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Absorbed dose heterogeneity in kidney tissues is an important issue in radiopharmaceutical therapy. The effect of absorbed dose heterogeneity in nephrotoxicity is, however, not fully understood yet, which hampers the implementation of treatment optimization by obscuring the interpretation of clinical response data and the selection of optimal treatment options. Although some dosimetry methods have been developed for kidney dosimetry to the level of microscopic renal substructures, the clinical assessment of the microscopic distribution of radiopharmaceuticals in kidney tissues currently remains a challenge. This restricts the anatomical resolution of clinical dosimetry, which hinders a thorough clinical investigation of the impact of absorbed dose heterogeneity. The potential of absorbed dose–response modelling to support individual treatment optimization in radiopharmaceutical therapy is recognized and gaining attraction. However, biophysical modelling is currently underexplored for the kidney, where particular modelling challenges arise from the convolution of a complex functional organization of renal tissues with the function-mediated dose distribution of radiopharmaceuticals. This article reviews and discusses the heterogeneity of absorbed dose distribution in kidney tissues and the absorbed dose–response modelling of nephrotoxicity in radiopharmaceutical therapy. The review focuses mainly on the peptide receptor radionuclide therapy with beta-particle emitting somatostatin analogues, for which the scientific literature reflects over two decades of clinical experience. Additionally, detailed research perspectives are proposed to address various identified challenges to progress in this field. [ABSTRACT FROM AUTHOR]

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. • This study assembled inorganic nanoparticles and antibody based radiopharmaceuticals in a single nanoplatform. • The assembly improved the tumor targeting and retention of USINPs and 131I, and maintained their bioactivity. • The study uncovers the link between ferroptosis and 131I-mediated radiopharmaceutical therapy. • USINAs(131I-aPD-L1) present an effective SPECT imaging guided ferroptosis enhanced radio-immunotherapeutic approach. [ABSTRACT FROM AUTHOR]

The massic activity of 225Ac in 0.1 mol/L HCl was measured by multiple primary methods over four consistent measurement campaigns. Results from the triple-to-double coincidence ratio (TDCR) method of liquid scintillation (LS) counting were in accord with other LS-based primary methods. The calibration of commercial radionuclide calibrators ("dose calibrators") is described, with discussion of current literature values. Comparisons between experimental ionization chamber and NaI(Tl) well counter responses and benchmarked Monte Carlo models are addressed. • Ac-225 activity was determined by primary liquid scintillation methods. • Settings for radionuclide calibrators ("dose calibrators") were determined. • Comparison with Monte Carlo models. • An ampoule was submitted to the International Reference System (SIR). [ABSTRACT FROM AUTHOR]

Cancer radiopharmaceutical therapies (RPTs) have demonstrated great promise in the treatment of neuroendocrine and prostate cancer, giving hope to late-stage metastatic cancer patients with currently very few treatment options. These therapies have sparked a large amount of interest in pre-clinical research due to their ability to target metastatic disease, with many research efforts focused towards developing and evaluating targeted RPTs for different cancer types in in vivo models. Here we describe a method for monitoring real-time in vivo binding kinetics for the pre-clinical evaluation of cancer RPTs. Recognizing the significant heterogeneity in biodistribution of RPTs among even genetically identical animal models, this approach offers long-term monitoring of the same in vivo organism without euthanasia in contrast to ex vivo tissue dosimetry, while providing high temporal resolution with a low-cost, easily assembled platform, that is not present in small-animal SPECT/CTs. The method utilizes the developed optical fiber-based γ-photon biosensor, characterized to have a wide linear dynamic range with Lutetium-177 (177Lu) activity (0.5–500 μCi/mL), a common radioisotope used in cancer RPT. The probe's ability to track in vivo uptake relative to SPECT/CT and ex vivo dosimetry techniques was verified by administering 177Lu-PSMA-617 to mouse models bearing human prostate cancer tumors (PC3-PIP, PC3-flu). With this method for monitoring RPT uptake, it is possible to evaluate changes in tissue uptake at temporal resolutions <1 min to determine RPT biodistribution in pre-clinical models and better understand dose relationships with tumor ablation, toxicity, and recurrence when attempting to move therapies towards clinical trial validation. [ABSTRACT FROM AUTHOR]

