Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-23
2001-02-20
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S511000, C514S449000
Reexamination Certificate
active
06191290
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the biochemical pharmacology of the anti-cancer drug, paclitaxel. More specifically, the present invention relates to the design and synthesis of the first tumor-directed derivatives of paclitaxel.
2. Description of the Related Art
The diterpenoid molecule paclitaxel (taxol) (FIG.
1
), extracted in 1971 from the western yew,
Taxus brevifolia
(1) , and taxotere (docetaxel) (2) are considered to be two of the most important and promising anticancer drugs currently in clinical use for breast and ovarian cancers which also hold promise for the treatment of skin, lung and head and neck carcinomas (3, 4). Paclitaxel was approved by the FDA earlier this decade for the treatment of advanced ovarian cancer and breast cancer after showing outstanding efficacies in the chemotherapy of malignancies particularly in refractory ovarian and breast cancers. Docetaxel, a semisynthetic derivative of paclitaxel, has also shown exceptional clinical results and was approved by the FDA for the treatment of breast cancer in 1996 and is now in phase II and III clinical trials for lung cancer and ovarian cancer (3, 4).
Perhaps one of the most distinguishing properties of paclitaxel is its high activity against solid tumors compared to leukemias, when tested in animal models. The drug has also been reported to be a radiosensitizer. At the molecular level, paclitaxel exerts its antitumor activity through the stabilization of microtubule assemblies thus interrupting mitosis and the cell division process. The taxol-induced microtubules have been shown to be resistant to depolymerization. Based on this mechanism and the fact that taxol increases the fraction of cells in G
2
or M phase, Tishler et al. (5), and more recently, O'Donnell et al. (6), reported a radiosensitizing effect for taxol on G18 human astrocytoma cells and in nude mice bearing Burkitts lymphoma xenografts, respectively. Furthermore, Distefano et al. have shown apoptosis-inducing properties for Taxol (7). These observations may result in still more applications for taxanes in the form of combined modality therapy.
Despite these ideal therapeutic features, paclitaxel suffers from such significant drawbacks as aqueous insolubility and side-effects at the clinically administered doses. The present formulation of this drug contains 30 mg of Taxol in 5 mL of a 50/50 mixture of Cremophore EL (polyhydroxylated castor oil, a solubilizing surfactant) and ethanol. Cremophore EL has been reported to cause histamine release and result in severe allergic reactions and cause potential clinical problems (8, 9). Reported side effects of the drug, based on clinical trials, include neutropenia, mucositis, cardiac and neurological toxicities in addition to hypersensitivity (10-14).
Taxol is nearly slightly insoluble in water (around 0.25 &mgr;g/mL) and this has created significant problems in developing suitable pharmaceutical formulations useful for chemotherapy. Some formulations of taxol for injection or I.V. infusion have been developed utilizing CREMOPHOR EL.RTM (polyoxyethylated castor oil) as the drug carrier because of taxol's aqueous insolubility. For example, taxol supplied by the NCI has been formulated in 50% CREMOPHOR EL.RTM. and 50% dehydrated alcohol. CREMOPHOR EL.RTM., however, is itself toxic and produces, when given in a large volume single dose without taxol, vasodilation, labored breathing, lethargy, hypotension and death in dogs. Therefore, the use of this carrier would not be recommended.
In an attempt to increase taxol's solubility and to develop more safe clinical formulations, studies have been directed to synthesizing taxol analogs where 2′- and/or 7-position is derivatized with groups that would enhance water solubility. These efforts yielded protaxol compounds that are more water soluble than the parent compound and that deploy the cytotoxic properties upon activation.
It would be highly desirable, therefore, to develop a mechanism through which a soluble Taxol derivative could be delivered specifically to the site of the disease in a targeted fashion. Possible advantages of such an approach may include i) elimination of allergenic surfactants from the formulation due to increased solubility, ii) efficient delivery of the drug to micrometastatic hidden tumors, and iii) reduction of the administered dose as a result of site-specific delivery of the drug. The latter advantage should, in turn, lead to a reduction of toxicity, enhancement in efficacy, lower drug doses, and thereby safer, and more economic formulations.
Pretargeted therapy of malignancies has gained momentum during the past several years based on its well-justified rationale, the efficient delivery of the oncolytic agent to the neoplastic tissue. Receptor-based targeted treatment of cancer through the application of tumor-recognizing molecules has advanced considerably during the past several years with t h e development of monoclonal antibodies (15, 16), and later, the application of small molecule peptides capable of binding to tumor cell surface receptors (17). A number of drug, toxin, and radioisotope conjugates of tumor-recognizing molecules have been developed with some in clinical use currently. None of the designs of the large number of synthetic taxane derivatives reported so far, however, contain an element of specific tumor recognition. Despite the large body of work in this field, there are no reports of tumor-recognizing molecules of paclitaxel or any derivative of this drug.
Thus, the prior art is deficient in methods through which a soluble Taxol derivative could be delivered specifically to the site of the disease in a targeted fashion. The present invention fulfills this long-standing need and desire in the art.
SUMMARY OF THE INVENTION
The present invention demonstrates for the first time the design and synthesis of a soluble tumor-directed paclitaxel prodrug which may establish a new mode of utilization of the taxane class of anticancer agents in cancer therapy.
In one embodiment of the present invention, there is provided a pharmaceutical compound comprising a taxane moiety conjugated to a receptor ligand peptide. The taxane moiety can be a taxane derivative. Representative examples are paclitaxel (taxol), taxotere (docetaxel), and their analogs. The receptor ligand can be peptides such as bombesin/gastrin-releasing peptide (BBN/GRP) receptor-recognizing peptide (BBN[7-13]), a somatostatin receptor recognizing peptide, an epidermal growth factor receptor recognizing peptide, a monoclonal antibody or a receptor recognizing carbohydrate.
In another embodiment of the present invention, the pharmaceutical compound is water soluble and tumor directed. Specifically, such compound can readily dissolve in water at the concentration of 250 mg/ml or higher, corresponding to at least 40 mg/ml of the unconjugated paclitaxel. This is a major improvement considering the 0.25 mg/ml solubility of Taxol.
In still another embodiment of the present invention, there is provided a method of synthesizing the pharmaceutical compound described herein, comprising the steps of: conjugating covalently said receptor ligand peptide to a solubilizing linker; and ligating the peptide-conjugated linkers to said taxane moiety. Preferably, the ligation can occur at the sites selected from a taxane moiety such as 2-, 7- and 10-hydroxyl group of the taxane moiety with solubilizing linker and receptor recognizing moiety. As a result, the synthesized pharmaceutical compound has improved cytotoxicities in a concentration-dependent manner by a factor of 1.5-3 compared to corresponding unconjugated taxane moiety at an equimolar concentration.
In still yet another embodiment of the present invention, there is provided a method of treating an individual having a cancer by administering the pharmaceutical compound of the present invention to the individual. Preferably, the cancer is selected from the group consisting of breast cancer, ovarian cancer, skin carcino
Adler Benjamin Aaron
Trinh Ba K.
UAB Research Foundation
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