文章：

通过可转化的核糖蛋白纳米颗粒诱导类似线粒体病的损伤以实现膀胱癌的靶向治疗

Inducing mitochondriopathy-like damages by transformable nucleopeptide nanoparticles for targeted therapy of bladder cancer

原文发布日期：2024-01-22

DOI: 10.1093/nsr/nwae028

类型: Journal Article

开放获取: 是

英文摘要：

Mitochondriopathy inspired adenosine triphosphate (ATP) depletions have been recognized as a powerful way for controlling tumor growth. Nevertheless, selective sequestration or exhaustion of ATP under complex biological environments remains a prodigious challenge. Harnessing the advantages of in vivo self-assembled nanomaterials, we designed an Intracellular ATP Sequestration (IAS) system to specifically construct nanofibrous nanostructures on the surface of tumor nuclei with exposed ATP binding sites, leading to highly efficient suppression of bladder cancer by induction of mitochondriopathy-like damages. Briefly, the reported transformable nucleopeptide (NLS-FF-T) self-assembled into nuclear-targeted nanoparticles with ATP binding sites encapsulated inside under aqueous conditions. By interaction with KPNA2, the NLS-FF-T transformed into a nanofibrous-based ATP trapper on the surface of tumor nuclei, which prevented the production of intracellular energy. As a result, multiple bladder tumor cell lines (T24, EJ and RT-112) revealed that the half-maximal inhibitory concentration (IC50) of NLS-FF-T was reduced by approximately 4-fold when compared to NLS-T. Following intravenous administration, NLS-FF-T was found to be dose-dependently accumulated at the tumor site of T24 xenograft mice. More significantly, this IAS system exhibited an extremely antitumor efficacy according to the deterioration of T24 tumors and simultaneously prolonged the overall survival of T24 orthotopic xenograft mice. Together, our findings clearly demonstrated the therapeutic advantages of intracellular ATP sequestration-induced mitochondriopathy-like damages, which provides a potential treatment strategy for malignancies.

摘要翻译： 

受线粒体病启发的三磷酸腺苷（ATP）耗竭已被视为控制肿瘤生长的有效途径。然而，在复杂生物环境下选择性隔离或耗尽ATP仍是一项巨大挑战。我们利用体内自组装纳米材料的优势，设计了一种细胞内ATP隔离系统，该系统能在肿瘤细胞核表面特异性构建具有暴露ATP结合位点的纳米纤维结构，通过诱导类似线粒体病的损伤，实现对膀胱癌的高效抑制。简言之，所报道的可变形核肽在水相条件下自组装成核靶向纳米颗粒，并将ATP结合位点包裹于内部。通过与KPNA2蛋白相互作用，NLS-FF-T在肿瘤细胞核表面转化为基于纳米纤维的ATP捕获器，从而阻遏细胞内能量生成。实验结果表明，在多种膀胱肿瘤细胞系中，NLS-FF-T的半抑制浓度较NLS-T降低约4倍。静脉注射后，NLS-FF-T在T24异种移植小鼠肿瘤部位呈现剂量依赖性蓄积。更重要的是，根据T24肿瘤的恶化情况及原位移植小鼠总体生存期的延长，该ATP隔离系统显示出极强的抗肿瘤功效。综上，我们的研究明确揭示了细胞内ATP隔离诱导类似线粒体病损伤的治疗优势，为恶性肿瘤提供了潜在的治疗策略。

原文链接：

Inducing mitochondriopathy-like damages by transformable nucleopeptide nanoparticles for targeted therapy of bladder cancer