Efficient and safe delivery of nucleic acids has been a pivotal, technological bottleneck in basic biomedical research well as in gene therapy. Shielding viral vectors not only ensures safe administration of immunogenic viral particles but also allows to engineer the physic-chemical properties of viral vectors using synthetic macromolecules. Effects of a genetic modification are often insufficient to achieve biological and therapeutic outcomes (e.g., apoptosis of cancer cells) at a desired level, because of an antagonistic pathway (e.g., overly activated survival signal). In this study, adeno-associated virus (AAV) was shelled with acid-responsive polyketal (PK) polymers (vial/nonviral chimeric nanoparticles; ChNPs) in that the PK shell shields the AAV core from the immune response. In addition, the PK assists the AAV core's facilitated intracellular trafficking. Most importantly, the PK shell encapsulates small interfering RNA (siRNA) to obtain simultaneous dual mode expression and silencing of multiple genes. The resulting ChNPs have demonstrated 1) stimuli-triggered, differential release of AAV and siRNA, 2) enhanced transduction by the AAV core, and 3) simultaneous expression and silencing of multiple target genes in a cell. ChNPs consisting of the Bim-encoding AAV core and Mcl-1 siRNA-encapsulating PK shell (BimAAV/Mcl-1siRNA ChNPs) were synthesized in exploration of treating Bcr-Abl(+) leukemia. Bcr-Abl is a molecular cause of chromic myelogenous leukemia (CML) and subsets of other human leukemia. The BimAAV/Mcl-1siRNA ChNPs efficiently interfered with the proliferation of human leukemia cells in vitro and in vivo.

Dual mode gene therapy using viral/nonviral chimeric nanoparticles

246th National Meeting (2013)

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