[go: up one dir, main page]

EP1747018A2 - Procede de production de nanotubes en carbone remplis en partie par voie ferromagnetique, qui portent des biomolecules, et leur utilisation en matiere de diagnostic et de therapie - Google Patents

Procede de production de nanotubes en carbone remplis en partie par voie ferromagnetique, qui portent des biomolecules, et leur utilisation en matiere de diagnostic et de therapie

Info

Publication number
EP1747018A2
EP1747018A2 EP05731324A EP05731324A EP1747018A2 EP 1747018 A2 EP1747018 A2 EP 1747018A2 EP 05731324 A EP05731324 A EP 05731324A EP 05731324 A EP05731324 A EP 05731324A EP 1747018 A2 EP1747018 A2 EP 1747018A2
Authority
EP
European Patent Office
Prior art keywords
nanotubes
carbon nanotubes
filled
ferromagnetic
partially
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05731324A
Other languages
German (de)
English (en)
Inventor
Jens Ingolf MÖNCH
Axel Meye
Albrecht Leonhardt
Gerd Hammermann
Manfred P. Wirth
Bernd BÜCHNER
Kai KRÄMER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hamstein Consult GmbH
Technische Universitaet Dresden
Leibniz Institut fuer Festkorper und Werkstofforschung Dresden eV
Original Assignee
Hamstein Consult GmbH
Technische Universitaet Dresden
Leibniz Institut fuer Festkorper und Werkstofforschung Dresden eV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hamstein Consult GmbH, Technische Universitaet Dresden, Leibniz Institut fuer Festkorper und Werkstofforschung Dresden eV filed Critical Hamstein Consult GmbH
Publication of EP1747018A2 publication Critical patent/EP1747018A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1268—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules host-guest, closed hollow molecules, inclusion complexes, e.g. with cyclodextrins, clathrates, cavitates, fullerenes
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0097—Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes
    • 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
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • A61K9/5094—Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting

