A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models
详细信息 查看全文
- 作者：Benjamin Spangler ; Shaun D. Fontaine ; Yihui Shi ; Lidia Sambucetti ; Aras N. Mattis ; Byron Hann ; James A. Wells ; Adam R. Renslo
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：December 22, 2016
- 年：2016
- 卷：59
- 期：24
- 页码：11161-11170
- 全文大小：570K
- ISSN：1520-4804
文摘
Here we describe a new approach for tumor targeting in which augmented concentrations of Fe(II) in cancer cells and/or the tumor microenvironment triggers drug release from an Fe(II)-reactive prodrug conjugate. The 1,2,4-trioxolane scaffold developed to enable this approach can in principle be applied to a broad range of cancer therapeutics and is illustrated here with Fe(II)-targeted forms of a microtubule toxin and a duocarmycin-class DNA-alkylating agent. We show that the intrinsic reactivity/toxicity of the duocarmycin analog is masked in the conjugated form and this greatly reduced toxicity in mice. This in turn permitted elevated dosing levels, leading to higher systemic exposure and a significantly improved response in tumor xenograft models. Overall our results suggest that Fe(II)-dependent drug delivery via trioxolane conjugates could have significant utility in expanding the therapeutic index of a range of clinical and preclinical stage cancer chemotherapeutics.