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

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

Genes that are essential for tumor growth and progression, such as Akt1 (RAC-alpha serine/threonine-protein kinase B) and c-myc, are evaluated as RNAi targets. Akt1 is an important mediator of cell growth, proliferation and survival of non-small cell lung cancer (NSCLC). Activation of Akt1 pathway is observed in most NSCLC patients. It is found to reduce chemo-and radiation-induced apoptosis to extend the survival of tumor cells [100, 101] . Sorbitol diacrylatepolyethylenimine (SDA-PEI) was employed to deliver shRNA targeting Akt1 (shAkt1) and cDNA encoding programmed cell death protein 4 (Pdcd4) in a dual expression vector via pulmonary route to murine lung cancer model. Simultaneous Akt1 inhibition and Pdcd4 overexpression could induce potent anticancer effect. The total tumor number and the tumor size larger than 1 mm in the lung were significantly reduced after eight doses [101] . Glycerol triacrylate-spermine (GT-SPE) polyspermine [102] and lentivirus [103] were also employed as carriers of shRNA targeting Akt1 signaling pathway for pulmonary delivery. Although repeated aerosol delivery of lentiviral-based shRNA can achieve potent knockdown of the target, inhalation is a procedure that generates large number of viral particles. There are safety concerns regarding the use of viral vectors for inhalation, including the potential mutagenicity, immunogenicity and the risk of aerosol-transmitted infections [104] . Therefore, aerosol delivery of RNAi molecules using viral vectors must go through vigorous biosafety evaluation for clinical use. Notes: AIMP2-DX2, aminoacyl-tRNA synthetases (ARS)-interacting multifunctional protein 2 lacking exon 2; Akt1, RAC-alpha serine/threonine-protein kinase B; Bcl-2, B-cell lymphoma 2; DOX: doxorubicin; EGFP, enhanced green fluorescence protein; GPT-SPE: glycerol propoxylate triacrylate and spermine; GT-SPE, glycerol triacrylate-spermine; MRP1, multidrug resistance protein 1; NPT2b: sodium-dependent phosphate co-transporter 2b; Pdcd4: programmed cell death protein 4; PEI: polyethylenimine; RGD, Arginine-glycine-aspartic acid peptide; RPN2, ribophorin II; NPs, nanoparticles; SDA-PEI, sorbitol diacrylatepolyethylenimine; TAX, paclitaxel.