WO1999012578A1

WO1999012578A1 - Radiation dosimetry with magnetic resonance detectable compounds

Info

Publication number: WO1999012578A1
Application number: PCT/US1998/018969
Authority: WO
Inventors: Francesco D'errico; Vincenza Viti
Original assignee: Yale University
Priority date: 1997-09-10
Filing date: 1998-09-10
Publication date: 1999-03-18
Also published as: AU9661598A

Abstract

A method for radiation dosimetry utilizes magnetic resonance spectroscopy and/or imaging of radiation-sensitive compounds in irradiated tissue or samples. Typical embodiments employ coated or uncoated superparamagnetic iron oxide particles which are administered to a patient to provide a means to assess the amount of radiation which a tumor target receives during radiotherapy.

Description

RADIATION DOSIMETRY WITH MAGNETIC RESONANCE DETECTABLE COMPOUNDS

Related Application Data

This application claims priority benefit of co-pending U.S. application serial number 60/058,489, filed 10 September 1997.

Technical Field of the Invention

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.

Background of the Invention

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. By contrast, 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. Additionally, as a tumor shrinks with therapy, its 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). However, presently there is not any non-invasive dosimetry method to verify the local delivery of a radiation treatment within the tumor or the adjacent normal tissues. 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. Summary of the Invention

It is an objective of the invention to provide for the direct measurement of radiation-absorbed doses in irradiated tissues and organs.

It is another objective of the invention to provide for the determination of the spatial (three-dimensional) distribution of radiation doses delivered to an irradiated tissue or sample.

It is an additional objective of the invention to provide for the assessment of an in vitro sample of any kind such as a tissue biopsy using magnetic resonance spectroscopy (relaxometry) as well as the dose mapping of an in vivo tissue or organ using magnetic resonance imaging.

These and other objectives of the invention are accomplished by the present invention, which provides a method for the measurement of radiation, particularly ionizing radiation such as photon-radiation, applied to a tissue or tissue sample. In the practice of a typical embodiment of the invention, 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.

Detailed Description of the Invention

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). For example, 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.

In the practice of one embodiment of the invention, 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. As used herein, "tissue" is generic and includes tissue samples, organized tissues comprising organs, and surrounding cell groupings. As shown in the Examples that follow, it was found that the efficiency of the agent in enhancing the relaxation times of water protons (relaxitivity) is modified in a measurable way by the application of ionizing radiation. In particular, the "transversal relaxation time" T₂ of materials containing SPIO particles is characterized by a multiexponential behavior, one of whose components is sensitive to ionizing radiation. The relaxation rate R₂= l/T₂ varies linearly with the dose. Therefore, nuclear magnetic resonance (NMR) spectrometry of samples containing SPIO is weighted by this component of T₂ and provides a quantitative, spatial measurement of the radiation dose received by an irradiated tissue or other sample.

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. In addition, 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. In some embodiments, 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). It is an advantage of the invention that many monoclonal antibodies to tumors are known and useful for this purpose, and that monoclonal antibody-coated magnetite particles have been used as contrast agents in magnetic resonance imaging of tumors by coating Fe₃O₄ with monoclonal antibodies directed against a tumor antigen (Cerdan, S. , et al., Magn. Res. Med. 12: 151-163, 1989). Such preparations maintain both the immunoreactivity of the monoclonal antibody and the full relaxing capability of the magnetite particle (ibid.).

It is a further and more important advantage of the invention that direct measurement of radiation absorbed doses in target organs 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. Moreover, 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.

In addition to the treatment of pathological conditions treated by radia- tion can Advantageously also be employed to assess radiation doses in vitro to tissue samples such as biopsies.

Examples

The following examples are presented to further illustrate and explain the present invention and its background, and should not be taken as limiting in any regard.

Example 1

This example summarizes background work reported by Luciani, et al., Phys. Med. Biol. 41: 509-521 (1996).

NMR relaxation times T, and T₂ 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 T₂ values, ranging from few to hundred milliseconds, can be attributed to different species of water molecules present in the gel. Two of these components are characterized by relaxation rates, R₂ ^a and R₂ ^b, more sensitive than R_! to 7-irradiation, being the sensitivity S S(R,) =0.066 s^" ^lGγ S(R₂ ^a) =0.088 s 'Gy ¹, S(R₂ ^b)=0.17 s 'Gy ¹. The three T₂ 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. Thus it was possible to estimate the radiation yield from three independent parameters, R,, R₂ ^a and R₂ ^b. No effect of the dose rate nor of the energy source was observed for any of these parameters.

