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

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 pl...

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Detalles Bibliográficos
Autores: Díaz, Raquel, Pallarès, Victor|||0000-0002-9851-0345, Cano-Garrido, Olivia|||0000-0002-5504-2131, Serna, Naroa|||0000-0001-5682-8198, Sánchez-García, Laura|||0000-0002-8420-1701, Falgàs, Aïda|||0000-0002-5040-2265, Pesarrodona Roches, Mireia|||0000-0001-9669-8471, Unzueta Elorza, Ugutz|||0000-0001-5119-2266, Sánchez Chardi, Alejandro|||0000-0002-8789-1883, Sánchez, Julieta M.|||0000-0001-6676-5776, Casanova Rigat, Isolda|||0000-0002-1196-4724, Vázquez, Esther|||0000-0003-1052-0424, Mangues, Ramon|||0000-0003-2661-9525, Villaverde, Antonio|||0000-0002-2615-4521
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:236681
Acceso en línea:https://ddd.uab.cat/record/236681
https://dx.doi.org/urn:doi:10.1002/smll.201800665
Access Level:acceso abierto
Palabra clave:Acute myeloid leukemia
Nanoparticles
Protein engineering
Self-assembling
Targeted drug delivery
Descripción
Sumario: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.

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