National
Cancer Institute (NCI) Contracts with Aphios to Develop
Nannotech Combination Therapy for Certain Cancers
March
31, 2009 —
Aphios Corporation
today announced that it has entered into a contract with
the National Cancer Institute (NCI) to develop Tdp-1 inhibitors
either as a primary therapy or in combination with camptothecins
for colon, breast, ovarian, leukemia and other cancers.
The contract was made through the Small Business Innovative
Research (SBIR) Phase I program.
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.
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