Selective CXCR4+ cancer cell targeting and potent antineoplastic effect by a nanostructured version of recombinant ricin

RAQUEL DÍAZ ; VÍCTOR PALLARÉS ; OLIVIA CANO-GARRIDO ; NAROA SERNA ; LAURA SÁNCHEZ-GARCIA; AÏDA FALGÀS ; MIREIA PESARRODONA1; UGUTZ UNZUETA; ALEJANDRO SÁNCHEZ-CHARDI ; JULIETA M. SÁNCHEZ; ISOLDA CASANOVA ; ESTHER VÁZQUEZ ; RAMÓN MANGUES ; ANTONIO VILLAVERDE

SMALL

WILEY-V C H VERLAG GMBH

Lugar: Weinheim; Año: 2018 vol. 000 p. 1 - 15

1613-6810

Under the unmet need of efficient tumor-targeted drugs for oncology, a recombinant version of the plant toxin ricin (the modular protein T22-mRTA-H6) was engineered to self-assemble as protein-only CXCR4-targeted nanoparticles. The soluble version of the construct self-organized as regular 11 nm-planar entities that were 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 was, contrarily, moderately active, indicating that free, nanostructured protein is the optimal drug form. In animal models of acute myeloid leukemia T22-mRTA-H6 nanoparticles showed an impressive and highly selective therapeutic effect, dramatically reducing the leukemia cells affectation of clinically relevant organs. Functionalised T22-mRTA-H6 nanoparticles are then promising prototypes of chemically homogeneous, highly potent anti-tumor nanostructured toxins for precise oncotherapies based on self-mediated intracellular drug delivery.