WO1989011873A1

WO1989011873A1 - Magnetic particle-containing compositions

Info

Publication number: WO1989011873A1
Application number: PCT/EP1989/000613
Authority: WO
Inventors: Jo Klaveness; Terje Thomassen
Original assignee: Nycomed As
Priority date: 1988-06-03
Filing date: 1989-05-31
Publication date: 1989-12-14
Also published as: AU623408B2; AU3682089A; EP0422021A1; GB8813144D0; JPH03504723A

Abstract

The invention relates to the use in diagnosis or therapy, especially magnetic resonance imaging, of a combination of magnetic particles, that is particles which are ferromagnetic, ferrimagnetic, or superparamagnetic, and a chelating agent for the metal species of the magnetic particles or a bioprecursor for such a chelating agent.

Description

Magnetic Particle-Containing Compositions

The present invention relates to therapeutic and diagnostic compositions, in particular to parent- erally administrable compositions containing magnetic particles, and to their use in methods of therapy and diagnosis, especially diagnoses employing nuclear magnetic resonance (nmr) techniques.

Compositions containing magnetic particles, that is particles which are ferromagnetic (or ferrimagneti or superparamagnetic, have been used widely in diagnostic investigations and therapeutic treatments. Thus for example parenterally administered magnetic particles have been proposed for the targeting of drugs using externally applied magnetic fields (see for example idder et al. in J. Pharm. Sci. .68: 79-82 (1979) , Advances in Pharmacology and Chemotherapy 16:213 (1979) and US-A-4247406 and also Ugelstad et al. in WO83/03920 (Sintef) and Morris in US-A-4331654) - for the repair of vascular damage and for arterial "clamping" during surgery (see for example Perry in Proceedings Int. Adv. Course Workshop (1977) pages 219-230 and Roth in J. Appl. Physics .40:1044-1045(1969) ) , for blood flow tracing (see for example Newbower in IEEE Transactions on Magnetics Mag9(3) :447-450 (1973) ) , and for killing cancer cells jj vivo using the heat generated by the magnetic particles on imposition of a rapidly alternating field (see for example T7S-*-4106488 (Gor c .

Recently, with the development of nmr in medicine, it has been shown that magnetic particles are useful both in magnetic resonance imaging (MRI) and in magnetic resonance spectroscopy (MRS) . For example the use of magnetic particles to obtain a selective signal from cancer tissue in MRS has been described by White et al. in Proceedings of the San Francisco Workshop on Magnetic Resonance Spectroscopy in vivo - April 4-5 1987, page 93 (1987) and the use of ferromagnetic and super aramagne- 5 tic particles as MRI contrast agents has been described by Nycomed AS in WO85/04330.

In MRI, the contrast in the images generated may be enhanced by introducing into the zone being imaged an agent, generally referred to as a contrast

10 agent, which affects the spin reequilibration character¬ istics of the nuclei (the "imaging nuclei" which generally are protons and more especially water protons) which are responsible for the resonance signals from which the images are generated. The

15 enchanced contrast obtained with the use of contrast agents enables particular organs or tissues to be visualized more clearly by increasing or by decreasing the signal level of the particular organ or tissue relative to that of its surroundings.

20. Contrast agents raising the signal level of the target site relative to that of its surroundings are termed "positive" contrast agents whilst those lowering the signal level relative to surroundings ^•are termed "negative" contrast agents.

25 The majority of materials now being proposed as MRI contrast agents achieve a contrast effect because they contain paramagnetic, superparamagnetic or ferromagnetic species.

For ferromagnetic and superparamagnetic contrast

30 agents, which are negative MRI contrast agents, the^enhanced image contrast derives 'primarily from the 'reduction in the spin reequilibration coefficient known as T₂ or as the spin-spin relaxation time, a reduction arising from the effect on the imaging

35 nuclei of the fields generated by the ferromagnetic or superparamagnetic particles.

