Dendrimeric compounds

Details Dendrimeric compounds Dendrimeric compounds

1997-01-21

1998-11-10

Levy, Neil S.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Matrices

424485, 424486, 424DIG16, 424 111, 424 91, A61K 900

Patent

active

058340203

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB95/00898, filed Apr. 20, 1995 with priority as a PCT Great Britain # 9407812.8 filed Apr. 20, 1994.
This invention relates to novel therapeutically or diagnostically useful dendrimeric compounds and their applications in medicine, including the field of diagnostic imaging.
Chelants and their metal chelates have long found utility in therapeutic and diagnostic medicine, most notably in metal detoxification, therapeutic delivery of radioisotopes, and in particular in diagnostic imaging.
Medical imaging modalities, such as MRI, X-ray, gamma scintigraphy, and CT scanning, have become extremely important tools in the diagnosis and treatment of illnesses. Some imaging of internal parts relies on inherent attributes of those parts, such as bones, to be differentiated from surrounding tissue in a particular type of imaging, such as X-ray. Other organs and anatomical components are only visible when they are specifically highlighted by particular imaging techniques.
Researchers have recognized for many years that chelating various metals increases the physiologically tolerable dosage of such metals and so permits their use in vivo as contrast agents to enhance images of body parts (see for example C. D. Russell and A. G. Speiser, J. Nucl. Med. 21: 1086 (1988) and U.S. Pat. No. 4,647,447 (Gries et al.)). However, such simple metal chelate image enhancers, without further modification, do not generally provide any particularly significant site specificity.
In recent years many developments in the field of chelate-based contrast agents have taken place and new and more diverse chelants have been developed which enable specific application, eg. imaging of target organs, of blood flow, of axonal transport, etc. For example, the hepatobiliary system may be selectively imaged by MRI using lipophilic contrast agents, or the contrast agent may be targetted to a specific organ or area of the body by means of a target-specific biomolecule, such as an antibody, to which the chelant moiety is coupled.
More recently efforts have been directed to producing chelants, including target-specific site-directed chelants, which have a multiplicity of sites for metal chelation. This may be achieved by creating oligochelants, as described by Nycomed Salutar, Inc. in WO-91/05762, which have a linear or branched oligomeric structure comprising alternating chelant and linker moieties.
Alternatively, polychelant "magnifiers" may be formed which comprise a number of chelant moieties attached to a backbone or carrier structure, as described for example by Nycomed Salutar, Inc. in WO-90/12050 and by Torchlin et al. in Hybridoma, 6: 229-240 (1987). Such a backbone may comprise a simple chain-like polymer, eg. a polyamine or polypeptide, or a dendrimer (eg. a starburst dendrimer as described by Tomalia et al. in Polymer Journal 17: 117 (1985) and in U.S. Pat. No. 4,587,329). To produce a site-specific polychelant, one or more of such chelant moiety carrying backbone molecules may be conjugated to a site-directed macromolecule, eg. a protein.
Polychelants have the advantage that each molecule can be loaded with several metal ions, and thus metal ion delivery to the target site or area is increased, thereby enabling much more effective targeting of a therapeutic or diagnostic metal and achieving enhanced efficacy as a contrast agent. Also, in view of their increased size, soluble metal-containing polychelates have a unique localisation and biodistribution in the body which renders them particularly useful as so-called "blood-pool" contrast agents; by virtue of their non-particulate nature and relatively high molecular weights, such polychelants do not diffuse immediately into the extravascular space (as is the case with the monomeric chelates presently used in MRI contrast enhancement such as Gd DTPA-BMA and Gd DTPA) and remain circulating in the blood pool. This extended intravascular residence time means that the polychelates may function as target-specific blood pool agents without requiring attachment to a site

REFERENCES:
patent: 5157095 (1992-10-01), Smid
patent: 5338532 (1994-08-01), Tomalia et al.
Gerhard et al., "Dynamic Contrast-Enhanced MR Imaging of the Upper Abdomen: Enhancement Properties of Gadobutrol, Gadolinium-DTPA-Polylysine . . . " Magn. Reson. Med., 32(5):622-628 (1994).
Wiener et al., "Dendrimer-Bates Metal Chelates: A New Class of MRI Contrast Agents" Magnetic Resonance in Medicine, 31(1):1-8 (1994).

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