Definitions

  • the invention relates to a process for the production of partially ferromagnetically filled single or multi-walled carbon nanotubes (carbon nanotubes, CNTs) which are filled with iron, cobalt, nickel or an alloy thereof or an alloy of these elements with platinum and carry biomolecules where - with the biomolecules enclosed in the tube and / or with the outer
  • the nanotubes according to the invention can contain two or more different active substances in the tube, which are released one after the other when used in the body.
  • the invention also relates to the use of the partially ferromagnetically filled materials according to the invention
  • Carbon nanotubes in diagnosis and therapy especially tumor diagnosis and therapy.
  • Nanoparticles for use in diagnostics and therapy are already known from the literature. So z. B. in the patent EP 0625055 (DE 69328550 T2) fullerene-like compounds with magnetic molecules, ions, etc. and used in particular for diagnostic imaging methods. The aim here is to realize particles that are as small as possible and thus superparamagnetic, which is useful for the contrast agents sought in diagnostic imaging methods. Due to the superparamagic state, however, an energy conversion and thus, in addition to the diagnosis, a therapeutic application, eg. B. in hyperthermia, only possible to a limited extent.
  • Magnetic nanoparticles for use in diagnosis and therapy are also known from the literature (compare, for example, QA Pankhurst et al., J. Phys. D .: Appl. Phys. 36 (2003), R161-R181). But they show an irregular
  • Diagnostic and therapeutic agents also strive for a very tight tolerance in the geometric dimensions and the diagnostic / therapeutic volume of the active phase. These requirements cannot be met with the geometrically irregular nanoparticles.
  • the object of the invention was therefore to provide magnetic compounds which can be used universally as diagnostic and therapeutic agents and which can advantageously simultaneously serve both as diagnostic agents and as therapeutic agents for the same disease and, if appropriate, can carry several therapeutic agents or can be implemented as a depot form.
  • the object of the invention was, in particular, to specify a method for producing such connections with their geometric dimensions and their magnetic properties can be produced in a stable and defined manner.
  • the metal filling is monocrystalline or polycrystalline to a high degree by volume and has a length-width ratio greater than 1.
  • the metal filling in the nanotubes is preferably only partially formed in order to to have the remaining volume available for diagnostically and / or therapeutically active compounds.
  • a 10 percent ferromagnetic filling, for example, is already sufficient to use the carbon nanotubes according to the invention in imaging processes, e.g. B. the MRI to use.
  • the ferromagnetic filling in the carbon nanotube has a higher coercive force than the same ferromagnetic material in the bulk material.
  • the carbon nanotubes according to the invention can be multi-walled but also single-walled.
  • the single-wall carbon nanotubes are preferred for the use according to the invention and were produced for the first time using the method according to the invention.
  • the partially ferromagnetically filled carbon nanotubes according to the invention are produced by providing a substrate over the entire surface with a layer on which the ferromagnetically filled carbon nanotubes do not grow, for example a gold layer, the thickness of which is selected depending on the desired length of the nanotubes. subsequently a photoresist layer is applied to this layer, subsequently a dot pattern in the form of holes, preferably cylindrical holes, of the same size is introduced by means of lithographic methods, the diameter of which is selected as a function of the desired outer diameter of the resulting nanotubes, now after exposure and resist development by a directional etching process at an angle of approx.
  • the layer on which the ferromagnetic carbon nanotubes do not grow is thinned at the points not covered with photoresist so that holes i n the depth are formed, which correspond • ren the desired length of Nanoröh-, then the bottom of the holes is coated with a catalytically active metal layer, hereinafter referred to primarily in the holes by means of chemical vapor deposition (by pyrolysis of metallor- ganic compounds and / or hydrocarbons) carbon nanotubes partially filled with the ferromagnetic materials are deposited, then superficial protrusions are removed by a directional etching process, then those partially with the ferromagnetic Materials filled nanotubes optionally a thermal treatment ⁇ lung are subjected, and then the nanotubes a) on the open side with diagnostically and / or therapeutically active compounds, sealed with a biocompatible and degradable in the body or disclose polymer or gel which detached from the substrate and optionally biofunctionalized on the surface by means of a carrier compound or b
  • Metal locenes of the elements iron, cobalt, nickel or their mixtures, carbonyls of these metals or their mixtures or other organometallic compounds of these elements are used individually or as mixtures, optionally in a mixture with readily thermally decomposable platinum compounds, as starting materials for chemical vapor deposition.
  • the nanotubes that can be produced with the method according to the invention have outer diameters between 10 and 100 nm and preferably a maximum
  • ferromagnetic carbon nanotubes can be produced by chemical vapor deposition (Chemical Vapon Deposition, CVD) (A. Leonhardt et al. In “Diamond and Related Materials 3-7: 790-793 (2002)")
  • CVD chemical Vapon Deposition
  • the nanotubes of the invention should contain sufficient ferromagnetic filling, for example, to also be used in hyperthermia, be associable.
  • the growth of the nanotubes as partially filled tubes can be carried out according to the invention using a Two-zone furnaces can be realized, the sublimation of the metal-containing compound used being implemented in the first low-temperature zone and the thermal decomposition of the sublimed compound and the hydrocarbon used being carried out in the high-temperature zone.
  • the temperature ranges are advantageously realized spatially separated.
  • the temperature for the decomposition of the individual starting materials can also be advantageous to control the temperature for the decomposition of the individual starting materials separately and thus to switch from a two-zone furnace to a multi-zone furnace.
