Wake Forest University

University of Pittsburgh

The United States Government As Represented by the Department of Veterans Affairs

William H Gmeiner

John C Schmitz, Sr

Edward Chu

Timothy S Pardee

Novel cytotoxic fluoropyrimidine polymers for treating cancer (e.g., colorectal cancer (CRC)) in a subject (e.g., a subject having cancer) are nucleic acid molecules including 5-fluoro-2'deoxyuridine monophosphate (FdUMP)[10] having a polyethylene glycol (PEG) spacer appended to the 5′ terminus and a cytarabine (AraC) nucleotide appended to 3′termius. These novel cytotoxic fluoropyrimidine polymers may be used in compositions, kits and methods for treating advanced and high-risk cancers, including CRC.

Cytotoxic fluoropyrimidine polymers and methods of use thereof

Provided herein are aptamers and pharmaceutical compositions comprising the same. In some embodiments, the aptamer selectively binds a protein of interest such as an extracellular receptor protein of interest (e.g., a cancer cell extracellular receptor protein, which may be differentially expressed in some embodiments). In some embodiments, the aptamer is directly linked by covalent bonding (e.g., via a geminal diamine linkage) to from 2 to 10 toxin compounds. Also provided herein is a method of selecting an aptamer that specifically binds to a protein expressed by a cell of interest, wherein in some embodiments the aptamer comprises at least one binding site for one or more active compounds. In some embodiments, primer regions flanking the variable region of the aptamers in the pool contains from 1 to 10 mismatches with respect to said forward or reverse primer.

Pharmaceutical compositions for high-capacity targeted delivery

A compound of the formula A-B-C, is provided, wherein: A is a first nucleic acid that specifically binds to an extracellular surface protein expressed by a cell of interest, B is an alkyl linker; and C is a second nucleic acid that hybridizes to a complementary nucleic acid. In some embodiments, the first nucleic acid is an aptamer. In some embodiments, the nucleic acid comprises an active compound, particularly cytotoxic nucleotides such as poly-FdUMP. Compositions and methods of using such compounds for treating and/or detecting cancer are also described.

Multivalent aptamer complexes

A synthesized siRNA molecule having the sense strand with one or more uridine bases replaced by one or more respective nucleoside analogs, such as 5-fluoro-2'-deoxyuridine (FdU).

Modified siRNA molecules incorporating 5-fluoro-2'-deoxyuridine residues to enhance cytotoxicity

The present invention relates to active compounds for treating acute myelogenous leukemia (AML) in a subject in need thereof and methods of treating AML carried out by administering the subject an active compound in an amount effective to treat the leukemia. The active compound comprises a 10-mer oligonucleotide covalently linked via 3' to 5&#x2032; phosphodiester linkages of 5-fluorodeoxyuridine, FdUMP[10], or a pharmaceutically acceptable salt thereof.

Method of treating acute myelogenous leukemia

The present invention provides a method of generating a nucleic acid, which specifically binds to an extracellular surface protein expressed by a cell of interest, and which nucleic acid comprises a compound of interest to be delivered to the cell of interest.

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Yadkinville, NC, United States of America

William H Gmeiner