Selective CXCR4+ Cancer Cell Targeting and Potent Antineoplastic Effect by a Nanostructured Version of Recombinant Ricin

Raquel Díaz, Victor Pallarès, Olivia Cano-Garrido, Naroa Serna, Laura Sánchez-García, Aïda Falgàs, Mireia Pesarrodona, Ugutz Unzueta, Alejandro Sánchez-Chardi, Julieta M. Sánchez, Isolda Casanova, Esther Vázquez, Ramón Mangues, Antonio Villaverde

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

Abstract

© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Under the unmet need of efficient tumor-targeting drugs for oncology, a recombinant version of the plant toxin ricin (the modular protein T22-mRTA-H6) is engineered to self-assemble as protein-only, CXCR4-targeted nanoparticles. The soluble version of the construct self-organizes as regular 11 nm planar entities that are highly cytotoxic in cultured CXCR4+ cancer cells upon short time exposure, with a determined IC50 in the nanomolar order of magnitude. The chemical inhibition of CXCR4 binding sites in exposed cells results in a dramatic reduction of the cytotoxic potency, proving the receptor-dependent mechanism of cytotoxicity. The insoluble version of T22-mRTA-H6 is, contrarily, moderately active, indicating that free, nanostructured protein is the optimal drug form. In animal models of acute myeloid leukemia, T22-mRTA-H6 nanoparticles show an impressive and highly selective therapeutic effect, dramatically reducing the leukemia cells affectation of clinically relevant organs. Functionalized T22-mRTA-H6 nanoparticles are then promising prototypes of chemically homogeneous, highly potent antitumor nanostructured toxins for precise oncotherapies based on self-mediated intracellular drug delivery.
Original languageEnglish
Article number1800665
JournalSmall
Volume14
Issue number26
DOIs
Publication statusPublished - 27 Jun 2018

Keywords

  • acute myeloid leukemia
  • nanoparticles
  • protein engineering
  • self-assembling
  • targeted drug delivery

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