High-precision targeting and destruction of cancer-associated PDGFR-ß(+) stromal fibroblasts through self-assembling, protein-only nanoparticles.
Por:
Voltà-Durán E, Alba-Castellón L, Serna N, Casanova I, López-Laguna H, Gallardo A, Sánchez-Chardi A, Villaverde A, Unzueta U, Vázquez E, Mangues R
Publicada:
15 oct 2023
Ahead of Print:
6 sep 2023
Resumen:
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 ß (PDGFR-ß)(+) 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-ß-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-ß(+) stromal fibroblasts in a dose-dependent manner, by means of the PDGFR-ß 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-ß/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-ß(+) stromal fibroblasts in a dose-dependent manner, by means of the PDGFR-ß 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-ß/PDGFD pair as a fully versatile toolbox for targeted drug delivery in the tumor microenvironment intended as a synergistic treatment.
Filiaciones:
Voltà-Durán E:
Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain
Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain
CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain
Alba-Castellón L:
CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona 08041, Spain
Josep Carreras Leukaemia Research Institute, Barcelona 08025, Spain. Electronic address:
Serna N:
Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain
Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain
CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain
Casanova I:
CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona 08041, Spain
Josep Carreras Leukaemia Research Institute, Barcelona 08025, Spain
López-Laguna H:
Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain
Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain
CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain
Gallardo A:
Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona 08041, Spain
Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Sánchez-Chardi A:
Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona, Av. Diagonal 643, Barcelona 08028, Spain
Villaverde A:
Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain
Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain
CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain. Electronic address:
Unzueta U:
CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona 08041, Spain
Josep Carreras Leukaemia Research Institute, Barcelona 08025, Spain
Vázquez E:
Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain
Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain
CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain
Mangues R:
CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona 08041, Spain
hybrid, All Open Access; Hybrid Gold
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