WO2011064577A1

WO2011064577A1 - Contrast agents for medical microwave imaging

Info

Publication number: WO2011064577A1
Application number: PCT/GB2010/051956
Authority: WO
Inventors: Ian James Craddock; Maciek Bartlomiej Klemm; Andrew Farley; Alan Preece; Jack Leendertz
Original assignee: The University Of Bristol
Priority date: 2009-11-27
Filing date: 2010-11-24
Publication date: 2011-06-03
Also published as: GB0920839D0; EP2384203A1

Abstract

A method of generating information from a search volume using microwaves. A physiologically tolerable magnetic, ionic or semiconducting contrast agent is administered to said search volume. The contrast is physiologically and is capable of absorbing or scattering microwave radiation in the frequency range 0.1 - 40 GHz. The search volume is subjected to microwave radiation emitted from one or more antennas. Microwave radiation is received with one or more antennas the effect of the contents of the search volume on the propagation of the microwave energy is detected by processing the antenna signals to form a measurement of the presence of the contrast agent in the search volume at the location of a given voxel.

Description

CONTRAST AGENTS FOR MEDICAL MICROWAVE IMAGING

FIELD OF THE INVENTION

This invention relates to the use of contrast agents in microwave radar imaging.

DESCRIPTION OF THE RELATED ART

In recent years there has been interest in medical imaging techniques that use nonionizing radiation in the microwave frequency range. Of these, microwave radar imaging show particular promise, being cheap and free of ionizing radiation. In microwave radar imaging, one or more transmitting antennas radiates short duration pulses which are then scattered by targets in which there is a mismatch in dielectric properties. These scattered signals are recorded by one or more receiving antennas and then used to map the position and characteristics of the dielectric anomalies under examination. For example, a method of measuring the contents of a search volume using microwave energy is described in US-A-5920285. Individual transmit elements of a transmit array are actuated in turn in order to interrogate the search volume. Reflected signals are recorded, and appropriate phase or time shifts are inserted to simulate, post reception, the shifts that would have occurred if either or both of the transmit and receive array had been focused on a voxel using phased array beam steering techniques. Another method of measuring the contents of a search volume is described in WO 2006/085052 A2.

The performance of such a system in a breast cancer screening application or a stroke imaging application will ultimately depend on the actual dielectric properties of tissue, blood and their spatial variation. Originally a number of studies reported substantial contrast in the dielectric properties of normal and malignant breast tissues at microwave frequencies, indicating that there should be enough contrast in microwave imaging techniques to for example identify tumours at an early stage and in dense as well as lucent breasts. A more recent and comprehensive study covering the full frequency range used in UWB microwave imaging (0.5 to 20GHz) ("A large-scale study of the ultrawideband microwave dielectric properties of normal, benign and malignant breast tissues obtained from cancer surgeries", Lazebnik et al, 2007 Phys. Med. Biol. 52 6093) indicates that the microwave frequency dielectric property contrast between malignant breast tissue and normal adipose dominated breast tissue is large, ranging up to 10: 1 when considering almost entirely adipose breast tissue as the reference. However, dielectric properties contrast between malignant and normal fibroconnective/glandular tissue was found to be considerably lower, no more than 10%. This finding brings in to question the capability of microwave radar imaging to detect for example malignant tumours in certain types of breast with high fibroconnective/glandular tissue levels, especially dense breasts. This is despite the potential high sensitivity of microwave radar imaging to small variations in dielectric constant.

SUMMARY OF THE INVENTION

A first aspect of the invention provides a method of generating information from a search volume using microwaves, said search volume containing a physiologically tolerable magnetic, ionic or semiconducting contrast agent which has been administered to said search volume and is capable of absorbing or scattering microwave radiation in the frequency range 0.1 - 40 GHz, the method comprising:

(a) subjecting said search volume to microwave radiation emitted from one or more antennas,

(b) receiving the microwave radiation with one or more antennas, and

(c) detecting the effect of the contents of the search volume on the propagation of the microwave energy by processing the antenna signals to form a measurement of the presence of the contrast agent in the search volume at the location of a given voxel.

A further aspect of the invention provides apparatus for generating information from a search volume in an animate human or non-human animal body using microwaves, the apparatus comprising:

(a) a physiologically tolerable magnetic, ionic or semiconducting contrast agent capable of absorbing or scattering microwave radiation in the frequency range 0.1 - 40 GHz;

(b) one or more antennas for subjecting said search volume to microwave radiation and receiving microwave radiation from said search volume; and (c) a computer processor for processing the antenna signals to form a measurement of the presence of the contrast agent in the search volume at the location of a given voxel.

