WO2014187800A1 - Agent de contraste - Google Patents

Agent de contraste Download PDF

Info

Publication number
WO2014187800A1
WO2014187800A1 PCT/EP2014/060301 EP2014060301W WO2014187800A1 WO 2014187800 A1 WO2014187800 A1 WO 2014187800A1 EP 2014060301 W EP2014060301 W EP 2014060301W WO 2014187800 A1 WO2014187800 A1 WO 2014187800A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
agent
agent according
imaging
cores
Prior art date
Application number
PCT/EP2014/060301
Other languages
English (en)
Inventor
Sarah Fredriksson
Fredrik Olsson
Pontus KJELLMAN
Renata MADRU
Sven-Erik Strand
Original Assignee
Geccodots Ab
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 Geccodots Ab filed Critical Geccodots Ab
Publication of WO2014187800A1 publication Critical patent/WO2014187800A1/fr

Links

Classifications

    • 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
    • A61K51/1241—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 particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—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 particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • 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
    • A61K49/1854—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 by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly(meth)acrylate, polyacrylamide, polyvinylpyrrolidone, polyvinylalcohol
    • 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

  • This invention relates in general to the field of forming an agent for use as a contrast agent in medical imaging or for radio isotope therapy.
  • the agent has unique chelating properties.
  • the chelating properties enable an easy, very quick and robust labelling with radionuclides or metals metal ions active as contrast agents in a manner that is feasible in practical applications both pre clinically and for clinical purposes.
  • the agent contains nanoparticles as contrast agents in multimodal imaging for diagnostic purposes and for guidance during surgery as well as for use in cancer treatment.
  • Nanotechnology is based on the use of structures that have one or more dimensions measuring loo nanometers or less. These nanoparticles have a higher surface area to volume ratio than larger particles. Taken together these features turn nanoparticles into interesting structure candidates as novel contrast agents and as drug delivery vehicles. This is due to the fact that they are small enough to reach out in the finest capillaries, yet large enough to display longer circulation times than conventional small molecules and finally the huge surface area/volume provide the possibility to display or carry other molecules on the surface. Imaging and therapy of disease with
  • radionuclides has been routine clinically for half a century and has developed into molecular imaging in the last decades.
  • the design of the nanostructures requires a safe, easy and robust method for attaching said metals, ions or radionuclides.
  • it has been accomplished by introducing ligands carrying chelating structures to the nanoparticle surfaces.
  • Nanotechnology in combination with chemistry generates many various chemical platforms for design of nanostructures.
  • Some examples are nanostructures built up by, dendrimers, liposomes, magnetic nanoparticles, metal nanoparticles, metal oxide nanoparticles, metal hydroxide nanoparticles, metal sulphide nanoparticles, micelles, nano-assemblies, polymeric nanoparticles, and viral nanoparticles.
  • Medical imaging is a rapidly evolving and highly multidisciplinary field that involves technologies from a variety of disciplines including physics, chemistry, physiology, and biology as well as engineering and computer science. Information generated through medical imaging is of interest in biology, drug development and in the clinic.
  • Imaging has become an increasingly important tool in drug development/ drug discovery and the understanding of basic pathological physiology, where changes at the organ, tissue, cell or molecular level in animal models must be closely monitored over time.
  • imaging the number of animals can be reduced substantially compared with classical studies using histology methods, where animals had to be sacrificed at every time/data point throughout the study.
  • imaging it is possible to follow one and the same individual animal over time, over days, weeks and even months. This increases the reliability and accuracy of the imaging since errors due to individual differences or inaccuracies due to non representative choice of tissue slices.
  • Clinical endpoints or outcomes are used to determine whether the therapy is safe and effective. Once a patient reaches the endpoint, he/she is generally excluded from further experimental interaction. Trials that rely solely on clinical endpoints are very costly as they have long durations and tend to need large number of patients. In contrast to clinical endpoints, surrogate endpoints have been shown to cut down the time required to confirm whether a drug has clinical benefits. Imaging is able to reveal subtle change that is indicative of the progression of therapy that may be missed out by more subjective, traditional approaches. Statistical bias is reduced as the findings are evaluated without any direct patient contact. For example, measurement of tumour shrinkage is a commonly used surrogate endpoint in solid tumour response evaluation.
  • Medical imaging has become an important tool not only in applications such as drug development but also in clinical diagnosis and surgery. Therapy areas including diagnosis of cancer, cardiovascular disease, gastrointestinal condition orthopaedics and trauma are some examples.
  • the imaging technology platform is non-invasive and can reduce health care costs and improve patient management.
  • therapies such as stem cell therapy and cell transplantation is on the way of exploring the benefits from medical imaging in the process of tracing implanted cells and as a tool to monitor the progress of the therapy related to the transplanted cells.