I Paramagnetic contrast agents on the other hand may be either positive or negative MRI contrast agents. The effect of paramagnetic substances on magnetic resonance signal intensities is dependent on many factors, the most important of which are the concentration of the paramagnetic substance at the imaged site, the nature of the paramagnetic substance itself and the pulse sequence and magnetic field strength used in the imaging routine. Generally, however, paramagnetic contrast agents are positive MRI contrast agents at conventional concentrations where their .^ lowering effect dominates but they may become negative MRI contrast agents at higher concentrations where their T~ lowering effect is dominant. In either event, the relaxation time reduction results from the effect on the imaging nuclei of the magnetic fields generated by the paramagnetic centres.

The use of ferromagnetic and superparamagnetic materials as MRI contrast agents has been widely advocated and broad ranges of suitable materials have been suggested in the literature, such as for example in WO85/04330 (Nyσomed AS) , WO85/02772 (Schroder et al.) , US-A-4675173 (Widder) , WO88/00060 (Advanced Magnetics Inc.), WO86/01112 (Fox Chase Cancer Center) , DE-A-3443252 (Schering AG) , Widder et al. AJR 14_8:399-404 (1987), Renshaw et al. Magnetic Resonance in Medicine 3_-²17-225 (1986), Saini et al. Radiology 162:211-216 (1987) , Mendonca Dias et al. Magnetic Resonance in Medicine 3_:328-330

(1986), Hemmingsson et al. Acta Radiologica 28:703- 705 (1987) and Bacon et al. J. Lab. Clin. Med. llp_:164-171 (1987) .

The literature contains many suggestions for the formulation of parenterally administrable magnetic particle containing compositions and in particular suggests that the magnetic particles can be administered either free (i.e. uncoated and not bound to any other substance) or coated (e.g. dextran coated - see for example US-A-4452773) , or carried by or embedded in a matrix particle (e.g. a polysaσcharide - see for example WO85/02772) , or bound to an organ- or tissue-targeting species, e.g. a biomolecule such as an antibody or a hormone (see for example WO88/00060) .

Parenterally administrable magnetic particles are of particular interest in the imaging of the liver and the spleen due to the action of the reticulo- endothelial system in removing such particles from the blood stream. However parenterally administered magnetic particles may be caused to locate at other organs or tissues, e.g by using particles which are bound to tissue-or organ-targeting substances thus enabling contrast enhanced MR images of the targetted tissues or organs to be generated.

Furthermore the suggestion has been made in WO88/00060 that the serum life of parenterally administered magnetic particles may be increased, so perhaps allowing such particles to act as blood pooling MRI contrast agents, if before administration of the magnetic particles the subject's reticuloendo- thelial system is "overloaded" by administration of chemically and physically similar non-magnetic particles.

It is of course desirable in both therapeutic treatments and in diagnostic investigations using magnetic particles that the magnetic particles should be excreted once they have performed their desired function. For orally administered magnetic particles and for particles administered into organs having external voiding ducts, e.g. the bladder and the uterus, excretion of the magnetic particles is unlikely to be problematic. However for parenterally, and especially intravascularly, administered particles to be excreted they must first be broken down. In vivo biodegradation of intravascularly administered magnetic particles appears not to have been studied in great detail but the results of various studies do indicate that it does occur gradually over a period of days or months and that the rate of biodegra- dation is dependent on the nature of the particles and in particular on whether or not they are free or coated (see for example Bacon et al. supra and WO88/00060) .

It is an object of the present invention to provide means by which biodegradation of parenterally administered magnetic particles may be facilitated or accelerated.

We have surprisingly found that the rate of degradation of parenterally, especially intravascu- larly, administered magnetic particles is increased in the presence of chelating agents.

Thus in one aspect the present invention provides a method of treatment or diagnostic investiga¬ tion of the human or non-human animal body, eg involving generating an image of said body, which method comprises parenterally administering to said body a plurality of magnetic particles, the improvement comprising administering to said body a chelating agent or bioprecursor therefor. By a chelating agent or bioprecursor is meant an agent capable of chelating metal species of the magnetic particles (particularly iron ions) or an agent which following parenteral administration will release a chelating agent capable of chelating the metal species of the magnetic particles. The term chelating agent will however be used hereafter to refer both to chelating agents and to prochelating agents (i.e. those moieties of chelating agent bioprecursors which form the basis for chelating agents that will in due course be released) .

