Search Results (29)

Rationale: Radium-223 dichloride (²²³RaCl₂) is an FDA-approved alpha-emitting radiopharmaceutical that targets bone metastases in metastatic castration-resistant prostate cancer (mCRPC). This study investigates the therapeutic and immunological effects of combining ²²³RaCl₂ with immune checkpoint inhibitors (ICIs) in a clinically relevant, immunocompetent murine model of prostate cancer bone metastasis. Methods: Luciferase-expressing MyC-CaP prostate cancer cells were implanted intratibially into FVB mice to establish bone metastases. Mice were treated with escalating doses of ²²³RaCl₂ (0.04–0.27 µCi) alone or a single dose combined with anti-CTLA-4 and anti-PD-L1 ICIs. Tumor growth was monitored using bioluminescence imaging. Micro-CT, alpha camera imaging, histology, and qPCR were used to assess bone remodeling, radiopharmaceutical distribution, immune infiltration, and gene expression. Ex vivo biodistribution and blood analyses quantified tissue uptake and toxicity. Results: Escalating doses of ²²³RaCl₂ did not significantly inhibit tumor growth or improve survival. Biodistribution and imaging showed preferential localization of ²²³RaCl₂ to tumor-adjacent bone, with minimal signal in isolated tumor tissue. Immunohistochemistry revealed increased CD4⁺ and CD8α⁺ T-cell infiltration in regions of high γH2AX expression, indicating localized immune modulation. However, combination therapy with ICIs did not enhance tumor control or immune infiltration beyond monotherapy. qPCR demonstrated significant upregulation of Mhc1 only in the combination group, suggesting localized immune activation. Toxicity profiles remained acceptable. Conclusions: ²²³RaCl₂ localizes primarily to bone surfaces, limiting direct cytotoxic and immunomodulatory effects within the tumor microenvironment. While combination with ICIs did not improve efficacy, these findings provide a platform for studying spatial dose distribution and support future development of tumor-targeted alpha therapies to potentiate immunotherapy in mCRPC. Full article

Introduction: Acute ischemic stroke demands interventions that restore perfusion and protect neurons within a narrow therapeutic window. We propose a unified theranostic platform that couples adaptive imaging, topology-aware decision-making, and immediate neuroprotective and micro-dosimetric intervention. Methods: The platform integrates three components. First, a topology-preserving MR–PET engine employs adaptive Poisson-disc sampling, partial Fourier constraints, and structured Hankel low-rank priors in a closed loop. Persistent-homology metrics quantify vascular graph uncertainty and guide subsequent k-space and PET projections, reducing acquisition time while preserving collateral topology. Second, immediate post-reperfusion delivery of glycolic acid attenuates glutamate-driven calcium influx and stabilizes mitochondrial function. Third, trace doses of sol–gel-derived, neutron-activated ⁹⁰Y₂O₃ microspheres provide sharply confined beta irradiation for micro-scale metabolic modulation. Results: In a porcine stroke model replicating the human recanalization workflow, the imaging engine maintained vascular Betti-number invariants within three percent of fully sampled reference scans while reducing acquisition time by nearly half. Glycolic acid reduced glutamate-induced intracellular calcium rise by approximately sixty percent in vitro and decreased infarct volume by thirty-eight percent in vivo. Micro-dosimetry confirmed a mean perivascular beta dose of twenty-eight grays, and histology demonstrated a forty-two percent increase in NeuN-positive neuronal survival compared with standard recanalization. Conclusions: These results demonstrate that intelligent compressed-sensing MR–PET, targeted micro-radioembolization, and glycolic acid neuroprotection can act synergistically to bridge diagnostic imaging and immediate intervention. By coupling imaging, decision-making, and therapy in a closed-loop manner and elevating topological fidelity from a reconstruction byproduct to a control variable, the proposed platform reframes MR–PET from passive diagnostics into an active, decision-driven theranostic system and establishes a foundation for future human trials. Full article