  • the composition of the individual ferromagnetic components in the carbon nanotubes can then also be controlled in a simple manner by the temperature for the decomposition of the individual components.
  • the sublimed metallocenes Fe, Co, Ni
  • carbonyls of these metals or organometallic compounds see individually or as a mixture over a metal-coated
  • Substrate (preferably Fe) transported.
  • a hydrocarbon can optionally be added to the gas.
  • the location of the nanotube growth is determined by the location of the catalytic metal particles on the precoated substrate.
  • the length of the filled tubes is determined by the duration of the CVD process, the sublimation temperature and thus the concentration of the precursors, the reaction temperature and the flow conditions in the reactor.
  • the growth of an empty carbon tube can first be achieved by introducing only the hydrocarbon (eg acetylene) and thereby the tubes into the
  • Holes which are coated with the catalyst grow unfilled and then the tubes continue to grow filled by changing the gas phase (introduction of an organometallic compound and termination of the hydrocarbon supply).
  • This change in the gas phase e.g. metallocene / acetylene Change
  • two- or multi-component alloys are used as the catalytic metal coating on the bottoms of the etched holes in the process described
  • Single-walled nanotubes can also be produced by strongly shifting the ratio of metal component to carbon component to the side of the metal component in the gas phase in such a way that the carbon component is completely converted in the gas phase.
  • the nanotubes produced can be thermally treated before the biofunctionalization so that the carbon shell is stable enough for biofunctionalization or for the connection of carrier molecules which are intended to bring the nanotubes to the site of action. This would require approx. 3,000 ° C to 4,000 ° C.
  • this thermal treatment is carried out as a plasma chemical treatment in an argon or argon / hydrogen atmosphere (at approx. 800 ° C. to 900 ° C.), as a result of which any structural defects in the carbon shell can be effectively healed and thereby a high one Degree of crystalline perfection is achieved.
  • the ferromagnetic filling which may also be carbide or paramagnetic
  • Components can contain, subsequently (but before the biofunctionalization) thermally treated and converted in such a way that the filling consists exclusively of the ferromagnetic modifications (usually the ⁇ -modifications) of the elements iron, cobalt or nickel.
  • the subsequent thermal conversion can take place, for example, by annealing, in the case of an iron filling at approx. 650 ° C., just below the Curie temperature.
  • the annealing temperature for nickel fillings is 350 ° C Cobalt filling at 1000 ° C.
  • alloy fillings e.g. Ni / Co
  • Annealing temperature can be selected, which, depending on the composition of the alloy, lies between the Curie temperatures of the individual components (here between 350 and 1000 ° C).
  • thermal treatment therefore means a plasma-chemical treatment for healing structural defects in the carbon shell and / or a thermal treatment of the filling in order to achieve an exclusively ferromagnetic filling.
  • the directional etching with ions is preferably carried out by means of IBE (Ion Beam Etching), RIBE (Reactive Ion Beam Etching) or CAIBE (Chemical Assisted Ion Beam Etching).
  • the biocompatible and biodegradable polymer with which the nanotubes produced can be closed is, for example, polyethylene glycol, a copolymer of lactic acid and glycolic acid, a copolymer of lactic acid, glycolic acid and PEG or other structurally related polymers.
  • the release of an active ingredient from the nanotubes depends on the type of polymer or gel used. Hydrogels which contain water as a solvent have proven to be particularly favorable. These hydrogels are harmless to health and have favorable thermosensitive swelling behavior. For example, hydroxypropyl
  • thermo-reversible connection can be achieved by further crosslinking with divinyl sulfone, but this entails high toxicity.
  • This problem can be solved by crosslinking on an isocyanate basis, since a urethane bond is formed in the course of the reaction.
  • such polymers / gels are used to close the nanotubes, the swelling and shrinking behavior of which can be influenced in a defined manner by varying the degree of crosslinking.
  • a reversibly adjustable degree of swelling between 100% and> 1,500% can be achieved. With this type of release is above the
  • Such gels are e.g. Block copolymers based on PNIPAAm (poly (N-isopropylacrylamide)).
  • the block copolymers should be produced with a modified poly (ethylene oxide) PEO macroinitiator by ATRP (Atom Transfer Radical Polymerization).
  • ATRP Atom Transfer Radical Polymerization
  • the temperature of the volume increase can be in sufficiently wide temperature ranges, e.g. can be set to 47 ° C and the opening of the nanotubes can be achieved by increasing the volume of the polymer.
  • variants F1 or F2 are known.
  • the solubility properties of the gels used can vary according to the expected environmental conditions, e.g. Tissue, blood or other body fluids can be adjusted and thus the opening of the nanotubes in the body can be controlled.
  • Filling the unilaterally opened nanotube with a diagnostically and / or therapeutically active compound can e.g. by separating this compound from the gas phase.
  • a diagnostically and / or therapeutically active compound can e.g. by separating this compound from the gas phase.
  • These can also be fullerenes containing metal ions, for example.
  • the nanotubes produced and partially filled with ferromagnetic materials which are still open at one end, are alternately filled with therapeutically / diagnostically active compounds and biocompatible polymers, the biocompatible polymers being selected such that each is different from the other Conditions, preferably at a different temperature in the body is degradable.
  • partially ferromagnetically filled carbon nanotubes of basic type 1 (FIG. 6) and basic type 2 (FIG. 7) are produced.
  • the nanotubes are first filled and then unfilled to such a length that in process step a), after filling with a first active ingredient and sealing with a first polymer / gel (polymer 1), another active ingredient or the same Active ingredient can be introduced again and with a second, for example degradable in the body at a lower temperature, polymer / gel (polymer 2) is closed.
