Degradable FeCuS-Lipid Nanoparticles Confer Ultrasound-Activated CO Release and O2‑Independent Radical Production for Synergistic Therapy

• Published in: ACS nano Vol. 15; no. 10; pp. 16298 - 16313
• Main Authors: Sun, Yidan, An, Chunyue, Wu, Luyan, Zeng, Wenhui, Wang, Jiafeng, Wang, Yanfeng, He, Jian, Gao, Guandao, Ye, Deju
• Format: Journal Article
• Language: English
• Published: American Chemical Society 26.10.2021
• Subjects: nanoparticles; ferroptosis; synergistic therapy; gastric tumors; ultrasound
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.1c05485

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 in vivo. 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 (Fe3(CO)12), 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, Fe2+, and Cu2+, allowing us to (1) enhance tumor uptake of AIBA@FeCuS-FeCO through CO-mediated vasodilation, (2) promote hydroxyl radical production and induce tumor ferroptosis via intracellular accumulation of Fe2+/Cu2+, and (3) kill tumor cells. Moreover, the subsequent administration of disulfiram (DSF) could further chelate with the liberated Cu2+, yielding toxic bis­(N,N-diethyl dithiocarbamato)­copper­(II) chelates to synergize the therapeutic effect to ablate deep-seated orthotopic gastric tumors.