A pH sensitive co-delivery system of siRNA and doxorubicin for pulmonary administration to B16F10 metastatic lung cancer

Abstract

Pulmonary co-delivery to the lungs offers a potential therapy for pulmonary diseases. In this study, doxorubicin was conjugated to polyethyleneimine by hydrazone bonds to form a pH sensitive conjugate (PEI-HZ-DOX). A co-delivery carrier was constructed by complexing Bcl2 siRNA with PEI-HZ-DOX. The complex particles could be used by pulmonary administration for metastatic lung cancer treatment. DOX release from the PEI-HZ-DOX conjugate was in a pH-dependent pattern and accelerated by decreasing pH. The cell uptake of DOX and siRNA from PEI-HZ-DOX/siRNA and efficient intracellular release of DOX from PEI-HZ-DOX in B16F10 cells were further confirmed. Cell apoptosis and antitumor effects of the combined therapy were evaluated in vitro, the results showed that co-delivery of DOX and siRNA had better antitumor efficacy than mono-delivery of DOX or siRNA. Furthermore, the biodistribution results showed that pulmonary administration could improve the deposition amounts of DOX and siRNA in the lungs and prolong the retention time compared with systemic administration, which demonstrated that the present delivery system is suitable for pulmonary co-delivery. Overall, pH sensitive PEI-HZ-DOX/siRNA complex nanoparticles exhibit great potential for clinical combination therapy of lung cancer by pulmonary administration in local delivery strategies.