Department of Dentistry - Regenerative Biomaterials, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Philips van Leydenlaan 25, 6525, EX, Nijmegen, The Netherlands.
Nuclear Research & Consultancy Group, Westerduinweg 3, 1755, LE, Petten, The Netherlands.
Sci Rep. 2020 Apr 3;10(1):5889. 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 (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 Pt-BP complexes were synthesized using Pt(NO)(en) as precursor and injected intravenously into mice. Specific accumulation of 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 Pt BP co-localized with calcium in the trabeculae of mice tibia.
基于铂的化疗药物表现出优异的抗肿瘤特性。然而，这些药物会引起严重的副作用，包括毒性、耐药性和缺乏肿瘤选择性。肿瘤靶向药物递送已被证明具有克服这些缺点的巨大潜力。在此，我们旨在设计放射性双膦酸盐功能化的铂（Pt-BP）配合物，以确认这些基于铂的药物在代谢活跃的骨中优先积累。体外 NMR 研究表明，Pt 从 Pt-BP 配合物中的释放随着 pH 值的降低而增加。在小鼠中系统给药后，与缺乏骨靶向双膦酸盐部分的铂配合物相比，Pt-BP 对骨的亲和力高 4.5 倍。与不含双膦酸盐的铂配合物相比，这些 Pt-BP 配合物形成的 Pt-DNA 加合物较少，表明 Pt 从 Pt-BP 配合物中的体内释放相对较慢。随后，使用 Pt(NO)(en) 作为前体合成放射性 Pt-BP 配合物，并静脉注射到小鼠体内。使用 micro-SPECT/CT 成像观察到在代谢活性高的骨骼部位特异性积累了 Pt-BP。此外，对近端胫骨切片的激光烧蚀-ICP-MS 成像证实，Pt-BP 与小鼠胫骨小梁中的钙共定位。
