Nucleic acid-based therapeutics offer significant promise in treatment of difficult diseases by providing high sequence specificity against target genes including “non-druggable targets”. Different nucleic acid constructs, single-stranded antisense oligonucleotides, microRNA mimetics, miRNA-specific antagomirs (AntimiR), and double-stranded short-interfering RNAs (siRNAs), provide diverse therapeutic platforms to access targets in treatment of cancer and other diseases. Single-stranded oligonucleotides require additional modifications for increased serum stability, nuclease resistance, and to minimize immune response. Conformationally restricted nucleotide (CRN)-substituted AntimiRs targeting miR-21 and miR-122 demonstrated significant improvement in hybridization affinity with a concomitant increase in potency. A CRN-substituted AntimiR targeting microRNA-122 dosed at up to 50 mg/kg/day over three consecutive days led to a dose-dependent effect on de-repression of downstream liver-specific target genes, Aldolase A (AldoA), Glycogen Synthase I (GYS1) and Solute Carrier Family 7 member 1 (SLC7A1). This CRN-modified AntimiR produced up to a 5-fold increase in AldoA mRNA while demonstrating a good tolerability profile with no body weight changes and normal serum chemistry. Development of therapeutic siRNA constructs can be hampered by off-target effects and cytokine induction. Substitution of unlocked nucleobase analogs (UNAs) at specific positions in the passenger and guide strands of siRNA confers high specificity with minimal to no off-target activity. UsiRNAs were successfully delivered to bladder or abdominal tumors when encapsulated in DiLA2- or SMARTICLES®-derived liposomes. DiLA2−encapsulated polo-like kinase 1 (PLK1) UsiRNA demonstrated 95% mRNA reduction and up to 70-fold tumor growth inhibition in a bladder cancer orthotopic mouse model and 40-70% mRNA inhibition and ∼80% reduction in tumor-specific bioluminescence in a malignant ascites mouse model following intravesical or intraperitoneal dosing, respectively. In an orthotopic liver tumor animal model, liposomal encapsulated miRNA mimetics provided ∼80% reduction in tumors compared to buffer control. Combinations of formulations and construct capitalize on the advantages of nucleic acid-based therapeutics for precise targeting and flexible delivery to challenging drug targets in cancer and other indications.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 281. doi:1538-7445.AM2012-281