Nanohydroxyapatite-Based In Vivo ²¹² Pb/ ²¹² Bi Generator for Targeted Alpha Therapy of Pulmonary Metastatic Cancer

Targeted alpha therapy (TAT) based on 212 Bi has demonstrated potent antitumor activity in preclinical studies. Its short half-life (∼60.5 min) facilitates patient management, yet presents challenges in radiopharmaceutical preparation. 212 Pb, the parent nuclide of 212 Bi (∼60.5 min), possesses a more practical half-life (∼10.6 h) but is limited by off-target toxicity associated with the redistribution of secondary radioactivity. To address this, we developed an in vivo 212 Pb/ 212 Bi generator based on nanohydroxyapatite (nHAP) for the treatment of pulmonary metastases. By leveraging the dense crystal lattice of nHAP to anchor 212 Pb/ 212 Bi, we aimed to enhance the radioactivity retention in the targeted organ and reduce systemic toxicity associated with endoradiotherapy. The synthesized 212 Pb-nHAP@DOPA exhibited a satisfactory radiochemical yield (68.02 ± 0.25%), excellent in vitro stability, and potent cytotoxicity against cancer cells. Biodistribution studies confirmed significant lung accumulation of 212 Pb-nHAP@DOPA with reduced renal uptake. Therapeutic evaluation showed that repeated high-dose treatment (740 kBq × 3) effectively suppressed tumor growth but caused severe systemic toxicity, while lowering the dose to 555 kBq with 3-day intervals could alleviate renal damage of tumor-bearing mice and maintain antitumor efficacy. Nevertheless, persistent immune suppression underscores the need for further carrier optimization to better control hematologic and skeletal toxicity.