Development of Fibroblast Activation Protein–Targeted Radiotracers with Improved Tumor Retention
Anastasia Loktev,Anastasia Loktev,Thomas Lindner,Eva Maria Burger,Annette Altmann,Annette Altmann,Frederik L. Giesel,Clemens Kratochwil,Jürgen Debus,Jürgen Debus,Frederik Marmé,Dirk Jäger,Walter Mier,Uwe Haberkorn +13 more
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In this paper, quinoline-based radiotracers were synthesized by organic chemistry and evaluated in radioligand binding assays using FAP-expressing HT-1080 cells.Abstract:
Cancer-associated fibroblasts constitute a vital subpopulation of the tumor stroma and are present in more than 90% of epithelial carcinomas. The overexpression of the serine protease fibroblast activation protein (FAP) allows a selective targeting of a variety of tumors by inhibitor-based radiopharmaceuticals (FAPIs). Of these compounds, FAPI-04 has been recently introduced as a theranostic radiotracer and demonstrated high uptake into different FAP-positive tumors in cancer patients. To enable the delivery of higher doses, thereby improving the outcome of a therapeutic application, several FAPI variants were designed to further increase tumor uptake and retention of these tracers. Methods: Novel quinoline-based radiotracers were synthesized by organic chemistry and evaluated in radioligand binding assays using FAP-expressing HT-1080 cells. Depending on their in vitro performance, small-animal PET imaging and biodistribution studies were performed on HT-1080-FAP tumor–bearing mice. The most promising compounds were used for clinical PET imaging in 8 cancer patients. Results: Compared with FAPI-04, 11 of 15 FAPI derivatives showed improved FAP binding in vitro. Of these, 7 compounds demonstrated increased tumor uptake in tumor-bearing mice. Moreover, tumor–to–normal-organ ratios were improved for most of the compounds, resulting in images with higher contrast. Notably two of the radiotracers, FAPI-21 and -46, displayed substantially improved ratios of tumor to blood, liver, muscle, and intestinal uptake. A first diagnostic application in cancer patients revealed high intratumoral uptake of both radiotracers already 10 min after administration but a higher uptake in oral mucosa, salivary glands, and thyroid for FAPI-21. Conclusion: Chemical modification of the FAPI framework enabled enhanced FAP binding and improved pharmacokinetics in most of the derivatives, resulting in high-contrast images. Moreover, higher doses of radioactivity can be delivered while minimizing damage to healthy tissue, which may improve therapeutic outcome.read more
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Research progress on the role of fibroblast activation protein in diagnosis and treatment of cancer
TL;DR: The characteristics of FAP and its role in the occurrence and development of cancer are described and the potential value of targeting FAP is highlighted to improve current diagnostic and therapeutic approaches.
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Organotrifluoroborate enhances tumor targeting of fibroblast activation protein inhibitors for targeted radionuclide therapy
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Research progress on the role of fibroblast activation protein in diagnosis and treatment of cancer
Zhaoye Wu,S. B. Rosenfeld +1 more
TL;DR: In this article , the characteristics of FAP and its role in the occurrence and development of cancer are described and the potential value of targeting FAP to improve current diagnostic and therapeutic approaches.
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Benign lesions with 68Ga-FAPI uptake: a retrospective study.
TL;DR: In this article , the authors retrospectively analyzed the characteristics of benign lesions with FAPI uptake on 68Ga-FAPI PET/CT imaging in the Department of Nuclear Medicine of our hospital.
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Fibroblast Activation Protein Triggers Release of Drug Payload from Non-internalizing Small Molecule Drug Conjugates in Solid Tumors
TL;DR: In this article , a new series of OncoFAP-Drug derivatives based on monomethyl auristatin E (MMAE; a potent cytotoxic tubulin poison) and dipeptide linkers are selectively cleaved by FAP in the tumor microenvironment.
References
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The biology and function of fibroblasts in cancer
TL;DR: Cancer-associated fibroblasts (CAFs) become synthetic machines that produce many different tumour components and have a role in creating extracellular matrix structure and metabolic and immune reprogramming of the tumour microenvironment with an impact on adaptive resistance to chemotherapy.
Journal ArticleDOI
Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake
TL;DR: Through CD8+ T cell-mediated killing of tumor-associated fibroblasts, this vaccine successfully suppressed primary tumor cell growth and metastasis of multidrug-resistant murine colon and breast carcinoma and opens a new venue for the combination of immuno- and chemotherapies.
Journal ArticleDOI
Development of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein
Thomas Lindner,Anastasia Loktev,Anastasia Loktev,Anastasia Loktev,Annette Altmann,Annette Altmann,Frederik L. Giesel,Clemens Kratochwil,Jürgen Debus,Jürgen Debus,Dirk Jäger,Walter Mier,Uwe Haberkorn +12 more
TL;DR: FAPI-04 represents a promising tracer for both diagnostic imaging and, possibly, targeted therapy of malignant tumors with a high content of activated fibroblasts, such as breast cancer.
Journal ArticleDOI
68Ga-FAPI PET/CT: Biodistribution and Preliminary Dosimetry Estimate of 2 DOTA-Containing FAP-Targeting Agents in Patients with Various Cancers.
Frederik L. Giesel,Clemens Kratochwil,Thomas Lindner,Manfred M. Marschalek,Anastasia Loktev,Wencke Lehnert,Jürgen Debus,Jürgen Debus,Dirk Jäger,Paul Flechsig,Annette Altmann,Walter Mier,Uwe Haberkorn +12 more
TL;DR: FAPI PET/CT is a new diagnostic method in imaging cancer patients in contrast to 18F-FDG, no diet or fasting in preparation for the examination is necessary, and image acquisition can potentially be started a few minutes after tracer application.
Journal ArticleDOI
A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts.
Anastasia Loktev,Anastasia Loktev,Anastasia Loktev,Thomas Lindner,Walter Mier,Jürgen Debus,Jürgen Debus,Annette Altmann,Annette Altmann,Dirk Jäger,Frederik L. Giesel,Clemens Kratochwil,Philippe Barthe,Christian Roumestand,Uwe Haberkorn,Uwe Haberkorn +15 more
TL;DR: Radiolabeled FAPIs allow fast imaging with very high contrast in tumors having a high stromal content and may therefore serve as pantumor agents.
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