Bone tumor-targeted delivery of theranostic Pt-bisphosphonate complexes promotes killing of metastatic tumor cells.

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