  • the imaging instruments that are available to the medical community can thus provide anatomical information using computer tomography (CT), magnetic resonance imaging (MRI) and ultrasound (US) and functional information using positron emission tomography (PET), single photon emission computed tomography (SPECT) and functional magnetic resonance imaging fMRI.
  • CT computer tomography
  • MRI magnetic resonance imaging
  • US ultrasound
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • fMRI functional magnetic resonance imaging
  • optical imaging can be used for functional information, however as of today mostly utilized in preclinical settings and it is under development for clinical use.
  • the trend in imaging instrumentation is not only to build instruments with higher resolution and performance but also to combine modalities such as MRI and PET in one and the same instrument.
  • a medical contrast medium is a substance used to enhance the contrast of structures or fluids within the body in medical imaging.
  • Traditional contrast agents are often small molecules, for example iodine or bromine as X-ray contrast agents and gadolinium complex in MRI.
  • PET and SPECT the imaging is based on a radionuclide, which is hence necessary for those imaging modalities.
  • Radionuclides commonly used are 99mTc, niln and 6yGa for both planar and SPECT imaging studies.
  • positron emitting radio metals specifically 64C11, 68Ga and 89 ⁇ 1 ⁇ have shown significant potential as molecular imaging probes based on PET.
  • Molecular Imaging emerged in the early twenty-first century as a discipline at the intersection of molecular biology and in vivo imaging. It enables the visualisation of the cellular function and the follow-up of the molecular process in living organisms without perturbing them. The multiple and numerous potentialities of this field are applicable to the diagnosis of diseases such as cancer, and neurological and cardiovascular diseases.
  • Molecular imaging differs from traditional imaging in that probes known as biomarkers are used to help image particular targets or pathways. Biomarkers interact chemically with their surroundings and in turn alter the image according to molecular changes occurring within the area of interest.
  • SLN-biopsy is performed by 2-24 hours prior to surgery injecting a Tc" m -labelled nanocoUoid into or around the primary tumor. In the case of breast cancer the injection may also be placed under the areola. Two to four hours preoperatively a
  • lymphoscintigram is acquired to visualize the SLN.
  • a blue dye is injected, in the same manner as the nanocoUoid, to help visualize the lymphatic vessels and the SLN.
  • the surgeon can localize and excise the SLN.
  • the radioactive colloid, and in some cases the blue dye as well will have spread to adjacent lymph nodes, it can be difficult to identify the SLN. To manage this uncertainty, more lymph nodes have to be resected for histological examination. While the pathologist examines the SLN, the surgeon proceeds to remove the primary tumor.
  • a multimodal contrast agent that only targets the SLN in combination with several days of lymphatic retention time would simplify the logistics related to the current method of sentinel lymph node dissection. It could also help visually guide the surgeon intraoperatively and hence avoid the risk of hypersensitivity reactions that can occur when using the blue dye.
  • a nanoparticle consisting of an iron oxide core with a biocompatible coating carrying a radionuclide can be imaged with magnetic resonance imaging (MRI) or PET/SPECT 1-2 days prior to surgery.
  • MRI magnetic resonance imaging
  • PET/SPECT PET/SPECT 1-2 days prior to surgery.
  • the pharmacokinetics of nanoparticles for visualizing SLN depends on the choice of material, surface charge, size, colloidal stability and biological compatibility. Out of these, size has shown to be most significant for the uptake of particles in the lymphatics after subcutaneous injection. Numerous studies have concluded that the ideal size of a particle intended for lymphatic uptake is io to loo nm. A smaller particle will be absorbed directly into the bloodstream while a larger particle will remain at the site of injection. Particles that are taken up in the lymphatic system will travel with the lymph to the regional lymph nodes where they, depending on size and surface characteristics get trapped. Lymph enters the node through the afferent vessel, flows through the subcapsular sinus, followed by the cortical sinus and finally the medullary sinuses before exiting through the efferent lymphatic vessel.
  • particles can get mechanically filtered out in the reticular meshwork of the sinuses and phagocytized by macrophages and dendritic cells. Sufficiently small particles may also be taken up by the endothelial cells through pinocytosis. Particles that are not trapped by the SLN will follow the lymph downstream to the next lymph node, eventually reaching the blood stream via the ductus thorascicus ending up in the reticuloendothelial system.
  • Systemic radioisotope therapy is a form of targeted therapy.
  • Targeting can be due to the chemical properties of the isotope such as radioiodine which is specifically absorbed by the thyroid gland.
  • Targeting can also be achieved by attaching the radioisotope to another molecule, nanoparticle or antibody to guide it to the target tissue.
  • the nanoparticles will have to carry a specific targeting ligand on their surfaces.
  • One option is to use antibodies specific for the target cells or fragments thereof. The antibody will not carry any radionuclides, rather the nanoparticle coating will be loaded with radionuclides. It is further possible to label each nanostructure with a mixture of multiple radionuclides to increase the therapeutic effects.
  • a major use of systemic radioisotope therapy is in the treatment of bone metastasis from cancer.
  • the radioisotopes travel selectively to areas of damaged bone, and spare normal undamaged bone.
  • Isotopes commonly used in the treatment of bone metastasis are strontium-89 to yttrium-90.
  • RIT examples include the infusion of Metaiodbenzylguanidine (MIBG) to treatneuroblastoma of oral iodone-131 to treat thyroid cancer or thyrotoxosis, and of hormone bound lutetium-177 and yttrium-90 to treat neuroendocrine tumours.
