<sup>177</sup>Lu-Labeled Albumin-Binder–Conjugated PSMA-Targeting Agents with Extremely High Tumor Uptake and Enhanced Tumor-to-Kidney Absorbed Dose Ratio

Kuo, Hsing‐Chun; Lin, Kuo-Chi; Zhang, Zhengxing; Uribe, Carlos; Merkens, Helen; Zhang, Chengcheng; Bénard, François

doi:10.2967/jnumed.120.250738

Cited by 59 publications

(109 citation statements)

References 31 publications

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“…4-(piodophenyl) butyric acid and truncated Evans blue moieties are the most widely used albumin binders. The previous studies suggest that they can enhance the tumor uptake and retention of radiopharmaceuticals, resulting in improved therapeutic efficacy (18)(19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

Albumin Binder–Conjugated Fibroblast Activation Protein Inhibitor Radiopharmaceuticals for Cancer Therapy

Zhang

Ding

et al. 2021

J Nucl Med

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Fibroblast activation protein (FAP) has become an attractive target for diagnosis and therapy, and a series of FAP inhibitor (FAPI) based radiotracers have been developed and performed excellent diagnosis outcomes in clinical applications. Yet, their fast clearance and insufficient tumor retention have hampered their further clinical applications for cancer treatment. In this study, we developed two albumin binder-conjugated FAPI radiotracers, TEFAPI-06 and TEFAPI-07. They are derived from FAPI-04, and optimized by conjugating two types of well-studied albumin binders, 4-(p-iodophenyl) butyric acid moiety (TEFAPI-06) and truncated Evans blue moiety (TEFAPI-07), to try to overcome the above limitations at the expense of prolonging the blood circulation.Methods: TEFAPI-06 and TEFAPI-07 were synthesized and labeled with 68 Ga, 86 Y and 177 Lu successfully. A series of cell assays were performed to identify the binding affinity and FAP specificity in vitro. PET imaging, SPECT imaging and biodistribution study were performed to evaluate the pharmacokinetics in the pancreatic cancer patient-derived xenografts (PDX) animal models. The cancer treatment efficacy of 177 Lu-TEFAPI-06 and 177 Lu-TEFAPI-07 have been evaluated in pancreatic cancer PDX-bearing mice. Results:The binding affinity (Kd) to FAP of 68 Ga-TEFAPI-06 and 68 Ga-TEFAPI-07 is 10.16 ± 2.56 nM and 7.81 ± 2.28 nM, respectively, which were comparable with that of 68 Ga-FAPI-04. Comparative PET imaging of HT-1080-FAP and HT-1080 tumor-bearing 2 mice and blocking study showed the FAP targeting ability in vivo of these two tracers.Compared with 177 Lu-FAPI-04, PET imaging, SPECT imaging and biodistribution studies of TEFAPI-06 and TEFAPI-07 have demonstrated their remarkably enhanced tumor accumulation and retention, respectively. Notable tumor growth inhibitions of 177 Lu-TEFAPI-06 and 177 Lu-TEFAPI-07 have been observed, while the control groups and the group treated by 177 Lu-FAPI-04. Conclusion:Two albumin binder-conjugated FAPI radiopharmaceuticals have been developed and evaluated in vitro and in vivo. Significantly improved tumor uptake and retention have been observed compared to the original FAPI tracer. Both 177 Lu-TEFAPI-06 and 177 Lu-TEFAPI-07 showed remarkable growth inhibition to PDX tumors while the side effect is almost negligible, showing that they are promising for further clinical translational studies.purpose of the study is to evaluate whether the modification improves tumor retention in vivo, and which albumin binder matches FAPI molecules better. A series of detailed experiments and comparisons including cell binding assay, PET imaging, biodistribution and radiotherapy study have been performed. And the results demonstrated the high FAP binding affinity and specificity, the enhanced tumor retention and the improved radiotherapy efficacy of these two albumin binders conjugated FAPI radiotracers. MATERIALS AND METHODS Ligands and RadionuclidesThe synthesis route and chemical characterization of TEFAPI-06 and TEFAPI-07 were described in the s...

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Section: Introductionmentioning

confidence: 99%

Albumin Binder–Conjugated Fibroblast Activation Protein Inhibitor Radiopharmaceuticals for Cancer Therapy

Zhang

Ding

et al. 2021

J Nucl Med

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“…Extensive studies have been reported related to LMW albumin-binding PSMA inhibitors, such as the initially reported series of inhibitors by Kelly et al [99] or the more recent Evans-Blue-modified PSMA-617 derivative, which is currently in phase I trials [100,101]. Other remarkable efforts related to albumin-binding PSMA inhibitors were reported by Benesova et al [102], Umbricht et al [103], Kuo and co-workers [104,105] and more recently Deberle et al [106]. In all instances, the tumour uptake of the modified radiopharmaceutical was higher than for PSMA-617, although the longer circulation times also implied higher absorbed doses to non-target tissue.…”

Section: Pharmacokinetic Modifications: Albumin Binders Charged Spacers and Cleavable Linkersmentioning

confidence: 99%

PSMA-Targeting Radiopharmaceuticals for Prostate Cancer Therapy: Recent Developments and Future Perspectives