  • a first polymer / gel polymer 1
  • another active ingredient or the same Active ingredient can be introduced again and with a second, for example degradable in the body at a lower temperature
  • polymer / gel polymer 2
  • the active ingredient concentration can be kept constant over a longer period of time.
  • the nanotubes are manufactured as described above in such a way that the ferromagnetic filling is included in the center and the same or different active substances are enclosed on both sides by polymers / gels that are degradable in the body at different temperatures. Since nanotubes are closed on one side during the manufacturing process, they have to be opened on the closed side. This is preferably achieved with an argon / oxygen low-pressure plasma.
  • the closing of the nanotubes filled with active ingredient is preferably by means of
  • bio-functionalization of the nanotubes according to the invention on the outer surface is carried out using known methods. These are described in detail in EP 0625055, for example.
  • the biofunctionalization can be carried out, for example, via a covalent substitution on the carbon shell or, as described above, a closable polymer cap.
  • Functional group means a chemical group that can bind to a specific component and thus associates the nanocontainer with a specific component. Examples include monoclonal or polyclonal antibodies, Fab fragments of polyclonal and Fab2 fragments of monoclonal antibodies, fused and unfused single and multi-chain recognition motifs.
  • the biofunctionalization of the outer surface of the carbon nanotubes is carried out in such a way that the nanotubes are partially provided with a metal on the outside, which enables the targeted connection of the diagnostically and / or therapeutically active compounds at this point.
  • Holes in the gold layer according to embodiment 1 are not first deposited as a metal which acts catalytically for the growth of the nanotubes, but rather a metal which is preferred for binding the biomolecules, e.g. Niobium and only in the subsequent coating step the catalytically active metal. After removal of the photoresist, this is also done here
  • Embodiment 1 the growth of the ferromagnetic partially filled carbon nanotubes.
  • growth takes place starting from the metal layer and implementing these metal parts.
  • the niobium is not removed from the ferromagnetic and possibly agent-filled nanotubes and is therefore available for binding the biomolecules.
  • the partially coated portion is located opposite the nanotube opening that is closed by the biocompatible polymer.
  • nanotubes are subjected to the necessary cleaning and rinsing processes, the nanotubes being held to the vessel wall by permanent magnets. After that, they are ready for use according to pharmaceutical formulation for diagnosis and / or therapy.
  • the manufacturing process cedures, preparation, functionalization and galenical formulation are always carried out under sterile conditions as are customary for the production of pharmaceutical agents.
  • Carbon nanotubes are decisively determined or co-determined by the diameter of the structure etching, the length of the biofunctionalized carbon nanotubes by the depth of this etching in the gold layer. This is the only way - in contrast to other manufacturing methods - that close tolerances in the end product can be maintained.
  • the use of substrates can in principle be dispensed with and the ferromagnetically filled carbon nanotubes can be represented as "powder" in the CVD reactor.
  • the biofunctionalization takes place in an analogous manner after the additional chemical cleaning steps then required.
  • diagnostic units are understood to be biomolecules, elements with atomic numbers above 50, chromophores or fluorophores.
  • therapeutically active units are molecules which represent chemically or genetically engineered pharmaceutical active substances, e.g. B. Chemotherapy drugs.
  • biomolecules are preferably peptides, proteins, nucleic acids, antibodies, their fragments, enzymes, hormones or polysaccharides.
  • the diagnostically effective biomolecules are affinity molecules for specific recognition and binding to one or more target molecules.
  • These can be, for example, peptides or proteins (e.g. antibodies, receptors, antigens, lectins, avidine oligopeptides, lipoproteins, glycoproteins, peptide hormones), nucleic acids, carbohydrates or ligands with a low molecular weight.
  • the nanotubes according to the invention can be used on the outer surface exclusively or in addition to the diagnostic or therapeutic inputs.
  • Carrier molecules such as cationic lipids or antibodies, carry the
  • biomolecules and / or carrier molecules associated on the outer surface of the tube can be conjugated or bound directly or via a linker.
  • the invention also relates to the carbon nanotubes produced in this way.
  • the carbon nanotubes according to the invention can advantageously be used for therapy.
  • the biomolecules on the surface of the nanotube allow, for example, the nanotubes to be transported to a specific biological unit (cell, tissue or organ) in the body.
  • a nanotube coated with antibodies is transported in the body to the corresponding antigen.
  • the carbon nanotubes according to the invention can contain an active ingredient, e.g.
  • an antitumor agent doxorubicin (trade name Adriamycin), paclitaxel and its derivatives (taxol, taxanes, etc.), vincristine, carboplatin, cisplatin, epirubicin, fluorouracil, ifosfamide, methotrexate, mitomycin, vinblastine, irinotecan, or containing mitoxantruide, in the desired target region, e.g. the tumor can be transported.
  • the carbon nanotubes according to the invention can also function as depot forms, which release the drug with a defined delay, the depot function being realized by various sections of the tube containing the active substance, the boundaries of which are gradually broken down and the active substance is thus released at different times and in doses. The gradual dismantling can e.g. depending on the temperature.
  • the carbon nanotubes according to the invention to enclose a nucleic acid-based vector which carries the therapeutic gene or parts thereof, and to bring this into contact with the tissue at the desired site of action in order to increase the efficiency of the To increase gene transfection and expression. It is also possible to bring the viral vector that carries the therapeutic gene onto the surface of the carbon nanotubes. Due to external magnetic fields This carrier can then be kept at the destination to keep the virus in for extended periods
