Structure-Invertible Nanoparticles for Triggered Co-Delivery of Nucleic Acids and Hydrophobic Drugs for Combination Cancer Therapy

摘要

Here, a new type of structure-invertible, redox-responsive polymeric nanoparticle for the efficient co-delivery of nucleic acids and hydrophobic drugs in vitro and in vivo is reported for the first time, to combat the major challenges facing combination cancer therapy. The co-delivery vector, which is prepared by conjugating branched poly(ethylene glycol) with dendrimers of two generations (G2) through disulfide linkages, is able to complex nucleic acids and load hydrophobic drugs with high loading capacity through structure inversion. The cleavage of disulfide linkages at intracellular glutathione-rich reduction environment significantly decreases the cytotoxicity, and promotes more efficient drug release and gene transfection in vitro and in vivo. The co-delivery carrier also displays enhanced endosomal escape capability and improved serum stability in vitro as compared with G2, and exhibits prolonged residence time and stronger transfection activity in vivo. Most importantly, co-delivery of doxorubicin (DOX) and B-cell lymphoma 2 (Bcl-2) small interfering RNA (siRNA) exerts a combinational effect against tumor growth in murine tumor models in vivo, which is much more effective than either DOX or Bcl-2 siRNA-based monotherapy. The structure-invertible nanoparticles may constitute a promising stimuli-responsive system for the efficacious co-delivery of multiple cargoes in future clinical applications of combination cancer therapies.