<sup>177</sup>Lu-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 Uribe, Helen Merkens, Chengcheng Zhang, François Bénard
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 affinitymodifying group and optimized albumin binders to maximize the tumor-to-kidney absorbed dose ratio. Methods: 68 Ga-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 177 Lu and evaluated by SPECT/CT imaging and biodistribution studies in LNCaP tumorbearing mice. Radiation dosimetry was calculated using the OLINDA/EXM software. Results: Affinity-modifying group optimization revealed that 68 Ga-HTK03041 bearing a tranexamic acid-9anthrylalanine 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 68 Ga-HTK03055 and 68 Ga-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. 177 Lu-HTK03121 and 177 Lu-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 177 Lu-PSMA-617, 177 Lu-HTK03121 and 177 Lu-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, 177 Lu-HTK03121 and 177 Lu-HTK03123 have the potential to improve treatment efficacy using significantly lower quantities of 177 Lu and are promising candidates for clinical translation to treat metastatic castration-resistant prostate cancer.