  • nanotubes according to the invention are excited by a magnetic field or thermally to absorb heat, which they then transmit to the focus of the disease, e.g. the tumor.
  • nanotubes with a length between approximately 10-20 ⁇ m into malignant tissue, so that local concentration and the release of active substance or thermal excitation can take place there.
  • the nanotubes are additionally provided with diagnostic units, tumor diagnosis (primary tumor, recurrence and / or metastasis) can be carried out pretherapeutically.
  • tumor diagnosis primary tumor, recurrence and / or metastasis
  • the nanotubes can also be biofunctionalized in such a way that they are increasingly taken up by tumor cells (cf. Example 2).
  • An alternative therapeutic approach uses a magnetically-based in vivo movement of nanotubes of minimal dimensions, the length of which does not exceed 100 nm: with miniaturized super magnets that are implemented in a targeted manner, individually or multiple, temporarily peritumoral, biofunctionalized nanotubes can be used systemically or in close proximity to the focus of the tumor into a body fluid, concentrated at the focus of the tumor.
  • the efficiency of this transfer can be directly influenced by various parameters (e.g. strength of the magnetic field and degree of filling of the nanotubes).
  • the miniaturized super magnets are explanted again.
  • nanotubes are irradiated ex vivo, whereby the iron, which is the partial filling of the nanotubes, is converted to radioactive iron. These radionuclides can then be used as a therapeutic agent, packaged in the form of a nanotube.
  • the ferromagnetic carbon nanotubes according to the invention are also very suitable for diagnosis even without enclosed or associated biomolecules in the outer surface, since they can be excited magnetically and / or thermally by the ferromagnetic properties.
  • the biomolecules associated on the carbon surface have the advantage that additional binding to and transport to the target molecule can take place.
  • the invention also relates to the use of the carbon nanotubes produced according to the invention as a diagnostic and / or therapeutic agent, in particular for tumor diagnosis and therapy.
  • the diagnostic and / or therapeutic agent is provided by formulating the physiologically compatible carbon nanotubes produced according to the invention with pharmaceutically compatible adjuvants.
  • auxiliaries in the sense of the invention are formulation auxiliaries, such as e.g. Carriers, antioxidants, stabilizers or buffers.
  • the pharmaceutical compositions are intended for i.v. application.
  • the appropriate infusion or injection solutions are preferably provided with physiological saline.
  • the diagnostic or therapeutic agents can also i.m., i.p. or administered orally.
  • the CNTs are peri- or intratumoral, i.e. injected into the adjacent tumor tissue or directly into the tumor.
  • the invention thus also relates to a method for diagnosing and / or treating a tumor disease, in particular bladder and prostate cancer, in which the subject has an effective amount, preferably 10 mg to. 500 mg per target lesion depending on the size of the tumor which is administered according to the invention carbon nanotubes.
  • the ferromagnetically filled and biofunctionalized carbon nanotubes produced by the method according to the invention have a number of significant advantages over the prior art. They are especially special in their geometrical dimensions and their magnetic properties can be produced in a defined manner and can also be specifically filled through the possibility of controlled opening and closing. Through the process control in the representation of the carbon nanotubes according to the invention, it is also possible to influence the number of carbon shells around the core and thus to adapt the chemical resistance to the desired conditions of use. Single-wall ferromagnetic carbon nanotubes are being produced for the first time.
  • the CNTs produced according to the invention are extremely stable. In contrast to any other manufacturing method previously described for nanoparticles, the nanotubes can be partially provided with another metal on the outside, which enables the targeted connection of biomolecules at these locations.
  • Agent-filled nanotubes can advantageously be realized by growth and manipulation of the nanomaterials on substrates.
  • Figures 1 to 4 show the basic sketch for the production.
  • Fig. 1 shows a substrate with a 5 nm thick Fe layer on Au and on photoresist.
  • Fig. 2 shows the substrate with partially filled nanotube after the CVD
  • Fig. 3 shows the substrate after shortening, filling and sealing the nanotubes.
  • Fig. 4 shows the end product after etching the Au layer and processing the functionalized nanotubes.
  • a thermally oxidized silicon wafer with an oxide layer thickness of 1 ⁇ m serves as the substrate.
  • suitable coating methods - e.g. thermal Evaporation - a 200 nm thick gold layer is applied to the entire surface of this substrate.
  • a 1 ⁇ m thick photoresist layer is applied.
  • a regular dot pattern is realized using lithographic methods, for example electron beam lithography.
  • the individual structures have a diameter of 80nm at a distance of 400nm. The later outer diameter of the carbon nanotubes can be significantly determined by the size of these structures.
  • the substrates are rinsed in ultrapure water and dried.
  • Argon ion beam etching at an angle of 90 ° relative to the sample surface partially thinned the 200nm thick gold layer - at the locations that are not covered with photoresist - so that holes about 150nm deep were created in the Au layer.
  • the later length of the biofunctionalized nanotubes is determined by this etching depth.
  • This etching process is carried out under the following conditions: etching gas: argon, pressure: 6x10 "4 mbar, acceleration voltage: 400V, microwave power: 170 W.
  • the etched substrates are subjected to a further coating with the photoresist still present.
  • An approximately 5 nm thick iron layer is deposited by electron beam evaporation and the coated substrate is subsequently treated in acetone (15 min).
