Surgery – Miscellaneous – Methods
Reexamination Certificate
1998-11-10
2001-10-30
Nguyen, Dinh X. (Department: 3738)
Surgery
Miscellaneous
Methods
C604S019000, C604S022000
Reexamination Certificate
active
06308714
ABSTRACT:
The present invention relates to apparatus and methods for the delivery of active agents using ultrasonic energy.
It is well known that the clinical utility of many pharmaceutics is limited by drug delivery. That is, a great number of agents showing promising biological activity are not utilized because of problems of undesirable toxicity, bioavailability, solubility, and a requirement of local sustained drug concentration among others.
The present invention is directed to administration of anti-cancer agents which improves or enhances the activity of such agents or drugs.
Cancer results from an abnormal, rapid growth of cells which divide and multiply. Such cells may become tumors that invade healthy tissue. Many anti-cancer agents have been developed which work along different biological pathways in order to reduce or eliminate cancer cell growth; however, the human pharmacokinetics may make the agents difficult to deliver.
The present invention is not directed to any drug formulation or composition but rather to apparatus and method for delivering such drugs or agents.
Modalities for the treatment of malignant growths generally include surgery, radiation therapy and chemotherapy. Surgery, while often effective for solid tumors, is in many instances difficult to perform and a total removal of cancerous cell is often not obtainable.
Accordingly, in combination with surgery, or as a separate modality of treatment, radiation therapy and chemotherapy have been utilized. Radiation therapy has a disadvantage of killing healthy tissue as well as cancerous tissues in exposed areas, and chemotherapy also may result in damage to the surrounding normal tissue. This factor is particularly important in many anti-cancer drugs, such as anthracycline antibiotics such as adriamycin and daunorubricin. The beneficial facts of these drugs relate to their nucleotide base intercalation and cell membrane lipid binding activities. This particular class of drugs has dose limiting toxicities due to myelo suppression.
Ultrasound at high energy can generate heat within tissue and accordingly has been used in hyperthermic treatment of cancerous tumors. For example, hyperthermia induces doxorubicin release from long-circulating liposomes and enhances their anti-tumor efficacy.
The present invention utilizes low energy ultrasound and local drug delivery to enhance the effectiveness of anti-cancer drugs and or treatment. Such enhancement is beneficial in reducing the effective dose of the drugs necessary for sufficient anti-cancer activity. Such reduced dose levels translate into reducing unwanted toxicity of the anti-cancer agents.
SUMMARY OF THE INVENTION
A method of anti-cancer drug delivery in accordance with the present invention generally comprises introducing an anti-cancer agent into a solid tumor within a body, and thereafter introducing ultrasonic energy into the solid tumor with sufficient energy to increase the anti-cancer activity on the solid tumor, without significant heating of the solid tumor in surrounding tissue.
This enhanced activity is not caused by overall heating of the tumor and tissue with ultrasound in view of the fact that the ultrasound energy is at relatively low frequency and low power.
The ultrasonic energy may be generated external to the body and has an energy of less than 50 watts at an operating frequency of less than about 100 Kz. The ultrasonic energy may alternatively be introduced by a catheter.
More particularly, the method in accordance with the present invention may utilize an anti-cancer drug selected from the group consisting of alkylating agents, agents with alkylator activity, antimetabolites, antitumor antibiotics, plant alkaloids, enzymes, hormonal agents and anti-angiogenesis agents.
Still more particularly, the present invention may utilize an anti-cancer agent selected from the group consisting of:
Adriamycin, Alkeran, AntiVEGF monoclonal antibody SU5416, Aredia, Arimidex, BiCNU, Bleomycin, Blenoxane, Camptosar, Casodex, CeeNU, Celestone, CM101, Soluspan Suspension, CA1, Cerubidine, Cisplatin, Cosmegen, Cytosar U, Cytoxan, Daunorubricin, DaunoXome, Depo-Provera Sterile Aqueous Suspension, Didronel, Diethylstilbestrol, Diflucan, Doxil, Doxorubicin Hydrochloride, DTIC-Dome, Elspar, Emcyt, Epogen, Ergamisol Ethyol, Etopophos, Etoposide, Eulexin, Femara, Fludara, Fluorouracil, Gemzar, Gliade, Hexalen, Hycamtin, Hydrea, Hydroxyurea, Idamycin, Iflex, Intron A, Kytril, Leucovorin Calcium, Leukeran, Leukine, Leustatin, Lupron, Lysodren, Marinol, Matulane, Mesnex, Methotrexate Sodium, Mithracin, Mitoxantrosc, Mustargen, Mutamycin, Myleran, Navelbine, Neupogen, Nilandron, Nipent, Nolvadex, Novantrone, Oncaspar, Oncovin, Paraplatin, Photofrin, Platinol, Procrit, Proleukin, Purinethol, Roferon A, Rubex, Salagen, Sandostatin, Squalamine, Sterile FUDR, Taxol, Taxotere, Teslac, Thalidomide, TheraCys BCG, Thioguanine, Thioplex, Tice BCG, TNP 470, Velban, Vesanoid, VePesid, Vitaxin, Vumon, Zanosar, Zinecard, Zofran, Zoladex, Zyloprim and 2-methoxy-oestradiol.
The method of the present invention includes introducing an anti-cancer drug proximate cancer cells and promoting intracellular activation by irradiating the cancer cells with ultrasound to cause passage of the anti-cancer drug into the cancer cells.
More particularly, the anti-cancer drug may be an anti-angiogenesis agent.
The apparatus in accordance with the present invention for conducting the method generally includes a means for introducing an anti-cancer agent into a solid tumor within the body and ultrasonic means for radiating solid tumors with sufficient energy to increase the anti-cancer activity of the agent on the solid tumor without significant heating of the solid tumor, or surrounding tissue, by the radiated ultrasound. As part of the present invention, the means for introducing the anti-cancer agent may include microbubbles. In this embodiment, one or more of the hereinabove referenced active agents is incorporated into microbubbles introduced into a tumor. In conforming to the preferred method of the present invention, the preferred apparatus includes an ultrasonic generator for radiating the solid tumor, which is disposed outside of the body.
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Peterson Thomas M.
Siegel Robert J.
Coraje, Inc.
Hackler Walter A.
Nguyen Dinh X.
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