Rna aptamers for therapeutic and diagnostic delivery to pancreatic cancer cells

Abstract

In some embodiments, aptamers that specifically bind pancreatic cancer cells are provided. Such aptamers may include an RNA molecule that specifically binds a pancreatic cancer cell surface protein. In certain embodiments, the RNA molecule that is used as an aptamer may include a nucleotide sequence of GAAUGCCC (SEQ ID NO: 8). In other embodiments, the RNA molecule may include a nucleotide sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6. In certain embodiments, the aptamer may be conjugated to one or more therapeutic agents (e.g., an shRNA molecule, an siRNA molecule, an mRNA molecule, or an miRNA molecule), one or more diagnostic agents, or a combination thereof. The aptamers and their conjugates may be used to deliver therapeutic agents to a pancreatic cancer cell, and/or in methods for treating or diagnosing pancreatic cancer.

What is claimed is: 
     
         1 . An aptamer comprising an RNA molecule, wherein the RNA molecule comprises a nucleotide sequence of GAAUGCCC (SEQ ID NO: 8). 
     
     
         2 . The aptamer of  claim 1 , wherein the aptamer comprises one or more modified nucleosides. 
     
     
         3 . The aptamer of  claim 1 , wherein the aptamer comprises one or more 2-fluoropyrimidine nucleosides. 
     
     
         4 . The aptamer of  claim 1 , wherein the aptamer has a length of 87 nucleotides or less. 
     
     
         5 . The aptamer of  claim 1 , wherein the aptamer has a length of 40 nucleotides or less. 
     
     
         6 . The aptamer of  claim 1 , wherein the aptamer is conjugated to one or more therapeutic agents. 
     
     
         7 . The aptamer of  claim 1 , wherein the aptamer is conjugated to an agent selected from the group consisting of an shRNA molecule, siRNA molecule, mRNA molecule or an miRNA molecule. 
     
     
         8 . The aptamer of  claim 1 , wherein the aptamer is conjugated to a chemotherapeutic agent selected from the group consisting of 13-cis-Retinoic Acid, 2-Chlorodeoxyadenosine, 5-Azacitidine, 5-Fluorouracil, 6-Mercaptopurine, 6-Thioguanine, actinomycin-D, adriamycin, aldesleukin, alemtuzumab, alitretinoin, all-transretinoic acid, alpha interferon, altretamine, amethopterin, am ifostine, anagrelide, anastrozole, arabinosylcytosine, arsenic trioxide, amsacrine, am inocamptothecin, aminoglutethimide, asparaginase, azacytidine, bacillus calmette-guerin (BCG), bendamustine, bevacizumab, bexarotene, bicalutamide, bortezomib, bleomycin, busulfan, calcium leucovorin, citrovorum factor, capecitabine, canertinib, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, cortisone, cyclophosphamide, cytarabine, darbepoetin alfa, dasatinib, daunomycin, decitabine, denileukin diftitox, dexamethasone, dexasone, dexrazoxane, dactinomycin, daunorubicin, decarbazine, docetaxel, doxorubicin, doxifluridine, eniluracil, epirubicin, epoetin alfa, erlotinib, everolimus, exemestane, estramustine, etoposide, filgrastim, fluoxymesterone, fulvestrant, flavopiridol, floxuridine, fludarabine, fluorouracil, flutamide, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, hexamethylmelamine, hydrocortisone hydroxyurea, ibritumomab, interferon alpha, interleukin-2, interleukin-11, isotretinoin, ixabepilone, idarubicin, imatinib mesylate, ifosfamide, irinotecan, lapatinib, lenalidomide, letrozole, leucovorin, leuprolide, liposomal Ara-C, lomustine, mechlorethamine, megestrol, melphalan, mercaptopurine, mesna, methotrexate, methylprednisolone, mitomycin C, mitotane, mitoxantrone, nelarabine, nilutamide, octreotide, oprelvekin, oxaliplatin, paclitaxel, pamidronate, pemetrexed, panitumumab, PEG Interferon, pegaspargase, pegfilgrastim, PEG-L-asparag inase, pentostatin, plicamycin, prednisolone, prednisone, procarbazine, raloxifene, rituximab, romiplostim, ralitrexed, sapacitabine, sargramostim, satraplatin, sorafenib, sunitinib, semustine, streptozocin, tamoxifen, tegafur, tegafur-uracil, temsirolimus, temozolamide, teniposide, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, trimitrexate, alrubicin, vincristine, vinblastine, vindestine, vinorelbine, vorinostat, and zoledronic acid. 
     
     
         9 . The aptamer of  claim 1 , wherein the aptamer is conjugated to a chemotherapeutic agent selected from the group consisting of 5-Azacitidine, 5-Fluorouracil, adriamycin and gemcitabine. 
     
     
         10 . The aptamer of  claim 1 , wherein the aptamer is conjugated to one or more diagnostic agents. 
     
     
         11 . The aptamer of  claim 1 , wherein the aptamer is conjugated to a nanoparticle, a radioactive substance, a dye, a contrast agent, a fluorescent molecule, a bioluminescent molecule, an enzyme, or an enhancing agent. 
     
     
         12 . A pharmaceutical composition comprising the aptamer of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         13 . A method of delivering a therapeutic agent to a pancreatic cancer cell comprising contacting the pancreatic cancer cell with an aptamer conjugate, wherein the aptamer conjugate comprises an aptamer component and a therapeutic agent component; and wherein the aptamer component is an RNA molecule that specifically binds a pancreatic cancer cell surface protein, resulting in internalization of the pancreatic cell aptamer conjugate. 
     
     
         14 . The method of  claim 13 , wherein the therapeutic agent component comprises an shRNA molecule, an siRNA molecule, an mRNA molecule, or an miRNA molecule. 
     
     
         15 . The method of  claim 13 , wherein the RNA molecule comprises a nucleotide sequence of GAAUGCCC (SEQ ID NO: 8). 
     
     
         16 . A method for treating pancreatic cancer comprising administering a therapeutically effective amount of an aptamer, wherein the aptamer comprises an RNA molecule that specifically binds a pancreatic cancer cell surface protein. 
     
     
         17 . The method of  claim 16 , wherein the RNA molecule comprises a nucleotide sequence of GAAUGCCC (SEQ ID NO: 8). 
     
     
         18 . The method of  claim 16 , wherein the aptamer is conjugated to one or more therapeutic agents. 
     
     
         19 . The method of  claim 18 , wherein the therapeutic agent is a nucleic acid molecule. 
     
     
         20 . The method of  claim 16 , wherein the wherein the aptamer is conjugated to an agent selected from the group consisting of an shRNA molecule, siRNA molecule, mRNA molecule or an miRNA molecule.