Department of Restorative Dentistry, University of Washington, Seattle, Washington 98026.
Savannah River National Laboratory, Aiken, South Carolina 29801.
J Biomed Mater Res B Appl Biomater. 2009 Nov;91(2):489-496. doi: 10.1002/jbm.b.31402.
Metal-based drugs are largely undeveloped in pharmacology. One limiting factor is the systemic toxicity of metal-based compounds. A solid-phase, sequestratable delivery agent for local delivery of metals could reduce systemic toxicity, facilitating new drug development in this nascent area. Amorphous peroxotitanates (APT) are ion-exchange materials with high affinity for several heavy metal ions and have been proposed to deliver or sequester metal ions in biological contexts. In the current study, we tested a hypothesis that APTs are able to deliver metals or metal compounds to cells. We exposed fibroblasts (L929) or monocytes (THP1) to metal-APT materials for 72 h in vitro and then measured cellular mitochondrial activity (SDH-MTT method) to assess the biological impact of the metal-APT materials versus metals or APT alone. APT alone did not significantly affect cellular mitochondrial activity, but all metal-APT materials suppressed the mitochondrial activity of fibroblasts (by 30-65% of controls). The concentration of metal-APT materials required to suppress cellular mitochondrial activity was below that required for metals alone, suggesting that simple extracellular release of the metals from the metal-APT materials was not the primary mechanism of mitochondrial suppression. In contrast to fibroblasts, no metal-APT material had a measurable effect on THP1 monocyte mitochondrial activity, despite potent suppression by metals alone. This latter result suggested that "biodelivery" by metal-APT materials may be cell type-specific. Therefore, it appears that APTs are plausible solid-phase delivery agents of metals or metal compounds to some types of cells for potential therapeutic effect.
金属基药物在药理学中尚未得到充分发展。一个限制因素是基于金属的化合物的全身毒性。一种用于局部递金属的固相、可隔离的递送剂可以降低全身毒性，促进这一新兴领域的新药开发。无定形过氧钛酸盐（APT）是一种对多种重金属离子具有高亲和力的离子交换材料，并且已经被提议在生物环境中递送或隔离金属离子。在当前的研究中，我们测试了一个假设，即 APT 能够将金属或金属化合物递送到细胞中。我们将成纤维细胞（L929）或单核细胞（THP1）在体外暴露于金属-APT 材料 72 小时，然后测量细胞线粒体活性（SDH-MTT 法），以评估金属-APT 材料与金属或 APT 单独相比对细胞的生物学影响。APT 本身不会显著影响细胞线粒体活性，但所有金属-APT 材料均抑制成纤维细胞的线粒体活性（对照的 30-65%）。抑制细胞线粒体活性所需的金属-APT 材料的浓度低于单独使用金属所需的浓度，这表明从金属-APT 材料中简单的细胞外释放金属不是抑制线粒体的主要机制。与成纤维细胞相反，尽管金属单独具有很强的抑制作用，但没有一种金属-APT 材料对 THP1 单核细胞线粒体活性有可测量的影响。后一结果表明，金属-APT 材料的“生物递药”可能是细胞类型特异性的。因此，看来 APT 是某些类型的细胞中金属或金属化合物的合理固相递药载体，可能具有治疗效果。