The apparatus typically further comprises means, such as a syringe, for administering said contrast agent to the body.

A further aspect of the invention provides a physiologically tolerable magnetic, ionic or semiconducting contrast agent for use in a method of generating information from a search volume in an animate human or non-human animal body using microwaves, said contrast agent being capable of absorbing or scattering microwave radiation in the frequency range 0.1 - 40 GHz.

The use of contrast agents in microwave radar imaging is now proposed in response to the challenges mentioned above; that is to say materials which on administration serve to enhance contrast in the resulting images by increasing the scattering or absorption of microwave radiation in those tissues, organs or ducts into which they distribute. Where such contrast agents serve to increase scattering they function as positive contrast agents and where they reduce local scattering they function as negative contrast agents. The effect of a substantially absorbing contrast agent may not be directly detected as microwave radar is not normally configured to register variations in absorption. However modifications to such a system could be envisaged to measure such effects.

Contrast agents may be administered enterally or, particularly preferably, parenterally and insofar as parenteral agents are concerned there is particular scope for improvement in both target-specificity and biotolerability relative to saline.

Thus in one aspect the invention provides a method of microwave radar imaging of a human or animal, preferably mammalian, subject which method comprises parenterally administering to said subject a magnetic, ionic or semiconducting microwave radar imaging contrast agent, and generating a microwave radar image of at least part of said subject.

A wide range of materials can be used as parenteral microwave radar imaging contrast agents but particular mention should be made of five categories of contrast agent: ionic materials; relatively low molecular weight non-ionic materials; site-specific materials; nanoparticle materials.

Insofar as ionic materials are concerned, particular mention should be made of the ionic materials already proposed in the literature for use as X-ray and MRI contrast agents. Examples of such materials include many compounds with extremely low toxicity even compared with saline, and compounds may be selected which distribute preferentially within the body, e.g. which congregate at particular tissues, organs or tissue abnormalities or which are essentially confined to the circulatory system and act as blood pool agents.

Examples of ionic X-ray contrast agents suited for use according to the present invention include in particular the iodinated contrast agents, especially those containing one or more, generally one or two, triiodophenyl groups in their structure. The counterion for any ionic microwave radar imaging contrast agent are that it should itself be physiologically tolerable and in this regard particular mention should be made of alkali and alkaline earth metal cations and cations deriving from organic bases, especially sodium, zinc and ammonium ions, and more especially lysine, calcium and meglumine.

Besides ionic X-ray contrast agents, such as those mentioned above, one may advantageously use as microwave radar imaging contrast agents the ionic compounds (such as for example GdDTPA and GdDOTA) which have been used as MRI contrast agents, especially the salts of paramagnetic metal complexes (preferably chelate complexes) with physiologically compatible counterions, as well as similar complexes in which the complexed metal ion is diamagnetic (as paramagnetism is not a property required for the microwave radar imaging contrast agent to function as such). Preferred complexed paramagnetic metal ions will include ions of Gd, Dy, Eu, Ho, Fe, Cr and Mn and preferred non paramagnetic complexed ions will include ions of Zn, Bi and Ca The complexing agent will preferably be a chelating agent such as a linear, branched or cyclic polyamine or a derivative thereof, e.g. a polyaminocarboxylic acid or a polyammopolyphosphonic acid or a derivative of such an acid, e.g. an amide or ester thereof.

Several such chelates are inherently site-specific, otherwise chelating moieties may be attached to macromolecular carriers to yield site-specific contrast agents the site specificity of which derives primarily from the nature of the macromolecule. Thus, for example, by coupling chelating moieties to physiologically relatively inert high molecular weight (e.g. greater than 40 KD) dextrans, a blood pool agent may be produced. Alternatively chelating moieties may be coupled directly or indirectly, e.g. via a polymer linker such as polylysine or polyethyleneimine, to biologically active molecules, such as monoclonal antibodies etc., thereby producing a tissue- or organ-targeting contrast agent.

Nanoparticulate contrast agents, if administered into the cardiovascular system, will tend to be abstracted by the reticuloendothelial system and thus are particularly suited for use in imaging the liver.

