Abstract

Nanoformulations, prodrugs, and targeted therapies are among the most intensively investigated approaches to new cancer therapeutics. Human ferritin has been used extensively as a nanocarrier for the delivery of drugs and imaging agents to cancerous tumor cells both in vitro and in vivo. We report exploitation of the native properties of ferritin, which can be co-loaded with simple forms of iron (FeOOH) and arsenic (arsenate) in place of the native phosphate. The As(III) form arsenic trioxide has been successfully used to treat one blood cancer, but has so far proven too systemically toxic for use on solid tumors in the clinic. The As(V) form, arsenate, on the other hand, while much less systemically toxic upon bolus injection has also proven ineffective for cancer therapy. We extended the C-terminal ends of the human ferritin subunits with a tumor cell receptor targeting peptide and loaded this modified ferritin with ~ 800 arsenates and ~ 1100 irons. Our results demonstrate targeting and uptake of the iron, arsenate-loaded modified human ferritin by breast cancer cells. At the same arsenic levels, the cytotoxicity of the iron, arsenate-loaded human ferritin was equivalent to that of free arsenic trioxide and much greater than that of free arsenate. The iron-only loaded human ferritin was not cytotoxic at the highest achievable doses. The results are consistent with the receptor-targeted human ferritin delivering arsenate as a reductively activated ‘prodrug’. This targeted delivery could be readily adapted to treat other types of solid tumor cancers.

Graphic abstract

中文翻译：

---

砷酸盐作为还原活化前药的靶向癌细胞递送。

摘要

纳米制剂，前药和靶向疗法是对新的癌症疗法进行最深入研究的方法之一。人铁蛋白已广泛用作纳米载体，用于在体内外将药物和显像剂递送至癌性肿瘤细胞。我们报道了对铁蛋白天然特性的利用，可以与简单形式的铁（FeOOH）和砷（砷酸根）一起代替天然磷酸盐。As（III）形式的三氧化二砷已成功用于治疗一种血液癌，但迄今为止已被证明对临床上的实体瘤使用的系统毒性太大。另一方面，砷（As）的形态为砷酸盐，而大剂量注射后体内毒性低得多，也被证明对癌症治疗无效。我们用靶向肿瘤细胞受体的肽扩展了人类铁蛋白亚基的C末端，并向该修饰的铁蛋白中加载了约800个砷酸盐和1100个铁。我们的结果证明乳腺癌细胞靶向并摄取了铁，砷酸根修饰的人铁蛋白。在相同的砷水平下，载有砷酸铁的人铁蛋白的细胞毒性与游离三氧化二砷的细胞毒性相当，远大于游离砷酸的细胞毒性。仅铁负载的人铁蛋白在可达到的最高剂量下没有细胞毒性。该结果与靶向砷的人铁蛋白作为还原活化的“前药”递送砷酸盐一致。该靶向递送可以容易地适于治疗其他类型的实体瘤癌症。

图形摘要