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.
Highlights
Bone metastases are often associated with accelerated bone resorption leading to complications such as skeletal-related events (SREs), bone pain or hypercalcemia[6,7]
Among the limited number of studies that evaluated the therapeutic properties of 195mPt, Bodnar et al demonstrated that inhibition of the growth of Ehrlich solid carcinoma by 195mPt-cisplatin was 30% more effective compared to non-radioactive cisplatin[23]
Our present work focuses on the design of radioactive and bone-seeking chemotherapeutics based on 195mPt
Summary
We aimed to design radioactive bisphosphonate-functionalized platinum (195mPt-BP) complexes to confirm preferential accumulation of these Pt-based drugs in metabolically active bone. I.e. breast, prostate, lung, kidney, and thyroid, metastasize to bone since its physiological environment facilitates the formation and growth of cancer cells[1,2]. Targeted delivery of Pt-based chemotherapeutics comprising 195mPt could potentially increase the therapeutic efficacy of Pt-based drugs Such targeted theranostic approach for treatment of bone metastases has the potential for precision medicine to “see and treat bone metastases”[25]. Margiotta et al formulated various anticancer Pt-bisphosphonate complexes aimed at targeted delivery of Pt to bone[29,30,31], since BPs accumulate in bone of high metabolic activity[32]. We aimed to study the biodistribution of Pt-BP compounds in metabolically active bone using advanced elemental mapping and micro-SPECT imaging techniques
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