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WO2011095836A2 - Macrophages thérapeutiques détectables - Google Patents

Macrophages thérapeutiques détectables Download PDF

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Publication number
WO2011095836A2
WO2011095836A2 PCT/IB2010/050444 IB2010050444W WO2011095836A2 WO 2011095836 A2 WO2011095836 A2 WO 2011095836A2 IB 2010050444 W IB2010050444 W IB 2010050444W WO 2011095836 A2 WO2011095836 A2 WO 2011095836A2
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WO
WIPO (PCT)
Prior art keywords
therapeutic
trackable
macrophage
fatty acid
polyunsaturated fatty
Prior art date
Application number
PCT/IB2010/050444
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English (en)
Other versions
WO2011095836A3 (fr
Inventor
Fernando Moreno Egea
Jaime Lopez De La Osa
Pilar Ramirez Calvo
Fernando Gonzalez Santos
Maria De Los Angeles Cubillo De Dios
Mario Fernandez Montes
Original Assignee
Soluciones Extractivas Alimentarias, S.L. (Solutex)
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Publication date
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Priority to PCT/IB2010/050444 priority Critical patent/WO2011095836A2/fr
Publication of WO2011095836A2 publication Critical patent/WO2011095836A2/fr
Publication of WO2011095836A3 publication Critical patent/WO2011095836A3/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
    • A61K49/1806—Suspensions, emulsions, colloids, dispersions
    • A61K49/1812—Suspensions, emulsions, colloids, dispersions liposomes, polymersomes, e.g. immunoliposomes
    • 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
    • A61K49/1836—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 the small organic molecule being a carboxylic acid having less than 8 carbon atoms in the main chain
    • 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
    • A61K49/1839—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 the small organic molecule being a lipid, a fatty acid having 8 or more carbon atoms in the main chain, or a phospholipid
    • 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
    • A61K49/1896—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes not provided for elsewhere, e.g. cells, viruses, ghosts, red blood cells, virus capsides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5063—Compounds of unknown constitution, e.g. material from plants or animals
    • A61K9/5068—Cell membranes or bacterial membranes enclosing drugs
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • Polyunsaturated fatty acids n-3 are essential In the sense of human body cannot synthesize them de novo and therefore must be obtained from the diet.
  • Polyunsaturated fatty acids (PUFAs) can be classified in n-3 fatty acids and n-6 fatty acids. Modern habits In westernized diets have produced an imbalance between the n-3 and n-6 series of fatty acids In favor of the latter. Both types of fatty acids are precursors of signaling molecules with opposing effects, that modulate membrane composition, receptor signaling and gene expression.
  • n-6 fatty acid The predominant n-6 fatty acid Is arachidonic acid, which Is converted to prostaglandins, leukotrlenes and other lipoxygenase or cyclooxygenase products. These products are important regulators of cellular functions with Inflammatory, atherogenic and prothrombotlc effects.
  • Typical n-3 fatty acids are docosahexaenolc acid (DHA) and elcosapentaenoic acid (EPA), which are competitive substrates for the enzymes and receptors of arachidonic acid metabolism.
  • DHA docosahexaenolc acid
  • EPA elcosapentaenoic acid
  • Docosahexaenoic acid- and eicosapentaenoic acid-derived elcosanoids antagonize the pro-inflammatory effects of n-6 fatty acids, n-3 and n-6 fatty acids are llgands/modulators for the nuclear receptors NFKB, PPAR and SREBP-lc, which control various genes of inflammatory signaling and lipid metabolism, n-3 fatty acids down-regulate Inflammatory genes and lipid synthesis, and stimulate fatty acid degradation,
  • omega-3 fatty acids decrease risk of arrhythmias, which can lead to sudden cardiac death, decrease triglyceride levels, decrease growth rate of atherosclerotic plaque and lower blood pressure (slightly).
  • Systemic delivery involves administering a bioactive agent at a discrete location followed by the agent migrating throughout the patient's body including of course, to the afflicted organ or area of the vasculature.
  • Systemic delivery introduces the bioactive agent in two ways: into the digestive tract (enteral administration) or in the vascular system (parenteral administration), either directly, such as injection into a vein or an artery, or indirectly, such as injection into a muscle or into the bone marrow.
  • the ADMET factors (absorption, distribution, metabolism, excretion and toxicology) strongly influence delivery by each of these routes.
  • Magnetic nanoparticles have awakened great expectations on their nanomedical applications due to the potentiality of its magnetic properties on therapeutic (hyperthermia) or diagnostic uses (M I contrast agents).
  • Nanoparticles have been intensively used as injectable drug delivery systems.
  • a significant obstacle to the use of these injectable drug delivery materials was the rapid clearance of the materials from the blood stream by the macrophages of the reticuloendothelial system.
