State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, Guangxi 541004, China.
School of Pharmaceutical Sciences, Jiangxi Normal University, Nanchang, Jiangxi 330022, China.
J Med Chem. 2024 Oct 10;67(19):17243-17258. doi: 10.1021/acs.jmedchem.4c01133. Epub 2024 Sep 19.
To effectively inhibit the growth and metastasis of non-small cell lung cancer (NSCLC) and overcome its multidrug resistance (MDR), we designed and synthesized a series of rhodium (Rh, III) 2-benzoylpyridine thiosemicarbazone complexes. Through studying their structure-activity relationships, we identified the Rh(III) complex (Rh4) with excellent cytotoxicity against multidrug-resistant lung cancer cells (A549/ADR cells). Additionally, we successfully constructed an apoferritin (AFt) nanoparticle (NP) delivery system (AFt-Rh4 NPs). Importantly, AFt-Rh4 NPs not only exhibited excellent antitumor and antimetastatic capabilities against multidrug-resistant NSCLC but also demonstrated enhanced targeting ability and reduced systemic toxicity and adverse effects. Furthermore, we confirmed and elucidated the mechanisms by which Rh4/AFt-Rh4 NPs inhibit tumor metastasis and reverse MDR in NSCLC. This was achieved by reprogramming the immune and metabolic tumor microenvironments through induction of immunogenic cell death and inhibition of dual-energy metabolism.
为了有效抑制非小细胞肺癌（NSCLC）的生长和转移，克服其多药耐药性（MDR），我们设计并合成了一系列铑（Rh，III）2-苯甲酰吡啶缩硫代氨基脲配合物。通过研究它们的构效关系，我们确定了具有针对多药耐药肺癌细胞（A549/ADR 细胞）的优异细胞毒性的 Rh（III）配合物（Rh4）。此外，我们成功构建了脱铁铁蛋白（AFt）纳米颗粒（NP）递送系统（AFt-Rh4 NPs）。重要的是，AFt-Rh4 NPs 不仅对多药耐药性 NSCLC 表现出优异的抗肿瘤和抗转移能力，而且还表现出增强的靶向能力和降低的全身毒性和不良反应。此外，我们通过诱导免疫原性细胞死亡和抑制双重能量代谢，证实并阐明了 Rh4/AFt-Rh4 NPs 抑制肿瘤转移和逆转 NSCLC 多药耐药性的机制。这是通过重新编程免疫和代谢肿瘤微环境来实现的。