Particular mention may be made of bioprecursors which comprise chelating agents bound by biodegradable bonds, e.g. ester linkages, to other substances. e.g. biomolecules (such as antibodies and hormones) or biologically relatively inert macromolecules (such as for example polysaccharides) or other matrix or carrier materials. Where the chelating agent is bound on or to or otherwise incorporated in a further substance such further substance will be referred to herein as a carrier material. Thus typical carrier materials may be for example coatings, matrices and macromolecules and the composite chelating agent/carrier material may be particulate or not.

Where the chelating moiety of the chelating agent used according to the present invention is already chelating an ionic species on administration to the body then this ionic species clearly will most preferably one which forms a thermodynamically less stable chelate than does the metal species of the magnetic particles, e.g. an ion for which the chelate formation constant is lower (at body temperature and in blood serum) than that for iron ions. In this regard, it is thus preferred that where the chelating moiety is already chelating an ionic species that species is a Group la, lb, Ila or ib metal ion^', e.g. ions of Na, K, Ca, Mg or Zn. Generally such ionic species will also be non-paramagnetic and non-radioactive and will have a charge of no more than 2+.

The method of the present invention is thus distinguished from the techniques described by Carvlin et al. at the 5th Annual Meeting of the

Society for Magnetic Resonance Imaging, San Antonio, Texas, 2^β February - 4 March 1987 ?r^Λ bv Weissleder et al. in Magnetic Resonance Imaging 87 005/01 S. 0^Q135-136, techniques which sought to improve contrast enhancement in MRI by coadministration of the paramagnetic MRI contrast agent Gd-DTPA and a super-paramagnetic MRI contrast agent comprising ferrite particles. In the method of the invention, the magnetic particles and the chelating agent or bioprecursor may be administered separately or, more preferably, together. Where they are administered separately, the chelating agent may be administered parenterally or, where it is absorbable, enterally. In this regard mention may be made of 1,2-dimethyl-3-hydroxy- pyrid-4-one as an example of an absorbable chelating agent. Furthermore, the chelating agent may be administered before, during or after administration of the magnetic particles. Thus for example it may be desirable to administer or to continue to administer the chelating agent hours or days (e.g. up to 48 hours) after the magnetic particles have served their diagnostic or therapeutic function in order to ensure rapid degradation of the magnetic particles remaining in the body.

Preferably however the magnetic particles and the chelating agent will be coadministered and in another aspect the present invention provides a parenterally administrable composition, for use for example in therapy or diagnosis, comprising magnetic particles and a chelating agent or bioprecursor therefor in a physiologically tolerable dispersion medium.

In preferrred embodiments, the composition of the invention comprises composite particles comprising chelating agent and a carrier material or magnetic particles and a carrier material or, especially preferably, magnetic particles, chelating agent and a carrier material.

The use of: o^p os e particle? containing both the magnetic particles and the chelating agent is especially preferred since in this way delivery of free chelating agent to the vicinity of the magnetic particles during their biodegradation may be particularly facilitated. Where the chelating agent and/or magnetic particles are administered bound to or incorporated in a carrier material, the carrier may particularly conveniently be an organ- or tissue-targeting biomolecule, for example a hormone or antibody, or a biotolerable and generally biologically relatively inert material such as a polysaccharide (e.g. dextran or starch) , a protein (e.g. albumin) or another naturally occurring or synthetic macromolecule, e.g. as described by Schroder et al. in WO85/02772 or by Nycomed AS in EP-A-184899 and EP-A-186947.

Where the magnetic particles are administered in such a way as to enter particular cells, it will be desirable to attach the chelating agents, by means of biodegradable bonds, to particles, to lipophilic moieties or to biomolecules so as to facilitate the entry of the chelating agents into the targeted cells.