  • MIBG Metaiodbenzylguanidine
  • Another example is the injection of radioactive glass or resin microspheres into the hepatic artery to radioembolize liver tumours or liver metastases.
  • Photon activation radiotherapy relies on the administration of a drug containing a high-Z element prior to external irradiation with X-rays. Photo-interactions with the administered drug will then produce low-energy photo-electrons and Auger electrons, resulting in a high local absorbed dose. If the drug is targeted to tumour cells, this can potentially yield a very large therapeutic absorbed dose ratio between tumour and normal healthy tissue. Due to the very short range of these low-energy electrons, however, the drug needs to be accumulated into the cell close to the cell nucleus, in the close vicinity of the DNA, in order to be optimally effective which is possible with internalizing nanoparticles. Elements that have been suggested for PAT include indium, gadolinium and gold. Prior art
  • the invention It has now been unexpectedly found that by modifying the method described by Yu W et al stable multimodal agents ready for one step labeling process with a radio nuclide of choice.
  • the labelling process can be done in a very easy one step process without having to elevate temperatures or perform any chemical reactions. It can be done in vicinity to the source of radionuclide and hence even short half life nuclides (isotopes) are accessible for multimodal imaging using this invention as a therapeutic agent or as an imaging agent in PET/SPECT or in a combinatorial mode using any of the modalities CT/PET/SPECT/MRI/Ultrasound and optical imaging methods.
  • the invention is described in detail in the following:
  • a biocompatible, stable, functionalized nanostructure that can bind a huge variety of metals and radio nuclides tightly in one single and easy labelling step is provided.
  • the binding of the radionuclides or metals takes place in the interior of the coating avoiding interfering or competition with the surface of the structure or with surface ligands.
  • the outer surface of the coating offers many sites for further conjugation of ligands such as fluorescent dyes, peptides, toxins, antibodies or fragment thereof or other entities.
  • the conjugation chemistry can be chosen from a variety of molecules depending on the polymer chosen to act as the outer component of the surface coating.
  • Nanoparticles designed as contrast agents differ in many aspects from the traditional contrast agents.
  • the characteristics of the nanoparticles when used as contrast agents open up for other and novel type of imaging studies.
  • Nanoparticle based contrast agents have a size in the range of 5 - 100 nano meter, that is larger than a small molecule, which will influence their physiochemical and pharmacokinetic properties.
  • the surface coatings of the nanostructure can add a huge impact/effect on
  • recognition molecules or a combination of such molecules capable of binding to biomarkers, epitopes and cell receptors, or functional groups on the surface of the particle to promote the targeting of the contrast agent to a certain area within the body.
  • recognition molecules or a combination of such molecules capable of binding to biomarkers, epitopes and cell receptors, or functional groups on the surface of the particle to promote the targeting of the contrast agent to a certain area within the body.
  • the possibility to combine a certain size with coating materials and surface groups provide the designer of the nanoparticle with an interesting toolbox of varieties.
  • multimodal contrast agents are desirable for imaging in a combination of modalities like MRI/PET/SPECT/optical imaging, ultrasound and CT.
  • MRI in combination with PET.
  • PET has a high spatial resolution, however a low sensitivity.
  • PET/ SPECT on the other hand has a very high sensitivity and poor spatial resolution.
  • the combination of the two can overcome their individual drawbacks and multimodality instruments have recently been commercialized on the preclinical market as well as on the clinical market. If the contrast agent is multimodal, that is it gives rise to contrast in more than one imaging modality, the combined multimodal imaging study can be performed rather convenient using one contrast agent.
  • One example is the combination of MRI and PET.
  • a MRI contrast agent such as iron oxide or gadolinium together with an isotope and a fluorescent dye
  • the imaging study can be performed first in PET which have very low detection limits, followed by MRI to get the best spatial resolution. If one wants to follow up the imaging results using histology, the fluorescent dye can be used to track the contrast agent.
  • Another example is to use gold nanostructures carrying a radionuclide of choice, for instance 64 Cu in order to create a contrast agent for combined CT/PET imaging.
  • a radionuclide of choice for instance 64 Cu
  • Radionuclides sometimes have a very short half life and need to be prepared close to the site of intended use or close to the patient.
  • an agent labelled with a radio nuclide can be prepared within a few minutes at room temperature.
  • the multisite chelating coating enables a high concentration of isotopes within a small local volume, which in turn increases the effect and is promising for therapeutic purposes. It is further possible to combine targeting ligands, radionuclides, fluorescent molecules or drugs on the nanoparticle surface.
  • multipurpose or multimodal nanostructures that are contrast agents interesting in molecular imaging combined with surgical procedures such as surgery of tumour. Due the possibility to vary the size of the nanostructure it is possible to use size as a targeting properly in lymph node imaging and surgery.
  • a nanoparticle able to target and image the sentinel lymph node (SLN) of patients with breast cancer or malignant melanoma or other metastazing tumors can greatly improve and facilitate the surgical procedure.
  • SLN sentinel lymph node