One form of particulate contrast agent which may be used according to the invention comprises magnetic particles, especially ferromagnetic, ferrimagnetic and in particular superparamagnetic particles. Such particles are widely used as MRI contrast agents and generally are metallic or are of magnetic metal oxides, e.g. ferrites. Superparamagnetic particles, both free and carrier-bound, are widely available and their preparation is described in a large variety of references. Of particular interest are contrast media which have already been validated clinically by other medical imaging modalities or which have otherwise been shown to be non-toxic and otherwise safe to use for medical applications. Of these contrast media, superparamagnetic iron oxide particles (SPIOs) used for magnetic resonance imaging are particularly attractive as there are several FDA approved SPIOs available for clinical application and they have been shown to be safe, useful for a variety of clinical applications {Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MT imaging, Wang Y., Hussain S., Krestin G., Eur.Radiol. 11, 2319 (2001)), and able to generate enhanced contrast in microwave radar imaging. For parenteral use, the size and size distribution of the SPIO and the chemical nature of the surface of the overall particle are of great importance in determining the contrast generation efficacy, the blood half-life, and the biodistribution and biodegradation of the contrast agent. Ideally the magnetic particle size (i.e. the crystal size of the magnetic material) is within the single domain size range (such that the particles are superparamagnetic and thus have no hysteresis and a reduced tendency to aggregate) and the overall particle size distribution is narrow so that the particles have uniform bio-distribution, bio-elimination and contrast effects. The magnetic particles should be provided with a surface coating of a material which modifies particle bio- distribution, e.g. by prolonging blood half-life, or by increasing stability, or which acts as a targeting vector causing preferential distribution to a target site, such as a tumour site. Mean crystal sizes, i.e. of the magnetic core material, should generally be in the range 1 to 50 nm, preferably 1 to 20 nm and especially preferably 2 to 15 nm and, for use as blood pool agents, the mean overall particle size including any coating material should preferably be below 30 nm.

Paramagnetic and superparamagnetic contrast agents have been show to be safe for clinical applications, and thus do not entail a substantial health risk. Ferromagnetic, ferrimagnetic and antiferromagnetic particles are less preferred since they are subject to dipolar interactions which may cause them to aggregate.

Particulate contrast agents for parenteral administration should preferably have particle sizes of no more than 1.5 microns, especially 1.0 microns or less.

Parenteral administration of contrast agents according to the invention will generally be by injection or infusion, especially into the cardiovascular system. However the contrast media may also be administered into body cavities having external voidance ducts, e.g. by catheter into the bladder, uterus etc. Moreover the iodinated contrast agents, the magnetically targetable or electrically conductive contrast agents and the non-radioactive metal chelate contrast agents discussed above may also be used advantageously in microwave radar imaging of the gastrointestinal tract and such use and the use of such materials for the manufacture of microwave radar imaging contrast media for enteral administration constitute further aspects of the present invention.

The dosages of microwave radar imaging contrast media used according to the invention will vary over a broad range depending on a variety of factors such as administration route, the pharmacodynamic properties of the contrast agent (the more widely distributing the agent is the larger the dose may be), the chemical and physical nature of the contrast agent, and the strength of the interaction of the contrast agent with the microwave radiation.

Typically however agents will be administered in concentrations of 1 micromol/1 to 1 mo 1/1, preferably 0.01 to 10 mmol/1 and dosages will lie in the range 0.002 to 20 mmol/kg bodyweight, generally 0.05 to 5 mmol/kg. For matrix bound, carried or encapsulated contrast agents the overall dosage will generally be 1 to 100 ml when administered into the cardiovascular system or 10 ml to 1.5 litres of contrast media when administered into a body cavity having an external voidance duct, e.g. by oral or rectal administration. Contrast enhanced microwave radar imaging according to the present invention may be performed for a wide range of clinical indications with appropriate selection of the contrast agent (for its pharmacodynamic properties) and of the administration route. Thus non-absorbable microwave radar imaging contrast agents are particularly useful for imaging of the gastrointestinal tract for diagnosis of abnormalities therein or as markers of the gastrointestinal system. Such agents may also be used for dynamic studies, for example of gastric emptying. In studies of the gastrointestinal tract, it may be advisable to use an agent such as cimetidine to suppress naturally occuring pH variations which might otherwise reduce imaging accuracy.

Some of the microwave radar imaging contrast agents are absorbable from the gastrointestinal trace and may be taken up by the liver and excreted into the bile. Such agents can thus be used for imaging the hepatobiliary system and for liver function studies even following oral rather than parenteral administration.