Where the carrier material incorporates the chelating agent, this may be for example by simple entrapment or encapsulation within a biodegradable matrix or coating material whereby the chelating agent is released, preferably on a sustained release basis, as the carrier material breaks down. Alterna- tively the chelating agent may be deposited in voids within matrix particles, much as described in EP-A-184899, being released from the particles either as they degrade or as it dissolves on penetration of the matrix by body fluids. As a still further alternative, the composite particles may comprise particles of an insoluble derivative of the chelating agent which breaks down in vivo to release the chelating agent.

The chelating agent itself may conveniently be any biotolerable agent capable of chelating the metal species of the magnetic particles (especially iron ions) and in this regard particular mention may be made of the aminopolyacetic acids and of the many biotolerable chelating agents suggested in the literature for the parenteral administration of paramagnetic MRI contrast agents, see for example EP-A-184899 (Nycomed AS) , EP-A-186947 (Nycomed AS), EP-71564 (Schering AG) , EP-A-130934 (Schering AG) , GB-A-2137612(Schering AG) , US-A-4647447 (Schering AG) , US-A-4639365 (Sherry) , WO85/05554 (Amersha International PLC) , WO87/02893 (University of Texas), WO87/01594 (Amersham International PLC) , EP-A-136812 (Technicare Corp.) and EP-A-160552 (Vestar Research Inc) and by Nycomed AS in WO 89/00557. Particularly preferred chelating agents may thus include transferrin, N,N,N' ,N",N"-diethylenetriaminepentaacetic acid (DTPA) , the N,N" bismethylamide of DTPA (DTPA-BMA) , l-oxa-4,7,10-triaza-cyclododecane-triacetic acid (OTTA) , 1,4,7,10-tetraazacyclododecane-triacetic acid (D03A) 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) , desferrioxamine, ethylene-bis(2- hydroxyphenylglycine) (EHPG) and derivatives thereof, e.g. salts with physiologically tolerable counterions, espeσialy the metal ions referred to above or a non-toxic amine (e.g. tris (hydroxymethyl)-aminomethane, ethanolamine, diethanolamine and N-methylglucamine) , or a halogen or a non-toxic organic or inorganic acid. As mentioned above, in general, chelating agents used to chelate paramagnetic ions in parenterally administrable paramagnetic MRI contrast agents may be used as the chelating agents in the method of the present invention. Of particular interest however are the macromolecule -linker moiety-chelating agent compounds disclosed by Amersham in WO85/05554 and more especially by Nycomed AS in European Patent Application No. 89200168.6.

Where the chelating agent is bound by a biodegra- dable bond to a soluble carrier material, e.g. a dextran, then in order that the chelating agent should not be cleared from the cardiovascular system too rapidly, the carrier material/chelating agent composite will preferably have an overall molecular weight above the kidney threshold, i.e. preferably at least 20000, especially preferably 40000-2000000, particularly about 50000 to 150000. Moreover, where the chelating agent is administered in particulate form, e.g. in a composite matrix/chelating agent particle, the mean particle size will preferably be from 0.001 to 10 micrometer, especially preferably 0.01 to 5 micrometer, particularly preferably 0.05 to 2.0 micrometer.

The magnetic particles used according to the present invention may be of any material which, although preferably non-radioactive (unless the particles are intended to be detected by their radioactive decay emissions) , exhibits ferromagne- tism or superparamagnetism. The magnetic particles may conveniently be particles of a magnetic metal or alloy, e.g. of pure iron, but particularly preferably will be of a magnetic compound such as magnetite or a ferrite, such as for example gamma ferrite and cobalt, nickel or manganese ferrites.

The magnetic particles may conveniently be free or coated, aggregated or matrix carried or embedded; however the overall particle size, including any carrier material, will preferably be less than 10 micrometers, preferably 5nm to 5 micrometers, and the magnetic particles themselves will preferably be 1.5 micrometer or less, preferably 0.1 micrometer or less and especially preferably of superparamagnetic rather than ferromagnetic dimensions (i.e. sub- domain sized) , e.g. 5-50nm.

