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Nucleic Acids Research 2004 32(19):5757-5765; doi:10.1093/nar/gkh862
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Published online 27 October 2004

Nucleic Acids Research, Vol. 32 No. 19 © Oxford University Press 2004; all rights reserved

Application of locked nucleic acids to improve aptamer in vivo stability and targeting function

Kathrin S. Schmidt, Sandra Borkowski1, Jens Kurreck, Andrew W. Stephens1, Rolf Bald, Maren Hecht1, Matthias Friebe1, Ludger Dinkelborg1 and Volker A. Erdmann*

Institute of Chemistry (Biochemistry), Free University Berlin, Thielallee 63, D-14195 Berlin, Germany and 1 Research Laboratories Schering AG, 13342 Berlin, Germany

* To whom correspondence should be addressed. Tel: +49 30 83856002; Fax: +49 30 83856413; Email: erdmann{at}chemie.fu-berlin.de

Received June 25, 2004; Revised August 27, 2004; Accepted September 14, 2004

Aptamers are powerful candidates for molecular imaging applications due to a number of attractive features, including rapid blood clearance and tumor penetration. We carried out structure–activity relationship (SAR) studies with the Tenascin-C binding aptamer TTA1, which is a promising candidate for application in tumor imaging with radioisotopes. The aim was to improve its in vivo stability and target binding. We investigated the effect of thermal stabilization of the presumed non-binding double-stranded stem region on binding affinity and resistance against nucleolytic degradation. To achieve maximal thermal stem stabilization melting experiments with model hexanucleotide duplexes consisting of unmodified RNA, 2'-O-methyl RNA (2'-OMe), 2'-Fluoro RNA (2'-F) or Locked Nucleic Acids (LNAs) were initially carried out. Extremely high melting temperatures have been found for an LNA/LNA duplex. TTA1 derivatives with LNA and 2'-OMe modifications within the non-binding stem have subsequently been synthesized. Especially, the LNA-modified TTA1 derivative exhibited significant stem stabilization and markedly improved plasma stability while maintaining its binding affinity to the target. In addition, higher tumor uptake and longer blood retention was found in tumor-bearing nude mice. Thus, our strategy to introduce LNA modifications after the selection procedure is likely to be generally applicable to improve the in vivo stability of aptamers without compromising their binding properties.


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