Metal-glycoprotein complexes and photodynamic therapy of immune privileged sites with same
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Publication Number
US-10111936-B2
Publication Date
2018-10-30
Expiration Date
Abstract
Compositions of the invention include glycoproteins, such as transferrin, and metal-based coordination complexes, which are preferably chemotherapeutic compounds and more preferably tunable photodynamic compounds. The compositions are useful as in vivo diagnostic agents, and as therapeutic agents for treating or preventing diseases including those that involve hyperproliferating cells in their etiology, such as cancer. Compositions of the invention are further capable of destroying microbial cells, such as bacteria, fungi, and protozoa, and destroying viruses. Treatment methods of the invention can treat conditions throughout the body, including conditions located across the blood-brain barrier, the retina-blood barrier and the blood-cerebrospinal fluid barrier.
Core Innovation
The invention provides a method for treating a condition associated with hyperproliferating cells by administering to a subject a metal-binding glycoprotein together with a chemotherapeutic compound containing at least one transition metal. The metal-binding glycoprotein and the transition-metal-containing chemotherapeutic compound are administered in a combined amount effective to treat the condition, and in certain embodiments the metal-binding glycoprotein is transferrin or recombinant human transferrin (OPTIFERRIN).
The chemotherapeutic compound is defined by formula (I), including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, with M selected from osmium, manganese, molybdenum, rhenium, ruthenium, iron, cobalt, rhodium, iridium, nickel, platinum, and copper, and X selected from Cl−, PF6−, Br−, BF4−, ClO4−, CF3SO3−, and SO4^2−. The compound further includes defined integer values and ligand and substituent parameters, including bidentate ligands Lig1, Lig2, and Lig3 and substituent variables R1 through R8.
The combination is described as being used in photodynamic therapy, optionally with light irradiation and/or activation with ionizing radiation. The disclosed treatment is also described in contexts involving immune-privileged sites, including crossing the blood-brain barrier, retina-blood barrier, and blood-cerebrospinal fluid barrier, and accumulating at the immune-privileged site.
Claims Coverage
The partial content provides one independent claim. It centers on combined administration of a metal-binding glycoprotein with a transition-metal-containing chemotherapeutic compound in a combined effective amount, with the chemotherapeutic compound defined by formula (I) and specified transition-metal, counterion, ligand, and substituent ranges.
Combined administration of metal-binding glycoprotein and transition-metal chemotherapeutic compound for hyperproliferating-cell conditions
Administering to a subject a metal-binding glycoprotein and a chemotherapeutic compound containing at least one transition metal, wherein the metal-binding glycoprotein and the chemotherapeutic compound are administered in a combined amount effective to treat a condition associated with hyperproliferating cells.
Transition-metal chemotherapeutic compound defined by formula (I) with selected transition metals and counterions
The chemotherapeutic compound has formula (I), including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, where M is selected from osmium, manganese, molybdenum, rhenium, ruthenium, iron, cobalt, rhodium, iridium, nickel, platinum, and copper, and X is selected from Cl−, PF6−, Br−, BF4−, ClO4−, CF3SO3−, and SO4^2−.
Ligand and substituent variable framework for formula (I) compounds
The formula (I) compound further includes defined values and ranges for n, q, y, and z, bidentate ligands Lig1, Lig2, and Lig3, and substituent variables R1 through R8 with the listed selectable groups and ring-related constraints.
Across the independent claim, the inventive coverage is directed to treating hyperproliferating-cell associated conditions using a combined administration of a metal-binding glycoprotein with a transition-metal chemotherapeutic compound, where the compound is characterized by formula (I) and defined transition-metal, counterion, ligand, and substituent parameters.
Stated Advantages
Improved cancer-cell and tumor uptake.
Enhanced uptake and/or increased absorption of the chemotherapeutic compound in cancer/tumor contexts relative to treatment without the metal-binding glycoprotein.
Improved photodynamic therapy efficacy at wavelengths greater than 600 nm and wavelengths less than or equal to 600 nm.
Increased reactive oxygen species generation.
Increased reactive oxygen species (ROS) production and improved photodynamic therapy effect, including under hypoxic conditions and non-hypoxic conditions.
Higher LD50 and MTD.
Improved photostability and shelf-life.
Documented Applications
Treating a condition associated with hyperproliferating cells using the combined administration of a metal-binding glycoprotein and a transition-metal-containing chemotherapeutic compound.
Photodynamic therapy (PDT) for treating a condition associated with hyperproliferating cells, including use with light irradiation and/or activation with ionizing radiation as described.
Treating at immune-privileged sites with administration as a complex that crosses the blood-brain barrier, the retina-blood barrier, and/or the blood-cerebrospinal fluid barrier to accumulate at the immune-privileged site.
Treatment directed to an immune privileged site, including described complex crossing of the blood-brain barrier, retina-blood barrier, and/or blood-cerebrospinal fluid barrier to accumulate at the immune privileged site.
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