• Development of a novel spatiotemporal model aimed at scrutinizing the influence of diverse physiological parameters on the delivery of 177Lu-labeled PSMA RPTs while considering the intricate microenvironment of the tumor. • Introduction of a comprehensive model facilitating precise analysis of RPT delivery dynamics, extending from the injection site to the tumor cell. • Identification of substantial enhancements in tumor-absorbed doses because of reduced dissociation constant rates, underlining a critical determinant of treatment efficacy. • Insightful revelation that tumor geometry and size of the necrotic zone hold a minimal impact on the tumor absorbed dose, providing valuable guidance for treatment planning. 177Lu-labeled prostate-specific membrane antigen (PSMA) radiopharmaceutical therapy (RPT) represents a pivotal advancement in addressing prostate cancer. However, existing therapies, while promising, remain incompletely understood and optimized. Computational models offer potential insights into RPTs, aiding in clinical drug delivery enhancement. In this study, we investigate the impact of various physiological parameters on the delivery of 177Lu-PSMA-617 RPT using the convection-diffusion-reaction (CDR) model. Our investigation encompasses tumor geometry and surrounding tissue, characterized by well-defined boundaries and initial conditions. Utilizing the finite element method, we solve governing equations across a range of parameters: dissociation constant K D (1, 0.1, 0.01 [nM]), internalization rate (0.01–0.0001 [min−1]), diverse tumor shapes, and variable necrotic zone sizes. This model can provide an accurate analysis of radiopharmaceutical delivery from the injection site to the tumor cell, including drug transport in the vascular, interstitial, and intracellular spaces, and considering important parameters (e.g., drug extravasation from microvessels or to lymphatic vessels, the extracellular matrix, receptors, and intracellular space). Our findings reveal significant enhancements in tumor-absorbed doses as K D decreases. This outcome can be attributed to the higher affinity of radiopharmaceuticals for PSMA receptors as K D diminishes, facilitating a more efficient binding and retention of the therapeutic agent within the tumor microenvironment. Additionally, tumor-absorbed doses for K D ∼ 1 [nM] show an upward trend with higher internalization rates. This observation can be rationalized by considering that a greater internalization rate would result in a higher proportion of radiopharmaceuticals being taken up by tumor cells after binding to receptors on the cell surface. Notably, tumor shape and necrotic zone size exhibit limited influence on tumor absorbed dose. The present study employs the CDR model to explore the role of physiological parameters in shaping 177Lu-PSMA-617 RPT delivery. These findings provide insights for improving prostate cancer therapy by understanding radiopharmaceutical transport dynamics. This computational approach contributes to advancing our understanding of radiopharmaceutical delivery mechanisms and has implications for enhancing treatment efficacy. [ABSTRACT FROM AUTHOR]

• Fit function implies models of the underlying kinetics and should be selected carefully. • TACs should be reported with an uncertainty which can be estimated. • Sampling of TACs should be performed including early and late time points. • The optimal data sampling of the TAC can depend on the organ of interest. Absorbed radiation doses are essential in assessing the effects, e.g. safety and efficacy, of radiopharmaceutical therapy (RPT). Patient-specific absorbed dose calculations in the target or the organ at risk require multiple inputs. These include the number of disintegrations in the organ, i.e. the time-integrated activities (TIAs) of the organs, as well as other parameters describing the process of radiation energy deposition in the target tissue (i.e. mean energy per disintegration, radiation dose constants, etc). TIAs are then estimated by incorporating the area under the radiopharmaceutical's time-activity curve (TAC), which can be obtained by quantitative measurements of the biokinetics in the patient (typically based on imaging data such as planar scintigraphy, SPECT/CT, PET/CT, or blood and urine samples). The process of TAC determination/calculation for RPT generally depends on the user, e.g., the chosen number and schedule of measured time points, the selection of the fit function, the error model for the data and the fit algorithm. These decisions can strongly affect the final TIA values and thus the accuracy of calculated absorbed doses. Despite the high clinical importance of the TIA values, there is currently no consensus on processing time-activity data or even a clear understanding of the influence of uncertainties and variations in personalised RPT dosimetry related to user-dependent TAC calculation. As a first step towards minimising site-dependent variability in RPT dosimetry, this work provides an overview of quality assurance and uncertainty management considerations of the TIA estimation. [ABSTRACT FROM AUTHOR]

