State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
Departments of Nuclear Medicine & General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.
ACS Nano. 2021 Oct 26;15(10):16298-16313. doi: 10.1021/acsnano.1c05485. Epub 2021 Sep 30.
Ultrasound (US)-activated nanoagents capable of producing cytotoxic species have been promising for the treatment of deep-seated tumors; however, poor tumor uptake and insufficient generation of cytotoxic agents have largely limited their therapeutic efficacy . Herein, we report a hybrid FeCuS-lipid nanoparticle (AIBA@FeCuS-FeCO) by amphiphilic lipids-assisted emulsion of a free radical initiator (AIBA), a radical-sensitive CO donor (Fe(CO)), and radical-degradable FeCuS nanodisks for US-activated synergistic therapy of deep-located orthotopic gastric tumors in living mice. Upon US irradiation, AIBA@FeCuS-FeCO could be degraded and release cytotoxic AIBA radicals, CO, Fe, and Cu, allowing us to (1) enhance tumor uptake of AIBA@FeCuS-FeCO through CO-mediated vasodilation, (2) promote hydroxyl radical production and induce tumor ferroptosis intracellular accumulation of Fe/Cu, and (3) kill tumor cells. Moreover, the subsequent administration of disulfiram (DSF) could further chelate with the liberated Cu, yielding toxic bis(,-diethyl dithiocarbamato)copper(II) chelates to synergize the therapeutic effect to ablate deep-seated orthotopic gastric tumors.
超声（US）激活的纳米制剂能够产生细胞毒性物质，有望用于治疗深部肿瘤；然而，较差的肿瘤摄取和不足够的细胞毒性物质的产生在很大程度上限制了它们的治疗效果。在此，我们报告了一种通过两亲脂质辅助自由基引发剂（AIBA）、自由基敏感 CO 供体（Fe(CO)）和自由基降解的 FeCuS 纳米盘的乳液制备的杂交 FeCuS-脂质纳米颗粒（AIBA@FeCuS-FeCO），用于活体小鼠原位胃深部肿瘤的 US 激活协同治疗。在 US 照射下，AIBA@FeCuS-FeCO 可以降解并释放细胞毒性 AIBA 自由基、CO、Fe 和 Cu，使我们能够 (1) 通过 CO 介导的血管舒张增强 AIBA@FeCuS-FeCO 的肿瘤摄取，(2) 促进羟基自由基的产生并诱导肿瘤铁死亡和细胞内 Fe/Cu 的积累，以及 (3) 杀死肿瘤细胞。此外，随后给予双硫仑（DSF）可以进一步与释放的 Cu 螯合，生成有毒的双（β-二乙基二硫代氨基甲酰基）铜（II）配合物，以协同增效来消融深部原位胃肿瘤。
