WO1999012578A1 - Dosimetrie par rayonnements avec composes detectables par resonance magnetique - Google Patents

Dosimetrie par rayonnements avec composes detectables par resonance magnetique Download PDF

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Publication number
WO1999012578A1
WO1999012578A1 PCT/US1998/018969 US9818969W WO9912578A1 WO 1999012578 A1 WO1999012578 A1 WO 1999012578A1 US 9818969 W US9818969 W US 9818969W WO 9912578 A1 WO9912578 A1 WO 9912578A1
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WO
WIPO (PCT)
Prior art keywords
tissue
radiation
magnetic resonance
particles
tumor
Prior art date
Application number
PCT/US1998/018969
Other languages
English (en)
Inventor
Francesco D'errico
Vincenza Viti
Original Assignee
Yale University
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 Yale University filed Critical Yale University
Priority to AU96615/98A priority Critical patent/AU9661598A/en
Publication of WO1999012578A1 publication Critical patent/WO1999012578A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
    • 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
    • A61K49/1803—Semi-solid preparations, e.g. ointments, gels, hydrogels
    • 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
    • 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
    • A61K49/1863—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 a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N5/1048—Monitoring, verifying, controlling systems and methods

Definitions

  • This invention relates primarily to radiation dosimetry using magnetic resonance imaging of radiation-sensitive compounds administered to tissues or tissue samples such as tumor tissue, or tissue surrounding a tumor, prior to irradiation.
  • Radiation therapy has made major strides in instrumentation, physics, radiobiology, treatment planning, and applications to curative and palliative cancer treatment and management. Compared with surgery, radiation therapy has distinct advantages in the locoregional treatment of cancer. Radiation causes less acute morbidity and can be curative for some specific sites while preserving organ or tissue structure and function. Various forms of irradiation are used for differing therapeutic objectives. For example, electron beam irradiation deposits most of its energy at the entrance in tissues and can be useful for superficial therapy in skin neoplasms.
  • high energy (megavoltage) x-rays from a medical accelerator or 7-rays from a cobalt-60 source spare the skin, deposit their energy at greater depth, and provide a better approach to treating deep-seated neoplasms.
  • Use of permanent or temporary radioactive-source implants can also be useful in some settings.
  • Neutral or charged particles are also used in the treatment of some tumors, with advantages deriving from a higher ionization densiry and/or a more localized dose delivery.
  • the use of multiple irradiation fields reduces the dose to normal tissue while increasing the dose to the tumor.
  • the use of fractionated doses of radiation causes less cumulative damage to normal tissues than to the tumor in many cases, probably because the normal tissues are often able to repair damage more effectively.
  • oxygenation can improve and render it more radiosensitive.
  • the selection of treatment is based on the relative radiosensitivities of the tumor and of the normal organs and tissues within the radiation field.
  • a fundamental objective of all current irradiation techniques is that of delivering the radiation dose with great accuracy, according to the three-dimen- sional geometry of the target volume (conformal treatments).
  • Radiation doses within tissues must be inferred through indirect measurements possibly next to the treatment target, but mainly corresponding to the radiation entrance and excit surfaces of the patient, or from (delayed) clinical observation of the biological effects. It would be desirable to provide an in vivo dosimetric assessment of actual radiation dose received by specific organs or tissues of interest almost immediately after radiation therapy.
  • the present invention provides a method for the measurement of radiation, particularly ionizing radiation such as photon-radiation, applied to a tissue or tissue sample.
  • a radiation-sensitive compound such as coated and/or uncoated superparamagnetic iron oxide particles are administered to the tissue, and radiation is measured using magnetic resonance spectroscopy and/or imaging.
  • the invention is particularly useful for radiation dosimetry that assesses the absorbed radiation dose delivered to patholog- ical tissue during radiotherapy such as that employed in the treatment of certain tumors.
  • This invention is based on the use, as radiation dosimeters, of radiation- sensitive, magnetic resonance detectable compounds, which are typically employed as contrast agents for magnetic resonance (MR) imaging (MRI).
  • MR magnetic resonance
  • MRI magnetic resonance
  • radiation-induced variations in relaxivity, t ' .e., MR-detectable radiation effects are used to assess dose mapping of in vivo tissue as well as dose measurements of in vitro sample.
  • coated and/or uncoated superparamagnetic iron oxide (SPIO) particles are enterally or parenteral- ly administered to a patient in order to enhance the MRI of the tissues and organs where they concentrate.
  • tissue is generic and includes tissue samples, organized tissues comprising organs, and surrounding cell groupings.
  • T 2 of materials containing SPIO particles is characterized by a multiexponential behavior, one of whose components is sensitive to ionizing radiation.
  • the relaxation rate R 2 l/T 2 varies linearly with the dose. Therefore, nuclear magnetic resonance (NMR) spectrometry of samples containing SPIO is weighted by this component of T 2 and provides a quantitative, spatial measurement of the radiation dose received by an irradiated tissue or other sample.
  • NMR nuclear magnetic resonance
  • any radiation-sensitive, MR relaxivity-modifying compound that can be administered to tissue and imaged using MRI may be employed as contrast agents in dosimetric methods of the invention. It is an advantage of the invention that many such compounds are fully FDA-approved for in vivo use, and are already employed for imaging purposes. SPIO was employed in the Examples that follow, but others may be used. Radiation-sensitive compounds include, but are not limited to, uncoated and dextrane-coated SPIO particles, siloxane-coated com- pounds such as those provided by Berlex, pure iron oxide, mixtures of these compounds with each other and with iron, and the like radiation-sensitive paramagnetic particles.
  • the agents may in some embodiments be employed with compounds that extend the imaging time frame or signal intensity. In alternate embodiments, the contrast agent or agents are formulated to provide time frame and signal intensity enhancement.
  • Typical routes of administration of SPIO particles or other contrast agent or agents are oral or intravenous, but any other administration routes such as intraperitoneal injections or combinations of routes may also be employed.
  • the particles are typically suspended in a pharmaceutically acceptable carrier which may also contain other compounds such as those mentioned previously.
  • the particles are attached to tissue or tumor-specific agents such as receptor ligands, antibodies or antibody fragments (including, but not limited to, monoclonal and fusion phage antibodies) to enhance tissue selectivity (Fahlvik, A.K. , et al., J. Magn. Res. Imaging 3: 187-194, 1993; this papers and others cited herein are expressly incorporated in their entireties by reference).
  • the invention provides a considerable improvement to conventional measurements of entrance or exit doses with radiation sensors applied to patients externally or intracavitally now employed to estimate the extent of tumor irradiation.
  • the invention provides methods for assessing doses to any tissue, including not only tumor tissue but also tissues surrounding a tumor. It is an additional advantage that consistent techniques are used for the preliminary imaging and for designing the treatment regimen, and for the following verification of the correct delivery of the prescribed irradiation to target tissue using methods of the invention. This allows for improved treatment planning, including providing guidance for adjusting a sub- optimal treatment to assure that proper therapy is received during subsequent treatments.
  • the invention further provides for dosimetry images for later patient follow-up and/or for epidemiological studies.
  • the invention also provides a method for assessing the treatment of other pathological conditions unrelated to oncology for which radiation therapy is employed, such as the reduction of exophtalmus due to Grave's disease and the removel of keloids and hypertrophic scars.
  • NMR relaxation times T, and T 2 of agarose and Fricke-agarose gels were measured in the range 17-51 MHz.
  • the analysis of the spin-echo curves indicates a multiexponential behavior, characterized by three components, at all the examined frequencies.
  • the relative T 2 values ranging from few to hundred milliseconds, can be attributed to different species of water molecules present in the gel.
  • the three T 2 values decrease as a function of frequency, but no gain in dose sensitivity is obtained by changing the working frequency in the examined range.
  • Relaxivity of agarose gels containing ferrous or ferric ions have also been measured and found different from those of the corresponding solutions in the absence of agarose.
  • R,, R 2 a and R 2 b it was possible to estimate the radiation yield from three independent parameters, R,, R 2 a and R 2 b . No effect of the dose rate nor of the energy source was observed for any of these parameters.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Nanotechnology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Signal Processing (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • General Physics & Mathematics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une technique de dosimétrie par rayonnements qui consiste à utiliser la spectroscopie par résonance magnétique et/ou l'imagerie de composés sensibles aux rayonnements dans des tissus ou des échantillons irradiés. Dans les modes de réalisation types, on utilise des particules d'oxyde de fer superparamagnétiques enrobées ou non, qui sont administrées à un patient comme moyens permettant d'évaluer la dose de rayonnement qu'une cible tumorale reçoit pendant une radiothérapie.
PCT/US1998/018969 1997-09-10 1998-09-10 Dosimetrie par rayonnements avec composes detectables par resonance magnetique WO1999012578A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU96615/98A AU9661598A (en) 1997-09-10 1998-09-10 Radiation dosimetry with magnetic resonance detectable compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5848997P 1997-09-10 1997-09-10
US60/058,489 1997-09-10

