Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
2000-02-03
2001-10-09
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001110, C424S001650, C424S009100
Reexamination Certificate
active
06299856
ABSTRACT:
BACKGROUND OF THE INVENTION
In general, the invention relates to the use of collagen-based systems for delivery of anti-cancer agents and therapies.
Despite many advances in treatments, cancer still remains a major cause of death in aging Americans. For example, prostate cancer remains the second most common cause of cancer-related death among males. In 1995, over 240,000 men were diagnosed with prostate cancer in the United States, and more than 40,000 men lost their lives to this disease. Despite these statistics, the ideal treatment for this disease remains controversial. Common treatment recommendations include surgery, external-beam radiation, and brachytherapy.
Surgery is ideally a one-time procedure that may cure prostate cancer in its early stages and extend life in the later stages. However, surgery requires hospitalization, can produce side effects, including impotence and incontinence, and is expensive and can strain limited health care resources.
Alternatively, radiation therapy uses high-energy rays to kill cancer cells. Radiation therapy can be used to treat prostate cancer that has not spread to distant areas of the body. Like surgery, radiation therapy works best when the cancer is located in a small area and, in early stages of prostate cancer, can be very effective. However, since the rays cannot always be directed perfectly, radiation therapy can damage both cancer cells and healthy surrounding tissue.
A third treatment method for prostate cancer is brachytherapy, which is a form of radiation therapy in which radioactive sources are implanted directly into a malignant tumor. This approach offers the appealing concept of delivering a high dose of radiation to a confined volume while sparing adjacent normal tissue.
SUMMARY OF THE INVENTION
The present invention provides a method for treating a malignancy in an animal by introducing, at or near the site of the malignancy, collagen covalently linked to a radioactive isotope or stable element subsequently activated to become radioactive, in an amount sufficient to inhibit or reverse the malignancy.
In preferred embodiments, the malignancy to be treated is a lymphoma, sarcoma, adenoma, glioma, astrocytoma, neuroma, Schwannoma, epithelioma, or, preferably, a malignancy of the prostate or brain. In addition, the invention is suited for treating a malignancy in a mammal, preferably, a human.
In other preferred embodiments, the covalent linking of the collagen to the radioactive isotope is carried out by derivatizing free amine groups (for example, deprotonated free amine groups) of the collagen with the radioactive isotope, or stable element subsequently activated to become radioactive, preferably, at or above a pH of 9.0. Radioactive isotopes which may be used in the invention include
103
Pd,
169
Yb,
198
Au,
192
Ir,
10
B, or, most preferably,
125
I. In another embodiment, the covalent linking of the collagen to a radioactive isotope is performed by derivatizing carboxylic acid side chains with a radioactive isotope, preferably, by using a carbodiimide coupling agent.
The collagen may be in any form, including soluble, gelatinous, as a fibrillar matrix, powder, or bead, and can have a bioresorption rate that is different from naturally-occurring collagen, for example, a rate that is faster or slower (i.e., able to resist bioresorption). Preferably, the collagen has a bioresorption rate that is similar to the decay rate of the covalently-linked radioactive isotope.
The collagen may be used to deliver radioactivity of any appropriate dose, but preferably is used to deliver a covalently-linked isotope at a dose of 0.1 mCi or greater. The isotope may be a stable element subsequently activated to become radioactive using a neutron source. One preferred method of collagen delivery is by injection, for example, to a site at or near the malignancy. One particularly preferred method of delivery is by geodosimetric injection into the tumor.
In a related aspect, the invention also provides radioactive compositions useful for treating a malignancy in an animal. The compositions include collagen covalently linked to a radioactive isotope or stable element subsequently made radioactive, and preferred isotopes include
103
Pd,
169
Yb,
198
Au,
192
Ir,
10
B, and, most preferably,
125
I. The collagen may be, for example, soluble, gelatinous, a fibrillar matrix, powder, or bead and preferably has a faster or slower bioresorption rate than naturally-occurring collagen (for example, a bioresorption rate similar to the decay rate of the covalently-linked radioactive isotope). In other preferred embodiments, the collagen delivers a radioactive dose of 0.1 mCi or greater and is, preferably, designed as a gelling solution that polymerizes upon introduction into a mammal, for example, a human.
As used herein, by “malignancy” is meant an abnormal growth of any cell type or tissue. The term malignancy includes cell growths that are technically benign but which carry the risk of becoming malignant. This term also includes any cancer, carcinoma, neoplasm, neoplasia, or tumor.
By “at or near the site” is meant introducing the collagen implant of the invention to become as physically close to the malignancy as appropriate. This term shall include direct injection into a malignancy particularly, for example, if the malignancy is a solid tumor or encapsulated malignancy.
By “activating” is meant the exposing of a stable element to a radiation source (e.g., neutron source) such that the element is made radioactive.
By “derivatizing” is meant the conversion of a protein (e.g., collagen) into a derivative form of the protein having at least one free amine group or at least one other available reactive group (e.g., carboxylic or sulfhydryl group), covalently linked to a radioactive moiety.
By “radioactive isotope” is meant a chemical element that has the property of spontaneously emitting energetic particles or rays such as alpha particles, beta particles, or gamma rays.
By “solution” is meant any liquid mixture or suspension.
By “gelling solution” is meant any liquid mixture or suspension that has the ability to become a semi-solid gel either ex vivo or in vivo under appropriate conditions.
By “fiber” is meant any semi-solid or solid form of a material that includes fibrils.
By “covalently linked to a collagen” is meant that the radioactive isotope is joined to the collagen either directly through a covalent bond or indirectly through another covalently bonded moiety.
The present invention provides a number of advantages. For example, the methods described herein facilitate treatment of a human patient with a permanent bioresorbable implant for a malignancy that may be difficult to completely or effectively treat by surgery, external beam radiation, chemotherapy, or other means. In addition, these methods may be used in lieu of, or as an adjunct to, more conventional procedures to insure success in inhibiting or reversing malignancies. Because collagen can be bioresorbed, the invention also provides an ideal delivery matrix for chemotherapeutic radioactive isotopes. This feature of the invention allows the radioactive dose to be introduced close to, or within, a malignancy (or the site of a malignancy which has been removed by surgery) which may otherwise be difficult to treat. In addition, radiologic collagen implants can be introduced into a patient permanently and in a minimally invasive way using a hypodermic needle or trocar, thereby eliminating the need for more invasive surgery.
In yet another advantage, according to certain embodiments of the invention, health care workers can introduce a “cold” or non-radioactive implant into a patient and then, post-operatively (and behind protective shielding not possible during a surgical procedure), activate the radioactivity of the patient's collagen implant using an external neutron source. This approach minimizes the radioactive dose to the health care practitioner, providing an important safety advantage.
Other features and advantages of the invention will be apparent from the followin
DeVore Dale P.
Magerman Joel D.
Clark & Elbing LLP
Collagenesis Inc.
Jones Dameron L.
LandOfFree
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