  • MRI contrast agents Two types have been developed during the last two decades: one based on the paramagnetic nature of the Gadolinium, and the other on the superparamagnetic nature of ferrite nanocristals.
  • Superparamagnetic nanoparticles high transverse relaxivity has triggered the development of many interesting candidates to innovative MRI contrast agents, as a promising alternative to the Gadolinium based contrast agents (Neuwelt EA, 2008).
  • These developments on superparamagnetic contrast agents has come up with several commercial products as ferumoxides or ferucarbotran, based on superparamagnetic iron oxide (SPIOs) nanoparticles, extensively used on imaging diagnosis of liver disorders.
  • SPIOs superparamagnetic iron oxide
  • a very promising approach from systemic delivery is local delivery, which comprises administering the bioactive agent directly to the afflicted site.
  • localized delivery With localized delivery, the ADMET factors abovementioned tend to be less important that with systemic administration.
  • Localized delivery of bioactive agents is currently considered state-of-the-art approach to the treatment of many diseases such as cancer or atherosclerosis. However, administering locally nanoparticles without losing a substantial fraction of them is quite challenging.
  • a novel method described in patent application US20090047318A1 is an implantable medical 90 device that includes a coating containing a plurality of nanoparticles, wherein the nanoparticles include one or more bioactive agents encapsulated within, adhered to a surface of or integrated into the structure of the nanoparticles and further include one or more contrast enhancing agents encapsulated within, adhered to a surface or integrated into the structure of the nanoparticles.
  • an implantable medical device is too invasive for the 95 patient.
  • Macrophage is a phagocytic cell present in the conjunctive tissue of mammals and produced
  • monocytes by the differentiation of monocytes. It is a cell genuinely versatile as plays a role in the antigens processing, in the production of molecules with biological activity such as cytokines and in the lipid metabolism.
  • cytokines biological activity
  • a monocyte enters damaged tissue through the endothelium of a blood vessel (a process known as the leukocyte extravasation), it undergoes a series of changes to become a macrophage.
  • Monocytes are attracted to a damaged site by
  • the present application intends to conjugate the MRI technique with the therapeutic effect of the n-3 polyunsaturated fatty acids, using the macrophages as vehicles to target the 110 inflammation site.
  • Macrophages carrying the "magnetoliposome", (thus the liposome with magnetic nanoparticles incorporated), herein described with nanoparticles and the n-3 polyunsaturated fatty acid would go to the inflammation site in response to the chemotaxis. They will also deliver the polyunsaturated fatty acid to the inflammation site in order to compete with the proinflammatory metabolic cascade.
  • the superparamagnetic nanoparticle or 115 group of nanoparticles will allow imaging the inflammation site in order to see the performance of the polyunsaturated fatty acid in situ.
  • Macrophages travel to where there is a damaged tissue and start a healing process that comprises an inflammatory response. Macrophage is clearly, therefore, a very interesting target for cell therapy with the additional advantage of a longer survival than neutrophils in the body that can take up to several months.
  • the product hereby described takes advantage of the strategy of macrophages transfection with magnetic particles of different nature.
  • the methodology applied is lipofection (liposome transfection) because it makes use of liposomes, whose nature can be conveniently modified as explained below. Liposomes incorporating a magnetic load have been also
  • magnetoliposomes (De Cuyper M, 2007).
  • Magnetoliposomes have been proposed for several uses on nanomedicine, generally as drug delivery agents (J Cocquyt, 2008) or lipofection vehicles for magnetic particles (Soenen SJ, 2009).
  • the magnetoliposomes used for lipofection are formed by cationic phospholipids which help on the interaction with the cellular membrane (with negative net charge) (P L Feigner, 1987).
  • cationic phospholipids which help on the interaction with the cellular membrane (with negative net charge)
  • DOTAP cationic phospholipids
  • DODAP DODAP
  • DOTMA DOTMA-diol
  • EPA/DHA omega-3 enriched neutral and cationic phospholipids or just enriched
  • omega-3 enriched phospholipids in order to lipofect the macrophages, not only with magnetic nanoparticules but also with omega-3 enriched phospholipids.
  • the production of such omega-3 enriched phospholipids can be achieved by chemical or enzymatic procedures and has been described on several publications and patents as (WO/2005/038037) "Methods for preparing phospholipids containing omega-3 and omega-6 moieties" licensed from Enzymotec LTD (Piatt,
  • Macrophages are white blood cells derived from monocytes, and their role on immunity response makes them to be present on many diseases and disorders and therefore highly suitable as targets.
