The suppression of lung tumorigenesis by aerosol-delivered folate-chitosan-graft-polyethylenimine/Akt1 shRNA complexes through the Akt signaling pathway.
RNA interference (RNAi) represents a promising new approach to the inhibition of gene expression in vitro and in vivo, and has therapeutic potential for human diseases. Efficient delivery of small interfering RNA (siRNA) or small hairpin RNA (shRNA) is a critical concern in RNAi studies. Here we report the development of a new polymeric gene carrier for cancer cell-targeting, designed to enhance the intracellular delivery of shRNA and reduce cytotoxicity. Folate-chitosan-graft-polyethylenimine (FC-g-PEI) copolymer was prepared by an imine reaction between periodate-oxidized folate-chitosan (FC) and low molecular weight polyethylenimine (PEI). FC-g-PEI copolymer was investigated as a potential cancer cell-targeting gene carrier. The composition of FC-g-PEI was characterized using (1)H nuclear magnetic resonance ((1)H NMR), and particle size and zeta potential of FC-g-PEI/shRNA complexes were measured using dynamic light scattering (DLS). FC-g-PEI showed good shRNA condensation ability and high protection of shRNA from nuclease attack. It also exhibited lower cytotoxicity compared to PEI 25K control, and showed good cancer cell-targeting ability. Furthermore, aerosol delivery of FC-g-PEI/Akt1 shRNA complexes suppressed lung tumorigenesis in a urethane-induced lung cancer model mouse through the Akt signaling pathway. Together, these results suggest that FC-g-PEI may be useful for shRNA-based gene therapy.
Jiang
Hu-Lin
HL
Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, San 56-1, Sillim 9 dong, Gwanak-Gu, Seoul 151-921, Republic of Korea.
Xu
Cheng-Xiong
CX
Kim
You-Kyoung
YK
Arote
Rohidas
R
Jere
Dhananjay
D
Lim
Hwang-Tae
HT
Cho
Myung-Haing
MH
Cho
Chong-Su
CS
D000280:Administration, Inhalation; D000336:Aerosols / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use; D000818:Animals; D048271:Chitosan / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D005492:Folic Acid / Q000737:chemistry*; D020868:Gene Silencing; D018390:Gene Targeting / Q000379:methods; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011094:Polyethyleneimine / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics*; D016896:Treatment Outcome
D000336:Aerosols; D004337:Drug Carriers; D034741:RNA, Small Interfering; D011094:Polyethyleneimine; D048271:Chitosan; D005492:Folic Acid; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt