Redox-Active Iron Complex as Immunogenic Cell Death Inducer with NIR-II Photoacoustic Properties: Potential Theragnostic Agent for “Cold Tumors”

Abstract

Though immunogenic cell death (ICD) has garnered signifi-cant attention in the realm of “cold” tumor therapies, effectively stimulating strong immune responses with minimal side effects and 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 rationally designed and synthesized first class of five novel redox-active iron complexes ([FeIII(L1-L5)2]) of sirtinol analog with adamantane moiety that induces ICD. Iron-based compounds have never been known to induce ICD. The lead compound, Fe(L1)2, ex-hibits 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. This attribute facilitated cellular uptake pathways, enhancement of organelle accumulation, and multiple facets, resulting in en-hanced efficacy against MCF-7 cells. The Fe(L1)2 nanoaggre-gate undergoes an energy-dependent endocytic cellular-uptake pathway. In our proposed two-for-one approach, the DAMP marker indicate that our Fe(L1)2 nanoaggregates are the first ever iron-based complexes that have been known to warm up the tumor environment by maximizing the antitumor immune response, as well as Fe(L1)2 Fe(L2)2 Fe(L3)2 display a well-defined photoacoustic NIR-II spectrum that underscore their suitability for high-resolution imaging applications.