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Small interfering RNA (siRNA) is a highly potent drug in gene-based therapy with a challenge of being delivered in a sustained manner. Nanoparticle drug delivery systems allow for incorporating and controlled release of therapeutic payloads. We demonstrate that solid lipid nanoparticles can incorporate and provide sustained release of siRNA. Tristearin solid lipid nanoparticles, made by nanoprecipitation, were loaded with siRNA (4.4–5.5 weight percent loading ratio) using a hydrophobic ion pairing approach that employs the cationic lipid DOTAP. Intradermal injection of these nanocarriers in mouse footpads resulted in prolonged siRNA release over a period of 10–13 days. In vitro cell studies showed that the released siRNA retained its activity. Nanoparticles developed in this study offer an alternative approach to polymeric nanoparticles for encapsulation and sustained delivery of siRNA with the advantage of being prepared from physiologically well-tolerated materials.

The oxidation of 7,8-dihydro-8-oxoguanine (8-oxoG)-containing oligodeoxynucleotides has been investigated using a variety of oxidants, including one-electron oxidants (Ir(IV), Fe(III), NiCR/KHSO5, ...

Guanine-specific modification of both single- and double-stranded oligodeoxynucleotides via the autoxidation of sulfite is shown to be catalyzed by [NiCR]2+ (where CR = 2,12-dimethyl-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-1(17),2,11,13,15-pentaene) and [NiKGH-nh2]+ (where KGH = lysylglycylhistidine). In the latter case, the nickel complex is proposed to act as a catalyst in three separate steps of sulfur oxide chemistry. Oxidative damage of guanines led to strand scission after piperidine treatment. The observed reactivity represents the first demonstration of DNA damage by sulfite and nickel(II) complexes. Importantly, these reactions were conducted using sulfite concentrations relevant to levels known to be cytotoxic. Mechanistic studies suggest the importance of both monoperoxysulfate and sulfate radical anion in the observed DNA damage. Evidence for formation of guanine radical cation as the initial product of DNA oxidation was found by comparison of the sequence dependence of guanine reactivity i...