  • the photoresist is detached and the Fe layer portions deposited on the photoresist are lifted off.
  • the catalytic Fe components are now only in the deeper etched Au areas. Before the actual production of the nanotubes begins, it is advantageous to clean the pre-structured substrate in a hydrogen plasma.
  • the pre-structured substrate is then heated to 900 ° C. in the reaction zone of a chemical vapor deposition (CVD) reactor.
  • CVD chemical vapor deposition
  • the CVD reactor used allows the temperature in several zones to be set independently of one another and the growth process to be carried out under inert gas or vacuum conditions.
  • Ferocenes 0.3 g in a crucible
  • This precursor is sublimed at a temperature of 180 ° C outside the actual reaction zone.
  • argon is used as a carrier gas, which sublimates the precursor into the actual reaction zone transported.
  • the metallocene used here is both
  • Source of ferromagnetic material as well as source of carbon for the shell under the realized conditions, completely Fe-filled carbon tubes are deposited within the first 3 minutes, preferably within 1 minute, about 50 nm long.
  • the temperature of the metal precursors is now very quickly reduced from 180 ° C to a temperature ⁇ 100 ° C and a gaseous hydrocarbon (acetylene) is introduced into the reactor. This ensures that after a short time only the hydrocarbon is in the gas phase and the nanotubes only continue to grow unfilled, since no further filler material from the gas phase is offered.
  • acetylene acetylene
  • the carbon nanotubes produced can have a variation in length.
  • they are subjected to a directional etching process in the subsequent technology step.
  • the portions above the unetched Au surface are removed by argon ion beam etching at an angle of 8 ° relative to the sample surface.
  • This etching process is carried out under the following conditions: etching gas: argon, pressure: 6x10 "4 mbar, acceleration voltage: 400V, microwave power: 170 W.
  • the partially ferromagnetically filled carbon nanotubes are thus open on the side facing away from the substrate and can be treated with a first agent, e.g. a therapeutic agent can be partially filled.
  • a first agent e.g. a therapeutic agent can be partially filled.
  • the length of the agent filling is e.g. 20nm.
  • the still unfilled part of the carbon nanotube is filled with a biocompatible polymer that is degradable in the body at a certain temperature.
  • This biocompatible polymer is e.g. Degradable at 42.5 ° C. If necessary, additional sections with alternating proportions of agent and biocompatible polymer can be realized.
  • the release of the therapeutic agent can be controlled by changing the temperature in the later therapeutic application.
  • the change in temperature can can be easily controlled via the energy converted in the ferromagnetic filling.
  • the biocompatible polymers must therefore be selected so that the polymer that closes the tube is first broken down at the lowest temperature and then the further polymers are gradually broken down as the temperature increases gradually, so that one active ingredient is released after the other. If the same active ingredient is found in the individual sections of the tube, a delayed release (depot form, sustained release) can be achieved in this way.
  • the functionalized carbon nanotubes are separated from the substrate. For this, the gold on the substrate is treated in a solution (consisting of 0.06 mol / l KJ, 0.09 mol / l J 2 and 0.005 mol / l alcohol) for 10 min.
  • the gold located under the functionalized nanotubes is removed, thereby removing the hold from the nanotubes.
  • the nanotubes are now in the etching solution. Since the partially filled nanotubes have ferromagnetic properties, they can easily be held on the vessel wall by a permanent magnet. In this state, rinsing with water to remove the etchant residues is possible.
  • the use of permanent or electromagnets simultaneously separates the ferromagnetically filled from the insufficiently ferromagnetically filled nanotubes.
  • the insufficiently filled tubes are removed with the water.
  • the etchant residues can also be removed by flushing using ultrasound. It is advantageous to add a volume fraction of at least 1% alcohol to the water.
  • the outer surface of the tubes is biofunctionalized in solution. Analogous to the possibilities described in the literature for the functionalization of carbon nanotubes (Zheng et al. (2003), Nature Materials 2: 338-342), individual carbon
  • Nanotubes for example, are bound with single-stranded (ssDNA) and therapeutically active DNA molecules via " ⁇ -stacking".
  • the binding of an ssDNA molecule is achieved via various mechanisms and can take place partially or over the full length of this structure, whereby Examples include a helical packaging with left and right turns and a simple surface adsorption.
  • Such a dispersion functionalizes the carbon nanotube per se, since the hybrids are negatively charged due to the phosphate group of the ssDNA molecule.
  • This dispersion can also be used, for example short double-stranded DNA molecules (dsDNA), siRNA constructs or RNA molecules.
  • the carbon nanotube serves as a combined carrier-shuttle functional unit for the transport of therapeutically active substances to a site of action in the body of a living being.
  • a structural unit can also be encased and moved using an additional carrier, for example a cationic lipid.
  • PCa Advanced prostate cancer
  • the nanotubes can be labeled with choline, which leads to a relatively increased uptake by the tumor cells (in comparison to the surrounding, non-malignant cells)
  • the metastatic foci can be represented in this way from a size of a few millimeters, and can be treated immediately afterwards.
  • Fig. 5 shows the clinically local therapy against superficial tumors of the human urinary bladder (bladder carcinoma, BCa) using the carbon nanotubes produced according to Example 1, which are coated with antisense DNA constructs.
  • the tumor is removed using electroresection.
  • the resection margins (sediment margins after removal of the tumor mass) become corresponding
  • the carbon nanotubes produced in accordance with Example 1 are excited after application and targeting to a bladder carcinoma (BCa) by external radiation to absorb heat. Their localization requires a local heating of the tumor tissue and thus a therapy-efficient and selective destruction of tumor cells.