Boron neutron capture therapy (BNCT) is experiencing a global resurgence driven by advances in boron pharmacology, accelerator-based neutron sources, and molecular imaging-guided theranostics. BNCT produces high linear energy transfer particles with micrometer-range energy deposition, enabling cell-selective irradiation confined to boron-enriched tumor cells in a geometrically targeted region by the neutron beam. This mechanism offers the potential for exceptionally high therapeutic ratios, provided two core requirements are met: sufficient differential tumor uptake of ¹⁰B and a neutron beam with appropriate energy and penetration. After early clinical attempts in the mid-20th century were hindered by inadequate boron agents and reactor-based neutron beams, recent technological breakthroughs have made BNCT clinically viable. The development of hospital-compatible accelerator neutron sources, next-generation boron delivery systems (such as receptor-targeted compounds and nanoparticles), advanced theranostic approaches (such as ¹⁸F-BPA positron emission tomography and boron-sensitive magnetic resonance imaging), and AI-driven biodistribution modeling now support personalized treatment planning and patient selection. These innovations have catalyzed modern clinical implementation, exemplified by Japan’s regulatory approval of BNCT for recurrent head and neck cancer and the rapid expansion of clinical programs across Asia, Europe, and South America. Building on these foundations, BNCT has transitioned from a predominantly academic experimental modality into an increasingly commercialized and industrially supported therapeutic platform. The emergence of dedicated BNCT companies, international collaborations between accelerator manufacturers and hospitals, and pharmaceutical development pipelines for next-generation boron carriers has accelerated clinical translation. Moreover, BNCT now occupies a unique position among radiation modalities due to its hybrid nature, namely combining the biological targeting of radiopharmaceutical therapy with the external-beam controllability of radiotherapy, thereby offering new therapeutic opportunities where competitive approaches fall short. Emerging evidence suggests therapeutic promise in glioblastoma, recurrent head and neck cancers, melanoma, meningioma, lung cancer, sarcomas, and other difficult-to-treat malignancies. Looking ahead, continued innovation in compact neutron source engineering, boron nanocarriers, multimodal theranostics, microdosimetry-guided treatment planning, and combination strategies with systemic therapies such as immunotherapy will be essential for optimizing outcomes. Together, these converging developments position BNCT as a biologically targeted and potentially transformative modality in the era of precision oncology. Full article

Microdosimetry plays a critical role in particle therapy by quantifying energy deposition within microscopic domains to assess biological effects. This study evaluates the influence of different microdosimetric functions (MFs) and domain geometries (DGs) on relative biological effectiveness (RBE) predictions in carbon ion radiotherapy. Specifically, we compare the analytical microdosimetric function (AMF), calculated for spherical domains and implemented in PHITS, with the Kiefer–Chatterjee (KC) track structure model, which is conventionally applied to cylindrical geometries. To enable a direct comparison, we also introduce a novel implementation of the KC model for spherical domains. Using both models, specific energy distributions were calculated across a range of domain sizes and geometries. These distributions were input into the modified microdosimetric kinetic model (mMKM) to calculate RBE for the HSG cell line and compared against published in vitro data. The results show that both microdosimetric function and domain geometry significantly affect microdosimetric spectra and the resulting RBE, with deviations exceeding 10% when fixed mMKM parameters are used. Parameter optimization within the mMKM enables alignment across models. Our findings emphasize that microdosimetric function and domain geometry selection must be explicitly accounted for in microdosimetry-based RBE modeling, and that model parameters must be tuned accordingly to ensure consistent and biologically accurate predictions. Full article