  • the size of the nanoparticles are normally 5-100 nm, especially 10 to 100 nm.
  • Utilizing the possibility of creating multimodal nanostructures enables a combination of drug (radionuclide) delivery and the possibility to follow the delivery process with medical imaging.
  • Combining a core of a metal or metal oxide compound like iron oxide, gold or a gadolinium or manganese, with a well designed coating, that is capable of carrying radionuclides and other molecules as well as displaying targeting units with a minimum of nonspecific interactions gives on hand a multimodal contrast reagent useful for combined multimodal imaging and therapeutic applications.
  • the nanoparticle has to be: - designed to give contrast in the chosen imaging modality (ies)
  • systemic administration - capable of carrying a drug component and directed to specific target sites in the body following systemic administration - capable of being functionalized in order to carry additional imaging components following systemic administration
  • the contrast agent or drug delivery vehicle has to be stable enough to be shipped and stored with a reasonable long shelf life. Furthermore, it should be easy for the end-user to add a biomarker of or any other ligand of choice. This requires robust coating, which provides accessible functional groups for further modification.
  • the general object of the invention is to solve the problem of producing a new agent which can be used for administering a high local concentration of an isotope to a site in the body.
  • the chelating properties enable an easy, very quick and robust labelling with radionuclides in a manner that is feasible in practical applications both preclinically and for clinical purposes.
  • the coating material can be utilized to produce nanoparticles as contrast agents in multimodal imaging for diagnostic purposes and for guidance during surgery.
  • the nanostructures can further be very useful as drug delivery vehicles in radiotherapy and in combinations of therapy and imaging.
  • This innovation describes a coating material with the inherent capability to chelate metal ions and radionuclides in the interior of the coating.
  • This innovation provides a method in which the nanostructure can be pre-manufactured and then labelled with a metal ion or a radionuclide just prior to use in a quick one step protocol.
  • This surface modification can induce non specific interactions of the nanostructure when used as a contrast or therapeutic agent.
  • the surface modification can impact the stability of the nanostructure.
  • various nuclides may require different radionuclide specific chelator and in turn the labelling may involve elevated temperatures and unfavourable reaction conditions for the nanostructure.
  • a more general chelator has been created and the labelling procedure is done in a few minutes, usually between 1-15 minutes, preferably 1-10 minutes.
  • the chelating unit is in the interior of the coating leaving the surface unchanged and intact.
  • the coating is useful for coating surfaces. According to the present invention a coated nanostructure is predominantly being used. However in other areas it could also be used for surfaces on analytical chip, implants etc.
  • the surface to be coated needs to carry a hydrophobic surface film.
  • these are metal oxide cores, iron oxide cores, upconverting crystals etc.
  • Such cores are produced by seed growth in a solvent protected by a fatty acid such as oleic acid or fatty acid coated structures for instance gold nanoparticles conjugated with thiol-functionalized oleic acid.
  • the object of the invention is achieved by forming a coating material having an outer surface of a polymer and an inner chelating surface, which easily chelates metal ions and radionuclides by a) mixing and reacting a poly maleic anhydride having a hydrophobic tail of the formula (I) with
  • an agent in the form of nanoparticles in the range of 5-100 nanometer capable of chelating radionuclides or metal entities is prepared from cores in the size of 2 -50 nanometers having a hydrophobic layer from a fatty acid are further coated by
  • hydrophobic tail of compound I whereby the core is coated and a poly-chelator network is formed around the core during the coating process to form the final product which contains nanoparticles with the polymer(compoundll) as the outer component brought in close proximity with a radionucleotide or metal ion for a short period of time(i-i5 minutes), preferably 1-10 minutes, to form the agent for medical imaging or radiotherapy.
  • Metal chelates are well known in the art. Some well known are known as DOTA, DIPA, TETA NOTA. The above are only examples, also other macrocyclic metal chelates may be used.
  • the compound of the formula (I) is a poly maleic anhydride (see example PMAO (poly maleic anhydride-alt-i-octadecene)
  • n is between 80 and 135 and x is 16 reacted with an aminoterminal polymer, see example below with a Jeffamine® a
  • polyetheramine 0,0-Bis(2-aminopropyl) polypropylene glycol-block-polyethylene glycol-block-polypropylene glycol ), having the formula (II)
  • Pol stands for an otherwise inert non toxic hydrophilic polymer. Otherwise inert means that no unwanted reaction takes place.
  • suitable polymers are amino polyethylene glycol (m-PEG-NH2),polyetheramines, amino polyethylene amines (NH2-PEG-NH2), amino dextrans, 0,0-bis(2-aminopropyl) polypropylene glycol- block-polyethylene glycol-block-polypropylene glycol of various lengths .
  • the reaction results in a multi-amide structure with amides and carboxyl group side by side.
  • This reaction product is then added to the hydrophobic film coated surface of the core particles.
  • the hydrophobic film is formed by an unsaturated fatty acid found in nature.
  • One example is oleic acid.
  • the hydrophobic tale of the compound of formula I interacts with the fatty acid and forms an inner hydrophobic layer. This in turn displays the anhydride part connected to the hydrophilic polymer towards the surrounding hydrophilic solvent.
  • a multi site chelator is formed next to the hydrophobic layer. This chelator is strong and the amide and carboxylic groups in three dimensions create a network for metal (or nuclide) binding.