Precision medicine is the selection of a treatment modality that is specifically tailored to the genetic and phenotypic characteristics of a particular patient's disease. In cancer, the objective is to treat with agents that inhibit cell signalling pathways that drive uncontrolled proliferation and dissemination of the disease. To overcome the eventual resistance to pathway inhibition therapy, this treatment modality has been combined with chemotherapy. We propose that pathway inhibition therapy is more rationally combined with radiopharmaceutical therapy (RPT), a cytotoxic treatment that is also targeted. RPT exploits pharmaceuticals that either bind specifically to tumours or accumulate by a broad array of physiological mechanisms indigenous to the neoplastic cells to deliver radiation specifically to these cells. Consistent with pathway inhibition therapy and in contrast to chemotherapy, RPT is well tolerated. However, the potential of RPT has not been fully exploited; for the most part, treatment has been implemented without using the ability to customise RPT by imaging and deriving individual patient tumour and normal organ radiation absorbed doses. These are more closely related to biological response and their determination should enable RPT treatment administration to maximum therapeutic benefit by treating to normal organ tolerance or demonstrating futility via tumour dosimetry. This is the essence of precision medicine. [ABSTRACT FROM AUTHOR]

Purpose: Effective cancer treatment generally requires combination therapy. The combination of external beam therapy (XRT) with radiopharmaceutical therapy (RPT) requires accurate three-dimensional dose calculations to avoid toxicity and evaluate efficacy. We have developed and tested a treatment planning method, using the patient-specific three-dimensional dosimetry package 3D-RD, for sequentially combined RPT/XRT therapy designed to limit toxicity to organs at risk. Methods and Materials: The biologic effective dose (BED) was used to translate voxelized RPT absorbed dose (DRPT) values into a normalized total dose (or equivalent 2-Gy-fraction XRT absorbed dose), NTDRPT map. The BED was calculated numerically using an algorithmic approach, which enabled a more accurate calculation of BED and NTDRPT. A treatment plan from the combined Samarium-153 and external beam was designed that would deliver a tumoricidal dose while delivering no more than 50 Gy of NTDsum to the spinal cord of a patient with a paraspinal tumor. Results: The average voxel NTDRPT to tumor from RPT was 22.6 Gy (range, 1–85 Gy); the maximum spinal cord voxel NTDRPT from RPT was 6.8 Gy. The combined therapy NTDsum to tumor was 71.5 Gy (range, 40–135 Gy) for a maximum voxel spinal cord NTDsum equal to the maximum tolerated dose of 50 Gy. Conclusions: A method that enables real-time treatment planning of combined RPT-XRT has been developed. By implementing a more generalized conversion between the dose values from the two modalities and an activity-based treatment of partial volume effects, the reliability of combination therapy treatment planning has been expanded. [ABSTRACT FROM AUTHOR]

Despite ongoing efforts with new chemotherapeutics, small-molecule inhibitors and biologics, patients with distant metastases continue to have a grim prognosis. Radiopharmaceutical therapy (RPT) with alpha-particle–emitting radionuclides has shown efficacy against widespread disease. Alpha-particle emitters are particularly effective because their short range and high energy deposit density lead to complex and largely irreparable DNA double-strand breaks. The high potency against tumors can also lead to high toxicity. Unlike most systemic treatment of cancer, the biodistribution of RPT agents may be imaged in humans using nuclear medicine imaging modalities. In this context, dosimetry provides a precision medicine approach to implementing RPT with alpha-emitters. [ABSTRACT FROM AUTHOR]