A redox-active iron complex as an immunogenic cell death-I inducer with NIR-II photoacoustic properties: a potential theragnostic agent for “cold tumors”†

Abstract

Although immunogenic cell death (ICD) has garnered significant attention in the realm of “cold” tumor therapies, effectively stimulating strong immune responses with minimal side effects, their real-time monitoring in deep-seated tumors remains challenging. There is no available drug that covers these two bases with one swing. Herein, we report a proof-of-concept for the rational design and synthesis of a novel class of five redox-active iron(III) complexes, ([Fe^III(L1–L5)₂]), based on sirtinol analogs bearing adamantane moieties. These complexes show potential as modest stimulators of ICD, as indicated by the expression of key ICD markers. The lead compound, Fe(L1)₂, exhibits promiscuous nanoscale aggregation in RPMI-1640 cell culture media, characterized by a stable hydrodynamic effective diameter ranging from 50 nm to 70 nm over 48 hours. Fe(L1)₂ nanoaggregates with enhanced efficacy against MCF-7 cells undergo an energy-dependent endocytic cellular-uptake pathway. In our proposed two-for-one approach, the DAMP marker indicates that our Fe(L1)₂ nanoaggregates are iron-based complexes that warm up the tumor environment by maximizing the antitumor immune response, and Fe(L1–L3)₂ display well-defined photoacoustic NIR-II spectra that underscore their suitability in future for high-resolution imaging applications.