Abstract 3053: Aptamer-mediated cancer cell-specific delivery of therapeutic microRNAs and miRNA inhibitors.
Authors: Esposito Carla L. , Catuogno Silvia , Camorani Simona , di Costanzo Antonella , Iaboni Margherita , Condorelli Gerolama , Cerchia Laura , de Franciscis Vittorio 
Published: August 2014

Abstract
The most recent advances in the field of cancer therapy have shown the great potential of using RNA-based molecules for human cancer treatment. RNA-based oligonucleotides, such as siRNA, miRNA mimic or miRNA inhibitors are being developed to modulate the expression of genes important in cancer, thus blocking tumourigenesis, inhibiting tumour growth or preventing metastasis. However a major limitation in the translation to clinic of RNA oligonucleotides is represented by the need of technologies that mediate their selective delivery improving their efficacy and safety. Conjugation with nucleic acid aptamers represents an innovative and promising approach to overcome this obstacle. Aptamers are single-stranded oligonucleotides that have been shown as high-affinity ligands and potential antagonists of cancer-associated proteins. They discriminate between closely related targets and are characterized by high specificity and low toxicity thus revealing as compounds of choice for in vivo cell recognition as delivery agents for various secondary reagents such as nanoparticles, siRNA bioconjugates, chemotherapeutic cargoes and molecular imaging probes. We have recently generated and characterized two 2’fluoro-pyrimidines containing RNA aptamers, named GL21.T and Gint4, that bind at high affinity and high specificity to human Axl tyrosine kinase receptor and PDGFRβ, respectively. These aptamers not only bind to their proper RTK but are also rapidly internalized into target cell, getting about 30% of cell internalization following 15 min-incubation and reached about 60% following 2h of aptamer treatment. By using different approaches, we have generated several completely RNA-based chimeric molecules containing internalizing aptamers coupled to therapeutic miRNAs that are down-regulated in human tumors and whose expression results in selective tumour growth inhibition. We have shown that when applied to cells expressing the specific aptamer target, the chimeric molecules are internalized and processed by Dicer, thus increasing miRNA cellular level and inhibiting miRNA target protein. As a consequence, the depletion of the targeted protein leads to miRNA herapeutic effect. Remarkably, no binding or functionality of the chimeras has been detected in cells that do not express aptamer target receptor. In addition, since miRNAs are frequently up-regulated in different alignancies, acting as oncogenes, we have developed different pproaches to conjugate internalizing aptamers to therapeutic miRNA inhibitors. The ability of these molecules to bind to and internalize in aptamer target-positive cells has been verified. The characterization in vitro and in vivo of the different chimeras is ongoing in our laboratory revealing these hybrid compounds as potential tools for innovative anti-cancer targeted therapeutics.
Citation Format: Carla L. Esposito, Silvia Catuogno, Simona Camorani, Antonella di Costanzo, Margherita Iaboni, Gerolama Condorelli, Laura Cerchia, Vittorio de Franciscis. Aptamer-mediated cancer cell-specific delivery of therapeutic microRNAs and miRNA inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3053. doi:10.1158/1538-7445.AM2013-3053