Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Attached to or within viable or inviable whole...
Reexamination Certificate
1999-11-08
2002-04-30
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Attached to or within viable or inviable whole...
C424S001490, C424S001690, C424S009340, C424S009600
Reexamination Certificate
active
06379647
ABSTRACT:
The invention relates to a method of delivering imaging agents; means therefor including components thereof which have particular, but not exclusive, application in the development of therapies for cancer or coronary heart disease.
Macrophages often comprise 20-60% of the tumour cell mass in breast carcinomas and form intimate contacts with malignant cells. This has long been thought to represent part of the host's defence mechanisms against the tumour; however, their function at such sites in the body remains an enigma at present as macrophages isolated from human or murine tumours exhibit reduced tumouricidal, phagocvtic and antigen-presenting activities compared to those from normal tissues (
1
).
Monocites are produced in the bloodstream and extravasate (i.e. exit) into surrounding tissues including such diseased tissues as malignant tumours and atherosclerotic plaques, where they differentiate into macrophages and perform immune, secretory, phagocytic and other functions. Monocytes and macrophages are collectively termed mononuclear phagocytes. As tissue macrophages have a lifespan of 60 to 90 days and the number of macrophages in tumours remains constant, it is believed that there is a constant attachment of monocytes to the tumour endothelium and influx of monocytes into the tumour cell mass.
Hypoxia, that is, very low levels of oxygen, exist only in some forms of diseased tissue (e.g. malignant tumours, ischaemic heart tissue, retinal tissue etc.) (
2
). Hypoxia and/or hypoglycaemia is thought to occur in growing tumours when the increasing metabolic demands of the rapidly expanding tumour cell population outstrip the supply of oxygen/glucose etc., made available to them by simple diffusion across the tumour mass from vessels in surrounding normal tissues.
Recent and surprising data indicate that once monocytes enter a tumour from the bloodstream, they rapidly differentiate into macrophages and preferentially congregate in hypoxic (i.e. poorly vascularised and necrotic) sites deep within a tumour mass remote from blood vessels. Refer to
FIG. 1
, which represents a bar chart of the Distribution of Macrophages in Relation to Blood Vessels. Moreover, breast tumours, with more hypoxic
ecrotic areas, are more heavily infiltrated with macrophages, which preferentially locate to, or around, the necrotic sites (refer to
FIG. 2
, which represents a bar chart of the Association of Macrophage Index with Necrosis in Breast Carcinomas). Experimental hypoxia has been shown to induce the production of angiogenic factors by macrophages in vitro (
3
). Taken together these data could underpin our recent finding, that increased numbers of macrophages in breast tumours equate with increased fatalities in breast cancer (
4
).
We have also shown recently that human macrophages accumulate specifically in cell layers immediately adjacent to the central areas of necrosis in three-dimensional cultures of human cancer cells. Many previous studies have shown that this viable rim of tumour cells around the necrotic core of such spheroids are severely hypoxic relative to the outer layers of tumour cells in these cultures (
5
). That macrophages congregate in hypoxic diseased tissues other than malignant tissue has been shown for coronary heart disease (
6
), as well as such cerebrovascular disorders of the central nervous system as strokes and cerebral malaria (
7
).
The observation that tumour and other forms of ischaemic tissue are regions of poor oxygenation has lead to the development of a number of techniques to assess oxygen tension in these tissues. Invasive surgical procedures include the insertion of polarographic micro-electrodes into tumour tissue to measure directly the levels of oxygen in a given tissue (
2
). Non invasive techniques have also been adopted which involve the use of radiopharmaceuticals (eg F-18 Fluoromisonidazole) which bind to hypoxic cells (
8
). The concentration of the agents are then detected and quantified by methods such as whole body positron emission tomography (PET imaging) (
9
). A major problem with this imaging technique is that radiopharmaceuticals tend to be neurotoxic due to their lipid solubility. Clearly this problem would be overcome if it were possible to bind these products to a delivery means. A further major problem with this imaging technique is the poor level of resolution achieved by radiopharmaceuticals due to a relatively high background detection in tissues that do not have appreciable levels of hypoxia. An improvement of the level of detection in hypoxia sites can be achieved if sufficient time is allowed for the clearance of the radiopharmaceutical from non target tissues. However this can take several hours to achieve and is therefore not a desirable situation.
The current state of the art describes a number of means to enhance the localisation of imaging agents to hypoxic and/or ischaemic sites. In broad terms current techniques involve the encapsulation of imaging pharmaceuticals within microvesicles. Alternatively the imaging agents can be directly modified to enable either the localisation of the agent to the desired tissue or enhance their detection when the agent accumulates in the target tissue.
Typically microspheres encapsulating an imaging agent are liposomes composed of either pure phospholipid or a mixture of phospholipid and phosphoglyceride. They are advantageous due to the ease with which the microspheres can be produced containing the imaging pharmaceuticals. By altering conditions during manufacture microspheres can be produced that have diameters of less than 200 NH which enables them to be intravenously injected and able to pass through the pulmonary capillary bed. Furthermore the biochemical nature of the liposome confers permeability across blood vessel membranes to access the tumour site or region of ischaemia. Liposomes of this type show high echogenicity both in vitro and in vivo which would be a necessary requirement using techniques of magnetic resonance imaging (
11
), fluoroscopy and computerised tomography (
10
).
However this technology does suffer a major disadvantage in that the liposomes lack an intrinsic affinity for the targeted tissue and relies on a local intravenous injection of the liposome composition in the vicinity of the diseased tissue.
What patients require is a rapid and accurate diagnosis of their condition so that an effective treatment regime can be established as quickly and accurately as possible. The development of an effective means of targeting imaging means to hypoxic/ischaemic sites would obviously benefit both clinicians and patients in the diagnosis and treatment of diseases such as cancer and coronary heart disease.
An alternative strategy is to chemically modify an agent that has a natural affinity for tumour/ischaemic tissue to enable the detection of the agent at the targeted tissue.
Monosaccharide derivatives have been used as imaging agents (Patent application no. WO.9634872-A). Glucose levels have been shown to be an important indicator in diagnosis of Alzheimer's disease, Parkinson dementia, epilepsy, diabetes and myocardial ischaemia. The elevated levels of glucose consumption in tumour or ischaemic tissue has been exploited by using iodinated glucose to identify these regions. Although modified monosaccharides have excellent in vivo stability they have a general biodistribution in the body and problems with optimising the signal to noise ratio during treatment can arise.
The labelling of peptides with technetium-99m and there detection via scintigraphic imaging has been used in the diagnosis of tumours (Patent application no. WO.9310747-A). Peptides are typically composed of 4-100 amino acid residues. The technetium-99m labelled peptides have been successful used to diagnose kidney disorders by scintigraphic imaging. However although imaging peptides have excellent in vivo stability they lack an intrinsic targeting property making resolution somewhat problematic.
More recently the use of a radioactive copper complex of dithiosemicarbazone has been employed
Hartley Michael G.
Merchant & Gould P.C.
Oxford Biomedica (UK) Limited
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