  • One aspect of this invention is to provide with a method to design a magnetoliposome, consisting in a nanoparticle with magnetic properties and a polyunsaturated fatty acid from the group of n-3 or one derivative from them, linked to it and the complex being embedded by a liposome.
  • the liposome therefore shall bear properties for diagnosis and detection and 170 simultaneously a therapeutic one derived from the presence of the polyunsaturated fatty acid or one of its derivatives.
  • nanoparticle or group of nanoparticles will have magnetic properties and will be selected from iron oxide, cobalt ferrite, manganese ferrite or magnesium ferrite or 175 combinations thereof and such nanoparticle or group of nanoparticles could or not contain and outer coating consisting of metals, polymers, proteins, oxides or combinations thereof.
  • the fatty acid present in the magnetoliposome will be a polyunsaturated fatty acid of marine origin, preferably eicosapentaenoic acid, docosahexaenoic acid or one of its derivatives or a 180 conjugated fatty acid in the form of a free fatty acid, an ester, a salt, a solvate or any other pharmaceutical acceptable complex.
  • the phospholipid embedding the nanoparticle and the fatty acid will be natural or synthetic.
  • SPIOs Superparamagnetic iron oxide
  • a 50% NH 3 solution was dropped into 20 ml of an aqueous solution containing Fe(lll) chloride (7.5 mmol) and Fe(ll) chloride (5 mmol) and citric acid (2.9 mmol). Larger particle aggregates were removed by centrifugation, the resulting ferrofluid had a
  • Magnetoliposome preparation 210 magnetite content of 14.3 mg Fe 3 0 4 /ml and a core diameter of approximately 4 nm. The pH was adjusted to 7.0 by HCI (1M). Magnetoliposome preparation
  • DOTAP trimethylammonium-propane
  • Macrophages were isolated and purified from spleens of BN rats, then maintained in culture. 500 ⁇ of the magnetoliposome solution were added into 10 ml of macrophages culture (1 x 225 10 7 cells per ml) for overnight incubation. After proper washing the macrophages were resuspended in PBS to desirable cell densities (1 x 10 7 cells per ml).
  • TES buffer 5mM, pH 7.0
  • PBS buffer 5mM, pH 7.0
  • the particles obtained were washed twice with 15 ml of deionized water using ultracentrifigation (30.000 rpm for 30 min at 10 5 C), decanted and finally resuspended on 50 ml of eicosapentanoic acid (EPA) 80 wt %, (20 mM). A turbid supernatant appeared due to the excess of EPA that formed an emulsion, being removed during the washing steps.
  • EPA eicosapentanoic acid
  • 245 Magnetoliposome preparation Small unilamellar vesicles (SUVs) were prepared by mixing synthetically enriched phosphatidylcholine (250 mg), in which at least 80% of the fatty acids present are EPA, with 20 ml of TES buffer (5 mM, pH 7,0), followed by a 15 minutes sonication at 25 Q C.
  • synthetically enriched phosphatidylcholine 250 mg
  • TES buffer 5 mM, pH 7,0
  • Macrophages were isolated and purified from spleens of BN rats, then maintained in culture. 500 ⁇ of the SUVs PBS solution were added into 10 ml of macrophages culture (1 x 10 7 cells per ml) for overnight incubation. After proper washing the macrophages were resuspended in PBS to desirable cell densities (1 x 10 7 cells per ml).
  • ammonium hydroxide 5 M
  • DHA docosahexaenoico
  • Macrophages were isolated and purified from spleens of BN rats, then maintained in culture. 500 ⁇ of the magnetoliposome solution were added into 10 ml of macrophages culture (1 x 10 7 cells per ml) for overnight incubation. After proper washing the macrophages were 295 resuspended in PBS to desirable cell densities (1 x 10 7 cells per ml).
  • Small unilamellar vesicles were prepared by mixing synthetically enriched phosphatidylcholine (250 mg), in which at least 85% of the fatty acids present are DHA, with 20 ml of TES buffer (5 mM, pH 7,0), followed by a 15 minutes sonication at 25 5 C.
  • Macrophages were isolated and purified from spleens of BN rats, then maintained in culture. 500 ⁇ of the magnetoliposome solution were added into 10 ml of macrophages culture (1 x 10 7 cells per ml) for overnight incubation. After proper washing the macrophages were resuspended in PBS to desirable cell densities (1 x 10 7 cells per ml).
  • Magnetic nanoparticles were synthesized according to the method reported in the literature (Sun et al). 1,4 g of Iron(lll) acetylacetonate, 5 g of 1,2-hexadecanedio, 2,2g of oleylamine, and 3,6 g of EPA acid (90%), were dissolved on 50 ml of benzyl ether and mixed under a flow of argon by magnetic stirring. The mixture was heated to 200 °C for 3 h. The black mixture was cooled to room temperature and ethanol was added producing nanoparticles peptization. Supernatant was through up and the remaining precipitate was redissolved on hexane. Centrifugation at 5000 rpm for 10 min was used to remove any undispersed residue and the product was then precipitated with ethanol.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nanotechnology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Radiology & Medical Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Cell Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Botany (AREA)
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  • Hematology (AREA)
  • Immunology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
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Abstract