  • the resulting coating on the nano particle has an outer surface of the polymer of choice.
  • the inner space creates a poly-chelator network. It has been proven by binding various metal ions and isotopes. The binding takes place by contacting the nanoparticle coated with the polymer II as the outer surface component with a radionucleotide or metal ion. The inventors have also proven that the coating chelates strongly and the resulting nanostructure is perfect as combined contrast agent for MRI/PET (or SPECT) or optical imaging/PET (or SPECT) or CT/PET (or SPECT) or ultrasound/PET (or SPECT) or CT/PET (or SPECT) if the metal that is chelated is a radionuclide or multiple various radionuclides.
  • Suitable polymers in the outer layer are amino polyethylene glycol (m-PEG-NH2), polyether amines, amino polyethylene amines (NH2-PEG-NH2), amino dextranes, 0,0-bis (2-aminopropyl) polypropylene glycol-block-polyethylene glycol-block- polypropylene glycol of various lengths .
  • the present invention relates to chelating metal ions that give rise to a contrast in MRI such as gadolinium, manganese, cobalt and iron etc. in a coating of upconverting crystals or quantum dots or gold nanoparticles to create a multimodal agent for MRI/optical imaging or CT/optical imaging.
  • the size of the core is between ⁇ and 50 nm, preferably between 2 and 50 nm.
  • the core is coated with a micelle like structure of various molecules having one hydrophobic part and one hydrophilic part, the whole particle size is preferably between 2 and 100 nanometer.
  • the synthesis of cores, or production methods are important from a commercial stand point in order to handle scaling and GMP processes.
  • the core material is often essential for one imaging modality.
  • Suitable hydrophobic compounds are unsaturated fatty acids found in the nature, especially oleic acid and variants thereof as well as similar compounds.
  • Seed growth method by reducing FeO(OH) in i-octadecene and protected by oleic acid. All three ingredients are mixed and then heated to 320 C for 120 minutes under cooling and reflux of solvents. After 120 minutes the mixture is allowed to slowly cool down to room temperature. The cores are washed with diethyl ether and then precipitated with ether. This is a difference compared with earlier methods, where chloroform is used. Since chloroform is listed as an environmental hazard other solvents have to be tested in order to develop a sustainable production process. The procedure is repeated twice and the nanostructures are finally resuspended in diethyl ether.
  • Iron oxide cores are used to produce MRI contrast agents. b. Up-converting crystals
  • Upconverting crystals can be made using similar methods as described above as hydrophobic nano cores using oleic acid as protecting agent.
  • An upconverting crystal contains a mixture of, Ytterbium and Yttrium and in combination with small amounts of other ions like for instance Erbium or Thulium in order to set the wavelength optimum of adsorbed and emitted light from these crystals, one example of
  • composition is: Na 4 :Yb 3 VTm 3+ , which gives rise to emission of 8oo nm when illuminated with 980 nm light source.
  • Upconverting crystals are used as contrast agents in optical imaging, prefearably Near- IR fluorescence imaging.
  • the production of gold nanostructure is well known and was pioneered by J. Turkevich et al. in 1951 and it is the simplest known method.
  • the method is used to produce monodisperse spherical gold nanoparticles suspended in water of around 10-20 nm in diameter. It involves the reaction of small amounts of hot chlorauric acid with small amounts of sodium citrate solution.
  • the colloidal gold will form because the citrate ions act as both a reducing agent, and a capping agent.
  • the citrate ions can be exchanged with thiol groups known as the thiol ligand exchange method.
  • the thiol modified oleic acid is made to replace the citric acid on the nanostructure and the oleic acid stabilized gold nanostructures are then ready for the coating procedure.
  • Gold cores are used as contrast agent in CT and optical imaging. d. Quantum dots
  • Typical colloidal quantum dots are made of binary alloys such as cadmium selenide, cadmium sulfide, indium arsenide, and indium phosphide. These quantum dots are produced in a similar process like a and b above where the synthesis of colloidal quantum dots is based on a three-component system composed of precursors of the binary alloy, organic surfactants such as oleic acid, and solvents such as octadecene. When heating a reaction medium to a sufficiently high temperature, the precursors chemically transform into monomers. Once the monomers reach a high enough supersaturation level, the nanocrystal growth starts with a nucleation process. The nanostructures are washed using similar process as described under a for iron oxide nanostructures. Quantum dot cores are used to create contrast (or signal) in fluorescence optical imaging.
  • binary alloys such as cadmium selenide, cadmium sulfide, indium arsenide, and indium
  • Iron oxide core particles are important components in multimodal contrast nanostructures since the magnetic core give rise to contrast in MRI and ultrasound (in combination with an oscillating magnetic field or a magnetic pulse). It is further possible to label their coatings with fluorophors and/or nuclides for imaging in optical imaging and PET/SPECT respectively in combination with MRI and ultrasound - hence the expression multimodal nanoparticles. Gold cores gives rise to a contrast effect in CT and in some optical imaging applications and labelling their coatings with fluorophors and/or nuclides for imaging combinations optical imaging and
  • Upconverting crystals coated according to the invention can act as multimodal agent for optical imaging in combination with PET/SPECT if a radionuclide is chelated in the coating.
  • the cores mentioned above in combination with the coating can assemble chelated metal ions such as gadolinium and manganese or other metals that give rise to a specific contrast in MRI.
