671. Potent Anti-Tumor Effects of ApDCs (Aptamer Drug Conjugates) for Targeted Therapeutics in Pancreatic Cancer

Abstract

Aptamer Drug Conjugates (ApDCs) are a potential class of targeting therapeutics to improve therapeutic index over traditional chemotherapy. As most existing chemotherapies are absorbed into cells non-specifically through lipophilic interaction, to improve the therapeutic index, the drugs were attached to pancreatic cancer specific RNA aptamer, P19, as targeting moieties that preferentially delivered the payload to tumor cells. Active metabolites of gemcitabine (dFdCMP) and 5FdU (5FdUMP) were incorporated P19 intrinsically to make conjugates. The conjugates of P19-dFdCMP or P19-5FdUMP kept their structural functionality getting internalized in their target cells, PANC-1. P19-dFdCMP and P19-5FdUMP was incorporated into replicating DNA, resulting in chain termination and stalling of replication forks in nuclear. They induced the phosphorylation of histone H2AX on Ser139 (γ-H2AX), markers of double-strand DNA breaks, and increased the forms of nuclear foci at the sites of DNA damage. In consequence, the cell proliferation was significantly inhibited 51-53% in PANC-1 and 54-34% in gemcitabine resistance AsPC-1. Targeted anti-mitotic therapies have emerged as a new concept of cancer drugs. Chemotoxine, monomethyl auristatin E (MMAE) is a very potent antimitotic agent that inhibits cell division by blocking the polymerization of tubulin. However, it can't be used by drug itself because of high toxicity. Herein, toxic molecule, MMAE, was conjugated to P19 for the targeted anti-mitotic therapies. P19-MMAE caused mitotic G2/M phase arrest, consequently inhibited 56% of cell proliferation on dose-dependent manner comparing control. In vivo assay, P19-MMAE induced the tumor regression via tail vein injection. In this study, the drug attached aptamer significantly decreased non-specific uptake of the drug and increase specific uptake of the conjugate in tumor cells. Our approaches suggest guiding cytotoxic drugs into malignant cancer cells specifically without causing significant harm to the normal cells.