Ion radiotherapy requires accurate relative biological effectiveness (RBE) calculations to account for the markedly different biological effects of ions compared to photons. Microdosimetric RBE models rely on descriptions of the energy deposition at the microscopic scale, either through radial dose distributions (RDDs) or microdosimetric probability density distributions. While RDD approaches focus on the theoretical description of the energy deposition around the ion track, microdosimetric distributions offer the advantage of being experimentally measurable, which is crucial for quality assurance programs. As the results of microdosimetric RBE models depend on whether RDD or microdosimetric distributions are used, the model parameters are not interchangeable between these approaches. This study presents and validates a method to reproduce the published reference biological and clinical dose calculations at NIRS-QST for only carbon ion radiotherapy by using the modified microdosimetric kinetic model (MKM) alongside microdosimetric distributions instead of the reference RDD approach. To achieve this, Monte Carlo simulations were performed to estimate the variation of the radiation quality within and outside the field of pristine and spread-out Bragg peaks. By appropriately optimizing the modified MKM parameters for microdosimetric distributions assessed within water spheres, we successfully reproduced the results of calculations using the reference NIRS-QST RDD, generally within 2%. Full article

A constant proton relative biological effectiveness (RBE) of 1.1 for tumor control is currently used in proton therapy treatment planning. However, in vitro, in vivo and clinical experiences indicate that proton RBE varies with kinetic energy and, therefore, tissue depth within proton Bragg peaks. A number of published RBE models capture variations in proton RBE with depth. The published models can be sub-divided into empirical (or phenomenological) and biophysical (or mechanistic-inspired) RBE models. Empirical RBE models usually characterize the beam quality through the dose-averaged linear energy transfer (${\mathrm{LET}}_{\mathrm{D}}$), while most biophysical RBE models relate RBE to the dose-averaged lineal energy ($y_{\mathrm{D}}$). In this work, an analytic microdosimetry model and the Monte Carlo damage simulation code (MCDS) were utilized for the evaluation of the ${\mathrm{LET}}_{\mathrm{D}}$ and $y_{\mathrm{D}}$ of monoenergetic proton beams in the clinically relevant energy range of 1–250 MeV. The calculated ${\mathrm{LET}}_{\mathrm{D}}$ and $y_{\mathrm{D}}$ values were then used for the estimation of the RBE for five different cell types at three dose levels (2 Gy, 5 Gy and 7 Gy). Comparisons are made between nine empirical RBE models and two biophysical models, namely, the theory of dual radiation action (TDRA) and the microdosimetric kinetic model (MKM). The results show that, at conventional dose fractions (~2 Gy) and for proton energies which correspond to the proximal and central regions of the spread-out Bragg peak (SOBP), RBE varies from 1.0 to 1.2. At lower proton energies related to the distal SOBP, we find significant deviations from a constant $\mathrm{RBE}$ of 1.1, especially for late-responding tissues (low ${(\alpha /\beta )}_R$ of ~1.5–3.5 Gy) where proton RBE may reach 1.3 to 1.5. For hypofractionated dose fractions (5–7 Gy), deviations from a constant $\mathrm{RBE}$ of 1.1 are smaller, but may still be sizeable, yielding RBE values between 1.15 and 1.3. However, large discrepancies among the different models were observed that make the selection of a variable RBE across the SOBP uncertain. Full article

Targeted radionuclide therapy (TRT) for internal pathway-directed treatment is a game changer for precision medicine. TRT improves tumor control while minimizing damage to healthy tissue and extends the survival for patients with cancer. The application of theranostic-paired TRT along with cellular phenotype and genotype correlative analysis has the potential for malignant disease management. Chelation chemistry is essential for the development of theranostic-paired radiopharmaceuticals for TRT. Among image-guided TRT, ⁶⁸Ga and ^99mTc are the current standards for diagnostic radionuclides, while ¹⁷⁷Lu and ²²⁵Ac have shown great promise for β- and α-TRT, respectively. Their long half-lives, potent radiobiology, favorable decay schemes, and ability to form stable chelation conjugates make them ideal for both manufacturing and clinical use. The current challenges include optimizing radionuclide production processes, coordinating chelation chemistry stability of theranostic-paired isotopes to reduce free daughters [this pertains to ²²⁵Ac daughters ²²¹Fr and ²¹³Bi]-induced tissue toxicity, and improving the modeling of micro dosimetry to refine dose–response evaluation. The empirical approach to TRT delivery is based on standard radionuclide administered activity levels, although clinical trials have revealed inconsistent outcomes and normal-tissue toxicities despite equivalent administered activities. This review presents the latest optimization methods for chelation-based theranostic radiopharmaceuticals, advancements in micro-dosimetry, and SPECT/CT technologies for quantifying whole-body uptake and monitoring therapeutic response as well as cytogenetic correlative analyses. Full article

