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Title: METALLOCORRINOIDS AS BIOLOGICALLY COMPATIBLE CARRIERS OF PHARMACOLOGICAL AGENTS
Inventor(s): J. A. Bauer
Disclosure 315 U.S. Patent not yet issued
This invention relates to novel methods for site-specific delivery of pharmacological agents, such as nitric oxide (NO), in vivo using biologically compatible, metallocorrinoid carriers, such as a vitamin B12.
A need for site-specific delivery of pharmacological agents is well known in many fields of medicine. For example, when using chemotherapeutic agents a major concern is their toxicity to non-target cells. Thus, a site-specific carrier is needed that will deliver a chemotherapeutic agent capable of killing targeted cells without killing surrounding healthy cells.
Metallocorrinoids are corrin rings with a metal-atom center, such as Co, Fe, Ni, or Mn. A subclass of naturally occurring metallocorrinoids found in the human body is cobalamin, that is, a cobalt-centered corrin ring. Many cobalamins related to vitamin B12 compounds are a subclass of cobalamin that includes hydroxocobalamin, cyanocobalamin, nitrocobalamin, methylcobalamin, and 5'-deoxyadenocobalamin.
The pharmacological agent to be loaded to the metallocorrinoid can be any having an electron donating group capable of binding to a metal atom, including, but not limited to, free radicals and nucleophiles.
NO is a good chemotherapeutic agent because intracellular concentrations of NO have been shown to be deleterious to tumor cells. In addition, site-specific delivery of NO can be used for various treatments, including chemotherapy, post-arteriosclerosis therapy, wound healing and impotence therapy (i.e. male erectile dysfunction).
A complex of vitamin B12 and a chemotherapeutic agent, such as NO, may be effective in treating some types of cancer, especially those that rely on vitamin B12 in the cell proliferation process, by releasing toxic doses of NO inside the cell. Moreover, the present invention is particularly well-suited for pharmaceutical delivery to leukemia cells because lysosomes have a pH of about 5, and it is believed that leukemia cells use a lysosomal-cellular receptor pathway to process vitamin B12. Likewise, the present invention is particularly well-suited for other B12 pathways involving lysosomes, endosomes, or other acidic conditions.
Another anticipated application includes arteriosclerosis which is a condition where a blood vessel is at least partially blocked and blood flow is diminished. Accordingly, an implanted device having an NO donor of the present invention bound to it is more effective because the release of NO causes vasodilation, thereby providing a long term dilated state or preventing the accumulation of plaque. The NO donor of the present invention is suitable for this application for the additional reason that it has a long half-life, thereby providing long-term release.
Report published in Anti-Cancer Drugs, Vol 9, Issue 3, March 1998, plus available on the Internet at www.anticancerdrugs.com, via clicking on "Articles," then click on 1998 Vol. 09 Issue 03, scroll down to find article entitled "Synthesis, characterization and nitric oxide release profile of nitrosylcobalamin: a potential chemotherapeutic agent" Joseph A. Bauer, PP. 0239-0244