High-precision targeting and destruction of cancer-associated PDGFR-β+ stromal fibroblasts through self-assembling, protein-only nanoparticles
Voltà-Durán, Eric (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Alba-Castellón, Lorena (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Serna, Naroa (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Casanova Rigat, Isolda (Institut d'Investigació Biomèdica Sant Pau)
López-Laguna, Hèctor (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Gallardo, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Sánchez Chardi, Alejandro (Universitat de Barcelona. Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals)
Villaverde Corrales, Antonio (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Unzueta Elorza, Ugutz (Institut d'Investigació Biomèdica Sant Pau)
Vázquez Gómez, Esther (Universitat de Barcelona. Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals)
Mangues, Ramon 1957- (Institut d'Investigació Biomèdica Sant Pau)

Date:	2023
Abstract:	The need for more effective and precision medicines for cancer has pushed the exploration of new materials appropriate for drug delivery and imaging, and alternative receptors for targeting. Among the most promising strategies, finding suitable cell surface receptors and targeting agents for cancer-associated platelet derived growth factor receptor β (PDGFR-β)+ stromal fibroblasts is highly appealing. As a neglected target, this cell type mechanically and biologically supports the growth, progression, and infiltration of solid tumors in non-small cell lung, breast, pancreatic, and colorectal cancers. We have developed a family of PDGFR-β-targeted nanoparticles based on biofabricated, self-assembling proteins, upon hierarchical and iterative selective processes starting from four initial candidates. The modular protein PDGFD-GFP-H6 is well produced in recombinant bacteria, resulting in structurally robust oligomeric particles that selectively penetrates into PDGFR-β+ stromal fibroblasts in a dose-dependent manner, by means of the PDGFR-β ligand PDGFD. Upon in vivo administration, these GFP-carrying protein nanoparticles precisely accumulate in tumor tissues and enlighten them for IVIS observation. When GFP is replaced by a microbial toxin, selective tumor tissue destruction is observed associated with a significant reduction in tumor volume growth. The presented data validate the PDGFR-β/PDGFD pair as a promising toolbox for targeted drug delivery in the tumor microenvironment and oligomeric protein nanoparticles as a powerful instrument to mediate highly selective biosafe targeting in cancer through non-cancer cells. Statement of significance: We have developed a transversal platform for nanoparticle-based drug delivery into cancer-associated fibroblasts. This is based on the engineered modular protein PDGFD-GFP-H6 that spontaneously self-assemble and selectively penetrates into PDGFR-β+ stromal fibroblasts in a dose-dependent manner, by means of the PDGFR-β ligand PDGFD. In vivo, these protein nanoparticles accumulate in tumor and when incorporating a microbial toxin, they destroy tumor tissues with a significant reduction in tumor volume, in absence of side toxicities. The data presented here validate the PDGFR-β/PDGFD pair as a fully versatile toolbox for targeted drug delivery in the tumor microenvironment intended as a synergistic treatment.
Grants:	Agencia Estatal de Investigación PID2019-105416RB-I00 Agencia Estatal de Investigación PDC2022-133858I00 Agencia Estatal de Investigación PID2020-116174RB-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-00092 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-01140 Instituto de Salud Carlos III P21/00150 Instituto de Salud Carlos III PI20/00400 Ministerio de Sanidad y Consumo CB06/01/0014 Instituto de Salud Carlos III CP19/00028 Ministerio de Ciencia e Innovación FPU18/04615 Agència de Gestió d'Ajuts Universitaris i de Recerca 2019/FI_B00352
Note:	Altres ajuts: acords transformatius de la UAB
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Cancer ; Cell targeting ; Drug delivery ; Nanomedicine ; Nanoparticles ; Precision medicines ; Protein materials
Published in:	Acta biomaterialia, Vol. 170 (October 2023) , p. 543-555, ISSN 1742-7061

DOI: 10.1016/j.actbio.2023.09.001
PMID: 37683965

13 p, 4.1 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