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Home > Science, Technology & Agriculture > Technology: general issues > Interplay of Polymer and Oligonucleotide Properties in the Nature of Antisense Effects.
Interplay of Polymer and Oligonucleotide Properties in the Nature of Antisense Effects.

Interplay of Polymer and Oligonucleotide Properties in the Nature of Antisense Effects.


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About the Book

Antisense oligonucleotides can be utilized to silence the expression of a target gene via sequence-specific complementary base pairing. Antisense technology is applied as a basic research tool and is being developed therapeutically for a wide range of indications including cancer, inflammatory diseases and viral diseases. Its widespread application is impeded by the poor cellular delivery of oligonucleotides (ONs). Rational design of carriers for enhanced ON delivery demands a better understanding of the role of the vector on the extent and time course of antisense effects. This work highlights the interplay of polymer and ON properties in the nature of polymer mediated antisense responses. First, we demonstrate that ON structure exerts a significant influence on the strength of ON binding to, and dissociation from, the cationic polymer, poly-L-lysine. The finding implicates secondary structure as a relevant design parameter for antisense ONs and stresses the need for a comprehensive evaluation of ON-polymer structure-activity effects. Next, using well-characterized cationic polymer polyethyleneimine (PEI), we focus on understanding the effects of polymer molecular weight (MW) and ON backbone chemistry on antisense activity. We measure physico-chemical properties of complexes between PEI and phosphodiester and phosphorothioate backbone ONs, and evaluate their ability to deliver ONs to cells, leading to an antisense response. Our key finding is that the antisense activity is not determined solely by PEI MW or by ON chemistry, but rather by the interplay of both factors. Of particular importance is the strength of interactions between the carrier and the ON, which determines the rate at which the ONs are delivered intracellularly. Finally, we utilize the chemistry of the ONs as a means to influence the strength of interactions between PEI and ONs, and hence control the final antisense response. We show that it is possible to improve dramatically the efficiency of lower PEI MWs as ON carriers by manipulating the degree of phosphorothioate substitution in the ON chemistry. By correlating the PEI MW & ON chemistry with the observed antisense effects, we draw insightful structure-property relationships that will aid the rational design of ON carriers.


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Product Details
  • ISBN-13: 9781243601674
  • Publisher: Proquest, Umi Dissertation Publishing
  • Publisher Imprint: Proquest, Umi Dissertation Publishing
  • Height: 254 mm
  • Weight: 318 gr
  • ISBN-10: 1243601671
  • Publisher Date: 01 Sep 2011
  • Binding: Paperback
  • Spine Width: 10 mm
  • Width: 203 mm


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Interplay of Polymer and Oligonucleotide Properties in the Nature of Antisense Effects.
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Interplay of Polymer and Oligonucleotide Properties in the Nature of Antisense Effects.
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