Radiolysis Impact on Lu-177 PSMA: Quality Control and Clinical Implications

In an inter-laboratory study, [177Lu]Lu-PSMA-I&T radiolysis reduced the tumor-to-kidney uptake ratio in vivo, shifting biodistribution and narrowing the therapeutic index.

In head-to-head comparisons (~97% vs ~50% radiochemical purity), higher radiolytic impurity produced a statistically significant reduction in tumor-to-kidney ratio (p < 0.05). This pattern suggests reduced tumor targeting alongside relatively increased renal exposure.

Inter-laboratory HPLC comparisons and coordinated biodistribution experiments across multiple sites confirmed that radiolytic impurities are detectable, although the measured magnitude varied between laboratories.

Comparative QC testing evaluated standard radio‑HPLC methods against the European Pharmacopoeia phosphate‑buffered protocol, assessing recovery, peak separation, and impurity detection. The phosphate method improved peak separation but reduced recovery and did not materially enhance detection of radiolytic impurities in practice. Relying on phosphate‑buffered HPLC alone therefore offers limited added value for routine QC.

Radiolysis generates reactive species that can chemically alter the labeled ligand or create degraded fragments, changing pharmacokinetics and lowering the tumor‑to‑kidney ratio. Practical mitigations include adding radical scavengers or antioxidants, minimizing activity concentration and hold times, adding cold carrier, and optimizing formulation pH.

Key Takeaways:

• Radiolysis can reduce tumor targeting and increase relative kidney uptake.
• Phosphate‑buffered HPLC alone does not reliably detect radiolytic impurities.
• Mitigation strategies require parallel QC checks (RCP, timing, imaging).