Delivery of RNAi Therapeutics to the Airways—From Bench to Bedside

Qiu, Yingshan; Lam, Jenny K. W.; Leung, Susan W. S.; Liang, Wanling

Besides the inhibition of MDR associated proteins alone, the co-delivery of anticancer drugs with RNAi therapeutics is as an alternative approach to tackle MDR in various types of cancers [112, [115] [116] [117] . Combination therapy offers the potential advantages of synergistic activity, overcoming the drug resistance and reducing the side effects of chemotherapy. Bcl-2 is a main player of nonpump cellular resistance [118] and MRP1 is responsible for drug efflux in cancer cells [119] . They were investigated in the combination approach. Taratula et al. prepared a lipid-based nanoparticles containing siRNA targeting Bcl-2 and MRP1, as well as anticancer drugs (doxorubicin or paclitaxel). The nanoparticles were delivered to the lung of tumor mouse model using a nose only exposure chamber for inhalation. Almost complete disappearance of lung tumor was observed in animals treated with paclitaxel plus the siRNAs. In contrast, treatment with paclitaxel alone only slowed down the growth of the tumor [110] . Xu et al. developed a polyethylenimine (PEI)-based delivery system that simultaneously delivered siRNA targeting Bcl-2 and doxorubicin to the lungs of mice with metastatic lung cancer. Synergistic antitumor efficacy was achieved compared with the delivery of doxorubicin or siRNA alone [105] . These studies indicated that suppression of resistance gene by RNAi molecules via inhalation could restore the sensitivity of chemotherapeutic drugs, leading to the death of tumor cells.