  • the polymer length can further be adjusted by using various polymers of various lengths to the coating and provide various thickness of the coatings in a very controlled process.
  • the size distribution is still kept very narrow and that is a necessity in order to perform quality control and batch-to-batch consistency.
  • the coating can be made thicker if that is of importance to the final application of the particle by adding polymers to the functional amino groups on the particle surfaces.
  • the choice of length of the first Jeffamine/ amino dextran coating step can obviously be varied as well in order to obtain a certain coating thickness and final radius of the nanostructure.
  • the amino terminal polymer used in the reaction can have amino group on each side of the polymer. With the amino groups not reacted with PMAO the polymer then have free amino groups are generated on the surface of the nanostructure and these amino groups are free to serve as conjugation candidates with other functional groups, e.g. antibodies.
  • the coating has as characteristics that it is very stable in pH from 2 to 12, in serum and in molar range salt. It can be made with various coating thickness, which opens up for designing nanostructures with various size which can be crucial for the final application. Coating thickness between 3 and 30 nm are favourable, however other size ranges can be of interest as well.
  • Isotopes of interest to chelate with the agent in the form of nanoparticles (the list is not limiting):
  • Gallium ( ⁇ Ga, 68 Ga), Strontium ( 89 Sr), Samarium ( ⁇ Sm), Ytterbium ( l6 9Yb), Thallium ( 201 T1),
  • Astatine ( 211 At), Lutetium ( 177 Lu), Actinium ( 225 Ac), Yttrium (9°Y), Antimony ( n 9Sb), Tin ( ii ySn, n 3Sn), Dysprosium ( 159 Dy), Cobalt ( 56 Co), Iron ( 59 Fe), Ruthenium (97Ru, 10 3Ru),
  • Gadolinium ⁇ Gd, ⁇ Gd
  • Terbium l6o Tb
  • Lanthanum ⁇ La
  • Radium 223 Ra, 22 4Ra
  • Metal ions of interest to chelate with the nanoparticles in the agent according to the invention (but not limited to):
  • the chelating effect is strong for multiple ions and isotopes. It is further shown that: a) The chelating effect is not depending on any surface functional groups such as for instance amino groups b) The chelating effect is not depending on the length of the hydrophilic polymer c) It is possible to combine the chelating interior without disturbing chemistry on functional surface groups where we have added fluorophores, antibodies etc. d) The chelating effect is stable at physiological pH and in serum e) The reaction is extremely quick, and normally takes 1-15 minutes, especially 1- 10 minutes. It is formed by simply mixing the metal ion or isotope at low pH with the nanostructure of choice. No incubation time is needed.
  • the temperature may be raised to 40-50 C, but this is not necessary.
  • nanostructure is then separated from nuclides by magnetic separation or HPLC or desalting chromatography or any other suitable separation process that can be applied.
  • the ready to use nanostructures are eluted in physiological salt solution.
  • the iron oxide cores of the nanoparticles were produced according to the process described by Yu W et al. Briefly, 12.7 g Octadecene (Sigma- Aldrich, St Louise, MO, USA), 4.5 g Oleic acid (Sigma-Aldrich) and 356 mg Iron(III) oxide-hydroxide (Sigma- Aldrich) were mixed in a reaction vessel. The mixture was heated to 323 °C for 60 minutes with constant stirring and then allowed to cool to 35 °C, before removing it from the reaction vessel. A sample of the cores was dissolved in hexane and passed through a 0.1 ⁇ PTFE filter (Whatman, Maidstone, UK).
  • the size of the filtered particles was determined with Dynamic Light Scattering (DLS) in a Malvern Zeta Sizer Nano Series (Malvern Instruments Ltd, Worcestershire, UK) using an acrylic cuvette and measurement parameters for Fe 3 0 4 .
  • the core size was also confirmed by transmission electron microscopy (TEM). Particles were deposited on a carbon grid and imaged with a FEI Tecnai Spirit BioTWIN transmission electron microscope.
  • nanoparticles Three variants of nanoparticles were designed using the same core size but varied coating thickness.
  • the three nanoparticles had a final hydrodynamic diameter of 15 nm, 34 nm and 57 nm respectively. They were produced according to the following protocol.
  • the iron oxide cores were washed by dissolving the reaction mixture in
  • the volume of water solution containing the particles was measured and an equal volume of 300 mM NaCl was added, to make the SPIONs solution ready for injection.
  • the particles were passed through a filter paper (454, VWR) to remove larger debris. Excess coating material and large complexes were removed by diafiltration in three steps (KrosFlo Research Hi TFF System, Spectrum Laboratories, Inc.). First the particles were passed through a 0.2 ⁇ PES filter (X32E-300-02N, Spectrum
  • the volume was first reduced to approximately 50 mL and the particles were then washed over night against 5 L 150 mM NaCl at constant volume mode. The next day the volume was reduced to the void volume of the system and the filter was exchanged for a smaller surface area filter with the same rating (C02-E300-05-N, Spectrum Laboratories, Inc.). The tubing of the system was also exchanged for a smaller size tubing. The volume was further reduced to a final volume of 4-5 mL.
  • the fluorescent dye DY- 647 (Dyomics) was conjugated to the particles. Amino groups in the coating are used to conjugate the dye through N-Hydroxysuccinimide (NHS) chemistry.
  • NHS N-Hydroxysuccinimide
  • carbonate buffer 0.2 M NaHC0 3 , 0.5 M NaCl
  • the three different sized agents mentioned above having a hydrodynarnic diameter of 15, 34 and 52 nanometer, respectively were used to identify the sentinel node in a animal model using MRI, briefly it could, be concluded that there were clear differences in lymphatic uptake and drainage between the three sizes.
  • the thickness of the coating can be used in the design of a targeted nanostructure.
