⁶⁸Ga/¹⁶¹Tb-Labeled CXCR4-Targeted Probe with Enhanced Positive Charge: Improved Affinity and Longer Tumor Retention...

This study developed and evaluated a positively charged CXCR4-targeted theranostic probe, ⁶⁸Ga/¹⁶¹Tb-Pentikra, to enhance the affinity and therapeutic efficacy of the benchmark compound PentixaTher. The novel probe, modified with a d-Lys-d-Arg-d-Ala linker, demonstrated a 13-fold higher in vitro affinity for hCXCR4, as well as superior cellular retention. In CXCR4-expressing xenografted mice, ¹⁶¹Tb-Pentikra exhibited potent antitumor efficacy, reducing the mean tumor volume to 13.8% of the baseline. However, despite this enhanced in vitro and tumor-targeting performance, it conferred no survival benefit due to elevated off-target toxicity in the bone marrow and the digestive tract. Crucially, comparative biodistribution revealed significant species differences, with human models showing higher potential marrow exposure than mouse models. This study underscores a critical translational challenge: optimizing ligand affinity must be rigorously balanced against minimizing normal organ uptake to achieve therapeutic success in CXCR4-targeted radioligand therapy.