Nanoplex delivery of siRNA and prodrug enzyme for multimodality image-guided molecular pathway targeted cancer therapy

摘要

The ability to destroy cancer cells while sparing normal tissue is highly sought after in cancer therapy. Small interfering RNA (siRNA)-mediated silencing of cancer-cell-specific targets and the use of a prodrug enzyme delivered to the tumor to convert a nontoxic prodrug to an active drug are two promising approaches in achieving this goal. Combining both approaches into a single treatment strategy can amplify selective targeting of cancer cells while sparing normal tissue. Noninvasive imaging can assist in optimizing such a strategy by determining effective tumor delivery of the siRNA and prodrug enzyme to time prodrug administration and detecting target down-regulation by siRNA and prodrug conversion by the enzyme. In proof-of-principle studies, we synthesized a nanoplex carrying magnetic resonance imaging (MRI) reporters for in vivo detection and optical reporters for microscopy to image the delivery of siRNA and a functional prodrug enzyme in breast tumors and achieve image-guided molecular targeted cancer therapy. siRNA targeting of choline kinase-α (Chk-α), an enzyme significantly up-regulated in aggressive breast cancer cells, was combined with the prodrug enzyme bacterial cytosine deaminase (bCD) that converts the nontoxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU). In vivo MRI and optical imaging showed efficient intratumoral nanoplex delivery. siRNA-mediated down-regulation of Chk-α and the conversion of 5-FC to 5-FU by bCD were detected noninvasively with ~1H MR spectroscopic imaging and ~(19)F MR spectroscopy. Combined siRNA and prodrug enzyme activated treatment achieved higher growth delay than either treatment alone. The strategy can be expanded to target multiple pathways with siRNA.