title: Disulfide bond-conjugated dual PEGylated siRNAs for prolonged multiple gene silencing.
abstract: Many human diseases carry at least two independent gene mutations, further exacerbating clinical disorders. In this work, disulfide bond-conjugated dual PEGylated siRNAs were synthesized, capable of specifically targeting and silencing two genes simultaneously. To achieve efficient delivery, the conjugated siRNAs were formulated with the cationic chitosan together with an anionic polymer, poly(γ-glutamic acid) (γPGA), to form a ternary complex. Experimental results indicate that the incorporated γPGA could significantly enhance their intracellular delivery efficiency, allowing for reduction of the disulfide bond-conjugated PEGylated siRNAs delivered to the PEGylated siRNAs in the reductive cytoplasmic environment. The PEGylated siRNAs could more significantly increase their enzymatic tolerability, effectively silence multiple genes, and prolong the duration of their gene silencing capability than the unmodified siRNAs could. Silencing of different genes simultaneously significantly contributes to the efforts to treat multiple gene disorders, and prolonged duration of gene silencing can reduce the need for frequent administrations.
authors.affiliation: Department of Chemical Engineering and Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan, ROC.
authors.forename: Zi-Xian
authors.initials: ZX
authors.lastname: Liao
authors.forename: Chun-Wen
authors.initials: CW
authors.lastname: Hsiao
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Ho
authors.forename: Hsin-Lung
authors.initials: HL
authors.lastname: Chen
authors.forename: Hsing-Wen
authors.initials: HW
authors.lastname: Sung
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry*; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D006801:Humans; D056004:Molecular Dynamics Simulation; D011092:Polyethylene Glycols / Q000737:chemistry*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology
chemical_list: D034741:RNA, Small Interfering; C511775:poly(gamma-glutamic acid); D011099:Polyglutamic Acid; D011092:Polyethylene Glycols; D048271:Chitosan