Achieving efficient in vivo delivery of siRNA to the appropriate target cell would be a major advance in the use of RNAi in gene function studies and as a therapeutic modality. Hepatocytes, the key parenchymal cells of the liver, are a particularly attractive target cell type for siRNA delivery given their central role in several infectious and metabolic disorders. We have developed a vehicle for the delivery of siRNA to hepatocytes both in vitro and in vivo, which we have named siRNA Dynamic PolyConjugates. Key features of the Dynamic PolyConjugate technology include a membrane-active polymer, the ability to reversibly mask the activity of this polymer until it reaches the acidic environment of endosomes, and the ability to target this modified polymer and its siRNA cargo specifically to hepatocytes in vivo after simple, low-pressure i.v. injection. Using this delivery technology, we demonstrate effective knockdown of two endogenous genes in mouse liver: apolipoprotein B (apoB) and peroxisome proliferator-activated receptor alpha (ppara). Knockdown of apoB resulted in clear phenotypic changes that included a significant reduction in serum cholesterol and increased fat accumulation in the liver, consistent with the known functions of apoB. Knockdown of ppara also resulted in a phenotype consistent with its known function, although with less penetrance than observed in apoB knockdown mice. Analyses of serum liver enzyme and cytokine levels in treated mice indicated that the siRNA Dynamic PolyConjugate was nontoxic and well tolerated.pH labile bonds ͉ nonviral siRNA delivery ͉ siRNA-polymer conjugates ͉ endosomolytic polymers
A series of 3-halo-substituted bicyclo[1.1.1]pentane-1-carboxylic acids 1 (Y = COOH; X = F, Cl, Br, I, and CF(3)) as well as the parent compound 1 (Y = COOH, X = H) have been prepared, and a study of some of their properties have been made. It was found that their reactions with xenon difluoride cover a wide range of reactivities. On one hand, the fluoro acid 1 (Y = COOH, X = F) displayed no apparent reaction at all while, on the other, the bromo acid 1 (Y = COOH, X = Br) and parent compound 1 (Y = COOH, X = H) underwent ready reaction with complete disintegration of the ring system. A possible explanation is advanced based on polar kinetic and thermodynamic effects governing the lifetime of an intermediate acyloxy radical species. The relative ease of oxidation of the carboxylates 1 (Y = COO(-); X = H, F, Cl, Br, I, CF(3), and COOCH(3)), as mirrored by their peak oxidation potential values (E(p)) determined by cyclic voltammetry, also covers a wide range. These data coupled with the dissociation constants (pK(a)) of some of the acids 1 (Y = COOH; X = H, F, Cl, and CF(3)) reflect significantly on the modes of transmission of electronic effects acting through the bicyclo[1.1.1]pentane ring system.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.