A Bivalent Radiopharmaceutical Targeting PSMA and Hypoxia for Improved Theranostics in Prostate Cancer

Prostate cancer continues to rank among the most frequently diagnosed cancers in men globally and remains a leading cause of cancer-related deaths. Even with significant progress in early detection and treatment strategies, many patients still develop advanced stages of the disease—particularly metastatic castration-resistant prostate cancer (mCRPC). At this stage, therapeutic options are often limited and outcomes remain poor. A key challenge in managing mCRPC lies in the complex and often hostile tumor microenvironment. One especially problematic feature is hypoxia—localized areas of low oxygen that are common in solid tumors like prostate cancer. These hypoxic regions not only support tumor progression but also make the cancer more resistant to both chemotherapy and radiotherapy. On the other hand, prostate-specific membrane antigen (PSMA) has emerged as an attractive molecular target in prostate cancer. It’s a surface protein that is significantly overexpressed in aggressive and treatment-resistant forms of the disease, particularly in metastatic lesions. This makes PSMA an excellent candidate for targeted imaging and therapy, and indeed, several PSMA-targeting radiopharmaceuticals have already received regulatory approval. These agents have shown high specificity and effectiveness in binding to PSMA-positive cancer cells. However, a major limitation persists: they often don’t penetrate evenly into the tumor mass and may struggle to reach or accumulate in hypoxic areas, where drug delivery is inherently more difficult. At the same time, researchers have been exploring hypoxia-sensitive radiotracers, such as 2-nitroimidazole derivatives, for detecting oxygen-deficient tumor zones. These agents work through a redox-dependent trapping mechanism, becoming chemically reduced and retained in hypoxic tissues. Despite their theoretical promise, these molecules often fail to deliver clinically meaningful results due to poor cell penetration and rapid washout from healthy tissues, limiting their diagnostic accuracy. So, a pressing question arose in the field: what if these two approaches—PSMA targeting and hypoxia trapping—could be combined into a single, multifunctional molecule? Could such a design improve tumor penetration, ensure better retention in challenging tumor zones, and provide superior diagnostic and therapeutic value? To this account, new research paper published in Journal of Medicinal Chemistry and conducted by Dr. Yang Luo, Dr. Wenbin Jin, Dr. Ran Wang, Dr. Ruiyue Zhao, and Professor Lin Zhu from the Beijing Normal University together with Professor Hank Kung from the University of Pennsylvania, developed a new class of bivalent radiopharmaceuticals that are capable of dual-targeting: binding with high affinity to PSMA on prostate cancer cells while simultaneously trapping in hypoxic tumor regions via nitroimidazole moieties. This innovative design allows the agents to exploit both the biological specificity of PSMA and the redox-sensitive nature of hypoxia for more effective localization and retention within tumors.

Driven by the need for smarter, more biologically informed therapies, researchers aimed to push the boundaries of current diagnostic and therapeutic tools. Their goal was not just to match existing PSMA-targeted agents but to surpass them by addressing the long-standing issues of uneven tumor distribution and poor hypoxia targeting. The result is a promising step toward next-generation theranostics—radiolabeled compounds designed to locate cancer, analyze its microenvironment, and adapt therapeutically. To explore their concept of a dual-targeting radiopharmaceutical, the research team developed eight novel compounds capable of binding to both PSMA and hypoxic tumor regions. Each molecule contained a PSMA-targeting component and a nitroimidazole group, which accumulates in low-oxygen environments. They also incorporated different chelators, allowing labeling with gallium-68 for imaging or lutetium-177 for therapy. Among these, one compound—referred to as compound 8—stood out for its strong labeling efficiency and promising biological behavior. It featured the PSMA-093 backbone, a clinically validated structure, combined with a nitroimidazole moiety and an AAZTA chelator.

After confirming the structures through standard analytical methods, the team radiolabeled the compounds. Most achieved high radiochemical purity without requiring further purification—an essential factor for future clinical applications. Compound 8, in particular, demonstrated easy labeling with both isotopes, enhancing its theranostic potential. The researchers then tested the compounds in prostate cancer cells overexpressing PSMA. [⁶⁸Ga]Ga-8 exhibited significantly greater uptake under hypoxic conditions compared to normal oxygen levels, whereas compounds lacking the nitroimidazole group did not show this difference. When PSMA was blocked with an unlabeled compound, uptake dropped, confirming target specificity. In PSMA-negative cells, uptake was minimal, reinforcing the tracer’s selectivity. In animal models with PSMA-positive tumors, PET imaging showed that [⁶⁸Ga]Ga-8 had excellent tumor uptake and image clarity just one hour post-injection. It also cleared quickly from healthy tissues—an ideal characteristic. Compared to existing clinical tracers, it performed better in tumor-to-background ratios and remained in tumors longer, likely due to hypoxia-driven retention. Finally, the team labeled compound 8 with lutetium-177 and tested it in mice. SPECT imaging at 24 and 48 hours showed sustained tumor localization with minimal off-target activity.

Conclusion

This research presents an innovative and well-executed approach to a major challenge in prostate cancer: identifying and treating hypoxic tumor regions that resist conventional therapies. By integrating PSMA binding and hypoxia trapping into a single molecule, the researchers developed a compound that not only targets prostate cancer cells but also remains in oxygen-poor areas where treatment is less effective.

Compound 8 emerged as particularly promising due to its strong performance in both imaging and therapy. When labeled with gallium-68, it produced clear PET images with high tumor-to-background contrast. As a therapeutic, its lutetium-177-labeled form demonstrated sustained tumor retention with minimal off-target accumulation. This dual-functionality—diagnosis and treatment in one agent—could simplify clinical workflows and improve patient care, especially for advanced or treatment-resistant prostate cancer. Moreover, [⁶⁸Ga]Ga-8’s superior tumor-to-background ratios suggest it could detect smaller lesions or tumors near high-background organs, improving early detection and precise staging. While this study focuses on prostate cancer, the approach could extend to other hypoxia-related solid tumors, such as renal cell carcinoma, glioblastoma, and pancreatic cancer. A key takeaway is the use of the AAZTA chelator, which enabled efficient labeling with both imaging and therapeutic isotopes under mild conditions—an advantage for radiopharmacies facing time and regulatory constraints. Perhaps most exciting is the broader implication: this research exemplifies how leveraging the tumor microenvironment can lead to smarter, more effective radiopharmaceuticals. By accounting for tumor biology, rather than relying solely on receptor targeting, the researchers have pioneered a shift toward biologically responsive, personalized approaches to cancer imaging and therapy.