The particles of the superparamagnetic or ferromagnetic material may be coated or carried in or on particles of a non-magnetic matrix material, for example of a polysaσcharide such as dextran or starch or a protein such as.albumin and when targeting of the ferromagnetic or superparamagnetic substance onto a specific tissue is desired it may be desirable to use a ferromagnetic or superparamag¬ netic material which is bound to a tissue- or organ- specific biomolecule, e.g. as described in WO88/00060. Where the superparamagnetic or ferromagnetic material is provided with a non-magnetic coating or matrix, the coating or matrix material is particularly preferably a polysaσcharide material, such as starch or dextran (as suggested Schroder in WO83/01738) or a biotolerable polymer such as is suggested by Ugelstad et al. in WO83/03920.

Where the ferromagnetic or superparamagnetic material is provided with a coating or matrix, the iron content of the overall particles will preferably be from 0.1 to 80%, especially 1 to 70%, by weight.

Generally however magnetic particles as suggested by the literature may be used, e.g. magnetite dextrans as suggested by Schering AG and by Molday (in US- A-4452773) and carrier bound or free magnetic particles

II as suggested by Schroder et al, Nycomed AS and Advanced Magnetics Inc.

Where the magnetic particles are to be administered in composite particles containing carrier material, chelating agent and magnetic particles, the composite particles may for instance be prepared by precipitation of the magnetic particles and the chelating agents into a carrier material matrix using the method

II of Schroder et al. Alternatively such composite particles may be prepared by binding a chelating agent to a magnetic particle containing composite particle by use of a coupling agent.

The compositions of the invention may contain further components besides the chelating agent, carrier material, magnetic particles and dispersion medium (e.g. water for injections or physiological saline) . In particular the compositions may contain viscosity modifiers, pH adjusting agents, os olality regulators, stabilizers, antioxidants, buffers and emulsifying or dispersing agents as well as other conventional pharmaceutical or veterinary formulation aids. The carrier medium will however preferably be isotonic or somewhat hypertonic. Where the chelating agent is administered separately from the magnetic particles it too will preferably be in a standard parenteral or enteral administration form, e.g. parenteral administration forms such as solutions, suspensions or dispersions in a physiologically tolerable medium, e.g. water for injections, etc., and oral administration forms such as tablets, coated tablets, capsules, solutions, suspensions, dispersions, syrups, etc. Where the chelating agent is formulated for enteral administration, the composition may of course contain diluents, flavouring or colouring agents or other conventional pharmaceutical or veterinary formulation aids such as for example those mentioned earlier. Enteral administration forms may also, if desired, be formulated in sustained or delayed release form using conventional techniques.

The preferred dosages of the chelating agent and magnetic particles used according to the present invention will vary over a wide range and the chosen dosage will depend upon such factors as the administration route, the nature of the subject, the biodistribution, pharmacokinetics and chemical nature of the materials administered the purpose of administration, (i.e. therapy or diagnosis etc) and the characteristics of the externally imposed magnetic field, e.g. the strength and pulse sequence used in the imaging routine. In general, for MRI the magnetic particle dosages will be similar to the conventional dosages, and thus conveniently the dosage for the ferromagnetic or, preferably, superparamagnetic substance will be in the range 0.0001 to 5 mmol/kg bodyweight, preferably 0.001-1 mMFe/kg bodyweight. Preferably, the molar ratio between the chelating groups of the chelating agent and the magnetic metal species (e.g. Fe) in the magnetic particles should be at least 3. By increasing this ratio the half life of the magnetic particles may be reduced but the doses of chelating agent administered should not exceed and preferably should not approach closely to the toxic dosage levels.

In a further aspect of the present invention there is provided the use of magnetic particles and/or chelating agents or bioprecursors therefor in the manufacture of agents for use in a treatment or diagnosis of the human or animal body involving administration thereto of a chelating agent or bioprecursor therefor and parenteral administration thereto of magnetic particles.

