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European Journal of Nuclear Medicine and Molecular Imaging

Erschienen in:

15.08.2022 | Original Article

Hetero-bivalent agents targeting FAP and PSMA

verfasst von: Srikanth Boinapally, Alla Lisok, Gabriela Lofland, Il Minn, Yu Yan, Zirui Jiang, Min Jay Shin, Vanessa F. Merino, Lei Zheng, Cory Brayton, Martin G. Pomper, Sangeeta Ray Banerjee

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 13/2022

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Abstract

Purpose

We developed a theranostic radiopharmaceutical that engages two key cell surface proteases, fibroblast activation protein alpha (FAP) and prostate-specific membrane antigen (PSMA), each frequently overexpressed within the tumor microenvironment (TME). The latter is also expressed in most prostate tumor epithelium. To engage a broader spectrum of cancers for imaging and therapy, we conjugated small-molecule FAP and PSMA-targeting moieties using an optimized linker to provide ⁶⁴Cu-labeled compounds.

Methods

We synthesized FP-L1 and FP-L2 using two linker constructs attaching the FAP and PSMA-binding pharmacophores. We determined in vitro inhibition constants (K_i) for FAP and PSMA. Cell uptake assays and flow cytometry were conducted in human glioma (U87), melanoma (SK-MEL-24), prostate cancer (PSMA + PC3 PIP and PSMA − PC3 flu), and clear cell renal cell carcinoma lines (PSMA + /PSMA − 786-O). Quantitative positron emission tomography/computed tomography (PET/CT) and tissue biodistribution studies were performed using U87, SK-MEL-24, PSMA + PC3 PIP, and PSMA + 786-O experimental xenograft models and the KPC genetically engineered mouse model of pancreatic cancer.

Results

⁶⁴Cu-FP-L1 and ⁶⁴Cu-FP-L2 were produced in high radiochemical yields (> 98%) and molar activities (> 19 MBq/nmol). K_i values were in the nanomolar range for both FAP and PSMA. PET imaging and biodistribution studies revealed high and specific targeting of ⁶⁴Cu-FP-L1 and ⁶⁴Cu-FP-L2 for FAP and PSMA. ⁶⁴Cu-FP-L1 displayed more favorable pharmacokinetics than ⁶⁴Cu-FP-L2. In the U87 tumor model at 2 h post-injection, tumor uptake of ⁶⁴Cu-FP-L1 (10.83 ± 1.02%ID/g) was comparable to ⁶⁴Cu-FAPI-04 (9.53 ± 2.55%ID/g). ⁶⁴Cu-FP-L1 demonstrated high retention 5.34 ± 0.29%ID/g at 48 h in U87 tumor. Additionally, ⁶⁴Cu-FP-L1 showed high retention in PSMA + PC3 PIP tumor (12.06 ± 0.78%ID/g at 2 h and 10.51 ± 1.82%ID/g at 24 h).

Conclusions

⁶⁴Cu-FP-L1 demonstrated high and specific tumor targeting of FAP and PSMA. This compound should enable imaging of lesions expressing FAP, PSMA, or both on the tumor cell surface or within the TME. FP-L1 can readily be converted into a theranostic for the management of heterogeneous tumors.

Graphical abstract

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Titel: Hetero-bivalent agents targeting FAP and PSMA
verfasst von: Srikanth Boinapally
Alla Lisok
Gabriela Lofland
Il Minn
Yu Yan
Zirui Jiang
Min Jay Shin
Vanessa F. Merino
Lei Zheng
Cory Brayton
Martin G. Pomper
Sangeeta Ray Banerjee
Publikationsdatum: 15.08.2022
Verlag: Springer Berlin Heidelberg
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 13/2022
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-022-05933-3

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

Graphical abstract

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