La présente invention concerne un procédé de thérapie cellulaire selon lequel des macrophages précédemment isolés sont soumis à une lipofection ex vivo avec un magnétoliposome contenant une nanoparticule magnétique ou un groupe de nanoparticules magnétiques et un acide gras polyinsaturé ou un de ses dérivés, les transformant en un produit approprié pour l'imagerie et la thérapie simultanées pour différentes maladies.
PCT/IB2010/050444 2010-02-02 2010-02-02 Macrophages thérapeutiques détectables WO2011095836A2 (fr)

Priority Applications (1)

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PCT/IB2010/050444 WO2011095836A2 (fr) 2010-02-02 2010-02-02 Macrophages thérapeutiques détectables

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Application Number Priority Date Filing Date Title
PCT/IB2010/050444 WO2011095836A2 (fr) 2010-02-02 2010-02-02 Macrophages thérapeutiques détectables

Publications (2)

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WO2011095836A2 true WO2011095836A2 (fr) 2011-08-11
WO2011095836A3 WO2011095836A3 (fr) 2012-01-12

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112773905A (zh) * 2021-02-08 2021-05-11 暨南大学 一种巨噬细胞背包系统及其制备方法与应用

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* Cited by examiner, † Cited by third party
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IL158553A0 (en) * 2003-10-22 2004-05-12 Enzymotec Ltd Method for preparing phosphatidylserine containing omega-3 acid moieties
JP2006335745A (ja) * 2005-06-06 2006-12-14 Fujifilm Holdings Corp リポソームを含むｍｒｉ造影剤

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* Cited by examiner, † Cited by third party
Title
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112773905A (zh) * 2021-02-08 2021-05-11 暨南大学 一种巨噬细胞背包系统及其制备方法与应用

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