  • Triplicates of 400 ⁇ of SPIO34 (2 mg Fe/ml) were buffer exchanged using a magnetic separation column, M Column (Miltenyi Biotech, Germany) to trap the particle and then elute them in 0.05 M ammonium acetate buffer pH 4.0 (Buffer A).
  • the samples were each divided into two vials. To the first vial 200 ⁇ of 100 mM GdCl3 dissolved in Buffer A was added and to the second vial only Buffer A was added. All samples were incubated for 5 minutes.
  • each particle can bind at least 1000 Gd 3+ ions in the coating.
  • Other metals tested were Cu 2+ , Al 3+ and Ga 2+ , which showed similar results.
  • Iron oxide (Fe 3 0 4 ) crystals with a diameter of 10 nm ⁇ mm were synthesized and coated with according to the method described in example 1 and example 2 using PMAO in combination with Jeffamine ED-2003.
  • 68 Ga was generated from a 68 Ga/ 68 Ge - generator system (IDB, Holland) and the 68 Ga was eluted in 0.6 M HC1.
  • a fraction containing 40-80 Mbq of 68 Ga was used for labeling 4x1 ⁇ 14 nanostructures.
  • the nanostructures were labeled with 68 Ga in various pH from 3.5 to pH 5.0 with successful results. Labeling in pH above pH 5.0 reduced the labeling ratio per nanostructure most probably due to insoluble metal hydroxides formed by 68 Ga 2+ .
  • the labeling efficiency and stability of the labeling in human serum were determined using instant thin layer chromatography.
  • An amount of 0.07-0.1 mL (-5-10 MBq, 0.13 mg Fe) of 68 Ga -SPIONs was subcutaneously injected in the hind paw of 9 normal rats.
  • the animals were imaged with PET/CT and 9.4T MR systems at 0-3 h and 25 h post injection (p.i.) in vivo.
  • Three rats were imaged ex-vivo with a CCD-based Cherenkov optical system.
  • a biodistribution study was performed by dissecting and measuring the radioactivity in lymph nodes, kidneys, spleen, liver and the injection site.
  • the labeling yield was 97.3 % after 15 min and the 68 Ga -SPIONs were stable in human serum. All three imaging modalities, PET/MR together with Cherenkov luminescence imaging, clearly visualized the SLN.
  • the mean uptake of 68 Ga-SPIONs after 3 h p.i. was 123 % IA/g in SLN (popliteal node), 47 % IA/g in the inguinal node, a mean of 0.05 % IA/g in kidneys, 0.1 % IA/g in the spleen and 0.3 % IA/g in the liver.
  • the solution from 3 was washed according to a procedure, where ether and ethanol were added to precipitate the cores. After a centrifugation step at 5 min, 4000xg the supernatant was discarded and the precipitated nanostructures were resuspended in Hexane.
  • the core size was approximately 35 nano meters and they showed a high emission peak at 800 nano meters when illuminated with a 980 nm laser source.
  • the Jeffamine was added to a round bottom flask and the PMAO was mixed in in smaller fractions while the flask was swirled to avoid areas with a locally high concentration of PMAO cross binding with the Jeffamine.
  • the flask was placed on a rotary evaporator and spun for 5 minutes after which the upconverting cores were added and the mixture was spun for an additional 5 minutes.
  • An equal amount of Milli- Q (MQ) water and chloroform was added and the flask was lowered into a 61 °C water bath. The flask was spun at 230 rpm and the pressure was gradually lowered to 100 mbar to evaporate the chloroform.
  • the volume of water solution containing the particles was measured and an equal volume of 300 mM NaCl was added.
  • the particles were passed through a filter paper (454, VWR) to remove larger debris. Excess coating material and large complexes were removed by diafiltration in three steps (KrosFlo Research Hi TFF System, Spectrum Laboratories, Inc.). First the particles were passed through a 0.2 ⁇ PES filter (X32E-300-02N, Spectrum Laboratories, Inc.) followed by a 500 kD PES filter (P-D1-500E-100-01N, Spectrum Laboratories, Inc.), removing unwanted complexes and larger particles.
  • a 300 kD mPES filter (P-D1-300-E- 100-oiN, Spectrum Laboratories, Inc.) was applied that retains the particles but excess coating material will pass through.
  • the pump was run at the maximum flow rate (480 mL/min) with the inlet pressure of the membrane kept at approximately 28 psid for the 0.2 ⁇ and 500 kD filters.
  • the filtration was run at a constant volume and was allowed to proceed until the permeate was clear.
  • the volume was first reduced to approximately 50 mL and the particles were then washed over night against 5 L 150 mM NaCl at constant volume mode.
  • the tubing of the system was also exchanged for smaller sized tubing.
  • the volume was further reduced to a final volume of a few ml in 0.15 M NaCl and was ready for imaging using optical near IR imaging in combination with PET or SPECT.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Nanotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Dispersion Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un agent sous la forme de nanoparticules dans la plage de 5 à 100 nanomètres comportant des radionucléides ou des poly-chélateurs de métaux dans leur matériau de revêtement. L'agent est produit par revêtement de noyaux ayant une taille de 2 à 50 nanomètres ayant une couche hydrophobe d'un acide gras par a) mélange et réaction d'un anhydride d'acide polymaléique ayant une queue hydrophobe (composé I) avec b) un polymère amino-terminal (composé II) en une quantité d'au moins un groupe amino du polymère amino-terminal (composé II) pour au moins un groupe maléimide de (composé I) pour former c) une structure multi-amide avec des amides et des groupes carboxyliques côte à côte d) après quoi ladite structure est ajoutée à la surface revêtue de couche hydrophobe des noyaux, de sorte que la couche hydrophobe soit amenée à entrer en contact avec la queue hydrophobe du composé I et de sorte que le noyau soit révêtu et qu'un réseau de poly-chélateur soit formé autour du noyau pendant le processus de revêtement pour former le produit final qui est une nanoparticule avec le polymère (composé II) lorsque le composant externe de la nanoparticule formée ainsi que l'utilisation de l'agent en radiothérapie et/ou en imagerie médicale.
PCT/EP2014/060301 2013-05-21 2014-05-20 Agent de contraste WO2014187800A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE1350620 2013-05-21
SE1350620-9 2013-05-21

