Platinum-based drugs such as cisplatin are very potent chemotherapeutics, whereas radioactive platinum (^195mPt) is a rich source of low-energy Auger electrons, which kills tumor cells by damaging DNA. Auger electrons damage cells over a very short range. Consequently, ^195mPt-based radiopharmaceuticals should be targeted toward ​tumors to maximize radiotherapeutic efficacy and minimize Pt-based systemic toxicity. Herein, we show that systemically administered radioactive bisphosphonate-functionalized platinum (^195mPt-BP) complexes specifically accumulate in intratibial bone metastatic lesions in mice. The ^195mPt-BP complexes accumulate 7.3-fold more effectively in bone 7 days after systemic delivery compared to ^195mPt-cisplatin lacking bone-targeting bisphosphonate ligands. Therapeutically, ^195mPt-BP treatment causes 4.5-fold more γ-H2AX formation, a biomarker for DNA damage in metastatic tumor cells compared to ^195mPt-cisplatin. We show that systemically administered ^195mPt-BP is radiotherapeutically active, as evidenced by an 11-fold increased DNA damage in metastatic tumor cells compared to non-radioactive Pt-BP controls. Moreover, apoptosis in metastatic tumor cells is enhanced more than 3.4-fold upon systemic administration of ^195mPt-BP vs. radioactive ^195mPt-cisplatin or non-radioactive Pt-BP controls. These results provide the first preclinical evidence for specific accumulation and strong radiotherapeutic activity of ^195mPt-BP in bone metastatic lesions, which offers new avenues of research on radiotherapeutic killing of tumor cells in bone metastases by Auger electrons.

铂基药物（例如顺铂）是非常有效的化学疗法，而放射性铂（^195m Pt）是低能俄歇电子的丰富来源，其通过破坏DNA杀死肿瘤细胞。俄歇电子会在非常短的范围内损坏细胞。因此，基于^195m Pt的放射性药物应针对肿瘤，以最大程度地提高放射治疗功效并最小化Pt的全身毒性。在这里，我们显示系统地管理放射性双膦酸酯官能化的铂（^195m Pt-BP）复合物具体积累在小鼠的胫骨骨转移性病变中。该^195米铂-BP复合物积累相比，在骨骼更有效7.3倍全身给药后7天^195米铂-顺铂缺乏靶向骨的双膦酸酯配体。在治疗上，与^195m Pt-顺铂相比，^195m Pt-BP治疗引起的γ-H2AX形成多4.5倍，这是转移性肿瘤细胞中DNA损伤的生物标记。我们显示全身给药的^195m Pt-BP具有放射治疗活性，与非放射性Pt-BP对照相比，转移性肿瘤细胞中DNA损伤增加了11倍，证明了这一点。而且，细胞凋亡的转移性肿瘤细胞被增强后的全身性施用多于3.4倍^195米的Pt-BP与放射性^195米Pt-顺铂或非放射性Pt-BP对照。这些结果为^195m Pt-BP在骨转移病灶中的特异性蓄积和强大的放射治疗活性提供了首个临床前证据，这为利用俄歇电子对骨转移瘤细胞进行放射治疗杀伤提供了新的研究途径。