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Fatty acid-conjugated radiopharmaceuticals for fibroblast activation protein-targeted radiotherapy

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

An Editorial to this article was published on 25 March 2022

Abstract

Introduction

Radiopharmaceuticals that target cancer-associated fibroblasts (CAFs) have become an increasingly attractive strategy for cancer theranostics. Recently, a series of fibroblast activation protein inhibitor (FAPI)-based radiopharmaceuticals have been successfully applied to the diagnosis of a variety of cancers and exhibited excellent tumor selectivity. Nevertheless, CAF-targeted radionuclide therapy encounters difficulties in cancer treatment, as the tumor uptake and retention of FAPIs are insufficient. To meet this challenge, we tried to conjugate albumin-binding moiety to FAPI molecule for prolonged circulation that may increase the accumulation and retention of radiopharmaceuticals in tumor.

Methods

Two fatty acids, lauric acid (C12) and palmitic acid (C16), were conjugated to FAPI-04 to give two albumin-binding FAPI radiopharmaceuticals, denoted as FAPI-C12 and FAPI-C16, respectively. They had been radiolabeled with gallium-68, yttrium-86, and lutecium-177 for stability study, binding affinity assay, PET and SPECT imaging, biodistribution, and radionuclide therapy study to systematically evaluate their potential for CAF-targeted radionuclide therapy.

Results

FAPI-C12 and FAPI-C16 showed high binding affinity to FAP with the IC50 of 6.80 ± 0.58 nM and 5.06 ± 0.69 nM, respectively. They were stable in both saline and plasma. The tumor uptake of [68Ga]Ga-FAPI-04 decreased by 56.9% until 30 h after treated with FAPI-C16 before, and the uptakes of [86Y]Y-FAPI-C12 and [86Y]Y-FAPI-C16 in HT-1080-FAP tumor were both much higher than that of HT-1080-Vehicle tumor which identified the high FAP specific of these two radiopharmaceuticals. Both FAPI-C12 and FAPI-C16 showed notably longer circulation and significantly enhanced tumor uptake than those of FAPI-04. [177Lu]Lu-FAPI-C16 had the higher tumor uptake at both 24 h (11.22 ± 1.18%IA/g) and 72 h (6.50 ± 1.19%IA/g) than that of [177Lu]Lu-FAPI-C12 (24 h, 7.54 ± 0.97%IA/g; 72 h, 2.62 ± 0.65%IA/g); both of them were much higher than [177Lu]Lu-FAPI-04 with the value of 1.24 ± 0.54%IA/g at 24 h after injection. Significant tumor volume inhibition of [177Lu]Lu-FAPI-C16 at the high activity of 29.6 MBq was observed, and the median survival was 28 days which was much longer than that of the [177Lu]Lu-FAPI-04 treated group of which the median survival was only 10 days.

Conclusion

This proof-of-concept study validates the hypothesis that conjugation of albumin binders may shift the pharmacokinetics and enhance the tumor uptake of FAPI-based radiopharmaceuticals. This could be a general strategy to transform the diagnostic FAP-targeted radiopharmaceuticals into their therapeutic pairs.

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Funding

This work was funded by the Natural Science Foundation of Beijing, China (Grant No. Z200018), the National Science Foundation for Post-doctoral Scientists of China (Grant No. 2020M670047), the Special Foundation of Beijing Municipal Education Commission (Grant No. 3500–12020123), the National Natural Science Foundation of China (No. NSFC U1867209 and No. NSFC 21778003), and the Ministry of Science and Technology of the People’s Republic of China (2017YFA0506300, 2020YFC2002702). Pu Zhang was supported in part by the Postdoctoral Fellowship of Peking-Tsinghua Center for Life Science.

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Correspondence to Li Huo or Zhibo Liu.

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All animal care and experimental procedure were performed following the guidelines of the care and use of laboratory animals approved by the ethics committee of Peking University. This article does not contain any studies with human participants performed by any of the authors.

Conflict of interest

Pu Zhang, Mengxin Xu, Junyi Chen, and Zhibo Liu are the consultant of Borui Biotech. Co. Ltd.

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Zhang, P., Xu, M., Ding, J. et al. Fatty acid-conjugated radiopharmaceuticals for fibroblast activation protein-targeted radiotherapy. Eur J Nucl Med Mol Imaging 49, 1985–1996 (2022). https://doi.org/10.1007/s00259-021-05591-x

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