Efficiency of Cationic Rosette Nanotubes for siRNA Delivery
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Efficiency of Cationic Rosette Nanotubes for siRNA Delivery Aws Alshamsan1,2, Mounir EL Bakkari2,3 and Hicham Fenniri2,3 1 Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia 2 National Institute for Nanotechnology (NINT-NRC), Edmonton, AB, Canada 3 Department of Chemistry, Faculty of Science, University of Alberta, Edmonton, AB, Canada ABSTRACT Cationic rosette nanotubes (RNTs) were generated by functionalization of selfcomplementary twin guanine-cytosine (G∧C) motifs with up to 15 L-lysine residues (Kn.T, n = 1–15). siRNA binding capacity was determined by gel retardation assay on agarose gel. Up to K5.T, siRNA complexation was a function of oligolysine-chain length and mole ratio of Kn.T. At higher Kn.T, local cationic density employed by supramolecular assembly emerged as a contributor to siRNA complexation. We have shown that no effective siRNA binding was achieved with equivalent mole ratios of corresponding oligolysine peptides (not conjugated to the G∧C motif). With K12.T, siRNA complexation gave spherical structures in the range of 200 nm, which was internalized and retained by human cell lines without noticeable cytotoxicity. In this report, we demonstrate for the first time the capacity of the RNTs as siRNA carriers that can be tailored to achieve maximum siRNA loading efficiency without carrier-associated cell toxicity. We anticipate these cationic RNTs to be effective in the delivery of biologicallyfunctional siRNA. INTRODUCTION Small-interfering RNA (siRNA) is a Nobel-Prize winning technology that carries promising therapeutic potentials and has shown effective gene downregulation in animal models [1]. Upon introduction to the cytoplasm, siRNA integrates with intracellular protein machinery that identifies, binds, and cleaves the mRNA of interest [2-4]. However, several drawbacks precluded the direct application of siRNA in therapy, and highlighted the importance of developing an optimal siRNA carrier system [5,6]. In this regard, nanotechnology opens an important avenue to develop optimum carriers that effectively deliver siRNA to the site of action and mediate its therapeutic activity in a more specific fashion [7]. Nanomaterial design and synthesis has seen great progress over the past several years [8]. In addition to devising methods to synthesize these materials with controlled dimensions, there has also been considerable effort in functionalizing them with biologically-relevant molecules [9,10]. Rosette nanotubular systems (Figure 1), in particular, have a great potential to serve as siRNA carrier owing to their selfassembly properties that allow for surface functionalization to enhance siRNA capture and delivery [10-13]. In this study, we conjugated up to 15 lysine residues to twin G∧C motifs (KnT, n = 1–15). We hypothesized that the RNTs formed from these Kn.Ts can bind and stabilize siRNA as a function of the oligolysine chain length, and deliver siRNA efficiently to multiple types of human cell lines. Moreover, we studied the carrier-related cytotoxic
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