Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Molecular bilayer structure
Reexamination Certificate
1995-06-07
2001-08-14
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Molecular bilayer structure
C424S450000
Reexamination Certificate
active
06274115
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method of targeting specific locations as, for example, tumors, in a body, by use of micellular particles such as phospholipid vesicles. The invention may be used for diagnosis and/or treatment of such abnormalities.
DESCRIPTION OF PRIOR ART
Before various abnormalities in a patient's body can be diagnosed and treated, it is often necessary to locate the abnormalities. This is particularly true of abnormalities such as malignant tumors since the treatment of such tumors is often on a localized basis. For example, the location of cancer cells has to be identified so that a therapeutic agent can be directed to such cells to eliminate the tumor.
Various attempts have been made over an extended number of years to identify specific locations, such as tumors, in a patient's body by simple techniques. For example, it would be desirable to identify the location of cancer cells by a simple method involving the introduction of a particular chemical to the patient's body and the movement of such chemical to such specific locations. It would also be desirable to treat the cancer by introducing modified chemicals into the patient's body and having such chemicals move to specific locations to combat the cancer cells at such locations. In spite of such attempts, however, simple delivery systems for targeting specific locations, such as tumors, for treatment or diagnosis do not exist as yet.
Placing a chemotherapeutic drug in the body orally, subcutaneously or intravenously can result in harm to the normal cells in the body which take up the drug and a worsening in the patient's condition, without achieving the desired reduction in tumor cell activity. In the past, this toxicity to normal cells in the patient's body has been a major disadvantage in the treatment of tumors with chemotherapeutic agents. The lack of efficacy of such chemotherapy is also attributable to the failure of the freely circulating drug to localize within tumor cells before it is excreted or taken up by other cells in the body.
Prior attempts to improve treatment of tumors by chemotherapeutic agents have included encapsulation of such agents within biodegradable phospholipid micellular particles in the form of vesicles or liposomes. Encapsulation is thought to reduce the potential toxicity from the circulating drugs. Researchers have also sought to utilize such encapsulation to selectively target tumors within a body for delivery of chemotherapeutics. However, until the invention disclosed in the present application and the related application Ser. No. 363,593, efforts to locate or treat tumor cells with drug-encapsulating targeting particles have not been successful.
The inability to provide a satisfactory targeting method is believed to be due to the nature of the solid tumors and their metastases which are located in extravascular tissues. Thus, to accomplish targeting of intravenously injected radiolabelled or chemotherapeutic agents to the tumor cells, the agents must leave the normal circulation by crossing the blood vessel membranes to enter the extravascular tissues. This movement is known as “extravasation”. In addition the encapsulated agent must cross the tumor cell membrane. Normally, small substances such as small molecular weight proteins and membrane-soluble molecules can cross cell membranes by a process known as passive diffusion. However, passive diffusion will not allow sufficient accumulation of larger particles carrying drugs within cells to reach therapeutic levels. Additionally, cells can actively transport materials across the membrane by a process such as pinocytosis wherein extracellular particles are engulfed by the membrane and released inside the cell. Entry of encapsulating particles into individual cells may occur by pinocytosis.
Progress in targeting such specific locations with chemotherapeutic drugs has been hampered by the inability to accomplish and detect movement of drug carriers across blood vessel membranes. In the usual case, large structures such as drug encapsulating vesicles cannot escape from blood vessels such as capillaries, and thus remain in circulation.
An understanding of extravasation, however, requires an examination of the structure of the vascular morphology of a tumor. Various blood vessels are associated with tumors, in particular capillaries. It is now known that tumor capillaries may exhibit alterations in their structure, such as fenestrations, as a result of tumor cell growth patterns. H. I. Peterson,
Vascular and Extravascular Spaces in Tumors: Tumor Vascular Permeability,
Chapter III, Tumor Blood Circulation, H. I. Peterson, Ed. (1979). Studies of tumor capillary permeability reveal morphologic variations in the capillaries which allow some substances to cross the capillary membrane. Such variations include defects in vascular endothelium from poor cell differentiation, or breaks in vascular walls as a result of invading tumor cells. H. I. Peterson, supra.
Notwithstanding such knowledge of tumor vascular morphology, researchers such as Peterson have concluded that transport of large molecules or materials across the tumor capillary wall occurs as a result of passive diffusion and that “concentrations of active drugs sufficient for therapeutic effect are difficult to reach.” H. I. Peterson, supra, at 83.
Prior to such morphologic studies, early reports suggested that vesicles might undergo transcapillary passage across the capillary membranes into tumor cells. G. Gregoriadis,
Liposomes in Biological Systems,
Gregoriadis, Ed., Ch 2, (1980). However, available data indicated that the vesicles were unstable in vivo and that the radiolabel may have leaked, thus apparently prompting alternative theories such as longer circulation of vesicles in the blood with release of drugs at a slower rate and interaction of the liposomes with the capillary walls without crossing the wall surface, which presumably resulted in the drugs within tumors. Id. Other researchers simply have concluded that the vesicles do not penetrate vascular walls after intravenous administration. B. Ryman et al.,
Biol. Cell,
Vol 47, pp. 71-80 (1983); G. Poste,
Biol. Cell,
Vol. 47, pp. 19-38 (1983).
Thus, although the prior art has recognized that vesicles carrying therapeutic drugs must cross vascular barriers to reach tumor cells, the experience of the art has taught that intravenous administration is not effective to deliver encapsulated drugs to extravascular tumor cells. This invention accordingly provides simple methods of enhancing extravasation of encapsulated chemotherapeutic agents to tumor cells within a body. The method of this invention further provides for the identification of such tumor sites in the body.
SUMMARY OF THE INVENTION
The method of this invention includes the provision of phospholipid micellular particles such as vesicles. Pure (more than approximately 98% pure), neutral phospholipid molecules are incorporated into small (less than 2000A°) micelles so that they are a component of the external surface. The phospholipid molecules and/or vesicle contents may be radiolabeled to enhance the identity of the specific location and the diagnosis of the tumor at the specific location.
The phospholipid molecules may constitute distearoyl phosphatidylcholine. The stability of the distearoyl phosphatidylcholine micelles may be enhanced by the incorporation of cholesterol. Positively charged molecules such as stearylamine or aminomannose or aminomannitol derivatives of cholesterol or negatively charged molecules such as dicetyl phosphate may also be incorporated into the vesicles.
When phospholipid micelles are introduced into the blood stream of a patient, the micelles move to the specific locations of cancerous growth in the patient's body, which may then be identified and treated. Drugs may be included in phospholipid vesicles and such drug-bearing vesicles may then be introduced into the patient's body for targeting the tumor locations.
To enhance movement of the phospholipid vesicles
Presant Cary A.
Proffitt Richard T.
Teplitz Raymond L.
Tin George W.
Williams Lawrence E.
Bosse Mark L.
Gilead Sciences, Inc.
Hartley Michael G.
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