Abstract
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.
Highlights
Auger electrons are low-energy electrons emitted by specific radionuclides, which decay by electron capture
The induction of osteolytic or mixed lesions was validated at weeks 1 (W1), 3 (W3), and 5 (W5) after intratibial injection
Ex-vivo high-resolution micro-CT imaging of the tibial lesion and control tibia was performed to quantify the change in bone volume (BV) and BV/TV (BV in the total volume of interest (VOI))
Summary
Auger electrons are low-energy electrons emitted by specific radionuclides, which decay by electron capture. Auger-emitting radiopharmaceuticals are promising candidates for cancer treatment because the energy is deposited over a very short range in the order of nanometers [1]. 195mPt-based Auger therapy would enable potent effective killing of tumor cells if delivered within the vicinity of a tumor cell, as the energy deposited per decay is much higher for 195mPt (2000 eV) as compared with 111In (450 eV), 123I (550 eV), or 125I (1000 eV) [2]. Platinum (Pt)-based drugs are widely used for the treatment of 24 specific types of cancer [3]. Traditional Pt drugs such as cisplatin consist of two non-leaving amine groups and two additional leaving ligands that can bind DNA to induce DNA damage [4]. Cisplatin comprising radioactive Pt core (191Pt, 193mPt, and 195mPt) has been explored between
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