Fakiri

Geis

Ayada

et al. 2021

Cancers

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Prostate cancer (PC) is the second most common cancer among men, with 1.3 million yearly cases worldwide. Among those cancer-afflicted men, 30% will develop metastases and some will progress into metastatic castration-resistant prostate cancer (mCRPC), which is associated with a poor prognosis and median survival time that ranges from nine to 13 months. Nevertheless, the discovery of prostate specific membrane antigen (PSMA), a marker overexpressed in the majority of prostatic cancerous tissue, revolutionised PC care. Ever since, PSMA-targeted radionuclide therapy has gained remarkable international visibility in translational oncology. Furthermore, on first clinical application, it has shown significant influence on therapeutic management and patient care in metastatic and hormone-refractory prostate cancer, a disease that previously had remained immedicable. In this article, we provide a general overview of the main milestones in the development of ligands for PSMA-targeted radionuclide therapy, ranging from the firstly developed monoclonal antibodies to the current state-of-the-art low molecular weight entities conjugated with various radionuclides, as well as potential future efforts related to PSMA-targeted radionuclide therapy.

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“…To make these FAPI based radiopharmaceuticals more suitable for radionuclide therapy, Loktev and co-workers focused on the direct chemical structure optimization and developed FAPI-21 and FAPI-46 to further increase the tumor uptake and retention for therapeutic outcome improving [18,19]. Though only the [ 177 Lu] Lu-FAPI-21 has an enhanced tumor retention when comparing with [ 177 Lu]Lu-FAPI-04, with the tumor uptake of 6.03 ± 0.68%IA/g and 2.86 ± 0.31%IA/g respectively at 24 h after injection [18], the rapid clearance from the circulation and the insufficient tumor accumulation still hamper the further application of FAPI radiopharmaceuticals for cancer therapy. A promising strategy to meet the challenge may be to prolong the blood circulation by conjugating FAPI with the albumin-binding moieties as illustrated by a series of studies that the radiopharmaceuticals conjugated with Evans blue [20,21] or 4-(p-iodophenyl) butyric acid [22,23] moieties can significantly improve the therapeutic dose delivery [24].…”

Section: Introductionmentioning

confidence: 99%

“…Head-to-head comparisons between radiolabeled FAPI-C12 and FAPI-C16 were conducted by in vitro competition binding, as well as by PET and SPECT imaging, biodistribution, and endoradiotherapy studies in FAP-expressing xenografts bearing mice. With greatly enhanced tumor uptake and treatment efficacy compared to [ 177 Lu]Lu-FAPI-04 in preclinical studies, [ 177 Lu]Lu-FAPI-C16 warrants further investigation for FAP-targeted radionuclide therapy.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Ding

et al. 2021

Eur J Nucl Med Mol Imaging

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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 IC 50 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 [ 68 Ga]Ga-FAPI-04 decreased by 56.9% until 30 h after treated with FAPI-C16 before, and the uptakes of [ 86 Y]Y-FAPI-C12 and [ 86 Y]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. [ 177 Lu]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 [ 177 Lu]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 [ 177 Lu]Lu-FAPI-04 with the value of 1.24 ± 0.54%IA/g at 24 h after injection. Significant tumor volume inhibition of [ 177 Lu]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 [ 177 Lu]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. KeywordsFAPI • Albumin binder • Radionuclide therapy Pu Zhang, Mengxin Xu and Jie Ding contributed equally to this work. This article is part of the Topical Collection on Theragnostic * Li Huo

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¹⁷⁷Lu-Labeled Albumin-Binder–Conjugated PSMA-Targeting Agents with Extremely High Tumor Uptake and Enhanced Tumor-to-Kidney Absorbed Dose Ratio

Cited by 59 publications

References 31 publications

Albumin Binder–Conjugated Fibroblast Activation Protein Inhibitor Radiopharmaceuticals for Cancer Therapy

Albumin Binder–Conjugated Fibroblast Activation Protein Inhibitor Radiopharmaceuticals for Cancer Therapy

PSMA-Targeting Radiopharmaceuticals for Prostate Cancer Therapy: Recent Developments and Future Perspectives

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

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177Lu-Labeled Albumin-Binder–Conjugated PSMA-Targeting Agents with Extremely High Tumor Uptake and Enhanced Tumor-to-Kidney Absorbed Dose Ratio

Cited by 59 publications

References 31 publications

Albumin Binder–Conjugated Fibroblast Activation Protein Inhibitor Radiopharmaceuticals for Cancer Therapy

Albumin Binder–Conjugated Fibroblast Activation Protein Inhibitor Radiopharmaceuticals for Cancer Therapy

PSMA-Targeting Radiopharmaceuticals for Prostate Cancer Therapy: Recent Developments and Future Perspectives

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

Contact Info

Product

Resources

About

¹⁷⁷Lu-Labeled Albumin-Binder–Conjugated PSMA-Targeting Agents with Extremely High Tumor Uptake and Enhanced Tumor-to-Kidney Absorbed Dose Ratio