The suppression of metastatic lung cancer by pulmonary administration of polymer nanoparticles for co-delivery of doxorubicin and Survivin siRNA

Abstract

A pH-sensitive co-delivery system was designed for the treatment of metastatic lung cancers by pulmonary delivery of doxorubicin (DOX) and Survivin siRNA. Conjugates PEI-BMPH-DOX (PMD) of polyethylenimine (PEI) with DOX were developed via a pH-sensitive hydrazine bond (3-maleimidopropionic acid hydrazide, BMPH). Furthermore, the PMD/Survivin siRNA complex nanoparticles were prepared by electrostatic interaction between cationic PMD and anionic Survivin siRNA. The drug release of DOX from PMD conjugates increased with decreasing pH values. The DOX and Survivin siRNA could be effectively delivered into the same cells and enhanced the cytotoxicity in B16F10 cells. In the B16F10 tumor-bearing mice models, local delivery of PMD/siRNA complex nanoparticles by pulmonary delivery resulted in the preferential accumulation of DOX and siRNA in the lungs, and a considerable amount of DOX and siRNA accumulated in tumor tissues of the lungs, but limited DOX and siRNA were observed in normal lung tissues. Moreover, the PMD/Survivin siRNA complex nanoparticles showed enhanced antitumor efficacy compared with the mono-delivery of DOX or Survivin siRNA. Taken together, our findings offer an effective local delivery strategy by pulmonary administration for the treatment of metastatic lung cancer.