Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity

• Published in: Scientific reports Vol. 10; no. 1; p. 5889
• Main Authors: Nadar, Robin A., Farbod, Kambiz, der Schilden, Karlijn Codee-van, Schlatt, Lukas, Crone, Barbara, Asokan, Nandini, Curci, Alessandra, Brand, Michael, Bornhaeuser, Martin, Iafisco, Michele, Margiotta, Nicola, Karst, Uwe, Heskamp, Sandra, Boerman, Otto C., van den Beucken, Jeroen J. J. P., Leeuwenburgh, Sander C. G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.04.2020; Nature Publishing Group
• Subjects: 140/125; 140/131; 140/133; 45/22; 59; 64/60; 692/308; 692/4017; 692/4028/67/1344; 692/4028/67/322/803; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Antineoplastic drugs; Antitumor agents; Bisphosphonates; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone Neoplasms - drug therapy; Bone Neoplasms - metabolism; Calcium; Computed tomography; Diphosphonates - administration & dosage; Diphosphonates - therapeutic use; DNA adducts; Drug delivery; Drug Delivery Systems - methods; Drug resistance; Humanities and Social Sciences; Injections, Intravenous; Magnetic Resonance Spectroscopy; Male; Metabolism; Mice; Mice, Inbred C57BL; multidisciplinary; NMR; Nuclear magnetic resonance; Platinum; Platinum Compounds - administration & dosage; Platinum Compounds - therapeutic use; Radioisotopes; Science; Science (multidisciplinary); Side effects; Single photon emission computed tomography; Tibia; Tibia - metabolism; Toxicity; Zebrafish
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-62039-2

Platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks. Herein, we aimed to design radioactive bisphosphonate-functionalized platinum ( 195m Pt-BP) complexes to confirm preferential accumulation of these Pt-based drugs in metabolically active bone. In vitro NMR studies revealed that release of Pt from Pt BP complexes increased with decreasing pH. Upon systemic administration to mice, Pt-BP exhibited a 4.5-fold higher affinity to bone compared to platinum complexes lacking the bone-seeking bisphosphonate moiety. These Pt-BP complexes formed less Pt-DNA adducts compared to bisphosphonate-free platinum complexes, indicating that in vivo release of Pt from Pt-BP complexes proceeded relatively slow. Subsequently, radioactive 195m Pt-BP complexes were synthesized using 195m Pt(NO 3 ) 2 (en) as precursor and injected intravenously into mice. Specific accumulation of 195m Pt-BP was observed at skeletal sites with high metabolic activity using micro-SPECT/CT imaging. Furthermore, laser ablation-ICP-MS imaging of proximal tibia sections confirmed that 195m Pt BP co-localized with calcium in the trabeculae of mice tibia.