Cargando…
Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents
Background: Cancer-associated fibroblasts (CAFs) comprise a major cell type in the tumor microenvironment where they support tumor growth and survival by producing extracellular matrix, secreting immunosuppressive cytokines, releasing growth factors, and facilitating metastases. Because tumors with...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254991/ https://www.ncbi.nlm.nih.gov/pubmed/32483418 http://dx.doi.org/10.7150/thno.41409 |
_version_ | 1783539644320710656 |
---|---|
author | Roy, Jyoti Hettiarachchi, Suraj U Kaake, Miranda Mukkamala, Ramesh Low, Philip S |
author_facet | Roy, Jyoti Hettiarachchi, Suraj U Kaake, Miranda Mukkamala, Ramesh Low, Philip S |
author_sort | Roy, Jyoti |
collection | PubMed |
description | Background: Cancer-associated fibroblasts (CAFs) comprise a major cell type in the tumor microenvironment where they support tumor growth and survival by producing extracellular matrix, secreting immunosuppressive cytokines, releasing growth factors, and facilitating metastases. Because tumors with elevated CAFs are characterized by poorer prognosis, considerable effort is focused on developing methods to quantitate, suppress and/or eliminate CAFs. We exploit the elevated expression of fibroblast activation protein (FAP) on CAFs to target imaging and therapeutic agents selectively to these fibroblasts in solid tumors. Methods: FAP-targeted optical imaging, radioimaging, and chemotherapeutic agents were synthesized by conjugating FAP ligand (FL) to either a fluorescent dye, technetium-99m, or tubulysin B hydrazide. In vitro and in vivo studies were performed to determine the specificity and selectivity of each conjugate for FAP in vitro and in vivo. Results: FAP-targeted imaging and therapeutic conjugates showed high binding specificity and affinity in the low nanomolar range. Injection of FAP-targeted (99m)Tc into tumor-bearing mice enabled facile detection of tumor xenografts with little off-target uptake. Optical imaging of malignant lesions was also readily achieved following intravenous injection of FAP-targeted near-infrared fluorescent dye. Finally, systemic administration of a tubulysin B conjugate of FL promoted complete eradication of solid tumors with no evidence of gross toxicity to the animals. Conclusion: In view of the near absence of FAP on healthy cells, we conclude that targeting of FAP on cancer-associated fibroblasts can enable highly specific imaging and therapy of solid tumors. |
format | Online Article Text |
id | pubmed-7254991 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-72549912020-05-31 Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents Roy, Jyoti Hettiarachchi, Suraj U Kaake, Miranda Mukkamala, Ramesh Low, Philip S Theranostics Research Paper Background: Cancer-associated fibroblasts (CAFs) comprise a major cell type in the tumor microenvironment where they support tumor growth and survival by producing extracellular matrix, secreting immunosuppressive cytokines, releasing growth factors, and facilitating metastases. Because tumors with elevated CAFs are characterized by poorer prognosis, considerable effort is focused on developing methods to quantitate, suppress and/or eliminate CAFs. We exploit the elevated expression of fibroblast activation protein (FAP) on CAFs to target imaging and therapeutic agents selectively to these fibroblasts in solid tumors. Methods: FAP-targeted optical imaging, radioimaging, and chemotherapeutic agents were synthesized by conjugating FAP ligand (FL) to either a fluorescent dye, technetium-99m, or tubulysin B hydrazide. In vitro and in vivo studies were performed to determine the specificity and selectivity of each conjugate for FAP in vitro and in vivo. Results: FAP-targeted imaging and therapeutic conjugates showed high binding specificity and affinity in the low nanomolar range. Injection of FAP-targeted (99m)Tc into tumor-bearing mice enabled facile detection of tumor xenografts with little off-target uptake. Optical imaging of malignant lesions was also readily achieved following intravenous injection of FAP-targeted near-infrared fluorescent dye. Finally, systemic administration of a tubulysin B conjugate of FL promoted complete eradication of solid tumors with no evidence of gross toxicity to the animals. Conclusion: In view of the near absence of FAP on healthy cells, we conclude that targeting of FAP on cancer-associated fibroblasts can enable highly specific imaging and therapy of solid tumors. Ivyspring International Publisher 2020-04-27 /pmc/articles/PMC7254991/ /pubmed/32483418 http://dx.doi.org/10.7150/thno.41409 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Roy, Jyoti Hettiarachchi, Suraj U Kaake, Miranda Mukkamala, Ramesh Low, Philip S Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents |
title | Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents |
title_full | Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents |
title_fullStr | Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents |
title_full_unstemmed | Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents |
title_short | Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents |
title_sort | design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254991/ https://www.ncbi.nlm.nih.gov/pubmed/32483418 http://dx.doi.org/10.7150/thno.41409 |
work_keys_str_mv | AT royjyoti designandvalidationoffibroblastactivationproteinalphatargetedimagingandtherapeuticagents AT hettiarachchisuraju designandvalidationoffibroblastactivationproteinalphatargetedimagingandtherapeuticagents AT kaakemiranda designandvalidationoffibroblastactivationproteinalphatargetedimagingandtherapeuticagents AT mukkamalaramesh designandvalidationoffibroblastactivationproteinalphatargetedimagingandtherapeuticagents AT lowphilips designandvalidationoffibroblastactivationproteinalphatargetedimagingandtherapeuticagents |