Selective CXCR4+ Cancer Cell Targeting and Potent Antineoplastic Effect by a Nanostructured Version of Recombinant Ricin
Díaz, Raquel (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Pallarès, Victor (Institut d'Investigació Biomèdica Sant Pau)
Cano-Garrido, Olivia (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Serna, Naroa (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Sánchez-García, Laura (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Falgàs, Aïda (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Pesarrodona Roches, Mireia (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Unzueta Elorza, Ugutz (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Sánchez Chardi, Alejandro (Universitat Autònoma de Barcelona. Servei de Microscòpia)
Sanchez, Julieta M. (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Casanova Rigat, Isolda (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Vázquez Gómez, Esther (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Mangues, Ramon 1957- (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Villaverde Corrales, Antonio (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)

Date:	2018
Abstract:	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.
Grants:	Ministerio de Ciencia e Innovación BIO2016-76063-R Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-229 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/FI_B100063 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/FI_B00680I
Note:	Altres ajuts: CIBER-BBN (project VENOM4CANCER) granted to A.V. The authors are also indebted to the Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) that is an initiative funded by the VI National R&D&I Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III, with assistance from the European Regional Development Fund. Protein production was partially performed by the ICTS "NANBIOSIS," more specifically by the Protein Production Platform of CIBER-BBN/ IBB (http://www.nanbiosis.es/unit/u1-protein-production-platform-ppp/) and the nanoparticle size analysis by the Biomaterial Processing and Nanostructuring Unit. The authors are also indebted to SCAC (UAB) for cell culture facilities and assistance. R.D. received an overseas predoctoral fellowship from Conacyt (Gobierno de México, 2016). N.S. was supported by a predoctoral fellowship from the Government of Navarra, V.P. received a postdoctoral fellowship from the Spanish Foundation of Hematology and Hemotherapy (FEHH), and U.U. a Sara Borrell postdoctoral fellowship from ISCIII. A.V. holds an ICREA ACADEMIA award.
Rights:	Aquest material està protegit per drets d'autor i/o drets afins. Podeu utilitzar aquest material en funció del que permet la legislació de drets d'autor i drets afins d'aplicació al vostre cas. Per a d'altres usos heu d'obtenir permís del(s) titular(s) de drets.
Language:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Subject:	Acute myeloid leukemia ; Nanoparticles ; Protein engineering ; Self-assembling ; Targeted drug delivery
Published in:	Small (Weinheim), Vol. 14, issue 26 (June 2018) , art. 1800665, ISSN 1613-6829

DOI: 10.1002/smll.201800665
PMID: 29845742

Postprint 34 p, 1.2 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles