Turning Waste into Treasure: Radiation Byproduct-Induced Fe(III)/Fe(II) Conversion for Efficient Ferroptosis to Improve Iodine-131-Based Transarterial Radioembolization for Liver Tumors

Transarterial radioembolization (TARE) is a primary palliative treatment for advanced liver cancer. Nonetheless, its therapeutic efficacy is frequently hindered by resistance to tumor cell apoptosis induced by inter-radiotherapy. Induction of multiple cell death modalities provides a potential solution to this challenge. Ferroptosis, a distinct form of cell death from apoptosis, is dependent on the intracellular Fe²⁺-mediated Fenton reaction for the production of hydroxyl radicals (·OH) and is gaining recognition as a promising approach for cancer treatment. In this study, we synthesized a therapeutic radionuclide iodine-131 (¹³¹I)-based TARE agent by combining ¹³¹I-labeled iron-based MIL-88B(Fe) nanoparticles (NPs) (abbreviated as ¹³¹I-MIL-88B(Fe)) with Lipiodol to achieve a combined apoptosis-ferroptosis tumor therapy. Specifically, a mixture of Lipiodol and ¹³¹I-MIL-88B(Fe) NPs was injected into the liver tumors through the hepatic artery. Lipiodol blocks the arterial blood supply of the tumor, causing tumor tissue necrosis, whereas ¹³¹I inter-radiotherapy damages deoxyribonucleic acid (DNA) through direct action or indirectly via the production of ·OH through H₂O radiolysis, leading to tumor cell apoptosis. Importantly, hydrated electrons (e_aq^-), a byproduct of H₂O radiolysis, promoted the conversion of Fe³⁺ to Fe²⁺ in MIL-88B(Fe) NPs, enhancing the efficacy of the Fenton reaction and triggering ferroptosis. <i>In vitro</i> experiments demonstrated that compared to ¹³¹I alone, ¹³¹I-MIL-88B(Fe) NPs significantly enhanced ferroptosis-mediated tumor cell death due to ¹³¹I-induced Fe²⁺ production, which increased catalytic activity in the Fenton reaction. In a rat model bearing orthotopic N1S1 liver tumors, TARE with Lipiodol and ¹³¹I-MIL-88B(Fe) NPs induced tumor cell necrosis, apoptosis, and ferroptosis, resulting in improved therapeutic outcomes. This study leverages e_aq^- to facilitate Fe³⁺/Fe²⁺ conversion for efficient ferroptosis, turning waste into a valuable resource. This demonstrated the innovative integration of multiple treatment strategies to augment the efficacy of TARE in liver cancer therapy.