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Research ArticleTheranostics

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

Hsiou-Ting Kuo, Kuo-Shyan Lin, Zhengxing Zhang, Carlos F. Uribe, Helen Merkens, Chengcheng Zhang and François Bénard
Journal of Nuclear Medicine April 2021, 62 (4) 521-527; DOI: https://doi.org/10.2967/jnumed.120.250738
Hsiou-Ting Kuo
1Department of Molecular Oncology, BC Cancer, Vancouver, British Columbia, Canada
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Kuo-Shyan Lin
1Department of Molecular Oncology, BC Cancer, Vancouver, British Columbia, Canada
2Department of Functional Imaging, BC Cancer, Vancouver, British Columbia, Canada; and
3Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada
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Zhengxing Zhang
1Department of Molecular Oncology, BC Cancer, Vancouver, British Columbia, Canada
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Carlos F. Uribe
2Department of Functional Imaging, BC Cancer, Vancouver, British Columbia, Canada; and
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Helen Merkens
1Department of Molecular Oncology, BC Cancer, Vancouver, British Columbia, Canada
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Chengcheng Zhang
1Department of Molecular Oncology, BC Cancer, Vancouver, British Columbia, Canada
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François Bénard
1Department of Molecular Oncology, BC Cancer, Vancouver, British Columbia, Canada
2Department of Functional Imaging, BC Cancer, Vancouver, British Columbia, Canada; and
3Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada
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Abstract

The use of an albumin binder has been shown to improve tumor uptake of prostate-specific membrane antigen (PSMA)–targeting radiotherapeutic agents. The aim of this study was to develop improved radiotherapeutic agents that combine an optimized affinity-modifying group and optimized albumin binders to maximize the tumor-to-kidney absorbed dose ratio. Methods: 68Ga-labeled DOTA-conjugated lysine-ureido-glutamate–based PSMA-targeting agents bearing various affinity-modifying groups or albumin binders were synthesized and evaluated by PET/CT imaging and biodistribution studies in LNCaP tumor–bearing mice. The optimized affinity-modifying group and albumin binders were combined, and the resulting derivatives were radiolabeled with 177Lu and evaluated by SPECT/CT imaging and biodistribution studies in LNCaP tumor–bearing mice. Radiation dosimetry was calculated using the OLINDA/EXM software. Results: Affinity-modifying group optimization revealed that 68Ga-HTK03041 bearing a tranexamic acid-9-anthrylalanine affinity-modifying group had the highest tumor uptake (23.1 ± 6.11 percentage injected dose [%ID]/g at 1 h after injection). Albumin binder optimization showed that 68Ga-HTK03055 and 68Ga-HTK03086 bearing the N-(4-(p-chlorophenyl)butanoyl)-Gly and N-(4-(p-methoxyphenyl)butanoyl)-Gly motifs, respectively, had relatively faster tumor accumulation (∼30 %ID/g at 3 h after injection) and lower average kidney uptake (<55 %ID/g at both 1 and 3 h after injection). Combining the tranexamic acid-9-anthrylalanine affinity-modifying group with N-(4-(p-chlorophenyl)butanoyl)-Gly and N-(4-(p-methoxyphenyl)butanoyl)-Gly albumin-binding motifs generated HTK03121 and HTK03123, respectively. 177Lu-HTK03121 and 177Lu-HTK03123 had extremely high peak uptake (104 ± 20.3 and 70.8 ± 23.7 %ID/g, respectively) in LNCaP tumor xenografts, and this peak was sustained up to 120 h after injection. Dosimetry calculation showed that compared with 177Lu-PSMA-617, 177Lu-HTK03121 and 177Lu-HTK03123 delivered 18.7- and 12.7-fold higher absorbed dose to tumor but only 6.4- and 6.3-fold higher absorbed dose to kidneys, leading to 2.9- and 2.0-fold improvement in the tumor-to-kidney absorbed dose ratios. Conclusion: With greatly enhanced tumor uptake and tumor-to-kidney absorbed dose ratio, 177Lu-HTK03121 and 177Lu-HTK03123 have the potential to improve treatment efficacy using significantly lower quantities of 177Lu and are promising candidates for clinical translation to treat metastatic castration-resistant prostate cancer.

  • prostate-specific membrane antigen
  • radioligand therapy
  • 177Lu
  • albumin binder
  • tumor-to-kidney absorbed dose ratio

Footnotes

  • Published online Aug. 28, 2020.

  • © 2021 by the Society of Nuclear Medicine and Molecular Imaging.
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Journal of Nuclear Medicine: 62 (4)
Journal of Nuclear Medicine
Vol. 62, Issue 4
April 1, 2021
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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
Hsiou-Ting Kuo, Kuo-Shyan Lin, Zhengxing Zhang, Carlos F. Uribe, Helen Merkens, Chengcheng Zhang, François Bénard
Journal of Nuclear Medicine Apr 2021, 62 (4) 521-527; DOI: 10.2967/jnumed.120.250738

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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
Hsiou-Ting Kuo, Kuo-Shyan Lin, Zhengxing Zhang, Carlos F. Uribe, Helen Merkens, Chengcheng Zhang, François Bénard
Journal of Nuclear Medicine Apr 2021, 62 (4) 521-527; DOI: 10.2967/jnumed.120.250738
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Keywords

  • Prostate-specific membrane antigen
  • radioligand therapy
  • 177Lu
  • albumin binder
  • tumor-to-kidney absorbed dose ratio
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