High-precision targeting and destruction of cancer-associated PDGFR-β+ stromal fibroblasts through self-assembling, protein-only nanoparticles

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-...

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Autores: Voltà-Durán, Eric|||0000-0003-0017-8274, Alba Castellón, Lorena|||0000-0003-3449-7820, Serna, Naroa|||0000-0001-5682-8198, Casanova Rigat, Isolda|||0000-0002-1196-4724, López-Laguna, Hèctor|||0000-0001-5249-8304, Gallardo, Alberto|||0000-0002-2514-2027, Sánchez Chardi, Alejandro|||0000-0002-8789-1883, Villaverde, Antonio|||0000-0002-2615-4521, Unzueta Elorza, Ugutz|||0000-0001-5119-2266, Vázquez, Esther|||0000-0003-1052-0424, Mangues, Ramon|||0000-0003-2661-9525
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:283513
Acceso en línea:https://ddd.uab.cat/record/283513
https://dx.doi.org/urn:doi:10.1016/j.actbio.2023.09.001
Access Level:acceso abierto
Palabra clave:Cancer
Cell targeting
Drug delivery
Nanomedicine
Nanoparticles
Precision medicines
Protein materials
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network_name_str España
repository_id_str
dc.title.none.fl_str_mv High-precision targeting and destruction of cancer-associated PDGFR-β+ stromal fibroblasts through self-assembling, protein-only nanoparticles
title High-precision targeting and destruction of cancer-associated PDGFR-β+ stromal fibroblasts through self-assembling, protein-only nanoparticles
spellingShingle High-precision targeting and destruction of cancer-associated PDGFR-β+ stromal fibroblasts through self-assembling, protein-only nanoparticles
Voltà-Durán, Eric|||0000-0003-0017-8274
Cancer
Cell targeting
Drug delivery
Nanomedicine
Nanoparticles
Precision medicines
Protein materials
title_short High-precision targeting and destruction of cancer-associated PDGFR-β+ stromal fibroblasts through self-assembling, protein-only nanoparticles
title_full High-precision targeting and destruction of cancer-associated PDGFR-β+ stromal fibroblasts through self-assembling, protein-only nanoparticles
title_fullStr High-precision targeting and destruction of cancer-associated PDGFR-β+ stromal fibroblasts through self-assembling, protein-only nanoparticles
title_full_unstemmed High-precision targeting and destruction of cancer-associated PDGFR-β+ stromal fibroblasts through self-assembling, protein-only nanoparticles
title_sort High-precision targeting and destruction of cancer-associated PDGFR-β+ stromal fibroblasts through self-assembling, protein-only nanoparticles
dc.creator.none.fl_str_mv Voltà-Durán, Eric|||0000-0003-0017-8274
Alba Castellón, Lorena|||0000-0003-3449-7820
Serna, Naroa|||0000-0001-5682-8198
Casanova Rigat, Isolda|||0000-0002-1196-4724
López-Laguna, Hèctor|||0000-0001-5249-8304
Gallardo, Alberto|||0000-0002-2514-2027
Sánchez Chardi, Alejandro|||0000-0002-8789-1883
Villaverde, Antonio|||0000-0002-2615-4521
Unzueta Elorza, Ugutz|||0000-0001-5119-2266
Vázquez, Esther|||0000-0003-1052-0424
Mangues, Ramon|||0000-0003-2661-9525
author Voltà-Durán, Eric|||0000-0003-0017-8274
author_facet Voltà-Durán, Eric|||0000-0003-0017-8274
Alba Castellón, Lorena|||0000-0003-3449-7820
Serna, Naroa|||0000-0001-5682-8198
Casanova Rigat, Isolda|||0000-0002-1196-4724
López-Laguna, Hèctor|||0000-0001-5249-8304
Gallardo, Alberto|||0000-0002-2514-2027
Sánchez Chardi, Alejandro|||0000-0002-8789-1883
Villaverde, Antonio|||0000-0002-2615-4521
Unzueta Elorza, Ugutz|||0000-0001-5119-2266
Vázquez, Esther|||0000-0003-1052-0424
Mangues, Ramon|||0000-0003-2661-9525
author_role author
author2 Alba Castellón, Lorena|||0000-0003-3449-7820
Serna, Naroa|||0000-0001-5682-8198
Casanova Rigat, Isolda|||0000-0002-1196-4724
López-Laguna, Hèctor|||0000-0001-5249-8304
Gallardo, Alberto|||0000-0002-2514-2027
Sánchez Chardi, Alejandro|||0000-0002-8789-1883
Villaverde, Antonio|||0000-0002-2615-4521
Unzueta Elorza, Ugutz|||0000-0001-5119-2266
Vázquez, Esther|||0000-0003-1052-0424
Mangues, Ramon|||0000-0003-2661-9525
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cancer
Cell targeting
Drug delivery
Nanomedicine
Nanoparticles
Precision medicines
Protein materials
topic Cancer
Cell targeting
Drug delivery
Nanomedicine
Nanoparticles
Precision medicines
Protein materials
description 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.
publishDate 2023
dc.date.none.fl_str_mv 2
2023-01-01
2023
2023-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/283513
https://dx.doi.org/urn:doi:10.1016/j.actbio.2023.09.001
url https://ddd.uab.cat/record/283513
https://dx.doi.org/urn:doi:10.1016/j.actbio.2023.09.001
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2019-105416RB-I00
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PDC2022-133858I00
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2020-116174RB-I00
Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2021/SGR-00092
Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2021/SGR-01140
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 P21/00150
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI20/00400
Ministerio de Sanidad y Consumo CB06/01/0014
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CP19/00028
Ministerio de Ciencia e Innovación https://doi.org/10.13039/501100004837 FPU18/04615
Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2019/FI_B00352
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling High-precision targeting and destruction of cancer-associated PDGFR-β+ stromal fibroblasts through self-assembling, protein-only nanoparticlesVoltà-Durán, Eric|||0000-0003-0017-8274Alba Castellón, Lorena|||0000-0003-3449-7820Serna, Naroa|||0000-0001-5682-8198Casanova Rigat, Isolda|||0000-0002-1196-4724López-Laguna, Hèctor|||0000-0001-5249-8304Gallardo, Alberto|||0000-0002-2514-2027Sánchez Chardi, Alejandro|||0000-0002-8789-1883Villaverde, Antonio|||0000-0002-2615-4521Unzueta Elorza, Ugutz|||0000-0001-5119-2266Vázquez, Esther|||0000-0003-1052-0424Mangues, Ramon|||0000-0003-2661-9525CancerCell targetingDrug deliveryNanomedicineNanoparticlesPrecision medicinesProtein materialsThe 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. 22023-01-0120232023-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/283513https://dx.doi.org/urn:doi:10.1016/j.actbio.2023.09.001reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2019-105416RB-I00Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PDC2022-133858I00Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2020-116174RB-I00Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2021/SGR-00092Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2021/SGR-01140Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 P21/00150Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI20/00400Ministerio de Sanidad y Consumo CB06/01/0014Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CP19/00028Ministerio de Ciencia e Innovación https://doi.org/10.13039/501100004837 FPU18/04615Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2019/FI_B00352open accesshttp://purl.org/coar/access_right/c_abf2Aquest 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.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2835132026-06-06T12:50:31Z
score 15.300724

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