title: Co-delivery of small interfering RNA and plasmid DNA using a polymeric vector incorporating endosomolytic oligomeric sulfonamide.
abstract: Cationic polymers are potential intracellular carriers for small interfering RNA (siRNA). The short and rigid nature of an siRNA chain often results in larger and more loosely packed particles compared to plasmid DNA (pDNA) after complexing with carrier polycations, and in turn, poor silencing effects are seen against the target mRNAs. A helper polyanion, pDNA, was incorporated along with siRNA to form compact nanosized polyplexes. At C/A (cation/anion) ratios of 2 and 5, poly(l-lysine) (PLL)/siRNA-pGFP and PLL/siRNA-pGFP-OSDZ (oligomeric sulfadiazine (OSDZ) for endosomolysis) complexes produced particles 90-150 nm in size with a 15-45 mV surface charge, while PLL/siRNA complexes yielded particles 1-2 μm in size at the same C/A ratios. The PLL/siRNA-pGFP (C/A 2) complexes showed significantly higher specific gene silencing (50-90% vs. 10-25%) than the complexes formed at C/A 5. PLL/siRNA-pGFP-OSDZ (C/A 2) complexes improved the specific gene silencing (90%) more dramatically than PLL/siRNA-pGFP (C/A 2) complexes (50%), demonstrating a potential role for OSDZ. PLL/siRNA-pGFP-OSDZ (C/A 2) complexes sustained higher specific gene silencing compared with PLL/siRNA-pGFP (C/A 2) complexes. Other oligomeric sulfonamides (OSA) with varying pK(a) used in PLL/siRNA-pGFP-OSA complexes also caused effective gene silencing. The pGFP in the PLL/siRNA-pGFP complexes successfully expressed GFP protein without interfering with the siRNA. In conclusion, this study demonstrates that long pDNA helps effectively form nanosized siRNA particles and that OSA enhances specific gene silencing. In a single nucleic acid carrier formulation, co-delivery of siRNA and pDNA is feasible to maximize therapeutic effects or to include therapeutic or diagnostic functionalities.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, The University of Utah, 421 Wakara way, Suite 318, Salt Lake City, UT 84108, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Chang Kang
authors.forename: You Han
authors.initials: YH
authors.lastname: Bae
mesh_terms: D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D020868:Gene Silencing; D005822:Genetic Vectors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008422:Materials Testing; D010957:Plasmids / Q000235:genetics* / Q000378:metabolism; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism; D000071228:Polyelectrolytes; D011108:Polymers / Q000737:chemistry / Q000378:metabolism; D034741:RNA, Small Interfering / Q000737:chemistry / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D004247:DNA; D004337:Drug Carriers; D008164:Luminescent Proteins; D011073:Polyamines; D000071228:Polyelectrolytes; D011108:Polymers; D034741:RNA, Small Interfering; D013449:Sulfonamides