Metal complexes incorporated within biodegradable nanoparticles and their use

#The invention relates to metal complexes which may be used in treating cancer. In an example, the invention relates to silver metal complexes that are incorporated within biodegradable materials, such as nanoparticles, and are used in treating cancer.

#Silver has long been used for its antimicrobial properties. This usage predates the scientific or medical understanding of its mechanism. For example, the ancient Greeks and Romans used silver coins to maintain the purity of water. Today silver is still used for this same purpose by NASA on its space shuttles. Treatment of a variety of medical conditions using silver nitrate was implemented before 1800. A 1% silver nitrate solution is still widely used today after delivery in infants to prevent gonorrheal ophthalmia. Since at least the later part of the nineteenth century, silver has been applied in a variety of different forms to treat and prevent numerous types of bacteria related afflictions.

#Other treatments, such as the application of silver foil to post surgical wounds to prevent infection survived as a medical practice into the 1980's in Europe, and silver nitrate is still used as a topical antimicrobial agent. In the 1960's the very successful burn treatment silver complex, silver sulfadiazine, shown in formula 1 below, was developed. Commercially known as Silvadene® Cream 1%, this complex has remained one of the most effective treatments for preventing infection of second and third degree burns. Silver sulfadiazine has been shown to have good antimicrobial properties against a number of gram-positive and gram-negative bacteria. It is believed that the slow release of silver at the area of the superficial wound is responsible for the process of healing. Studies on surgically wounded rats have shown the effectiveness of both silver nitrate and silver sulfadiazine to aid in the healing process. By using these common silver antimicrobial agents, inflammation and granulation of wounds were reduced, although the complete mechanism for these phenomena is not understood.

#FIG. 1 shows a graph of the activity of compounds in the treatment of the ovarian cancer cell line NuTu-19;

#FIG. 2 shows a chart comparing anti-proliferative effects of formula 23, cisplatin and carboplatin on A375 melanoma;

#FIG. 3 shows a graph measuring the percent control growth of formula 23, cisplatin and carboplatin on A375 melanoma at various concentrations;

#The use of metal compounds, including metal complexes, in conjunction with biodegradable nanoparticles, such as for use in the treatment of cancer, is set forth as an example of the invention. Other delivery systems are contemplated or may be developed. In an example, the present invention comprises, but is not limited to silver(I) metal complexes as simple salts, silver(I) macrocyclic metal complexes, and silver(I) N-heterocyclic carbenes (NHCs) incorporated within biodegradable nanoparticles for the treatment of cancer.

#Nanoparticles may generally vary in size from 10 nm to 1000 nm. These sub-micron sized particles possess certain distinct advantages over microparticles. Nanoparticles, including nanospheres, unlike microspheres, can be used to directly target the tissues via systemic circulation or across the mucosal membrane. This targeting is possible as a result of the capacity of these nanoparticles to be endocytosed by individual cells. It has also been observed that nanoparticles administered intravenously are taken up by cells of mononuclear phagocyte system, mainly in the Kuppfer cells. Such nanoparticles are rapidly cleared from the blood and are usually concentrated in the liver, spleen and blood marrow.

#In case of a nanoparticle type delivery system, the therapeutic agent is dissolved, encapsulated, entrapped or chemically conjugated to the nanoparticle matrix depending on the method of fabrication of the device. Typically, the drug is physically and uniformly incorporated and dispersed within a nanosphere matrix. The drug formulated in such a polymeric device is released by diffusion through the polymeric matrix, erosion of the polymeric matrix or by a combination of diffusion and polymer erosion mechanisms. In one embodiment of the invention, biodegradable, polymeric nanoparticles including poly(glycolic acid) (PGA), poly(lactic acid) (PLA), and poly(lactic-co-glycolic acid) (PLGA) are used.