Theranostics 2020; 10(13):5778-5789. doi:10.7150/thno.41409 This issue Cite

Research Paper

Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents

Jyoti Roy, Suraj U Hettiarachchi, Miranda Kaake, Ramesh Mukkamala, Philip S Low

Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States.

Citation:
Roy J, Hettiarachchi SU, Kaake M, Mukkamala R, Low PS. Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents. Theranostics 2020; 10(13):5778-5789. doi:10.7150/thno.41409. https://www.thno.org/v10p5778.htm
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Abstract

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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 99mTc 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.

Keywords: Fibroblast activation protein alpha, cancer-associated fibroblast, tumor microenvironment, tubulysin therapy, chemotherapy, optical imaging, SPECT imaging


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APA
Roy, J., Hettiarachchi, S.U., Kaake, M., Mukkamala, R., Low, P.S. (2020). Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents. Theranostics, 10(13), 5778-5789. https://doi.org/10.7150/thno.41409.

ACS
Roy, J.; Hettiarachchi, S.U.; Kaake, M.; Mukkamala, R.; Low, P.S. Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents. Theranostics 2020, 10 (13), 5778-5789. DOI: 10.7150/thno.41409.

NLM
Roy J, Hettiarachchi SU, Kaake M, Mukkamala R, Low PS. Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents. Theranostics 2020; 10(13):5778-5789. doi:10.7150/thno.41409. https://www.thno.org/v10p5778.htm

CSE
Roy J, Hettiarachchi SU, Kaake M, Mukkamala R, Low PS. 2020. Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents. Theranostics. 10(13):5778-5789.

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