Abstract
In this study, it was aimed to investigate 149Tb-PSMA-617 for targeted α-therapy (TAT) using a mouse model of prostate-specific membrane antigen (PSMA)-expressing prostate cancer. 149Tb-PSMA-617 was prepared with >98% radiochemical purity (6 MBq/nmol) for the treatment of mice with PSMA-positive PC-3 PIP tumors. 149Tb-PSMA-617 was applied at 1 × 6 MBq (Day 0) or 2 × 3 MBq (Day 0 & Day 1 or Day 0 & Day 3) and the mice were monitored over time until they had reached a pre-defined endpoint which required euthanasia. The tumor growth was significantly delayed in mice of the treated groups as compared to untreated controls (p < 0.05). TAT was most effective in mice injected with 2 × 3 MBq (Day 0 & 1) resulting in a median lifetime of 36 days, whereas in untreated mice, the median lifetime was only 20 days. Due to the β+-emission of 149Tb, tumor localization was feasible using PET/CT after injection of 149Tb-PSMA-617 (5 MBq). The PET images confirmed the selective accumulation of 149Tb-PSMA-617 in PC-3 PIP tumor xenografts. The unique characteristics of 149Tb for TAT make this radionuclide of particular interest for future clinical translation, thereby, potentially enabling PET-based imaging to monitor the radioligand’s tissue distribution.
Highlights
In this study, it was aimed to investigate 149Tb-PSMA-617 for targeted α-therapy (TAT) using a mouse model of prostate-specific membrane antigen (PSMA)-expressing prostate cancer. 149Tb-PSMA-617 was prepared with >98% radiochemical purity (6 MBq/nmol) for the treatment of mice with PSMA-positive PC-3 PIP tumors. 149Tb-PSMA-617 was applied at 1 × 6 MBq (Day 0) or 2 × 3 MBq (Day 0 & Days of Injections (Day) 1 or Day 0 & Day 3) and the mice were monitored over time until they had reached a pre-defined endpoint which required euthanasia
We propose 149Tb as a potential alternative α-emitter for targeted radioligand therapy, based on several attractive features: (i) 149Tb decays with a half-life of 4.1 h, which is relatively short as compared to 225Ac, but more than four-fold longer than the half-life of 213Bi. This situation makes 149Tb interesting in combination with small molecules that are characterized by fast accumulation in the tumor lesions and efficient clearance from healthy tissue. (ii) 149Tb emits low-energy α-particles (Eα = 3.97 MeV; I = 17%), but the decay does not involve relevant α-emitting daughter nuclides, which is advantageous over 213Bi and 225Ac (Fig. 1b). (iii) The co-emission of β+-particles is a unique feature of 149Tb, making it suitable to trace 149Tb-labeled radioligands using positron emission tomography (PET). This has recently been exemplified in a preclinical pilot study, in which we demonstrated the feasibility of visualizing 149Tb using PET and referred to this approach as “alpha-PET12”. (iv) 149Tb, as a radiolanthanide, can be stably coordinated with a DOTA chelator and, be used with any established tumor-targeting agent that is applied for 177Lu-therapy. (v) it is important to recognize that additional, medically-interesting Tb radioisotopes exist, among those 161Tb, which has similar characteristics to 177Lu but co-emits conversion and Auger electrons that were shown to potentiate the therapeutic efficacy in a preclinical setting[13,14,15,16]
After separation from zinc and isobar impurities, the final product (149Tb in HCl 0.05 M) was used for the labeling of PSMA-617. 149Tb-PSMA-617 was obtained at a molar activity of up to 6 MBq/nmol, with a radiochemical purity of >98%
Summary
It was aimed to investigate 149Tb-PSMA-617 for targeted α-therapy (TAT) using a mouse model of prostate-specific membrane antigen (PSMA)-expressing prostate cancer. 149Tb-PSMA-617 was prepared with >98% radiochemical purity (6 MBq/nmol) for the treatment of mice with PSMA-positive PC-3 PIP tumors. 149Tb-PSMA-617 was applied at 1 × 6 MBq (Day 0) or 2 × 3 MBq (Day 0 & Day 1 or Day 0 & Day 3) and the mice were monitored over time until they had reached a pre-defined endpoint which required euthanasia. PSMA-617 is a small-molecular-weight ligand used to target the prostate-specific membrane antigen (PSMA), which is overexpressed in most prostate cancer cases[2] It has been used in combination with 177Lu, a β−-particle-emitting radiolanthanide, for the treatment of mCRPC patients[3]. (v) it is important to recognize that additional, medically-interesting Tb radioisotopes exist, among those 161Tb, which has similar characteristics to 177Lu but co-emits conversion and Auger electrons that were shown to potentiate the therapeutic efficacy in a preclinical setting[13,14,15,16] This situation could enable using chemically-identical radioligands for either β−-/ Auger electron therapy or TAT, respectively. The therapeutic efficacy of 149Tb was investigated by our own group using a 149Tb-labeled DOTA-folate conjugate in a therapy study with KB tumor-bearing mice[12]
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