  • the carbon nanotubes according to the invention can be used to diagnose (locate) this tumor if they carry appropriate diagnostic units. This enables a timely and metered combination of tumor diagnosis and tumor treatment.
  • Carbon nanotube in an EJ28 tumor cell (before hyperthermia treatment).
  • a CNT solution (without cells, left) can be characterized using FACS (presentation of the overall result for 2x10E4 cells examined), whereby the detectable particles have a wide range of granularity, which indicates a significant adhesion or clustering of the CNT. If untreated cells (middle) are compared with the same cells, which are incubated for 2 h with a CNT solution and treated as in Example 5 (trypsinization and centrifugation) (right side), you can see a clear one
  • Figure 8 shows magnetization curves of Fe-filled carbon nanotubes, transferred into tumor cells, whereby these cells were recovered from treated tissue.
  • the magnetization curves show a typical ferromagnetic behavior of the Fe-filled carbon nanotubes taken up in the cells. A pronounced anisotropy cannot be demonstrated by the measurements. This is not to be expected due to the lack of preferential orientation in cells.
  • the level of saturation magnetization is clearly dependent on the transferred amount of ⁇ -iron in the filled carbon nanotubes.
  • a correlation of the detected elementary magnetic units (emu) which is directly related to the mass of the ⁇ -iron absorbed into the cells, proves that enough iron was absorbed into the cells for successful hyperthermia.
  • PC3 cells PCa xenograft tumor of human origin
  • PC3 cells PCa xenograft tumor of human origin
  • rough tissue sections with a thickness of 5 mm were obtained and transferred to the solution of the measuring chamber.
  • an intratumoral injection of a CNT solution 100 ⁇ g CNT in total, at 6 different injection sites, distributed over the tissue section area
  • the marked injection sites (marked and coupled with heat sensors by contact-free heating of the CNTs to a temperature of 44 ° C (average temperature in a 3 mm radius around the injection site or sensor location) were then heated by applying an external magnetic field. When this temperature was reached There was a change in conformity of polymer / gel 1 with subsequent release / exposure of carboplatin
  • the local antitumor effect of the therapeutic agent was determined by comparative studies with a placebo (filling with a non-toxic polymer) using a histological (TUNEL assay for late apoptosis detection) and Pathomorphological detection of apoptosis / necrosis in the tissue section in the period 24-96 h after release of the therapeutic agent or by FACS analysis (Annexin-V-PI analysis to detect early and late apoptosis and necrosis). Furthermore, some cuts were half
  • CNT-based heated tissue sample Hours after the release of carboplatin and non-contact heating heated to 48 ° C, the melting point of the second polymer (hereinafter referred to as CNT-based heated tissue sample).
  • the detection of the release of nucleic acid fragments was carried out by specific PCR detection of the non-human fragment (luciferase gene fragment), two different tissue samples serving as controls, which on the one hand filled with the same amount of CNT, but had not been heated (negative control 1) and, on the other hand, tissue samples without CNT injection, but with magnetic field treatment like CNT-injected sample (negative control 2). It could be clearly and exclusively for the double, CNT-based heated tissue sample that after the carboplatin release also at a locally detected temperature of 48 ° C, luciferase DNA fragments were released into the injected tissue.
  • An anesthetized nude mouse which had carried a PCa xenograft tumor (PC3 cells, as in Example 8) of 1 cm maximum diameter subcutaneously, is fixed in the measuring chamber according to Fig. 9.
  • CNT according to Example 8 total dose 200 ⁇ g
  • an external magnetic field is applied after 2 h.
  • a frequency of 40 kHz was realized in a magnetic field of 15 kA / m.
  • Tissue removal Tissue removal. TEM examinations of the outer tumor edges of the tumor confirmed the accumulation of CNT in and between tumor cells. Under histological control (H&E staining), therapy-induced antiproliferative effects (apoptosis induction) were also detected in the outer tissue areas.
  • H&E staining histological control
  • therapy-induced antiproliferative effects apoptosis induction
  • a second mouse was like above the. A second mouse was treated identically as described above, only after reaching target temperature 1 (44 ° C) was treatment continued in the magnetic field until target temperature 2 (48 ° C) was reached. The nucleic acid fragments released in this way could be made visible via a non-radioactive label in the tissue association.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Dermatology (AREA)
  • Dispersion Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé permettant de produire des nanotubes en matière plastique à une ou à plusieurs parois, remplis en partie par voie ferromagnétique (nanotubes en carbone (CNT)), qui sont remplis de fer, de cobalt, de nickel ou d'un alliage desdits éléments ou d'un alliage de ces éléments avec du platine et portent des biomolécules. Les biomolécules sont enfermées dans les tubes et/ou sont associées à la surface extérieure desdits tubes. Dans un mode de réalisation préféré, les nanotubes selon l'invention peuvent contenir deux principes actifs ou davantage dans les tubes, lesdits principes actifs étant libérés successivement lorsqu'ils sont utilisés dans le corps. L'invention concerne également l'utilisation des nanotubes en carbone selon l'invention, remplis en partie par voie ferromagnétique, dans le cadre de diagnostics et de thérapies, en particulier pour diagnostiquer et traiter des tumeurs.
EP05731324A 2004-04-07 2005-04-07 Procede de production de nanotubes en carbone remplis en partie par voie ferromagnetique, qui portent des biomolecules, et leur utilisation en matiere de diagnostic et de therapie Withdrawn EP1747018A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004017705A DE102004017705A1 (de) 2004-04-07 2004-04-07 Ferromagnetische Kohlenstoff-Nanoröhren, die Biomoleküle tragen, Verfahren zu deren Herstellung und deren Verwendung in Diagnose und Therapie
PCT/EP2005/003790 WO2005097672A2 (fr) 2004-04-07 2005-04-07 Procede de production de nanotubes en carbone remplis en partie par voie ferromagnetique, qui portent des biomolecules, et leur utilisation en matiere de diagnostic et de therapie

