Aptamer-siRNA Chimeras for Targeting Prostate Cancer

Targeted delivery of small interfering RNA (siRNA) remains the primary obstacle to the widespread therapeutic application of RNAi. We have previously demonstrated targeting of cancer-specific cytotoxic siRNAs to prostate cancer cells expressing prostate specific membrane antigen (PSMA) with a PSMA-specific RNA aptamer (McNamara, 2006). In this initial study, we reported in vivo efficacy following intratumoral injections of conjugates containing anti-PSMA aptamers and siRNAs against polo-like-kinase 1 (Plk1). We have subsequently optimized the design of the PSMA aptamer-Plk1 siRNA conjugate to (1) enable chemical synthesis and (2) achieve efficacy upon systemic administration (Dassie, 2009). In vivo assessment of the optimized conjugates showed a striking reduction in the volume of PSMA-positive xenograft tumors following intraperitoneal administration. While encouraging, these effects were demonstrated using in vitro transcribed material. Future clinical translation of this approach requires aptamer-siRNA conjugates that are generated using chemical synthesis. We are currently evaluating chemically-synthesized, pre-clinical grade PSMA-Plk1 conjugates for activity and specificity in cells in culture and in mouse models of prostate cancer. If successful, this work may lead to future clinical trials in humans.

Dassie JP, Liu XY, Thomas GS, Whitaker RM, Thiel KW, Stockdale KR, Meyerholz DK, McCaffrey AP, McNamara JO 2nd, Giangrande PH. Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors. Nat Biotechnol. 27(9):839-49 (2009). PMCID: PMC2791695.

McNamara JO 2^nd, Andrechek ER, Yong Wang, Kristi D. Viles, Rempel RE, Gilboa E, Sullenger BA, Giangrande PH. Cell-type specific delivery of siRNAs with aptamer-siRNA chimeras. Nat. Biotechnol. 24(8): 1005-15 (2006).