GRPR-targeted radionuclide conjugates evolve from agonists to antagonists, enhancing tumor retention for cancer theranostics

The gastrin-releasing peptide receptor (GRPR) is aberrantly expressed in several aggressive malignancies, including prostate cancer, breast cancer, and lung cancer, positioning it as a critical target for precision oncology. Traditional cancer therapies often lack specificity, leading to systemic toxicity and limiting efficacy. Radiopharmaceutical conjugates, particularly those designed to target GRPR, offer a promising theranostic approach by combining diagnostic imaging with targeted radionuclide therapy. However, early GRPR-targeted agonists faced significant limitations due to off-target effects and suboptimal pharmacokinetics, underscoring the urgent need for more selective and metabolically stable agents.

This article conducted a systematic review, comprehensively analyzing the molecular evolution of GRPR-targeted radionuclide conjugates. The review synthesized findings from numerous studies, meticulously tracing the development of these ligands from their initial agonist designs to contemporary antagonist-based approaches. It specifically focused on identifying key structural optimizations, including C-terminal peptide modifications, and the strategic design of linkers and chelators. The analysis evaluated how these advancements collectively impact the targeting capability, pharmacokinetic properties, and overall clinical applicability of these radiopharmaceuticals in the diagnosis and therapy of various cancers.

The systematic review revealed a significant evolutionary trajectory in GRPR-targeted ligand design, transitioning from early agonists, which were often limited by dose-limiting side effects and suboptimal pharmacokinetics, to more stable and tumor-retaining antagonists. Key structural optimizations, such as C-terminal modifications of peptides, along with refined designs of linkers and chelators, were identified as crucial for enhancing the targeting capability and pharmacokinetic profiles of these radiopharmaceuticals. These advancements have led to improved tumor retention and a reduction in off-target uptake compared to earlier generations of conjugates. Despite this progress, the review highlighted persistent challenges, including residual off-target uptake in non-cancerous tissues and inadequate metabolic stability of some current conjugates. The authors emphasized the ongoing necessity for further research into structure-activity relationships to design more selective and efficient diagnostic and therapeutic agents for cancers with high GRPR expression.

Structural optimizations, including C-terminal peptide modifications and refined linkers/chelators, collectively enhance targeting capability and pharmacokinetic properties of GRPR-targeted radiopharmaceuticals.