Novel 177Lu-labeled Albumin-binder-conjugated PSMA-targeting Agents with Extremely High Tumor Uptake and Enhanced Tumor-to-kidney Absorbed Dose Ratio.

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 linker 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 linkers or albumin binders were synthesized, and evaluated by PET/CT imaging and biodistribution studies in LNCaP tumor-bearing mice. The optimized linker 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: Linker optimization revealed that [68Ga]Ga-HTK03041 bearing a tranexamic acid-9-anthrylalanine linker had the highest tumor uptake (23.1±6.11 %ID/g at 1h post-injection). Albumin binder optimization showed that [68Ga]Ga-HTK03055 and [68Ga]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 3H post-injection) and lower average kidney uptake (<55 %ID/g at both 1h and 3H post-injection). Combining the tranexamic acid-9-anthrylalanine linker with N-(4-(p-chlorophenyl)butanoyl)-Gly and N-(4-(p-methoxyphenyl)butanoyl)-Gly albumin-binding motifs generated HTK03121 and HTK03123, respectively. [177Lu]Lu-HTK03121 and [177Lu]Lu-HTK03123 had extremely high peak uptake (104±20.3 and 70.8±23.7 %ID/g, respectively) in LNCaP tumor xenografts, which was sustained up to 120h post-injection. Dosimetry calculation showed that compared to [177Lu]Lu-PSMA-617, [177Lu]Lu-HTK03121 and [177Lu]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 [177Lu]Lu-HTK03121 and [177Lu]Lu-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.