Publications (1)

Publication Number Publication Date
WO2014187800A1 true WO2014187800A1 (fr) 2014-11-27

Family

ID=50771488

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2014/060301 WO2014187800A1 (fr) 2013-05-21 2014-05-20 Agent de contraste

Country Status (1)

Country Link
WO (1) WO2014187800A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220031873A1 (en) * 2020-07-29 2022-02-03 Board Of Trustees Of Michigan State University Multi-Modal Contrast Agent For Medical Imaging

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005102396A2 (fr) * 2004-04-20 2005-11-03 Emory University Nanostructures de multimodalite, procedes de fabrication et d'utilisation associes
WO2007008566A2 (fr) 2005-07-08 2007-01-18 Ut-Battelle, Llc Nanoparticules de radionucleides enrobees par une coque inorganique a laquelle sont reliees des biomolecules vecteurs
WO2011070203A2 (fr) 2009-12-11 2011-06-16 Universidad De Granada Nanostructures mutlifonctionnelles vectorisées pouvant être utilisées comme agents de diagnostic trimodal (irm, oi et spect)
WO2011163136A2 (fr) * 2010-06-21 2011-12-29 University of Washington Center for Commercialization Nanoparticules magnétiques multifonctionnelles modulables pour la biomédecine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005102396A2 (fr) * 2004-04-20 2005-11-03 Emory University Nanostructures de multimodalite, procedes de fabrication et d'utilisation associes
WO2007008566A2 (fr) 2005-07-08 2007-01-18 Ut-Battelle, Llc Nanoparticules de radionucleides enrobees par une coque inorganique a laquelle sont reliees des biomolecules vecteurs
WO2011070203A2 (fr) 2009-12-11 2011-06-16 Universidad De Granada Nanostructures mutlifonctionnelles vectorisées pouvant être utilisées comme agents de diagnostic trimodal (irm, oi et spect)
WO2011163136A2 (fr) * 2010-06-21 2011-12-29 University of Washington Center for Commercialization Nanoparticules magnétiques multifonctionnelles modulables pour la biomédecine

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
EMMA E. LEES ET AL: "The Preparation of Colloidally Stable, Water-Soluble, Biocompatible, Semiconductor Nanocrystals with a Small Hydrodynamic Diameter", ACS NANO, vol. 3, no. 5, 26 May 2009 (2009-05-26), pages 1121 - 1128, XP055132815, ISSN: 1936-0851, DOI: 10.1021/nn900144n *
PONTUS KJELLMAN ET AL: "Optimizing retention of multimodal imaging nanostructures in sentinel lymph nodes by nanoscale size tailoring", NANOMEDICINE: NANOTECHNOLOGY, BIOLOGY AND MEDICINE, vol. 10, no. 5, 1 July 2014 (2014-07-01), pages 1089 - 1095, XP055132911, ISSN: 1549-9634, DOI: 10.1016/j.nano.2014.01.007 *
WILLIAM W YU ET AL: "Aqueous dispersion of monodisperse magnetic iron oxide nanocrystals through phase transfer", NANOTECHNOLOGY, IOP, BRISTOL, GB, vol. 17, no. 17, 14 September 2006 (2006-09-14), pages 4483 - 4487, XP020104060, ISSN: 0957-4484, DOI: 10.1088/0957-4484/17/17/033 *
YU W ET AL.: "Aqueous dispersion of monodisperse magnetic iron oxide nanocrystals through phase transfer", NANOTECHNOLOGY, vol. 1, 2006, pages 4483 - 4487

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220031873A1 (en) * 2020-07-29 2022-02-03 Board Of Trustees Of Michigan State University Multi-Modal Contrast Agent For Medical Imaging

Similar Documents

Publication Publication Date Title
Arms et al. Advantages and limitations of current techniques for analyzing the biodistribution of nanoparticles
Aslan et al. Metallic nanoparticles as X-Ray computed tomography (CT) contrast agents: A review
Yang et al. PET-MR and SPECT-MR multimodality probes: Development and challenges
Smith et al. Nanomaterials for in vivo imaging
Holbrook et al. Gd (III)-dithiolane gold nanoparticles for T 1-weighted magnetic resonance imaging of the pancreas
Jain et al. Diagnostic nanocarriers for sentinel lymph node imaging
Chou et al. In vitro and in vivo studies of FePt nanoparticles for dual modal CT/MRI molecular imaging
Yang et al. Affibody modified and radiolabeled gold–iron oxide hetero-nanostructures for tumor PET, optical and MR imaging
Qiao et al. Dendrimer-based molecular imaging contrast agents
Liu et al. Passive tumor targeting of renal-clearable luminescent gold nanoparticles: long tumor retention and fast normal tissue clearance
Zhao et al. Chlorotoxin-conjugated multifunctional dendrimers labeled with radionuclide 131I for single photon emission computed tomography imaging and radiotherapy of gliomas
Glaus et al. In vivo evaluation of 64Cu-labeled magnetic nanoparticles as a dual-modality PET/MR imaging agent
Liberman et al. Color doppler ultrasound and gamma imaging of intratumorally injected 500 nm iron–silica nanoshells
Nune et al. Advances in lymphatic imaging and drug delivery
Kim et al. Development and in vivo imaging of a PET/MRI nanoprobe with enhanced NIR fluorescence by dye encapsulation
Frellsen et al. Mouse positron emission tomography study of the biodistribution of gold nanoparticles with different surface coatings using embedded copper-64
Soufi et al. Eco-friendly and sustainable synthesis of biocompatible nanomaterials for diagnostic imaging: current challenges and future perspectives
Mirabello et al. Metallic nanoparticles as synthetic building blocks for cancer diagnostics: from materials design to molecular imaging applications
Cheng et al. Chelator-free labeling of metal oxide nanostructures with zirconium-89 for positron emission tomography imaging
Augustine et al. Imaging cancer cells with nanostructures: Prospects of nanotechnology driven non-invasive cancer diagnosis
Gholipour et al. Development of Ga-68 labeled, biotinylated thiosemicarbazone dextran-coated iron oxide nanoparticles as multimodal PET/MRI probe
Chen Nanoplatform-based molecular imaging
Qin et al. Carbonized paramagnetic complexes of Mn (II) as contrast agents for precise magnetic resonance imaging of sub-millimeter-sized orthotopic tumors
Hsu et al. Nanomaterial-based contrast agents
CN105079826A (zh) 一种rgd@bbn双靶向mr/光学双模态分子探针的制备和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14725684

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14725684

Country of ref document: EP

Kind code of ref document: A1