Hsiou-Ting Kuo1, Kuo-Shyan Lin1,2,3, Zhengxing Zhang4, Carlos F Uribe2, Helen Merkens4, Chengcheng Zhang4, François Bénard4,2,3. 1. Department of Molecular Oncology, BC Cancer, Vancouver, British Columbia, Canada klin@bccrc.ca. 2. Department of Functional Imaging, BC Cancer, Vancouver, British Columbia, Canada; and. 3. Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada. 4. Department of Molecular Oncology, BC Cancer, Vancouver, British Columbia, Canada.
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.
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.
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