Development of safe and efficient
short interfering RNA (
siRNA) delivery system for RNA interference (
RNAi)-based therapeutics is a current critical challenge in drug delivery field. The major barriers in
siRNA delivery into the target cytoplasm are the fragility of
siRNA in the body, the inefficient cellular uptake, and the acidic endosomal entrapment. To overcome these barriers, this study is presenting a hybrid nanocarrier system composed of
calcium phosphate comprising the block copolymer of poly(
ethylene glycol) (PEG) and charge-conversional
polymer (CCP) as a
siRNA vehicle. In these nanoparticles, the
calcium phosphate forms a stable core to incorporate
polyanions,
siRNA and PEG-CCP. The synthesized PEG-CCP is a non-toxic endosomal escaping unit, which induces endosomal membrane destabilization by the produced polycation through degradation of the flanking cis-aconitylamide of CCP in acidic endosomes. The nanoparticles prepared by mixing of each component was confirmed to possess excellent
siRNA-loading efficiency (∼80% of dose), and to present relatively homogenous spherical shape with small size. With negligible cytotoxicity, the nanoparticles efficiently induced
vascular endothelial growth factor (
VEGF)
mRNA knockdown (∼80%) in
pancreatic cancer cells (PanC-1). Confocal
laser scanning microscopic observation revealed rapid endosomal escape of
siRNA with the nanoparticles for the excellent
mRNA knockdown. The results obtained demonstrate our hybrid nanoparticle as a promising candidate to develop
siRNA therapy.