Abstract
PurposeThe prostate-specific membrane antigen (PSMA) has emerged as an interesting target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). The aim of this study was to investigate 161Tb (T1/2 = 6.89 days; Eβ͞av = 154 keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to 177Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile.Methods161Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100 MBq/nmol. 161Tb-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for 177Lu-PSMA-617. The effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells. 161Tb-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice.Results161Tb-PSMA-617 and 177Lu-PSMA-617 displayed equal in-vitro properties and tissue distribution profiles in tumor-bearing mice. The viability and survival of PC-3 PIP tumor cells were more reduced when exposed to 161Tb-PSMA-617 as compared to the effect obtained with the same activities of 177Lu-PSMA-617 over the whole investigated concentration range. Treatment of mice with 161Tb-PSMA-617 (5.0 MBq/mouse and 10 MBq/mouse, respectively) resulted in an activity-dependent increase of the median survival (36 vs 65 days) compared to untreated control animals (19 days). Therapy studies to compare the effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 indicated the anticipated superiority of 161Tb over 177Lu.Conclusion161Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to 177Lu-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of 161Tb. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of 161Tb-PSMA-617 for the treatment of mCRPC.
Highlights
The prostate-specific membrane antigen (PSMA) is a cellsurface glycoprotein that is expressed in normal prostate tissue and overexpressed in prostate cancer [1, 2]
PSMA is, an interesting target to use for radionuclide therapy of metastasized castration-resistant prostate cancer [5,6,7,8]
We investigated 161Tb, a recently-introduced radiolanthanide for therapeutic applications [19]. 161Tb decays with a half-life of 6.89 days to stable 161Dy, while emitting β-particles (Eβav = 154 keV) suitable for therapeutic purposes and γ-radiation (Eγ = 49 keV, I = 17.0%; Eγ = 75 keV, I = 10.2%) useful for SPECT imaging
Summary
The prostate-specific membrane antigen (PSMA) is a cellsurface glycoprotein that is expressed in normal prostate tissue and overexpressed in prostate cancer [1, 2]. PSMA-617 and PSMA I&T, equipped with a DOTA and DOTAGA chelator, respectively, have been used for targeted radionuclide therapy of mCRPC in clinics [7, 12, 13]. For this purpose, they were mostly labeled with 177Lu (T1/2 = 6.65 d; Eβav = 134 keV; Eγ = 113 keV, I = 6.17%, Eγ = 208 keV, I = 10.36%), which is currently the mostoften applied radiometal for therapeutic purposes in the clinics [14]. The question arises, whether alternative radiometals could be used for targeted radionuclide therapy of mCRPC which would be potentially more powerful than the currently-employed 177Lu, without causing additional sideeffects
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