d'Alzheimer à un stade précoce.
PCT/IB2017/000517 2017-04-17 2017-04-17 Agent de contraste nanoparticulaire pour le diagnostic précoce de la maladie d'alzheimer par imagerie par résonance magnétique (irm) WO2018193278A1 (fr)

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CN109529883A (zh) * 2018-11-13 2019-03-29 北京工业大学 一种采用脉冲激光液相烧蚀法制备Cd/S核壳纳米结构的方法
CN109568180A (zh) * 2018-11-27 2019-04-05 常州良福朗清生物科技有限公司 一种精油和plga复合的壳核结构纳米粒子的制备方法及应用
CN111103365A (zh) * 2019-12-03 2020-05-05 山西大学 一种基于mrm-ida-epi模式同时定性定量分析酸枣叶总黄酮中6种成分的方法

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WO2010124623A1 (fr) * 2009-04-29 2010-11-04 香港科技大学 Médicament de prévention et de traitement de la maladie d'alzheimer et sa méthode de préparation
CN102284068A (zh) * 2011-08-11 2011-12-21 华中科技大学同济医学院附属同济医院 老年斑磁共振纳米诊断试剂及其优化方法
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WO2010124623A1 (fr) * 2009-04-29 2010-11-04 香港科技大学 Médicament de prévention et de traitement de la maladie d'alzheimer et sa méthode de préparation
CN102284068A (zh) * 2011-08-11 2011-12-21 华中科技大学同济医学院附属同济医院 老年斑磁共振纳米诊断试剂及其优化方法
CN105987888A (zh) * 2015-02-09 2016-10-05 复旦大学 一种从混合物中垂钓筛选活性成分单体或活性成分组的方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109529883A (zh) * 2018-11-13 2019-03-29 北京工业大学 一种采用脉冲激光液相烧蚀法制备Cd/S核壳纳米结构的方法
CN109529883B (zh) * 2018-11-13 2021-09-17 北京工业大学 一种采用脉冲激光液相烧蚀法制备CdS/C核壳纳米结构的方法
CN109568180A (zh) * 2018-11-27 2019-04-05 常州良福朗清生物科技有限公司 一种精油和plga复合的壳核结构纳米粒子的制备方法及应用
CN111103365A (zh) * 2019-12-03 2020-05-05 山西大学 一种基于mrm-ida-epi模式同时定性定量分析酸枣叶总黄酮中6种成分的方法

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