PUBLICATION
Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity
- Authors
- Nadar, R.A., Farbod, K., der Schilden, K.C., Schlatt, L., Crone, B., Asokan, N., Curci, A., Brand, M., Bornhaeuser, M., Iafisco, M., Margiotta, N., Karst, U., Heskamp, S., Boerman, O.C., van den Beucken, J.J.J.P., Leeuwenburgh, S.C.G.
- ID
- ZDB-PUB-201126-16
- Date
- 2020
- Source
- Scientific Reports 10: 5889 (Journal)
- Registered Authors
- Brand, Michael
- Keywords
- none
- MeSH Terms
-
- Animals
- Antineoplastic Agents/administration & dosage*
- Antineoplastic Agents/therapeutic use
- Bone Neoplasms/drug therapy
- Bone Neoplasms/metabolism
- Bone and Bones/drug effects
- Bone and Bones/metabolism*
- Diphosphonates/administration & dosage*
- Diphosphonates/therapeutic use
- Drug Delivery Systems/methods*
- Injections, Intravenous
- Magnetic Resonance Spectroscopy
- Male
- Mice
- Mice, Inbred C57BL
- Platinum Compounds/administration & dosage*
- Platinum Compounds/therapeutic use
- Radioisotopes
- Tibia/metabolism
- Zebrafish
- PubMed
- 32246003 Full text @ Sci. Rep.
Citation
Nadar, R.A., Farbod, K., der Schilden, K.C., Schlatt, L., Crone, B., Asokan, N., Curci, A., Brand, M., Bornhaeuser, M., Iafisco, M., Margiotta, N., Karst, U., Heskamp, S., Boerman, O.C., van den Beucken, J.J.J.P., Leeuwenburgh, S.C.G. (2020) Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity. Scientific Reports. 10:5889.
Abstract
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 (195mPt-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 195mPt-BP complexes were synthesized using 195mPt(NO3)2(en) as precursor and injected intravenously into mice. Specific accumulation of 195mPt-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 195mPt BP co-localized with calcium in the trabeculae of mice tibia.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping