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Radionuclide Therapy of Prostate Cancer Using PSMA Ligands with a 4-Phenylbutyric Acid-Derived Albumin Binder: Recent
Johanne Vanney1, Jade Torchio1, Lea Rubira1
1University of Montpellier, Department of Nuclear Medicine, Montpellier Cancer Institute (ICM), Montpellier, France.
Abstract:
Radioligand therapy (RLT) targeting the prostate-specific membrane antigen (PSMA) has become a key treatment modality for metastatic castration-resistant prostate cancer. However, the rapid clearance and suboptimal tumor uptake of current smallmolecule PSMA ligands limit their therapeutic index. Incorporating reversible albuminbinding moieties (ABM), particularly 4-phenylbutyric acid (PBA)-derived groups, has emerged as a powerful strategy to modulate pharmacokinetics by prolonging systemic circulation, enhancing tumor uptake, and improving radiation dose delivery. This review summarizes the chemical and translational advances of PSMA-targeting radiopharmaceuticals integrating PBA-type ABM. It details structure-activity relationships governing albumin affinity and linker design across all major chemical series. Emphasis is placed on the most clinically advanced candidates, i.e. PSMA-Trillium, HTK03170, Ludotadipep, P17-088, and CTT1403, highlighting their pharmacokinetics, tumor targeting, safety profiles, and early clinical outcomes. Key determinants of in vivo performance, including affinity for albumin and PSMA, polarity and length of linker elements, are examined in the context of tumor-to-kidney dose ratios and therapeutic efficacy. Collectively, PBA-derived ABM have proven highly effective but require careful tuning, as excessive albumin binding could lead to prolonged hematologic exposure and kidney irradiation, whereas insufficient affinity reduces therapeutic gains. The most successful ligands achieve a balanced interplay between albumin binding, PSMA affinity, and controlled renal clearance. As next-generation α- and β-emitters enter clinical development, optimized ABM-containing radiopharmaceuticals are expected to deliver higher tumor doses with improved safety, supporting their growing role in precision therapy for advanced prostate cancer.
Insights
Albumin-binding moieties enhance radioligand therapy for prostate cancer by improving tumor uptake and circulation time. Careful tuning of these moieties is crucial for balancing efficacy and safety in PSMA-targeted treatments.
Area of Science:
- Nuclear medicine
- Radiopharmaceutical chemistry
- Oncology
Background:
- Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is vital for metastatic castration-resistant prostate cancer.
- Current PSMA ligands face limitations due to rapid clearance and suboptimal tumor uptake, impacting therapeutic efficacy.
- Albumin-binding moieties (ABM), especially PBA-derived groups, offer a strategy to enhance RLT by modulating pharmacokinetics.
Purpose of the Study:
- To review chemical and translational advancements in PSMA-targeting radiopharmaceuticals incorporating PBA-type ABM.
- To analyze structure-activity relationships of ABM in PSMA ligands.
- To evaluate the in vivo performance and clinical outcomes of advanced ABM-containing PSMA-targeting agents.
Main Methods:
- Review of literature on PSMA-targeting radiopharmaceuticals with PBA-type ABM.
- Analysis of structure-activity relationships, focusing on albumin affinity and linker design.
- Examination of pharmacokinetic profiles, tumor targeting, safety, and clinical outcomes of leading candidates (PSMA-Trillium, HTK03170, Ludotadipep, P17-088, CTT1403).
Main Results:
- PBA-derived ABM significantly improve systemic circulation, tumor uptake, and radiation dose delivery in PSMA-targeted RLT.
- Key factors influencing efficacy include albumin affinity, PSMA affinity, and linker characteristics.
- Optimized ligands achieve a balance between albumin binding, PSMA targeting, and renal clearance, leading to improved tumor-to-kidney dose ratios.
Conclusions:
- PSMA-targeting radiopharmaceuticals with PBA-derived ABM represent a significant advancement in prostate cancer therapy.
- Careful optimization of ABM is essential to maximize therapeutic benefits while minimizing off-target toxicities like prolonged hematologic exposure and kidney irradiation.
- Next-generation radiopharmaceuticals with optimized ABM are poised to enhance precision therapy for advanced prostate cancer by delivering higher tumor doses with improved safety profiles.
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