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European Journal of Nuclear Medicine and Molecular Imaging

Erschienen in:

26.01.2024 | Original Article

Peptidic heterodimer-based radiotracer targeting fibroblast activation protein and integrin α_vβ₃

verfasst von: Kehuang Liu, Tao Jiang, Wanqian Rao, Bei Chen, Xiaoqin Yin, Pengfei Xu, Shuo Hu

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 6/2024

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Abstract

Purpose

Several studies have demonstrated the advantages of heterodimers over their corresponding monomers due to the multivalency effect. This effect leads to an increased number of effective targeted receptors and, consequently, improved tumor uptake. Fibroblast activation protein (FAP) and integrin α_vβ₃ are found to be overexpressed in different components of the tumor microenvironment. In our pursuit of enhancing tumor uptake and retention, we designed and developed a novel peptidic heterodimer that synergistically targets both FAP and integrin α_vβ₃.

Methods

FAP-RGD was synthesized from FAP-2286 and c(RGDfK) through a multi-step organic synthesis. The dual receptor binding property of ⁶⁸Ga-FAP-RGD was investigated by cell uptake and competitive binding assays. Preclinical pharmacokinetics were determined in HT1080-FAP and U87MG tumor models using micro-positron emission tomography/computed tomography (micro-PET/CT) and biodistribution studies. The antitumor efficacy of ¹⁷⁷Lu-FAP-RGD was assessed in U87MG tumor models. The radiation exposure and clinical diagnostic performance of ⁶⁸ Ga-FAP-RGD were evaluated in healthy volunteers and cancer patients.

Results

Bi-specific radiotracer ⁶⁸Ga-FAP-RGD exhibited high binding affinity for both FAP and integrin α_vβ₃. In comparison to ⁶⁸Ga-FAP-2286 and ⁶⁸Ga-RGDfK, ⁶⁸Ga-FAP-RGD displayed enhanced tumor uptake and longer tumor retention time in preclinical models. ¹⁷⁷Lu-FAP-RGD could efficiently suppress the growth of U87MG tumor in vivo when applied at an activity of 18.5 and 29.6 MBq. The effective dose of ⁶⁸Ga-FAP-RGD was 1.06 × 10⁻² mSv/MBq. ⁶⁸Ga-FAP-RGD demonstrated low background activity and stable accumulation in most neoplastic lesions up to 3 h.

Conclusion

Taking the advantages of multivalency effect, the bi-specific radiotracer ⁶⁸Ga-FAP-RGD showed superior tumor uptake and retention compared to its corresponding monomers. Preclinical studies with ⁶⁸Ga- or ¹⁷⁷Lu-labeled FAP-RGD showed favorable image contrast and effective antitumor responses. Despite the excellent performance of ⁶⁸Ga-FAP-RGD in clinical diagnosis, experimental efforts are currently underway to optimize the structure of FAP-RGD to increase its potential for clinical application in endoradiotherapy.

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Titel: Peptidic heterodimer-based radiotracer targeting fibroblast activation protein and integrin αvβ3
verfasst von: Kehuang Liu
Tao Jiang
Wanqian Rao
Bei Chen
Xiaoqin Yin
Pengfei Xu
Shuo Hu
Publikationsdatum: 26.01.2024
Verlag: Springer Berlin Heidelberg
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 6/2024
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-024-06623-y

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

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Peptidic heterodimer-based radiotracer targeting fibroblast activation protein and integrin α_vβ₃

Abstract

Purpose

Methods

Results

Conclusion

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

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