Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors

Abstract

Prostate cancer cells expressing prostate-specific membrane antigen (PSMA) have been targeted with RNA aptamer–small interfering (si)RNA chimeras, but therapeutic efficacy in vivo was demonstrated only with intratumoral injection. Clinical translation of this approach will require chimeras that are effective when administered systemically and are amenable to chemical synthesis. To these ends, we enhanced the silencing activity and specificity of aptamer-siRNA chimeras by incorporating modifications that enable more efficient processing of the siRNA by the cellular machinery. These included adding 2-nucleotide 3´-overhangs and optimizing the thermodynamic profile and structure of the duplex to favor processing of the siRNA guide strand. We also truncated the aptamer portion of the chimeras to facilitate large-scale chemical synthesis. The optimized chimeras resulted in pronounced regression of PSMA-expressing tumors in athymic mice after systemic administration. Anti-tumor activity was further enhanced by appending a polyethylene glycol moiety, which increased the chimeras’ circulating half-life.

A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells

“…In the past decade, much attention has been focused on RNAbased aptamers that are emerging as safe delivery vehicles for targeted cancer therapeutics [19]. In addition to inhibitory function of selected targets, aptamers raised against transmembrane receptors rapidly internalize into the target cell through recycling of the bound receptor [20]. So far, various therapeutic cargoes have been successfully conjugated to aptamers, including anti-cancer drugs, toxins, radionuclides, and short therapeutic RNAs (siRNAs and miRNAs) [19,21,22].…”

Special delivery: targeted therapy with small RNAs

“…Aptamer-siRNA chimeras that utilize an aptamer that recognizes prostate surface membrane antigen specifically deliver siRNAs and inhibit tumor outgrowth in a xenograft model of human prostate cancer. 45,46 Similarly, a chimeric RNA containing an aptamer to HIV env protein specifically delivers siRNAs to HIV-infected CD4 + cells, which are otherwise refractory to transfection, and when joined with siRNAs that target viral genes can be used to inhibit HIV replication in vitro. 47,48 An siRNA-aptamer encoding a CD4 aptamer knocks down gene expression specifically in human CD4+ T cells, macrophages and dendritic cells.…”

Therapeutic targeting in the silent era: advances in non-viral siRNA delivery

“…These complexes resulted in significant inactivation of PSMA-expressing tumours in an athymic mouse model by intravenous administration. More importantly, the in vivo circulating half-lives of the chimeras were dramatically increased from <35min to >30hour by the addition of the PEG group [121] .…”