The present invention will now be illustrated further with reference to the following non-limiting Examples in which ratios, percentages and parts referred to are by weight unless otherwise indicated:

Example 1

Suspension containing magnetic particles and DTPA covalently linked to cross-linked starch particles

100 mg of uncoated magnetic particles (superparamagnetic particles prepared in acordance with the description on page 43 of WO 88/00060) and 1.0 g of starch gel beads (1.5 microns) containing DTPA (prepared in accordance with the first part of Example 9 of EP-A-184899) are filled into a 20 ml vial. Before use, the particles are suspended in 10 ml of a sterile aqueous solution of 0.9 per cent NaCl by vigorous shaking for 2 minutes. The suspension contains 10 mg magnetic particles and 100 mg DTPA- starch gel beads per ml.

The suspension is preferably administered intravenously. Example 2

Kit comprising four components: one vial containing a suspension of superparamagnetic particles and three vials containing desferrioxamine

(a) Suspension of magnetic particles

100 mg of dextran magnetite (superparamagnetic particles from Meito Sangyo, Japan) are suspended in 10 ml of an aqueous solution of 0.9 per cent

NaCl and 0.1 per cent Pluroniσ^F-68 by sonication. The suspension is filled into a 10 ml vial and heat sterilized.

The suspension contains 10 mg dextran magnetite/ml.

(b) Three vials containing desferrioxamine

3.0 g of desferrioxamine methanesulfonate are dissolved in 30 ml of water. The solution is sterile filtered and filled into three 20 ml vials (10 ml in each) and the contents of the vials are freeze-dried.

Each vial contains 1000 mg of desferrioxamine methanesulfon as a white powder.

Before use, the contents of each vial are dissolved in 5ml of sterile water.

Both the suspension of superparamagnetic particles and the solutions of desfer ioxamine methanesulfonate are intended for parenteral administration. The suspension is preferably administered intravenously while the solutio s of desιerrio„c.ir. ι.ι._.y -_

intravenously or intramuscularly. If the solution is administered intravenously, it should be administered slowly to the patient at a dosage of less than 15 mg desferrioxamine methanesulfonate per kilogram bodyweight. Example 3

Kit comprising two components: one vial containing magnetic particles and one vial containing a suspension of a chelating agent

(a) Vial containing magnetic particles

150 mg of sterilized superparamagnetic particles (0.2 microns) coated with human serum albumin (prepared in accordance with the description on page 43 of WO 88/00060) are filled into a 20 ml vial.

Before use, the particles are suspended in 10 ml of a sterile aqueous solution of 0.9 per cent NaCl by vigorous shaking for 2 minutes.

The suspension contains 15 mg of superparamagnetic pariticles/ml.

(b) Suspension of chelating agent

Zn(II)-l,5-bis[ (1,2-dihydro-l-hydroxy-2-oxo-pyridin- 6-yl)carbonyl]-l,5-diazapentane (Zn(II)-LIHOPO) is prepared under aseptic conditions using the method of White e_t al. , J. Med. Chem. 31, 11 (1988).

4.0 g of Zn(II)-LIHOPO (particle size less than 2 microns) are suspended in 20 ml of a sterile aqueous solution of 0.9% NaCl. The suspension is filled aseptically into a 10 ml vial.

The suspension contains 400 mg Zn(II) -LIHOPO/ml.

Both suspensions are intended for parenteral administration The suspension of superparamagnetic particles is preferably administered intravenously; the suspension of chelating agent is preferably administered intravenously or intramuscularly. Example 4

Kit comprising a suspension of magnetic particles and 5 capsules of chelating agent

(a) Suspension of magnetic particles

200 mg of heat-denatured human serum albumin microspheres containing magnetite (prepared in accordance with US-A-4675173) is suspended in 10 ml of an aqueous solution of 0.9 per cent NaCl and 0.2 per cent polysorbate 80 by sonication for 1 minute.

The suspension contains 20 mg particles/ml.

(b) Capsules of chelating agent

l,2-Dimethyl-3-hydroxy-pyrid-4-one is prepared using the method of Kontohiorghes et al. Arzneimittelforsch 3_7 (11) , 1099 (1987).

