Dual-Target Binding Ligands with Modulated Pharmacokinetics for Endoradiotherapy of Prostate Cancer

Abstract

Prostate-specific membrane antigen (PSMA)-targeted radiotherapy of prostate cancer (PCa) has emerged recently as a promising approach to the treatment of disseminated disease. A small number of ligands have been evaluated in patients, and although early tumor response is encouraging, relapse rate is high and these compounds localize to the parotid, salivary, and lacrimal glands as well as to the kidney, leading to dose-limiting toxicities and adverse events affecting quality of life. We envision that dual-target binding ligands displaying high affinity for PSMA and appropriate affinity for human serum albumin (HSA) may demonstrate a higher therapeutic index and be suitable for treatment of PCa by targeted α-therapy. Six novel urea-based ligands with varying affinities for PSMA and HSA were synthesized, labeled withI, and evaluated by in vitro binding and uptake assays in LNCaP cells. Four compounds were advanced for further evaluation in a preclinical model of PCa. The compounds were compared with MIP-1095, a PSMA ligand currently in clinical evaluation. The compounds demonstrated affinity for PSMA on the order of 4-40 nM and affinity for HSA in the range of 1-53 μM. Compounds with relatively high affinity for HSA (≤2 μM) showed high and sustained blood-pool activity and reduced uptake in the kidneys.I-RPS-027, with a 50% inhibitory concentration (PSMA) of 15 nM and a dissociation constant (HSA) of 11.2 μM, cleared from the blood over the course of 48 h and showed good tumor uptake (10 percentage injected dose per gram) and retention and a greater than 5-fold decrease in kidney uptake relative to MIP-1095. The tumor-to-kidney ratio of I-RPS-027 was greater than 3:1 at 24 h after injection, increasing to 7:1 by 72 h. RPS-027 shows dual targeting to PSMA and albumin, resulting in a high tumor uptake, highly favorable tissue distribution, and promising therapeutic profile in a preclinical model of prostate cancer. In comparison to existing ligands proposed for targeted therapy of prostate cancer, RPS-027 has tumor-to-tissue ratios that predict a significant reduction in side effects during therapy. Using iodine/radioiodine as a surrogate for the radiohalogen At, we therefore propose dual-target binding ligands such as RPS-027 as next-generation radiopharmaceuticals for targeted α-therapy usingAt.

An Eighteen‐Membered Macrocyclic Ligand for Actinium‐225 Targeted Alpha Therapy

“…[36] These constructs bear ag lutamate-urea-lysine moiety which inhibits the prostate-specific membrane antigen (PSMA), [37][38][39][40][41] am embrane-bound glycoprotein which is overexpressed in prostate cancer cells. [36] These constructs bear ag lutamate-urea-lysine moiety which inhibits the prostate-specific membrane antigen (PSMA), [37][38][39][40][41] am embrane-bound glycoprotein which is overexpressed in prostate cancer cells.…”

Albumin-Binding PSMA Ligands: Implications for Expanding the Therapeutic Window

“…The compounds were labeled with 68 Ga as described above and loaded onto a Chiralpak HSA analytic high-performance liquid chromatography column, 100 · 2 mm, 5 mm (Daicel Corp.), as a solution in 10% v/v EtOH/ saline, with a maximum injected mass of 0.8 mg and a maximum injected volume of 40 mL. In addition, retention times for nonradioactive standards of known affinity for HSA (15) were measured. Analyses were performed in triplicate using an isocratic mobile phase of 5% v/v isopropanol/0.067 M phosphate buffer at a constant flow of 0.3 mL/min.…”

MRI‐guided transurethral insonation of silica‐shell phase‐shift emulsions in the prostate with an advanced navigation platform

“…In addition to being more frequent in the experimental treatment arms, the presence of thermal fixation correlated significantly with larger lesions and higher therapeutic temperatures, indicating that the presence of sUPEs could enhance heat deposition with TULSA. Intravenous injection of functionalized or ligand‐targeted sUPEs may improve the specificity of sUPEs for prostate cancer tissue, enhancing TULSA ablation of target areas. Increased absorption by sUPEs would also shield distal structures, allowing extension of treatment margins around the target.…”