Conventional X-ray therapy (XRT) is commonly applied to suppress cancerous tumors; however, it often inflicts collateral damage to nearby healthy tissue. In order to provide a better conformity of the dose distribution in the irradiated tumor, proton therapy (PT) is increasingly being used to treat solid tumors. Furthermore, radiosensitization with gold nanoparticles (GNPs) has been extensively studied to increase the therapeutic ratio. The mechanism of radiosensitization is assumed to be connected to an enhancement of the absorbed dose due to huge photoelectric cross-sections with gold. Nevertheless, numerous theoretical studies, mostly based on Monte Carlo (MC) simulations, did not provide a consistent and thorough picture of dose enhancement and, therefore, the radiosensitization effect. Radiosensitization by nanoparticles in PT is even less studied than in XRT. Therefore, we investigate the physics picture of GNP-enhanced RT using an MC simulation with Geant4 equipped with the most recent physics models, taking into account a wide range of physics processes relevant for realistic PT and XRT. Namely, we measured dose enhancement factors in the vicinity of GNP, with diameters ranging from 10 nm to 80 nm. The dose enhancement in the vicinity of GNP reaches high values for XRT, while it is very modest for PT. The macroscopic dose enhancement factors for realistic therapeutic GNP concentrations are rather low for all RT scenarios; therefore, other physico-chemical and biological mechanisms should be additionally invoked for an explanation of the radiosensitization effect observed in many experiments. Full article

The analytical microdosimetric function (AMF) implemented in the Monte Carlo code PHITS is a unique tool that bridges the gap between macro- and microscopic scales of radiation interactions, enabling accurate microdosimetric calculations over macroscopic bodies. The original AMF was published in 2006, based on the results of track structure calculations. Recently, a newer version of the AMF was proposed, incorporating an improved description of the energy loss at the microscopic scale. This study compares the older and the newer AMFs in computing microdosimetric probability distributions, mean values, and the relative biological effectiveness (RBE). To this end, 16000 microdosimetric lineal energy probability density distributions were simulated with PHITS for ions from ¹H to ²³⁸U over a broad energy range (1–1000 MeV/n). The newer AMF was found to offer superior performance, particularly for very heavy ions, producing results that align more closely with published in vitro clonogenic survival experiments. These findings suggest that the updated AMF provides a more reliable tool for microdosimetric calculations and RBE modeling, essential for ion radiation therapy and space radiation protection. Full article

This paper explores the role of microdosimetry in boron neutron capture therapy (BNCT), a cancer treatment involving the selective accumulation of boron-containing compounds in cancer cells, followed by neutron irradiation. Neutron interactions with ¹⁰B induces a nuclear reaction, releasing densely ionizing particles, specifically alpha particles and recoiling lithium-7 nuclei. These particles deposit their energy within a small tissue volume, potentially targeting cancer cells while sparing healthy tissue. The microscopic energy distribution, subject to significant fluctuations due to the short particle range, influences treatment efficacy. Microdosimetry, by studying this distribution, plays a crucial role in optimizing BNCT treatment planning. The methodology employs paired tissue equivalent proportional counters (TEPCs), one with cathode walls enriched with boron and the other without. Precise assessment of boron concentration is essential, as well as the ability to extrapolate results to the actual ¹⁰B concentration within the treatment region. The effective ¹⁰B concentrations within four boronated TEPCs, containing 10, 25, 70, and 100 ppm of ¹⁰B, have been determined. Results show variations of less than 3% from nominal values. Additionally, dose enhancement due to BNC interactions was measured and found to be proportional to the ¹⁰B concentration, with a proportionality factor of 7.7 × 10⁻³ per ppm of boron. Based on these findings, a robust procedure is presented for assessing the impact of BNCT in the treatment region, considering potential variations in boron content relative to the TEPC used. Full article

