Kyo Chul Lee

Prostate-specific membrane antigen (PSMA) has emerged as a clinically validated target for the diagnosis and treatment of prostate cancer using radioligand therapy (RLT). Among various PSMA-targeting ligands, urea-based small-molecules have gained limelight due to their favorable pharmacokinetic properties, high tumor penetration and convenient radiolabeling. Current preclinical research focuses on enhancing in vivo efficacy by optimizing ligand design, radionuclide selection, and improved pharmacokinetics. To reduce off-target toxicity in organs and enhance tumor accumulation, strategies involving the incorporation of albumin-binding moieties or linker modifications have been explored. Various studies have focused on PSMA-targeted therapies labeled with radionuclides, including β emitters (lutetium-177), α emitters (actinium-225 or astatine-211), and Auger electron emitters (iodine-125), that provide unique DNA damage mechanisms tailored to the tumor size and disease stage. This review summarizes recent approaches of PSMA-targeted small-molecules to optimize therapeutic efficacy while minimizing adverse effects on healthy tissues for RLT of prostate cancer.

We developed a novel therapeutic radioligand, [177Lu]1h, with an albumin binding motif and evaluated it in a prostate-specific membrane antigen (PSMA)-expressing tumor xenograft mouse model. Fourteen PSMA target candidates were synthesized, and binding affinity was evaluated with an in vitro competitive binding assay. First, four compound candidates were selected depending on binding affinity results. Next, we selected four compounds ([68Ga]1e, [68Ga]1g, [68Ga]1h, and [68Ga]1k) were screened for tumor targeting efficiency by micro–positron emission tomography/computed tomography (micro-PET/CT) imaging. Finally, [177Lu]1h compound was evaluated the tumor targeting efficiency and therapeutic efficiency by micro–single-photon emission computed tomography/computed tomography (micro-SPECT/CT), biodistribution, and radiotherapy studies. Estimated human effective dose was calculated by biodistribution data. Compound 1h showed a high binding affinity (Ki value = 4.08 ± 0.08 nmol/L), and [177Lu]1h showed extended blood circulation (1 hour = 10.32 ± 0.31, 6 hours = 2.68 ± 1.07%ID/g) compared to [177Lu]PSMA-617 (1 h = 0.17 ± 0.10%ID/g). [177Lu]1h was excreted via the renal pathway and showed high tumor uptake (24.43 ± 3.36%ID/g) after 1 hour, which increased over 72 hours (72 hours = 51.39 ± 9.26%ID/g). Mice treated with 4 and 6 MBq of [177Lu]1h showed a median survival rate of >61 days. In particular, all mice treated with 6 MBq of [177Lu]1h survived for the entire monitoring period. The estimated human effective dose of [177Lu]1h was 0.07 ± 0.01 and 0.03 ± 0.00 mSv/MBq in total body and kidney, respectively. The current study indicates that [177Lu]1h has the potential for further investigation of metastatic castration-resistant prostate cancer (mCRPC) therapy in clinical trials.

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

We developed a novel therapeutic radioligand, [177Lu]1h, with an albumin binding motif and evaluated it in a prostate-specific membrane antigen (PSMA)-expressing tumor xenograft mouse model. Fourteen PSMA target candidates were synthesized, and binding affinity was evaluated with an in vitro competitive binding assay. First, four compound candidates were selected depending on binding affinity results. Next, we selected four compounds ([68Ga]1e, [68Ga]1g, [68Ga]1h, and [68Ga]1k) were screened for tumor targeting efficiency by micro–positron emission tomography/computed tomography (micro-PET/CT) imaging. Finally, [177Lu]1h compound was evaluated the tumor targeting efficiency and therapeutic efficiency by micro–single-photon emission computed tomography/computed tomography (micro-SPECT/CT), biodistribution, and radiotherapy studies. Estimated human effective dose was calculated by biodistribution data. Compound 1h showed a high binding affinity (Ki value = 4.08 ± 0.08 nmol/L), and [177Lu]1h showed extended blood circulation (1 hour = 10.32 ± 0.31, 6 hours = 2.68 ± 1.07%ID/g) compared to [177Lu]PSMA-617 (1 h = 0.17 ± 0.10%ID/g). [177Lu]1h was excreted via the renal pathway and showed high tumor uptake (24.43 ± 3.36%ID/g) after 1 hour, which increased over 72 hours (72 hours = 51.39 ± 9.26%ID/g). Mice treated with 4 and 6 MBq of [177Lu]1h showed a median survival rate of >61 days. In particular, all mice treated with 6 MBq of [177Lu]1h survived for the entire monitoring period. The estimated human effective dose of [177Lu]1h was 0.07 ± 0.01 and 0.03 ± 0.00 mSv/MBq in total body and kidney, respectively. The current study indicates that [177Lu]1h has the potential for further investigation of metastatic castration-resistant prostate cancer (mCRPC) therapy in clinical trials.

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

Positronium (Ps) is an unstable system created by the temporary combination of electrons and negative electrons, and Ps generation technology under resonance conditions at millimeter waves is emerging as a new research topic. In general, Ps can be observed when an unstable separate state remains after electron and positron pair annihilation, as in positron emission tomography (PET). However, in this study, a plasma wakefield accelerator based on vacuum electronics devices (VEDs) was designed in the ponderomotive force generating electrons and positrons simultaneously using annular relativistic electron beams. It can induce Cherenkov radiation from beam–wave interaction by using dielectric materials. According to the size of dielectric materials, the frequency of oscillation is approximately 203 GHz at the range of millimeter waves. At this time, the output power is about 10⁹ watts-levels. Meanwhile, modes of millimeter waves polarized by a three-stepped axicon lens are used to apply the photoconversion technology. Thus, it is possible to confirm light emission in the form of a light-converted Bessel beam.

A number of researchers in Korea have tried to set-up the production of radionuclides and develop new radiopharmaceuticals for several decades. Thanks to their 60-year endeavor to advance the field of radiopharmaceutical sciences, now we have a lot of research units and facilities in Korea. Still, there are huge number of issues to be solved in radiopharmaceutical sciences; however, our efforts will be continued to develop new radiopharmaceuticals and to apply the new radiopharmaceuticals into nuclear medicine field.

To build a proton beam accelerator that can be applied to a boron neutron capture therapy system based on an electrostatic accelerator, a high-voltage direct-current (DC) power supply system equivalent to the generation of neutrons should be provided. The symmetrical Cockcroft–Walton voltage multiplier method is suitable for stable acceleration of the proton beam in the tandem electrostatic accelerator in this system. Before the second step-up with the Cockcroft–Walton circuit, the design of the inverter is prioritized by preponderantly considering the first voltage and resonance frequency. Moreover, the optimized stacking number is determined with consideration of the ripple voltage, voltage drop, average output voltage, and fundamental harmonics, and a design is performed to set related parameter values to be stable in the flat-top region of the voltage. A high-voltage DC power supply system of 1.2 MV/45 mA is needed for a stable terminal energy of 2.4 MeV/20 mA. Such a design can be optimized by securing reliable data using a simulation tool on the basis of theoretical calculations. This will become a formidable touchstone in manufacturing technology based on acquiring practical know-how for setting up a tandem electrostatic accelerator-based boron neutron capture therapy system in the future.

Lee I, et al. J Breast Cancer. 2022 Feb;25(1):69-73. https://doi.org/10.4048/jbc.2022.25.e5