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(12) Patent Application Publication (10) Pub. No.: US 2010/0261781 A1 Gmeiner (43) Pub US 2010O261781A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0261781 A1 Gmeiner (43) Pub. Date: Oct. 14, 2010 (54) MULTIVALENT APTAMER COMPLEXES Publication Classification (51) Int. Cl. (76) Inventor: William H. Gmeiner, Yadkinville, A63L/7088 (2006.01) NC (US) C7H 2L/04 (2006.01) C7H 2L/02 (2006.01) Correspondence Address: 44% 388: } MYERS BIGELSIBLEY & SAJOVEC (52) U.S. Cl. ....................... 514/44 R; 536/23.1:435/325 POBOX37428 RALEIGH, NC 27627 (US) (57) ABSTRACT A compound of the formula A-B-C, is provided, wherein: A is (21) Appl. No.: 12/759,216 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 (22) Filed: Apr. 13, 2010 complementary nucleic acid. In some embodiments, the first nucleic acid is anaptamer. In some embodiments, the nucleic Related U.S. Application Data acid comprises an active compound, particularly cytotoxic nucleotides such as poly-FdUMP. Compositions and methods (60) Provisional application No. 61/169,058, filed on Apr. ofusing Such compounds for treating and/or detecting cancer 14, 2009. are also described. Patent Application Publication Oct. 14, 2010 Sheet 1 of 6 US 2010/0261781 A1 y er Patent Application Publication Oct. 14, 2010 Sheet 2 of 6 US 2010/0261781 A1 ZGIRI[10][H aeraenaeº„€?{0VIAISH)nun „€~~~~(TOVINSÈ Patent Applica ion Publication Oct. 14, 2010 Sheet 3 of 6 US 2010/0261781 A1 Jøtue?dyoprøuuouoIN Patent Application Publication Oct. 14, 2010 Sheet 4 of 6 US 2010/0261781 A1 FIGURES Aptamer Rotation XAAAAAAAAAAAAAAAAA TTTTTTTTTTTTTTTTTX Aptamer Rotation Aptamer 2 Aptamer 1 FIGURE 7 Right Flank Tumor Wolume WS. Day 1) - () - - as Control Flwl P 8 - Study Foll Jr., P10 . sang (so to 5F Study Patent Application Publication Oct. 14, 2010 Sheet 5 of 6 US 2010/0261781 A1 FIGURE 6 C 42-Control C 42 - C 42- Control C42 Background i i APC-A c4. 2. s e 1 Monomer 10 P-A, 942-seq 1 T - A C42–se 1 T + A Dimeric Complex w/ flexible linkers Patent Application Publication Oct. 14, 2010 Sheet 6 of 6 US 2010/0261781 A1 FIGURE 8 PC3 PC3 PC3 (ATCC) flu PSMA- pip3PSMA+ Dimeric Aptamer PC3.W. PC3-PSMA US 2010/0261781 A1 Oct. 14, 2010 MULTIVALENT APTAMER COMPLEXES 0008 A further aspect of the invention is the use of a composition as described above, and further herein, for treat RELATED APPLICATIONS ing and/or detecting cancer, or for the preparation of a medi 0001. This application claims the benefit of U.S. Provi cament for treating and/or detecting cancer. sional Patent Application Ser. No. 61/169,058, filed Apr. 14, 0009. A further aspect of the invention is a method of 2009, the disclosure of which is incorporated by reference introducing a nucleic acid of interest into a cell of interest, herein in its entirety. comprising contacting a composition as described above, and further herein, to the cell under conditions in which the GOVERNMENT SUPPORT nucleic acid of interest is internalized into the cell. In some embodiments the method is carried out in vitro; in other 0002 This invention was made with government support embodiments the method is carried out in vivo. For example, under grants from the Department of Defense and the the cell of interest may be a cancer cell in a subject afflicted National Institutes of Health. The government has certain with cancer (e.g., prostate cancer), and the contacting is car rights to this invention. ried out by administering the composition to the Subject in an amount effective to treat or detect the cancer. FIELD OF INVENTION 0003. The present invention concerns chemotherapeutic BRIEF DESCRIPTION OF THE DRAWINGS molecules and compositions thereof, and methods of use thereof for the treatment of cancer. 0010 FIG. 1. Fluorescence microscopy images of the PSMAO1 DNA aptamer binding to (A) C4-2 cells; (B) BACKGROUND OF THE INVENTION LNCaP cells; (C)PC3 cells. (D) Binding of the A10-3 RNA aptamerto C4-2 cells. Live cells were incubated in PBS with 0004 Cancer is the second-leading cause of death in the 1x10 M Rhodamine-conjugated aptamer for 2 hat room United States and is a serious public health concern. The temperature. Cells were fixed with 3.7% formaldehyde for 2 current generation of cytotoxic chemotherapeutic agents used min prior to visualization using an Olympus inverted micro for the treatment of cancer is not curative for a majority of Scope. patients. For many cancer patients, the use of chemotherapy 0011 FIG. 2. Depiction of dimeric aptamer complex for extends patient-life by only a few months and often results in mation through Watson-Crick base pair formation. PSMA01 serious side effects that reduce the quality of life. aptamers were synthesized with either a dA16 or dT16 tail 0005 Anticancer drugs that are utilized for cancer chemo and dimers were formed upon annealing