The induction of tumor apoptosis in B16 melanoma following STAT3 siRNA delivery with a lipid-substituted polyethylenimine.
Persistent activation of signal transducer and activator of transcription 3 (STAT3) has been shown to impart several oncogenic features in many solid and blood tumors. In this study, we investigated the potential of nanoparticles based on polyethylenimine (PEI) modified with stearic acid (StA), to deliver siRNA for efficient STAT3 downregulation in B16 melanoma cells. The B16 cells were targeted with approximately 6-200 nm of siRNA complexes for 36 h. Compared to the PEI complexes, the PEI-StA complexes showed higher potency in STAT3 silencing in B16 cells accompanied by a significant induction of IL-6 secretion and a reduction of VEGF production. Moreover, with PEI-StA complexes, the level of the cellular Caspase 3 activity (an indicator of apoptotic activity) was found to be 2.5 times higher than that of PEI complexes. When the cells were treated with 50 nm of siRNA complexes on a daily basis, the cell viability was dramatically reduced reaching only to 16% after the third daily dose of PEI-StA complexes, as compared to the 69% viability observed with the PEI complexes at an equivalent time period. Consistently, in vivo results indicated significant regression in tumor growth and tumor weight after siRNA/PEI-StA treatment as compared to the siRNA/PEI. This was accompanied with significant increase in IL-6 levels and Caspase 3 activity, and a significant decrease in VEGF level and STAT3 activity in the tumor tissue. The lipid-modified PEI is a promising carrier for siRNA delivery and downregulation of STAT3 by polymer-mediated siRNA delivery is an effective strategy for cancer treatment especially when an optimum delivery system can potentiate the silencing activity of siRNA.
Alshamsan
Aws
A
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
Hamdy
Samar
S
Samuel
John
J
El-Kadi
Ayman O S
AO
Lavasanifar
Afsaneh
A
Uludağ
Hasan
H
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008422:Materials Testing; D008545:Melanoma / Q000235:genetics* / Q000628:therapy*; D011094:Polyethyleneimine / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics*
D004337:Drug Carriers; D008055:Lipids; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D011094:Polyethyleneimine