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J. Biol. Chem., Vol. 276, Issue 52, 48644-48654, December 28, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/52/48644    most recent M104651200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hicke, B. J. Articles by Warren, S. Search for Related Content PubMed PubMed Citation Articles by Hicke, B. J. Articles by Warren, S. Social Bookmarking                      What's this?

Tenascin-C Aptamers Are Generated Using Tumor Cells and Purified Protein^*

Brian J. Hicke^§, Chris Marion, Ying-Fon Chang, Ty Gould^¶, Cynthia K. Lynott, David Parma^**, Paul G. Schmidt, and Steve Warren^§§

From  SomaLogic, Boulder, Colorado 80301, the ^¶ Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262,  Novus Biologicals, Littleton, Colorado 80160, the ^** Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309,  PR Pharmaceuticals Inc., Ft. Collins, Colorado 80524, and ^§§ IOMED, Inc., Salt Lake City, Utah 84120

Tenascin-C (TN-C) is an extracellular matrix protein that is overexpressed during tissue remodeling processes, including tumor growth. To identify an aptamer for testing as a tumor-selective ligand, SELEX (systematic evolution of ligands by exponential enrichment) procedures were performed using both TN-C and TN-C-expressing U251 glioblastoma cells. The different selection techniques yielded TN-C aptamers that are related in sequence. In addition, a crossover procedure that switched from tumor cell to purified protein selections was effective in isolating two high-affinity TN-C aptamers. When targeting tumor cells in vitro, the observed propensity of naive oligonucleotide pools to evolve TN-C aptamers may be due to the abundance of this protein. In vivo, TN-C abundance may also be well suited for aptamer accumulation in the tumor milieu. A size-minimized and nuclease-stabilized aptamer, TTA1, binds to the fibrinogen-like domain of TN-C with an equilibrium dissociation constant (K_d) of 5 × 10⁹ M. At 13 kDa, this aptamer is intermediate in size between peptides and single chain antibody fragments, both of which are superior to antibodies for tumor targeting because of their smaller size. TTA1 defines a new class of ligands that are intended for targeted delivery of radioisotopes or chemical agents to diseased tissues.

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