Publications (1)

Publication Number Publication Date
WO1999012578A1 true WO1999012578A1 (fr) 1999-03-18

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WO (1) WO1999012578A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4863715A (en) * 1984-03-29 1989-09-05 Nycomed As Method of NMK imaging using a contrast agent comprising particles of a ferromagnetic material
US4932412A (en) * 1986-12-18 1990-06-12 Immunomedics, Inc. Intraoperative and endoscopic tumor detection and therapy
US5427767A (en) * 1991-05-28 1995-06-27 Institut Fur Diagnostikforschung Gmbh An Der Freien Universitat Berlin Nanocrystalline magnetic iron oxide particles-method for preparation and use in medical diagnostics and therapy

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4863715A (en) * 1984-03-29 1989-09-05 Nycomed As Method of NMK imaging using a contrast agent comprising particles of a ferromagnetic material
US4932412A (en) * 1986-12-18 1990-06-12 Immunomedics, Inc. Intraoperative and endoscopic tumor detection and therapy
US5427767A (en) * 1991-05-28 1995-06-27 Institut Fur Diagnostikforschung Gmbh An Der Freien Universitat Berlin Nanocrystalline magnetic iron oxide particles-method for preparation and use in medical diagnostics and therapy

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Publication number Publication date
AU9661598A (en) 1999-03-29

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