Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Molecular bilayer structure
Reexamination Certificate
2000-09-01
2003-05-13
Whisenant, Ethan (Department: 1634)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Molecular bilayer structure
C424S450000, C424S178100, C514S04400A
Reexamination Certificate
active
06562316
ABSTRACT:
BACKGROUND OF THE INVENTION
In order to increase the efficiency of tumour therapy, the possibilities of using tumour seeking molecules that deliver the toxic agent specifically to the tumour cells are being explored. Radionuclides have recently been applied for cell targeted radiotherapy of malignant lymphomas (Press, 1995) and curative treatments have been achieved in some cases. So far, this is the only known case when therapy, based on macromolecular targeting agents, has been successfully applied. The reasons for the good results are probably a combination of two fortunate circumstances. The lymphoma cells are unusually easy to find for the targeting agent due to the cells main localisation in the systemic circulation. Furthermore, lymphoma cells are among the most radiation sensitive human cells presently known.
In other diseases like melanomas, gliomas and a variety of adenocarcinomas (e.g. prostate, breast and colon tumours) it has not been possible to give curative treatments with targeted radionuclides yet. The limitations appear to be partly due to that the first step in the targeting process (to find the tumour cells) is not efficient enough. A further difficulty is that, when the targeting agent anyhow has succeeded to reach the tumour cells, the energy delivery (the ionisation energy) does not damage the cell enough. The low energy delivery is due to both the limited number of nuclides reaching the cell and the fact that the radioactivity to a large extent is located in the cellular membrane or in the cytoplasm. Such a cellular localisation means that far from all emitted radiation quanta passes through the nuclear DNA. This is very unfortunate since the nuclear DNA is the critical target in the cell and severe damage to DNA is necessary to stop the proliferation of the cell.
Localization in the cell nucleus may be accomplished by linking the nuclides to substances with high affinity for DNA. These nuclide-carrying substances may be DNA-intercalators such as phenantridinium, acridine and naphtalimide derivatives (Sjöberg et al 1997, Ghaneolhosseini et al 1997) or compounds which interact electrostatically with DNA such as spermine, spermidine, and putrecine derivatives (Sjöberg 1997).
Liposomes have for a long time been interesting as potential drug carriers. The unique structure allows transport of both fat soluble and water soluble substances. Furthermore, the endothelium of tumours is more permeable than normal endothelium and a spontaneous accumulation in tumour tissue can be achieved. To increase circulation time and increase the stability of the liposomes it is important to select a proper lipid composition in the liposome membrane. The destabilization of the liposomes can be further minimized when the surface of the liposome is provided with polymers. Several types of polymers give increased circulation time but polyethyleneglycol (PEG) has so far given the best result (Lasic and Martin 1995).
When the liposome, filled with a toxic substance, has reached the target cell the content of the liposome must be emptied. This occurs naturally by passive leakage and the permeability of the liposome membrane can also be modified by varying the composition of the lipids. The uptake by passive diffusion is not very efficient, most of the liposome content is lost already before it reaches the cell membrane. Furthermore, depending on the properties of the drug, such as fat solubility and charge, a substantial part can be trapped in the cell membrane.
A way of increasing the uptake and simultaneously avoid membrane localization, is to utilize ligands, antibodies and antibody fragments or other suitable agents, with high specificity for receptors or other target structures with endocytotoxic ability. Internalization of whole liposomes into cells has been shown in in vitro experiments where folic acid, or a Fab′ fragment directed against glycoprotein p185
HER2
was conjugated to stabilized liposomes (Kirpotin et al. 1997, Lee and Low 1994, Park et al. 1995). When the liposome has been internalized into the cell the enclosed substance can either diffuse through the liposome and endosome membranes into the cytoplasm or, in some cases, be released after lysozymal degradation of the carrier liposome. However, the problem of directing drugs to the nucleus of specific target cells still has to be solved.
SUMMARY OF THE INVENTION
The present invention solves the problem of directing drugs to the nucleus of specific target cells. By providing a new two-step targeting system for drug delivery, the invention provides for efficient delivery of different drugs to the nuclei of tumour cells. This means that the toxicity for normal organs is minimized. A further advantage is that the invention enables administration of therapeutic doses also to spread tumour cells and metastases. The purpose of the invention, is to treat or analyse both large tumour masses as well as small tumour cell clusters and single spread tumour cells.
According to the invention, large amounts of nuclides are delivered to the tumour cells and these nuclides will reach and bind to the nuclear DNA. The latter means that each radioactive decay will damage nuclear DNA and thereby the therapeutical process will be more efficient. In fact, the same amount of radioactive nuclides will impose at least ten times higher damage when the radioactivity is localised in the nuclear DNA than when localised outside the cell nucleus. The same arguments are valid when stable nuclides for neutron or photon activation are applied. The former characteristic of the invention, i.e. the delivery of large amounts of nuclides to the tumour cells, may for radioactive nuclides mean the difference between palliative and curative treatment. If conventional targeting processes with one step targeting are applied only palliative treatments appear possible.
Thus, in a first aspect the invention relates to a drug delivery system with two-step targeting, which comprises a combination of:
a) a lipid carrier provided with cell targeting agent(s) to target the drug delivery system to specific cells or tissue; and
b) drug(s) enclosed in said lipid carrier and provided with a DNA targeting agent to target the drug to the nuclei of specific target cells.
The ratio between a) and b) may vary between 1 to 10
−8
, depending on the selected drug. The possibility of enclosing a high number of drugs in a lipid carrier means that the therapeutical efficiency will increase dramatically compared to known tumour drugs.
Preferably, the drugs are nuclides which either can be radioactive or stable or other DNA damaging substances, such as PNA and DNA alkylating agents. The drugs can be used either for therapeutic or diagnostic purposes. For nuclides, the above ratio between a) and b) is preferably in the lower range. For other DNA damaging substances, a smaller drug amount will suffice.
The lipid carrier can be any lipid aggregate with ability to enclose a drug and the preferred lipid carrier is a liposome, but a cubosome, hexasome or micelle may be equally or more potent for certain applications.
The cell targeting agent associated with the liposomal surface is selected from the group consisting of natural or synthetic ligands, antibodies, antibody fragments or other biomolecules suitable for the purpose.
According to the invention, different types of toxic loads, such as nuclides, can be used. Nuclides such as
125
I (Auger radiation) and
211
At (&agr;-particles) provide high local ionization density and damage DNA very efficiently. These short range radiators require a targeting part which enables internalizing of the liposomes.
Among stable nuclides, boron (
10
B) and gadolinium (
157
Gd) are preferred types of cancer agents. After administration of the liposomes, the tumour area is, in this case, irrradiated by neutrons. Hereby, not stable
11
B is formed from
10
B and it rapidly disintegrates and gives particle radiation in the form of He (&agr; particles) and Li nuclei, which effectively will kill the targeted cell (Carlsson et al. 1994). Other
Carlsson Jörgen
Edwards Katarina
Sjöberg Stefan
Dinsmore & Shohl LLP
Whisenant Ethan
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