The contract is to develop a combination therapeutic based on research conducted by scientists at the National Cancer Institute who have discovered that the enzyme Tyrosyl-DNA phosphodiesterase (Tdp1) can repair topoisomerase I (Top1)-DNA covalent complexes by hydrolyzing the tyrosyl-DNA bond [US Patent Pending]. Inhibiting Tdp1 has the potential to enhance the anticancer activity of topoisomerase I inhibitors such as camptothecins and to act as anti-proliferative agents.
Dr. Yves Pommier, lead scientist of this invention at the NCI states that "The development of Tdp1 inhibitors as anticancer agents can be envisioned as combinations of Tdp1 and Top1 inhibitors. Moreover, Tdp1 inhibitors might also be effective by themselves as anticancer agents."
Scientists at Aphios are developing a co-encapsulation formulation of the selected camptothecin and Tdp1 inhibitor in phospholipid nanosomes (small, uniform liposomes). Camptothecins are quite hydrophobic and will be packaged in the lipid bilayer. Tdp1 inhibitors such as tetracycline and neomycin are quite water-soluble and will be packaged in the aqueous core of phospholipid nanosomes [US Patents and US Patent Pending].
We anticipate that this nanosomal formulation will result in reduced systemic toxicity, due to the masking of the cytotoxic effects of camptothecins and Tdp1 inhibitors. Additionally, the stability of the lactone ring in the nanosomes will be improved as a result of protection from the neutral pH of the blood stream. By increasing residence time in the circulatory system, the nanosomes increase therapeutic efficacy of the combination drugs. Optionally, pegylated phospholipids will be utilized to provide steric hindrance that will further increase residence time and therapeutic efficacy as is done with Doxil®, liposome encapsulated doxorubicin. Furthermore, phospholipids linked with specific antibodies or ligands will be utilized to target the co-encapsulated camptothecin and Tdp1 inhibitor to specific cancers in the colon, lung or ovary. Such smart targeting will further reduce toxicities associated with both Top1 and Tdp1 inhibitors while increasing efficacy and therapeutic index.
Aphios Corporation is a biotechnology company that is developing enabling technology platforms including nanotechnology drug delivery platforms such as phospholipid nanosomes, biodegradable polymer nanospheres, and protein and crystal nanoparticles for the improved delivery of poorly water-soluble anticancer drugs, therapeutic proteins and siRNA molecules, as well as enhanced therapeutic products for health maintenance, disease prevention and the treatment of certain cancers, infectious diseases and CNS disorders.
The project described herein is supported by NCI Contract No. HHSN-261200800026C (NCI Control No. N43CM-2008-00026). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI and the National Institutes of Health.