Collaborative membrane activity and receptor-dependent tumor cell targeting for precise nanoparticle delivery in CXCR4+ colorectal cancer
Sala, Rita (Institut d'Investigació Biomèdica Sant Pau)
Sánchez-García, Laura (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Serna, Naroa (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Céspedes, María Virtudes (Institut d'Investigació Biomèdica Sant Pau)
Casanova Rigat, Isolda (Institut d'Investigació Biomèdica Sant Pau)
Roldán, Mònica (Institut de Recerca Sant Joan de Déu)
Sánchez Chardi, Alejandro (Universitat de Barcelona. Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals)
Unzueta Elorza, Ugutz (Institut d'Investigació Biomèdica Sant Pau)
Vázquez Gómez, Esther (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Mangues, Ramon 1957- (Institut d'Investigació Biomèdica Sant Pau)
Villaverde Corrales, Antonio (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)

Date:	2019
Abstract:	By the appropriate selection of functional peptides and proper accommodation sites, we have generated a set of multifunctional proteins that combine selectivity for CXCR4 cell binding and relevant endosomal escape capabilities linked to the viral peptide HA2. In particular, the construct T22-GFP-HA2-H6 forms nanoparticles that upon administration in mouse models of human, CXCR4 colorectal cancer, accumulates in primary tumor at levels significantly higher than the parental T22-GFP-H6 HA2-lacking version. The in vivo application of a CXCR4 antagonist has confirmed the prevalence of the CXCR4 tumor tissue selectivity over unspecific cell penetration, upon systemic administration of the material. Such specificity is combined with improved endosomal escape, what overall results in a precise and highly efficient tumor biodistribution. These data strongly support the functional recruitment as a convenient approach to generate protein materials for clinical applications. More precisely, they also support the unexpected concept that enhancing the unspecific membrane activity of a protein material does not necessarily compromise, but it can even improve, the selective cell targeting offered by an accompanying functional module. Statement of Significance: We have shown here that the combination of cell-penetrating and tumor cell-targeting peptides dramatically enhances precise tumor accumulation of protein-only nanoparticles intended for selective drug delivery, in mouse models of human colorectal cancer. This fact is a step forward for the rational design of multifunctional protein nanomaterials for improved cancer therapies.
Grants:	Ministerio de Ciencia e Innovación BIO2016-76063-R Instituto de Salud Carlos III PI15/00272 Instituto de Salud Carlos III PI18/00650 Instituto de Salud Carlos III FI16/00017 Agència de Gestió d'Ajuts Universitaris i de Recerca 2018FI_B2_00051 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-865 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-229
Note:	Altres ajuts: EU COST Action CA 17140. AV received an ICREA ACADEMIA award.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Subject:	Protein materials ; Self-assembling ; Fusogenic peptide ; Colorectal cancer ; CXCR4 ; Active targeting
Published in:	Acta Biomaterialia, Vol. 99 (Nov. 2019) , p. 426-432, ISSN 1878-7568

DOI: 10.1016/j.actbio.2019.09.002
PMID: 31494293

Article. Postprint 24 p, 1.0 MB	Figura 1 1 p, 187.6 KB	Figura 2 1 p, 116.9 KB	Figura 3 1 p, 216.7 KB	Figura 4 1 p, 180.9 KB	Figura 5 1 p, 552.3 KB
Figura 6 1 p, 248.4 KB	Figura 9 1 p, 228.6 KB	Figura 10 1 p, 1.0 MB

The record appears in these collections:
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