Agmatine or aminoguanidine and dextran hydroxypolymer, Tc-99m radionuclide, Farmorubicine anticancer drug, Tamoxifen; intravesically, regiolocally, peritoneally, intratumorally, systemically or intravenously administrable
Inventors
Holmberg, Anders • Meurling, Lennart
Assignees
Publication Number
US-8106185-B2
Publication Date
2012-01-31
Expiration Date
2028-03-06
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Abstract
The present invention is related to a modified hydroxypolymer conjugates preferably a guanidine-dextran conjugate having a tumor cell killing activity. The modified hydroxypolymer conjugate is used as medicine, particularly for manufacturing a medicine or tumor killing composition for treating tumors. A method for producing said hydroxypolymer conjugate and a method for killing cancer cells and treating tumors is also disclosed. The invention is also related to a method for killing tumor cells and treating tumors by administering an effective amount of the modified hydroxypolymer conjugate.
Core Innovation
The invention relates to a modified hydroxypolymer conjugate, particularly a guanidine-dextran conjugate having a tumor cell killing effect. This conjugate comprises a hydroxypolymer, such as dextran, covalently substituted with guanidine compounds like agmatine or aminoguanidine, which have at least one free amino group. The guanidine compounds are coupled to activated hydroxyl groups of the dextran moiety, resulting in a conjugate that demonstrates high antitumor efficacy, comparable or at some dosages even higher than conventional antitumor drugs such as Adriamycin®.
The problem solved by the invention arises from the fact that guanidine compounds and dextrans individually have very low intrinsic toxicity and almost no tumor cell killing effect. The invention addresses the challenge of increasing the antitumor efficacy of these compounds while maintaining low toxicity. By covalently conjugating guanidine compounds to activated hydroxypolymers such as dextran, the resulting conjugates exhibit strong tumor cell killing activity with potentially more favorable handling and side-effect profiles compared to conventional chemotherapeutic agents.
The invention also includes methods of producing these conjugates, involving the activation of dextran via oxidative reaction with periodate and sulfuric acid, followed by purification and mixing with guanidine compounds having free amino groups to form stable covalent bonds. Furthermore, the conjugates can optionally include additional covalently coupled functional groups such as radio-nuclides, therapeutic compounds, anticancer drugs, and targeting agents. These novel medicines or tumor killing compositions can be administered locally, intravesically, regiolocally, peritoneally, intratumorally, systemically, or intravenously to treat tumors effectively.
Claims Coverage
The patent includes several independent claims covering the modified hydroxypolymer conjugate, methods of making the conjugate, and methods of using it for tumor treatment.
Modified hydroxypolymer conjugate with guanidine substitution
A hydroxypolymer dextran conjugate where 20-50% of the glucose moieties are substituted with guanidine compounds agmatine or aminoguanidine having at least one free amino group, covalently coupled to activated hydroxyl groups of dextran.
Molecular weight range of the hydroxypolymer
The hydroxypolymer has a molecular weight in the range of 10^3 to 10^6 Daltons, preferably approximately 70 kD ±25 kD.
Optional covalently coupled functional groups
The modified hydroxypolymer conjugate may further comprise covalently coupled functional groups, including radio-nuclides, therapeutic compounds, anticancer drugs, and targeting agents.
Administration routes
The conjugate is administrable locally, intravesically, regiolocally, peritoneally, intratumorally, systemically, or intravenously.
Method of production of the conjugate
The conjugate is produced by mixing a guanidine compound with an eluent containing activated dextran purified by gel filtration, where dextran activation involves oxidative reaction with periodate and sulfuric acid, stopped by ethylene glycol.
Methods for killing tumor cells and treating tumors
Administering an effective amount of the modified hydroxypolymer conjugate or the tumor killing composition comprising the conjugate to subjects with urothelial, breast, prostate, or renal tumors.
The claims collectively cover the novel modified dextran-guanidine conjugates with defined substitution and molecular weight ranges, their production methods, additional functionalization, multiple administration routes, and their therapeutic use in treating various tumor types.
Stated Advantages
The conjugates demonstrate high tumor cell killing efficacy similar or superior to established anticancer drugs like Adriamycin®.
The components of the conjugates (guanidine compounds and dextran) have very low intrinsic toxicity, suggesting more favorable handling and fewer treatment side-effects.
The medicine can be administered through various routes adapted to therapeutic needs.
Documented Applications
Use of the modified hydroxypolymer conjugate as a medicine or tumor killing composition for treating tumors.
Treatment of tumors including urothelial tumors, breast tumors, prostate tumors, and renal tumors.
Administration routes include local, intravesical, regiolocal, peritoneal, intratumoral, systemic, or intravenous delivery.
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