The clinical indications for parenteral microwave radar imaging contrast agents include CNS examination, perfusion studies including stroke imaging, blood pool imaging, examination of body cavities, of the pelvic region and of the kidneys, hepatobiliary studies and studies of liver and kidney function, tumour imaging, and diagnosis of infarcts, especially in the heart.

BRIEF DESCRIPTION OF THE DRAWINGS

An embodiment of the present invention will now be described with reference to the accompanying drawings, in which:

Figure 1 is a system overview of a breast tumour imaging system;

Figure 2 is a 3D image of a breast phantom containing a superparamagnetic particle contrasting agent; and Figure 3 is a 2D image of the breast phantom containing a superparamagnetic particle contrasting agent.

DETAILED DESCRIPTION OF EMBODIMENT(S)

A real aperture synthetically organised radar for breast cancer detection shown in Figure 1 operates by employing an array 2 of N antennas (e.g. 3) close to, or in contact with, the breast 1. Each antenna in turn transmits a pulse and the received signal y_t(t) at each of the other antennas is recorded. The pulse generator 8 and the detector 9 may be time-shared, by means of a switching matrix 5 as shown in Figure 1, as may any transmit or receive path amplification (6, 7). A computer processor 14 processes the antenna signals from the detector 9 to form a measurement of the presence of the contrast agent in the search volume at the location of a given voxel, and generate images which are displayed on a display device 15.

Monostatic operation is unattractive because of the difficulty of near-simultaneous transmission and reception on the same antenna, and, since interchanging transmit and receive antennas would not produce any additional information, the total number of transmissions recorded is N{N - 1) / 2 .

The recorded data is then synthetically focussed at any point of interest in the volume beneath this antenna array by time-aligning the signals yt(t), using the estimated propagation time T, from the transmit antenna to the receive antenna via any point of interest in the medium.

N(N-l)/2

v(t) = ∑w_iyi (t - T, ) (la)

i=l

- where Wt are weighting factors that are applied to compensate for differences in the predicted attenuation between the round-trip paths between transmit and receive antennas via the point of interest, and/or to apply various optimisation criteria. The returned signal energy associated with this point may then computed by integrating the data over a window corresponding to the transmit pulse width τ:

Alternative methods of obtaining a scalar quantity V from v(t) include computing the magnitude of a DFT at one or more frequencies or multiplying by the transmitted pulse:

- where x{t) is the transmitted pulse waveform.

This signal processing approach is similar in essence to other time-shift-and-sum beamforming algorithms (see for example S. C. Hagness, A. Taflove, and J. E. Bridges, Two-dimensional FDTD analysis of a pulsed microwave confocal system for breast cancer detection: fixed- focus and antenna-array sensors, IEEE Trans, on Biomed. Eng., vol. 45, pp. 1470-9, Dec. 1998; or E. C. Fear and M. A. Stuchly, Microwave detection of breast cancer, IEEE Trans. Microwave Theory and Tech., vol. 48, pp. 1854-1863, Nov. 2000). However, in utilising all possible transmit/receive combinations in the array, it differs from that described by Hagness et al and Fear et al, and the consequently increased number of observations offers additional opportunities for processing gain and clutter rejection.

The operation of the system of Figure 1 can be expressed as follows:

a) energising one or more of the transmitters 2 so as to transmit electromagnetic wave energy into the search volume;

b) detecting the effect of the contents of the search volume on the passage of the electromagnetic wave energy by recording two or more signals, each signal being associated with a different propagation path within the search volume;

c) time-aligning the signals in order to generate two or more time-aligned signals which are synthetically focused on a desired voxel in the search volume, each aligned signal being associated with a different monostatic or bistatic propagation path within the search volume; and d) processing the aligned signals to generate data values which are indicative of the presence of the contrast agent in the voxel.

Figure 2 is a 3D image of an inanimate experimental breast phantom showing the distribution of contrast agent within the search volume. A 1cm phantom "tumour" within the breast phantom was filled with 0.5 - 1 mg/g[tumour]magnetoferritin nano-particles (~10nm diameter) in a saline buffer liquid, using a syringe 10 shown in Figure 1 containing the contrast agent 11. The phantom was then imaged using the system of Figure 1. Next the phantom "tumour" was again filled only with the buffer, and imaged using the system of Figure 1. The two datasets were then subtracted from each other to give the images shown in Figures 2 and 3. The patches of dark voxels 12,13 in Figures 2 and 3 indicate a region which contains a large amount of contrast agent and coincide with the position of the phantom "tumour".

