Conversion of RNA Aptamer into Modified DNA Aptamers Provides for Prolonged Stability and Enhanced Antitumor Activity

Paola Amero, Ganesh L.R. Lokesh, Rajan R. Chaudhari, Roberto Cardenas-Zuniga, Thomas Schubert, Yasmin M. Attia, Efigenia Montalvo-Gonzalez, Abdelrahman M. Elsayed, Cristina Ivan, Zhihui Wang, Vittorio Cristini, Vittorio De Franciscis, Shuxing Zhang, David E. Volk, Rahul Mitra, Cristian Rodriguez-Aguayo, Anil K. Sood, Gabriel Lopez-Berestein

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Aptamers, synthetic single-strand oligonucleotides that are similar in function to antibodies, are promising as therapeutics because of their minimal side effects. However, the stability and bioavailability of the aptamers pose a challenge. We developed aptamers converted from RNA aptamer to modified DNA aptamers that target phospho-AXL with improved stability and bioavailability. On the basis of the comparative analysis of a library of 17 converted modified DNA aptamers, we selected aptamer candidates, GLB-G25 and GLB-A04, that exhibited the highest bioavailability, stability, and robust antitumor effect in in vitro experiments. Backbone modifications such as thiophosphate or dithiophosphate and a covalent modification of the 5′-end of the aptamer with polyethylene glycol optimized the pharmacokinetic properties, improved the stability of the aptamers in vivo by reducing nuclease hydrolysis and renal clearance, and achieved high and sustained inhibition of AXL at a very low dose. Treatment with these modified aptamers in ovarian cancer orthotopic mouse models significantly reduced tumor growth and the number of metastases. This effective silencing of the phospho-AXL target thus demonstrated that aptamer specificity and bioavailability can be improved by the chemical modification of existing aptamers for phospho-AXL. These results lay the foundation for the translation of these aptamer candidates and companion biomarkers to the clinic.

Original languageEnglish (US)
Pages (from-to)7655-7670
Number of pages16
JournalJournal of the American Chemical Society
Volume143
Issue number20
DOIs
StatePublished - May 26 2021

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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