Publications (1)

Publication Number Publication Date
EP1747018A2 true EP1747018A2 (fr) 2007-01-31

Family

ID=35070427

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05731324A Withdrawn EP1747018A2 (fr) 2004-04-07 2005-04-07 Procede de production de nanotubes en carbone remplis en partie par voie ferromagnetique, qui portent des biomolecules, et leur utilisation en matiere de diagnostic et de therapie

Country Status (3)

Country Link
EP (1) EP1747018A2 (fr)
DE (1) DE102004017705A1 (fr)
WO (1) WO2005097672A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102134732A (zh) * 2010-12-21 2011-07-27 北京化工大学 一种析氢模板法制备镍及镍基合金一维超结构纳米功能材料的方法

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8154093B2 (en) 2002-01-16 2012-04-10 Nanomix, Inc. Nano-electronic sensors for chemical and biological analytes, including capacitance and bio-membrane devices
US7948041B2 (en) 2005-05-19 2011-05-24 Nanomix, Inc. Sensor having a thin-film inhibition layer
DE102005005704B4 (de) * 2005-02-03 2010-08-12 Leibniz-Institut Für Festkörper- Und Werkstoffforschung Dresden E.V. Verwendung von Partikeln für die Ermittlung der lokalen Temperatur in organischen und nichtorganischen Körpern
EP2394639B1 (fr) * 2006-05-25 2014-07-30 Wake Forest University Health Sciences Technologies hyperthermiques et leurs utilisations thérapeutiques
US8501233B2 (en) 2007-03-13 2013-08-06 Wake Forest University Compositions and methods for treating cancer
US20100197783A1 (en) * 2007-03-26 2010-08-05 Tour James M Radiation Protection Using Single Wall Carbon Nanotube Derivatives
US8784866B2 (en) 2007-03-26 2014-07-22 William Marsh Rice University Water-soluble carbon nanotube compositions for drug delivery and medicinal applications
WO2009070380A2 (fr) * 2007-10-03 2009-06-04 William Marsh Rice University Compositions de nanotubes de carbone solubles dans l'eau pour l'administration d'un médicament et applications médicales
US8993346B2 (en) 2009-08-07 2015-03-31 Nanomix, Inc. Magnetic carbon nanotube based biodetection
CN102000349B (zh) * 2010-10-27 2013-11-27 上海师范大学 一种碳纳米管/聚合物/磁性铁酸盐纳米复合材料及其制备方法
CN114522242B (zh) * 2022-02-28 2023-02-03 深圳大学 磁驱螺旋微纳米马达及其制备方法和应用
CN116196416A (zh) * 2023-03-03 2023-06-02 罗馨 一种基于一维磁性纳米材料的肿瘤治疗系统

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7195780B2 (en) * 2002-10-21 2007-03-27 University Of Florida Nanoparticle delivery system
GB0200259D0 (en) * 2002-01-07 2002-02-20 Univ Reading The Encapsulated radioactive nuclide microparticles and methods for their production
TW200307563A (en) * 2002-02-14 2003-12-16 Sixty Inc C Use of BUCKYSOME or carbon nanotube for drug delivery
US20060199770A1 (en) * 2003-04-14 2006-09-07 Alberto Bianco Functionalized carbon nanotubes, a process for preparing the same and their use in medicinal chemistry
CN1546365A (zh) * 2003-12-04 2004-11-17 东南大学 磁性纳米管及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005097672A2 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102134732A (zh) * 2010-12-21 2011-07-27 北京化工大学 一种析氢模板法制备镍及镍基合金一维超结构纳米功能材料的方法

Also Published As

Publication number Publication date
DE102004017705A1 (de) 2005-11-03
WO2005097672A3 (fr) 2006-05-18
WO2005097672A2 (fr) 2005-10-20

Similar Documents

Publication Publication Date Title
Martincic et al. Filled carbon nanotubes in biomedical imaging and drug delivery
Soufi et al. Eco-friendly and sustainable synthesis of biocompatible nanomaterials for diagnostic imaging: current challenges and future perspectives
Hasanzadeh Kafshgari et al. Insights into theranostic properties of titanium dioxide for nanomedicine
Fan et al. Biodistribution, degradability and clearance of 2D materials for their biomedical applications
Reddy et al. Magnetic nanoparticles: design and characterization, toxicity and biocompatibility, pharmaceutical and biomedical applications
Lan et al. The role of nanoparticles and nanomaterials in cancer diagnosis and treatment: a comprehensive review
Navalakhe et al. Application of nanotechnology in biomedicine
Li et al. Au@ MnS@ ZnS core/shell/shell nanoparticles for magnetic resonance imaging and enhanced cancer radiation therapy
Singla et al. Metallic nanoparticles, toxicity issues and applications in medicine
DE112006004066B4 (de) Magnetischer Träger und medizinisches Präparat zur kontrollierbaren Zuführung und Freisetzung von Wirkstoffen, Herstellungsverfahren dafür und Behandlungsverfahren unter Verwendung davon
EP1747018A2 (fr) Procede de production de nanotubes en carbone remplis en partie par voie ferromagnetique, qui portent des biomolecules, et leur utilisation en matiere de diagnostic et de therapie
Thomas et al. Handbook of magnetic hybrid nanoalloys and their nanocomposites
WO2010096828A1 (fr) Nanoparticules à modalités multiples ayant une forme optiquement réactive
WO2008002101A1 (fr) Nanoparticules multifonctionnelles partiellement déposées sur un film en or
Wang et al. Potentiated cytosolic drug delivery and photonic hyperthermia by 2D free-standing silicene nanosheets for tumor nanomedicine
Shabnum et al. A comprehensive review on recent progress in carbon nanotubes for biomedical application
Patel et al. Nanomedicines: Applications and toxicological concerns
WO2021148973A1 (fr) Nanoparticules multifonctionnelles à base de nanoalliages métalliques à usage diagnostique et thérapeutique
US20150110882A1 (en) Multifunctional metallic nanostructure and method for manufacturing the same
Lagopati et al. Hybrid multifunctional nanomaterials for diagnostic and therapeutic applications
Uthman et al. Tunable theranostics: innovative strategies in combating oral cancer
Altintas Applications of magnetic nanomaterials in biosensors and diagnostics
CN112334154B (zh) 基于金纳米颗粒-适配体缀合物的抗体载体及其制备方法
Pantapasis et al. Bioengineered nanomaterials for chemotherapy
Almeida et al. Carbon Nanotubes for Biomedical Applications

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20061106

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
RIN1 Information on inventor provided before grant (corrected)

Inventor name: BUECHNER, BERND

Inventor name: MEYE, AXEL

Inventor name: HAMMERMANN, GERD

Inventor name: WIRTH, MANFRED, P.

Inventor name: KRAEMER, KAI

Inventor name: LEONHARDT, ALBRECHT

Inventor name: MOENCH, JENS, INGOLF

17Q First examination report despatched

Effective date: 20101119

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20131101