Many small molecule drugs are hydrophobic in nature, thereby enhancing their passage through lipid bilayers for gaining access to cells. In contrast, nucleic acids carry a negative charge and have considerable mass, making their entry into cells significantly more challenging. Attempts to deliver both small molecule drugs and nucleic acids in a single construct therefore poses several practical hurdles. Here we present chemical strategies that enable the co-delivery of such disparate molecules by modifications to our recently developed nucleic acid nanocapsule (NAN) delivery platform. Using NANs, we demonstrate the delivery of a hydrophobic gold(III) metallodrug alongside an siRNA against an apoptosis regulating gene, showing that their combined delivery enhances the overall cytotoxic effects of the metallodrug in cancer cells at lower concentrations of the drug (from micromolar to nanomolar). Additionally, we show the advantages that arise when such formulations are built from chemistries that can accommodate stimuli responsive elements, including temperature and pH responsive chemistries. The NANs enable a route to exogenous nucleic acid delivery and improved solubility of small molecule drugs that are normally prone to aggregation in aqueous conditions. We show that they achieve enhanced therapeutic efficacy in the form of improved cytotoxicity at lower drug doses and more potent gene regulation at lower concentrations of therapeutic nucleic acids delivered. Lastly, we demonstrate the the versatility of the platform for 1) functionalization with cell surface targeting agents including RNA aptamers, showing that they can bias the localization of these nanostructures, and 2) offer insights into the mechanism by which these materials are able to enhance cytosolic access for their nucleic acid cargo.

Improving the therapeutic efficacy of nucleic acids and small molecule drugs using stimuli-responsive nanostructures

2019 Fall National Meeting

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