Bone tumor–targeted delivery of theranostic (195m)Pt-bisphosphonate complexes promotes killing of metastatic tumor cells

Platinum-based drugs such as cisplatin are very potent chemotherapeutics, whereas radioactive platinum ((195m)Pt) 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, (195m)Pt-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 ((195m)Pt-BP) complexes specifically accumulate in intratibial bone metastatic lesions in mice. The (195m)Pt-BP complexes accumulate 7.3-fold more effectively in bone 7 days after systemic delivery compared to (195m)Pt-cisplatin lacking bone-targeting bisphosphonate ligands. Therapeutically, (195m)Pt-BP treatment causes 4.5-fold more γ-H2AX formation, a biomarker for DNA damage in metastatic tumor cells compared to (195m)Pt-cisplatin. We show that systemically administered (195m)Pt-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 (195m)Pt-BP vs. radioactive (195m)Pt-cisplatin or non-radioactive Pt-BP controls. These results provide the first preclinical evidence for specific accumulation and strong radiotherapeutic activity of (195m)Pt-BP in bone metastatic lesions, which offers new avenues of research on radiotherapeutic killing of tumor cells in bone metastases by Auger electrons.