ABSTRACT
Acknowledgments ............................................................................................ 325
References ........................................................................................................ 325
Unlike many small molecule drugs, oligonucleotides and short interference RNA
(siRNA) are of too high mass (4000-12,000 Da) to permeate freely into mammalian
cells. In addition, natural DNA and RNA, as well as many oligonucleotide analog
types, carry substantial numbers of negative charges due to their phosphate
backbones, and so are repelled by anionic charges, such as in sulfated
polysaccharides on cell surfaces. Thus, they are not ideal agents to enter cells
either in culture or in vivo. Surprisingly, perhaps, some modified antisense
oligonucleotides, notably those containing phosphorothioate linkages, have been
taken to clinical trials.1,2 The mechanisms by which such oligonucleotides may enter
cells in vivo are not well understood, but their uptake may be mediated by binding to
various serum proteins. By contrast, in cell culture, in order to be useful in gene
silencing or modulation, antisense and siRNA reagents usually require formulation
in some way to enhance their cell uptake and delivery into the cytosol or nucleus.3