Although the invention has been described above with reference to one or more preferred embodiments, it will be appreciated that various changes or modifications may be made without departing from the scope of the invention as defined in the appended claims.

Claims

1. A method of generating information from a search volume using microwaves, said search volume containing a physiologically tolerable magnetic, ionic or semiconducting contrast agent which has been administered to said search volume and is capable of absorbing or scattering microwave radiation in the frequency range 0.1 - 40 GHz, the method comprising:

(b) receiving the microwave radiation with one or more antennas, and

2. A method according to claim 1 wherein the contrast agent is a molecule, nanoparticle or particle in the size range 0.1-10,000nm.

3. A method according to claim 1 or 2 wherein the contrast agent is ionic.

4. A method according to claim 1 or 2 wherein the contrast agent is semiconducting.

5. A method according to claim 1 or 2 wherein the contrast agent is magnetic.

6. A method according to claim 5 wherein the contrast agent is paramagnetic, superparamagnetic or a combination of the above.

7. A method according to claim 1 in which the contrast agent is an iron oxide particle, a carbonyl iron particle, a cobalt particle, a nickel particle or an alloy of the above

8. A method according to claim 1 in which the contrast agent is a ferrite particle such as hematite or magnetite.

9. A method according to claim 1 in which the contrast agent is an alloy of a ferromagnetic materials and a metal.

10. A method according to claim 1 in which the contrast agent is chelated gadolinium.

11. A method according to claim 1 in which the contrast agent is a Superparamagnetic Iron Oxide (SPIO) particle or an Ultrasmall Superparamagnetic Iron Oxide (USPIO) particle.

12. A method according to claim 1 in which the contrast agent incorporates a targeting molecule

13. A method according to claim 12 in which the targeting molecule is biotin, avidin, antibody, monoclonal antibody, phage, folate, aptamer, protein or a binding fragment thereof

14. A method according to claim 12 in which the contrast agent is targeted to an organ including blood, cell, cell type, antigen, tumour marker, angiogenesis marker, blood vessel, thrombus, fibrin, or an invective agent

15. A method according to claim 14 in which the organ is the human breast.

16. A method according to claim 12 in which the target molecule is a ligand that binds to a breast cancer tumour marker such as HER2/neu.

17. A method according to any preceding claim further comprising administering said contrast agent to said search volume.

18. A method according to any preceding claim further comprising generating an image of said search volume, said image showing the distribution of said contrast agent within said search volume.

19. A method according to any preceding claim wherein said search volume is part of an animate human or non-human animal body.

20. A method according to any preceding claim wherein said search volume is part of an inanimate experimental phantom body.

21. A method according to any preceding claim, the method including:

a. energising one or more transmitters so as to transmit electromagnetic wave energy into the search volume; b. detecting the effect of the contents of the search volume on the passage of the electromagnetic wave energy by recording two or more signals, each signal being associated with a different propagation path within the search volume;

c. aligning the signals in order to generate two or more aligned signals which are synthetically focused on a desired voxel in the search volume, each aligned signal being associated with a different monostatic or bistatic propagation path within the search volume; and

d. processing the aligned signals to generate data values which are indicative of the presence of the contrast agent in the voxel.

22. Apparatus for generating information from a search volume in an animate human or non-human animal body using microwaves, the apparatus comprising:

a. a physiologically tolerable magnetic, ionic or semiconducting contrast agent capable of absorbing or scattering microwave radiation in the frequency range 0.1 - 40 GHz;

b. one or more antennas for subjecting said search volume to microwave radiation and receiving microwave radiation from said search volume; c. a computer processor for processing the antenna signals to form a measurement of the presence of the contrast agent in the search volume at the location of a given voxel.

23. A physiologically tolerable magnetic, ionic or semiconducting contrast agent for use in a method of generating information from a search volume in an animate human or non-human animal body using microwaves, said contrast agent being capable of absorbing or scattering microwave radiation in the frequency range 0.1 - 40 GHz.

24. The contrast agent of claim 23 in a concentration of 1 micromol/1 to 1 mol/1, preferably 0.01 to 10 mmol/1.

25. A contrast agent according to claim 23 wherein the contrast agent is a molecule, nanoparticle or particle in the size range 0.1-10,000nm.

26. A contrast agent according to claim 23 wherein the contrast agent is paramagnetic, superparamagnetic or a combination of the above.