Smart nanoplatform with programmed release of dihydroartemisinin and Fe²⁺ self-supply for synergistic cancer therapy

Abstract

Dihydroartemisinin (DHA) has caught worldwide attention as an innovative antitumor drug. However, the inherent defects of DHA reduce its transport efficiency in the bloodstream, and insufficient iron content in the tumor cells further leads to poor therapeutic efficacy. Therefore, it is highly desirable to exploit a DHA/Fe-loaded nanoplatform which releases its payload responding to the tumor microenvironment (TME). Herein, we reported the smart nanodrugs CaCO₃@DHA@Fe³⁺-tannic acid (TA)@polyethylene glycol (PEG) (CDFP) nanoparticles (NPs) that specifically release DHA and self-supply Fe²⁺ ions at the tumor site for synergistic cancer therapy. Fe³⁺-TA shell with good photothermal performance makes CDFP NPs suitable photothermal agents for photothermal therapy (PTT). Once CDFP NPs were internalized by tumor cells, TA, Fe³⁺, DHA, and Ca²⁺ could be released in the acidic TME. And TA can reduce Fe³⁺ to Fe²⁺, followed by Fe²⁺-DHA mediated chemodynamic reaction to yield reactive oxygen species (ROS). Meanwhile, intracellular overloaded Ca²⁺ ions lead to the mitochondrial dysfunction, which increases ROS production and further induces tumor cell apoptosis. Such CDFP NPs with PTT, Fe²⁺-DHA mediated ROS, and Ca²⁺ overloading show excellent antitumor effects in vitro and in vivo, certifying their great potential in further clinical application.

摘要

双氢青蒿素(DHA)作为一种新型的抗癌药物引起了全世界的广泛关注. 然而, DHA的固有缺陷降低了其在血液系统中的运输效率, 而肿瘤细胞中铁含量不足进一步导致疗效不佳. 因此, 构建一个可同时负载DHA和Fe³⁺并在肿瘤微环境中特异性释放出DHA/Fe的纳米药物具有重大意义. 本文报道了一种智能纳米药物CaCO₃@DHA@Fe³⁺-TA@PEG (CDFP NPs)用于肿瘤协同治疗. Fe³⁺-TA壳层的包覆赋予CDFPNPs良好的光热性能. 此外, CDFP NPs在酸性的肿瘤微环境中可以快速降解并释放出TA, Fe³⁺, DHA和Ca²⁺. Fe³⁺与TA反应生成Fe²⁺, Fe²⁺与DHA相互作用生成高毒性的自由基. 此外, 在氧化应激状态下, Ca²⁺过载导致线粒体功能紊乱, 最终诱导肿瘤细胞死亡. 在光热治疗, 活性氧,Ca²⁺过载的协同作用下, CDFP NPs在体内外均表现出良好的治疗效果.