Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Patent
1997-01-21
2000-01-04
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
424 936, 424 9364, 424 942, A61B 5055
Patent
active
060106816
DESCRIPTION:
BRIEF SUMMARY
This invention relates to diagnostic imaging contrast agents and in particular to blood pool agents, that is contrast agents which have a long residence time in the vasculature.
Medical imaging modalities, such as MR imaging, X-ray, PET, SPECT, magnetotomography, EIT, gamma-scintigraphy and CT scanning are becoming extremely important tools in the diagnosis and treatment of illnesses. Some imaging techniques can rely entirely on the inherent attributes of body components, such as bone and soft tissue, to achieve differentiation in the images between such components, others require the administration of agents (contrast agents) to permit such differentiation or to improve the image contrast between different such components or between viable and damaged tissue.
The use of contrast agents is well established in most imaging modalities.
The efficacy of a contrast agent, however, is dependant not only on its inherent capacity to improve image contrast in the imaging modality in question but also upon its pharmacokinetics, ie. its spatial and temporal distribution pattern following administration.
For contrast agents administered into the systemic vasculature, as a general rule, low molecular weight hydrophilic molecules (e.g. molecular weight beneath 5000 D) distribute into the extracellular fluid (ECF) and are relatively rapidly excreted through the kidneys by glomerular filtration, whereas particulates, liposomes or lipophilic molecules tend to accumulate relatively rapidly in the liver.
Several ECF and liver contrast agents are marketed or are in clinical development. However, while various blood pool agents (i.e. agents which do not distribute into the ECF and yet have relatively prolonged residence times in the blood pool) have been proposed, their development has not yet progressed very far.
Thus, in the field of MR imaging, early suggestions for blood pool agents included paramagnetic chelate-macromolecule conjugates, e.g. where the macromolecule was a soluble biotolerable material such as dextran with a molecular weight above the kidney threshold and where the chelate was for example GdDTPA. Later suggestions involved the proposal that polychelants, high molecular weight water soluble species capable of chelating many, e.g. 20-100, paramagnetic metal ions be used.
The materials proposed have encountered problems of poor characterization, unpredictable biodistribution, unsatisfactory blood pool residence times, liver accumulation, and inadequate bioelimination by glomerular filtration.
The demand for effective and tolerable blood pool agents, therefore still exists.
We now propose a novel class of blood pool contrast agents which have opsonization controlling moieties bound to a macrostructure which carries chelated paramagnetic or heavy metal ions.
Viewed from one aspect, therefore, the invention provides a blood pool contrast agent having an overall molecular weight of at least 10 KD (preferably at least 15 KD and especially about 20 KD or greater) comprising a macrostructure which has bound thereto a plurality of opsonization inhibiting moieties and carries chelated ionic paramagnetic or heavy metal moieties, the chelant groups for said chelated moieties being macrocyclic where said macrostructure is liposomal.
Opsonization is the process by which blood proteins attach to foreign matter in the vasculature to facilitate the rapid uptake of such matter by the reticuloendothelial system (RES), primarily liver, spleen and bone marrow.
Various opsonization inhibitors may be used according to the invention but in general they will be amphiphilic polymers, optionally terminally modified, e.g. for attachment to the macrostructure. By an amphiphilic polymer is meant a polymer having repeat units with lipophilic and hydrophilic segments. A preferred example of such a polymer is polyethyleneglycol which has a [CH.sub.2 CH.sub.2 O] repeat unit, the alkylene chain providing the lipophilic segment and the ether oxygen providing the hydrophilic segment.
Thus the opsonization inhibitor moieties used according to the
REFERENCES:
Tilcock et al., "Nuclear magnetic relaxation dispersion and phosphorus-32 NMR studies of the effect of covalent modification of membrane surfaces with poly(ethylene glycol)", Biochim. Biophys. Acta, 1110(2): 193-8, 1992, (Abstract only).
Torchilin et al, "Targeted Delivery of Diagnostic Agents by Surface Modified Liposomes" Journal of Controlled Release, 28:45-58, 1994.
Torchilin et al., "Polymers on the Surface of Nanocarriers: Modulation of Carrier Properties and Biodistribution" Vysokomol. Soedin., Ser. A. Ser. B, 36(11):1880-1893, 1994, (Abstract only).
Trubetskoy et al., "Controlled Delivery of Imaging Agents to Lymph Notes: Membranotropic Polychelating Agent for Incorporation into Liposomes" Proc. Int. Symp, Controlled Release Bioact. Mater., 20:380-381, 1993, (Abstract).
Wiener et al., "Dendrimer-Based Metal Chelates: A New Class of MRI Contrast Agents" Magnetic Resonance in Medicine, 30(1):1-8, 1994.
Campion Brian
Fellmann Jere Douglas
Garrity Martha
Margerum Larry
Varadarajan John
Hollinden Gary E.
Nycomed Salutar Inc.
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