the individual therapy include cytotoxic nucleoside analogs (Pratt et al., aptamer conjugates in a 1:1 ratio. Antimetabolites’ in The Anticancer Drugs, 2" ed. Oxford 0012 FIG. 3. Fluorescence microscopy images of (A) a University Press, New York. pp. 69-107 (1994)), such as monomeric aptamer conjugate of PSMA01 with a dT16 tail; analogs of the four nucleotides that are the principal compo (B) a dimeric aptamer complex consisting of 1:1 ratio of nents of DNA. Examples of cytotoxic analogs include the monomeric PSMA01 conjugates with dA16 and dT16 tails; fluoropyrimidines (FPS) such as 5FU and FdU, which are (C) the J591 mAb. All images were obtained using live C4-2 analogs of Ura and dU, the precursor for dT, the arabinosyl cells. For(A) and (B) cells were prepared as described in FIG. nucleotides AraC and AraA, which are analogs of dC and dA, 4. For (C), live cells were incubated with J591, fixed with respectively, dFdC (gemcitabine), which is an analog of dC. formalin, permeabilized with 0.5% Triton-X prior to addition and 6-mercaptopurine, which is an analog of dI, the precursor of secondary antibody (goat anti-mouse) and post-fixed with of dG. formalin prior to visualization. Yellow arrows point to inter nalized signal. SUMMARY OF THE INVENTION 0013 FIG. 4. Split x-y images using confocal microscopy 0006. A first aspect of the invention is a compound of the to detect two fluorescent dyes (Quasar 670 and Quasar 570). formula A-B-C, wherein: A is a first nucleic acid that specifi The PSMAO1 aptamer with the dA16 tail was labeled with cally binds to an extracellular Surface protein expressed by a Quasar 670 while the PSMA01 aptamer with the dT16 tail cell of interest, B is an alkyl linker; and C is a second nucleic was labeled with Quasar 570. The unconjugated PSMA01 acid that hybridizes to a complementary nucleic acid. In some aptamer was also labeled with Quasar 570. In each panel of embodiments, the first nucleic acid is an aptamer. In some four images is shown: (A) Quasar 670 image; (B) Quasar 570 embodiments, the first nucleic acid is from 30 to 150 nucle image; (C) overlay of (A) and (B); (D) Nomarski image. otides in length. In some embodiments, the alkyl linker com (Left) The PSMA01 monomeric aptamer is shown in the prises C2-C6 loweralkyl. In some embodiments, the second leftmost panel; (Center) Dimericaptamer complex consisting nucleic acid is from 8 to 100 nucleotides in length. In some of a 1:1 stoichiometry of PSMA01 aptamers with dA16 and embodiments, the cell of interest is a cancer cell, microbial dT16 tails; (Right) Dimeric Aptamer Complexes that also cell, or parasite cell. In some embodiments, the nucleic acid contain a flexible linker (see FIG. 5). The dimeric aptamer comprises an active compound, particularly cytotoxic nucle complex has greater internalized signal relative to the mono otides such as poly-FdUMP. meric aptamer. Inclusion of the alkyl spacer results in 0007. A second aspect of the present invention is a com enhanced cellular internalization relative to dimeric com position comprising a pair of compounds as described above plexes that do not have alkyl spacer (see FIG.9). Arrows point and further herein, each member of the pair having a second to internalized aptamer. nucleic acid that is complementary to and hybridized to the 0014 FIG. 5. Inclusion of flexible alkyl spacers (denoted second nucleic acid of the other member of the pair. The by “X”) in dimeric aptamer complexes. The flexible linkers composition may be provided in a pharmaceutically accept allow eachaptamer to rotate relative to the linker construct to able carrier. obtain maximal binding affinity. US 2010/0261781 A1 Oct. 14, 2010 0015 FIG. 6. Flow cytometry evaluation of the binding of 0020. The disclosures of all Patent references cited herein fluorescently labeled aptamers and dimeric aptamer com are incorporated herein by reference in their entirety. plexes with and without flexible linkers to C4-2 cells. Aptamer labeling with Quasar 570 and Quasar 670 was done 1. DEFINITIONS as described in FIG. 8. The mean fluorescence intensity for 0021 Aptamer(s) or “aptamer sequence(s) as used the monomeric aptamer is right-shifted relative to back herein are meant to refer to single stranded nucleic acids ground. Monitoring of Quasar 670 fluorescence clearly (RNA or DNA) whose distinct nucleotide sequence deter shows the dimeric complex shifted relative to background. mines the folding of the molecule into a unique three dimen Introduction of flexible linkers further increases the mean sional structure. Aptamers comprising 15 to 120 nucleotides fluorescence intensity. The results are consistent with dimeric can be selected in vitro from a randomized pool of oligonucle aptamer complexes having enhanced cellular binding relative otides (10.sup.
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