Grishagin Ivan V, Pollock J Bryant, Kushal Swati, Cook Timothy R, Stang Peter J, Olenyuk Bogdan Z
School of Pharmacy, University of Southern California, Los Angeles, CA 90089; and.
Department of Chemistry, University of Utah, Salt Lake City, UT 84112.
Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18448-53. doi: 10.1073/pnas.1418712111. Epub 2014 Dec 16.
The development of novel antitumor agents that have high efficacy in suppressing tumor growth, have low toxicity to nontumor tissues, and exhibit rapid localization in the targeted tumor sites is an ongoing avenue of research at the interface of chemistry, cancer biology, and pharmacology. Supramolecular metal-based coordination complexes (SCCs) have well-defined shapes and geometries, and upon their internalization, SCCs could affect multiple oncogenic signaling pathways in cells and tissues. We investigated the uptake, intracellular localization, and antitumor activity of two rhomboidal Pt(II)-based SCCs. Laser-scanning confocal microscopy in A549 and HeLa cells was used to determine the uptake and localization of the assemblies within cells and their effect on tumor growth was investigated in mouse s.c. tumor xenograft models. The SCCs are soluble in cell culture media within the entire range of studied concentrations (1 nM-5 µM), are nontoxic, and showed efficacy in reducing the rate of tumor growth in s.c. mouse tumor xenografts. These properties reveal the potential of Pt(II)-based SCCs for future biomedical applications as therapeutic agents.
开发在抑制肿瘤生长方面具有高效性、对非肿瘤组织毒性低且能在靶向肿瘤部位快速定位的新型抗肿瘤药物，是化学、癌症生物学和药理学交叉领域正在进行的研究方向。基于超分子金属的配位络合物（SCCs）具有明确的形状和几何结构，内化后，SCCs可影响细胞和组织中的多种致癌信号通路。我们研究了两种基于菱形Pt(II)的SCCs的摄取、细胞内定位和抗肿瘤活性。利用A549和HeLa细胞的激光扫描共聚焦显微镜来确定这些组装体在细胞内的摄取和定位，并在小鼠皮下肿瘤异种移植模型中研究它们对肿瘤生长的影响。这些SCCs在所研究的整个浓度范围（1 nM - 5 µM）内可溶于细胞培养基，无毒，并在降低小鼠皮下肿瘤异种移植瘤的生长速率方面显示出疗效。这些特性揭示了基于Pt(II)的SCCs作为治疗剂在未来生物医学应用中的潜力。
