Ferroptosis is an iron-dependent form of programmed cell death with the potential to reverse traditional cancer therapy resistance. The combination of ferroptosis with chemotherapy, photodynamic therapy and X-ray therapy has demonstrated remarkably improved therapeutic efficiency. Radiopharmaceutical therapy (RPT) is an emerging approach that achieves precise radiation to diseased tissues via radionuclide delivery. However, insufficient accumulation and retention of therapeutic radiopharmaceuticals in tumor region as well as cancer radioresistance impact treatment efficacy. Here, a nanoassembly of renal clearable ultrasmall iron nanoparticles (USINPs) and 131I-aPD-L1 is prepared via the affinity of fluorophenylboronic acid modified on the USINPs with 131I-aPD-L1. The 150 nm USINAs(131I-aPD-L1) nanoassembly is stable in blood circulation, effectively targets to the tumor and disassembles in the presence of ATP in the tumor microenvironment. Both in vitro and in vivo experiments prove that USINPs-induced ferroptosis boosted the tumor radiosensitization to 131I while 131I-mediated RPT further enhanced ferroptosis. Meanwhile, the immunogenic cell death caused by RPT and ferroptosis combined with PD-L1 immune checkpoint blockade therapy exhibits a strong antitumor immunity. This study provides a novel way to improve the tumor accumulation of ferroptosis inducer and radiopharmaceuticals, insights into the interaction between RPT and ferroptosis and an effective SPECT-guided ferroptosis-enhanced radio-immunotherapy.

Objective.For certain radionuclides that decay through emitting two or more gamma photons consecutively within a short time interval-called cascade gamma-rays, the location where a radiopharmaceutical molecule emits cascade gamma-rays can be identified through coincidence detection of the photons. If each cascade photon is detected through a collimation mechanism, the location of the molecule can be inferred from the intersection of the back-projections of the two photons.Approach.In this work, we report the design and evaluation of a three-dimensional stationary imager based on this concept for imaging distributions of cascade-emitting radionuclides in radiopharmaceutical therapy. The imager was composed of two gamma-ray cameras assembled in an L-shape. Both cameras were NaI(Tl) scintillator based, one with a multi-slit collimator, the other with a multi-pinhole collimator. The field of view (FOV) was 100 mm (∅) × 100 mm (L). Based on the unique characteristics of the cascade coincidence events, we used a direct back-projection algorithm to reconstruct point source images for assessing the imager\'s intrinsic spatial resolution and the standard maximum likelihood expectation maximization algorithm for reconstructing phantom images.Main results.We evaluated the performance of the imager in both simulated and prototype form with radionuclide177Lu (cascade photon emitter). On the simulated imager, the coincidence detection efficiency at the center of FOV was 3.85 × 10-6, the spatial resolution was 7.0 mm. On the prototype imager, the corresponding values were 3.20 × 10-6and 6.7 mm, respectively. Simulated hot-rod and experimental cardiac phantom studies demonstrate the first three-dimensional cascade gamma coincidence imager is fully functional.