Improving Theranostic Gallium-68/Lutetium-177–Labeled PSMA Inhibitors with an Albumin Binder for Prostate Cancer

Abstract

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.

Comparison of the Effects of DOTA and NOTA Chelators on 64Cu-Cudotadipep and 64Cu-Cunotadipep for Prostate Cancer

“…The radio-TLCs were performed using a radio-TLC imaging scanner (BioScan, DC) for radiodetection. 64 Cu-Cudotadipep and 64 Cu-Cunotadipep 64 Cu-Cudotadipep ( 64 Cu-FC705) and 64 Cu-cunotadipep ( 64 Cu-FC707) were provided by FutureChem Co., Ltd. (Seoul, Republic of Korea) [20]. A brief summary of the synthesis process is as follows: 64 CuCl 3 aqueous solution was dried in N 2 gas at 100 • C, 100 µg of dotadipep or notadipep was dissolved in 0.1 M ammonium acetate (0.1 mL, pH 4.5) and mixed with the dried 64 CuCl 3 , and the mixture was then stirred at room temperature for 10 min.…”

Dosimetric Analysis of a Phase I Study of PSMA-Targeting Radiopharmaceutical Therapy With [177Lu]Ludotadipep in Patients With Metastatic Castration-Resistant Prostate Cancer

“…[ 177 Lu]Ludotadipep has an iodophenylbutanoly group incorporated for affinity to serum albumin [ 14 ]. A couple of other PSMA-targeting radiopharmaceuticals that were modified to increase tumor uptake by increasing albumin binding have published dosimetry data obtained from patients with mCRPC.…”

“…1 ). In the PC3-PIP animal model, tumor uptake increased over 72 h, and tumor growth was inhibited in mice treated with 4 or 6 MBq of [ 177 Lu]Ludotadipep [ 14 ].…”

Evaluation of Therapeutic Efficacy and Imaging Capabilities of 153Sm2O3-Loaded Polystyrene Microspheres for Intra-Tumoural Radionuclide Therapy of Liver Cancer Using Sprague-Dawley Rat Model

“…In addition, these high γ-rays energy are not ideal for imaging due to the poor count detection sensitivity thus resulting in image degradation [ 12 ]. There are studies using combination of two radionuclides with the theranostic concept where the γ-rays are used for diagnostics imaging or treatment planning and β − particles for therapeutic such as Iodine-123 ( 123 I)/ 131 I and Galium-68 ( 68 Ga)/Lutetium-177 ( 177 Lu) for treatment of thyroid cancer and prostate cancer, respectively [ 13 , 14 ]. This idea of using more than one radionuclide has not been explored for liver cancer treatment.…”