title: The role of osmotic polysorbitol-based transporter in RNAi silencing via caveolae-mediated endocytosis and COX-2 expression.
abstract: Polymeric diversity allows us to design gene carriers as an alternative to viral vectors, control cellular uptake, target intracellular molecules, and improve transfection and silencing capacity. Recently, we developed a polysorbitol-based osmotically active transporter (PSOAT), which exhibits several interesting mechanisms to accelerate gene delivery into cells. Herein, we report the efficacy of using the PSOAT system for small interfering RNA (siRNA) delivery and its specific mechanism for cellular uptake to accelerate targeted gene silencing. We found that PSOAT functioned via a caveolae-mediated uptake mechanism due to hyperosmotic activity of the transporter. Moreover, this selective caveolae-mediated endocytosis of the polyplexes (PSOAT/siRNA) was regulated coincidently with the expression of caveolin (Cav)-1 and cyclooxygenase (COX)-2. Interestingly, COX-2 expression decreased dramatically over time due to degradation by the constant expression of Cav-1, as confirmed by high COX-2 expression after the inhibition of Cav-1, suggesting that PSOAT-mediated induction of Cav-1 directly influenced the selective caveolae-mediated endocytosis of the polyplexes. Furthermore, COX-2 expression was involved in the initial phase for rapid caveolae endocytic uptake of the particles synergistically with Cav-1, resulting in accelerated PSOAT-mediated target gene silencing.
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea.
authors.forename: Mohammad Ariful
authors.initials: MA
authors.lastname: Islam
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Shin
authors.forename: Jannatul
authors.initials: J
authors.lastname: Firdous
authors.forename: Tae-Eun
authors.initials: TE
authors.lastname: Park
authors.forename: Yun-Jaie
authors.initials: YJ
authors.lastname: Choi
authors.forename: Myung-Haing
authors.initials: MH
authors.lastname: Cho
authors.forename: Cheol-Heui
authors.initials: CH
authors.lastname: Yun
authors.forename: Chong-Su
authors.initials: CS
authors.lastname: Cho
mesh_terms: D000818:Animals; D021941:Caveolae / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics*; D004337:Drug Carriers / Q000378:metabolism*; D004705:Endocytosis; D005786:Gene Expression Regulation; D009995:Osmosis; D053495:Osteopontin / Q000235:genetics; D011091:Polyesters / Q000378:metabolism*; D011094:Polyethyleneimine / Q000031:analogs & derivatives* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics
chemical_list: D051242:Caveolin 1; D004337:Drug Carriers; D011091:Polyesters; D034741:RNA, Small Interfering; C569756:polysorbitol-based osmotically active transporter polymer; D053495:Osteopontin; D011094:Polyethyleneimine; D051546:Cyclooxygenase 2