A powdery mixture was prepared from: l,2-Dimethyl-3-hydroxy-pyrid-4-one . 500 mg Amylu maydis+ q.s.

+ a quantity is used that is sufficient to ensure that the capsules are filled.

The powder is mixed and filled into hard gelatin capsules (CapsugeJT^ Size 0).

The suspension is preferably administered intravenously; the capsules are preferably administered orally.

Example 5 Kit comprising a suspension of magnetic particles and a solution of ethylenediamine-di (ortho-hydroxyphenylac acid) (EHPG) (a) Suspension of magnetic particles

Human serum albumin - magnetite - protein A - conjugate in the form of microparticles is prepared in accordance with DE-A-3508000.

10 mg of these particles are filled into a 10 ml vial.

Before use, the particles are suspended in 10 ml of a sterile aqueous solution containing 0.9% NaCl and 0.1% polysorbate 80.

(b) Solution of ethylendia ine-di (ortho-hydroxyphenylace acid)

Ethylenediamine-di (ortho-hydroxyphenylacetic acid) (from SIGMA) 5.0 g

1 N HCL q.S.+ NaCl* q.s.

Sterile water ad 100 ml

The solution is sterile filtered, filled into a

100 ml vial and freeze dried. Before use, the white powder is dissolved in 100 ml of sterile water to yield a solution containing 50 mg EHPG/ml.

+ 2 equivalents of acid per equivalent of EHPG. * A quantity sufficient to ensure isotonicity is used.

ft I;I

Claims

CLAIMS :

1. A method of generating an image of a human or non-human animal body, which method comprises parenterally administering to said body a plurality of magnetic particles, the improvement comprising administering to said body a chelating agent or bioprecursor therefor.

2. A method as claimed in claim 1, comprising administering to said body an agent capable of chelating metal species of said magnetic particles, or a bioprecursor thereof.

3. A method as claimed in either one of claims 1 and 2 comprising administering to said body a said bioprecursor comprising a said chelating agent bound by a biodegradable bond to a biomolecule or to a biologically inert macromolecular matrix or carrier material.

4. A method as claimed in any one of claims 1 to 3 comprising administering said chelating agent or bioprecursor thereof in the form of a salt with a counterion selected from sodium, potassium, calcium, magnesium and zinc.

5. A method as claimed in any one of claims

1 to 4 wherein said magnetic particles are ferromagnetic or superparamagnetic particles.

6. A method as claimed in any one of claims

1 to 5 wherein saic cnelc.ting άjcrn. o_

is co-administered with said magnetic particles.

7. A method as claimed in any one of claims 1 to 6 wherein said magnetic particles comprise superparamagnetic particles.

8. A diagnostic composition comprising composite particles comprising magnetic particles, a chelating agent or a precursor thereof, and a carrier material.

9. A composition as claimed in claim 8 wherein said chelating agent and/or said magnetic particles are bound to or included within a said carrier material.

10. A composition as claimed in either of claims 8 and 9 wherein said chelating agent comprises an aminopolycarboxylic acid or derivative thereof.

11. A composition as claimed in any one of claims 8 to 10 comprising as said chelating agent a chelating moiety attached via an optionally biodegradable linker moiety to a macromolecule.

12. A composition as claimed in any one of claims 8 to 11 wherein said chelating agent has a molecular weight above the kidney threshold.

13. A composition as claimed in any one of claims 8 to 11 comprising composite particles of mean particle size of from 0.001 to 10 micrometers.

14. A composition as claimed in any one of claims 8 to 13 wherein said magnetic particles comprise superparamagnetic particles optionally provided with a non-magnetic matrix or coating.

15. Use of magnetic particles in the manufacture of ail agent, for use in <_ r.ietho o_ _.r atment or diagnostic investigation of the human or non-human animal body which method comprises parenterally administering to said body a plurality of magnetic particles and a chelating agent or bio precursor therefor.

16. A method of treatment or diagnostic investigation of the human or non-human animal body which method comprises parenterally administering to said body a plurality of magnetic particles, the improvement comprising administering to said body a chelating agent or bioprecursor therefor.