Example 2

This example summarizes further background work reported by Di

Capua, S., et al., in Magn. Res. Imaging, 1997.

Fricke-agarose gels were irradiated with a proton beam. Then samples were extracted at different depths with respect to the beam penetration distance, corresponding to different irradiation doses. Relaxation times T] and T₂, measured at 17 MHz, appear sensitive to this kind of radiation. In particular, T₂ exhibits three components, T₂ ^a, T₂ ^b and T₂ ^C, the first two being sensitive to proton irradiation. At 1 % agarose concentration, the relaxation rates R₁ = l/T₁, R₂ ^a 1/T₂ ^a, and R₂ ^b= l/T₂ ^b of samples irradiatied with both modulated and unmodulated beams, increase with the dose, irrespective of the beam energy. The yield G of Fe³⁺ ions per 100 eV of absorbed energy is always higher than that obtained for γ-irradiated samples.

Example 3

This example summarizes experiments illustrating changes upon irradiation of the relaxation times of superparamagnetic iron oxide particles imbedded in an agarose gel matrix as reported in Viti, V., et al. , Med. Biol. Eng. Computing 35 (Supplement 2) 902, 1997. Uncoated and dextrane-coated superparamagnetic particles of size 1 μm (PerSeptive Biosystems) and ~ 50 nm (Berlex) were dissolved in a 1 % agarose gel. Sample irradiations were performed with a °°Co source (AECL Gammacell 220). Inversion-recovery and spin echo curves (SPMG sequence) were obtained with a low resolution spectrophotometer (Spinmaster, Stelar) at 17 MHz and at 26 °C.

While magnetization recoveries are well characterized by a single relaxation time T,, T₂ exhibits a multiexponential behavior. T] does not change appreciably after irradiation with a dose ranging from 10 to 30 Gy. On the contrary, the T₂ component characterized by the longest relaxation is sensitive to γ-irradiation. In particular, its relaxation rate R₂= l/T₂ varies linearly with the dose for short echo times (up to 250 ms).

It is well known that the relaxation rate R₂ is a very sensitive parameter to the presence of supermagnetic particles in solution. As oxidation of magnetite to maghemite is a well known natural process, the present data indicates that γ- irradiation seems to favor a process of this kind that influences R₂, but not R, .

The above description is for the purpose of teaching the person of ordinary skill in the art how to practice the present invention, and it is not intended to detail all those obvious modifications and variations of it which will become apparent to the skilled worker upon reading the description. It is intended, however, that all such obvious modifications and variations be included within the scope of the present invention, which is defined by the following claims. The claims are intended to cover the claimed components and steps in any sequence which is effective to meet the objectives there intended, unless the context speci- fically indicates the contrary.

Claims

1. A method for the measurement of irradiation imparted to a tissue comprising the magnetic resonance imaging of a radiation-sensitive compound administered to the tissue.

2. A method according to claim 1 wherein the measurement is taken of a tissue in vivo.

3. A method according to claim 2 wherein the measurement assesses the amount of radiation which tumor tissue receives during radiotherapy.

4. A method according to claim 2 wherein the measurement assesses the amount of radiation which tissue surrounding tumor tissue receives during radiotherapy.

5. A method according to claim 1 wherein the measurement assesses the dose to an in vitro tissue sample.

6. A method according to claim 5 wherein the tissue is a biopsy sample.

7. A method according to claims 1, 2, 3, 4, 5, or 6 wherein the radiation- sensitive compound comprises superparamagnetic iron oxide particles.

8. A method according to claim 7 wherein the radiation is ionizing radiation.

9. A method according to claim 7 wherein the particles are attached to tissue- specific agents using receptor ligands, antibodies, or antibody fragments.

10. The use of superparamagnetic iron oxide particles administered to tissue as a magnetic resonance imaging contrast agent for radiation dosimetry to monitor radiation doses applied to the tissue. - lu ┬¼

ll. A use according to claim 10 wherein the tissue is tumor tissue and the particles are selectively directed to tumor tissue.

12. A use according to claim 10 wherein the tissue surrounds tumor tissue and the particles are selectively directed to tissue surrounding tumor tissue.