This paper creates an approximate three-dimensional model for normal and cancerous cervical cells using image processing and computer-aided design (CAD) tools. The model is then exposed to low-frequency electric pulses to verify the work with experimental data. The transmembrane potential, pore density, and pore radius evolution are analyzed. This work adds a study of the electrodeformation of cells under an electric field to investigate cytoskeleton integrity. The Maxwell stress tensor is calculated for the dispersive bi-lipid layer plasma membrane. The solid displacement is calculated under electric stress to observe cytoskeleton integrity. After verifying the results with previous experiments, the cells are exposed to a nanosecond pulsed electric field. The nanosecond pulse is applied using a drift-step rectifier diode (DSRD)-based generator circuit. The cells’ transmembrane voltage (TMV), pore density, pore radius evolution, displacement of the membrane under electric stress, and strain energy are calculated. A thermal analysis of the cells under a nanosecond pulse is also carried out to prove that it constitutes a non-thermal process. The results showed differences in normal and cancerous cell responses to electric pulses due to changes in morphology and differences in the cells’ electrical and mechanical properties. This work is a model-driven microdosimetry method that could be used for diagnostic and therapeutic purposes. Full article

The computation of the relative biological effectiveness (RBE) is a fundamental step in the planning of cancer radiotherapy treatments with accelerated ions. Numerical parameters derived analyzing the dose response of the chosen cell line after irradiation to photons (i.e., α and β, namely the linear and quadratic terms of the linear-quadratic model of cell survival) are generally used as input to biophysical models to predict the ion RBE. The α/β ratio for the photon exposure is generally regarded as an indicator of cell radiosensitivity. However, previous studies suggest that α/β might not be a sufficient parameter to model the RBE of relatively high linear energy transfer (LET) radiation such as carbon ions. For a fixed α/β, the effect of the absolute values of α and β on the computed RBE is underexplored. Furthermore, since α and β are anticorrelated during the fit of the photon-exposed in vitro survival data, different linear-quadratic fits could produce different sets of α and β, thus affecting the RBE calculations. This article reports the combined effect of the α/β ratio and the absolute values α and β on the RBE computed with the Mayo Clinic Florida microdosimetric kinetic model (MCF MKM) for ¹²C ions of different LET. Furthermore, we introduce a theory-based strategy to potentially mitigate the anticorrelation between α and β during the fit of the photon dose-response biological data. Full article

The relative biological effectiveness (RBE) calculations used during the planning of ion therapy treatments are generally based on the microdosimetric kinetic model (MKM) and the local effect model (LEM). The Mayo Clinic Florida MKM (MCF MKM) was recently developed to overcome the limitations of previous MKMs in reproducing the biological data and to eliminate the need for ion-exposed in vitro data as input for the model calculations. Since we are considering to implement the MCF MKM in clinic, this article presents (a) an extensive benchmark of the MCF MKM predictions against corresponding in vitro clonogenic survival data for 4 rodent and 10 cell lines exposed to ions from ¹H to ²³⁸U, and (b) a systematic comparison with published results of the latest version of the LEM (LEM IV). Additionally, we introduce a novel approach to derive an approximate value of the MCF MKM model parameters by knowing only the animal species and the mean number of chromosomes. The overall good agreement between MCF MKM predictions and in vitro data suggests the MCF MKM can be reliably used for the RBE calculations. In most cases, a reasonable agreement was found between the MCF MKM and the LEM IV. Full article

Active targeting gold nanoparticles (AuNPs) are a very promising avenue for cancer treatment with many publications on AuNP mediated radiosensitization at kilovoltage (kV) photon energies. However, uncertainty on the effectiveness of AuNPs under clinically relevant megavoltage (MV) radiation energies hinders the clinical translation of AuNP-assisted radiation therapy (RT) paradigm. The aim of this study was to investigate radiosensitization mediated by PSMA-targeted AuNPs irradiated by a 6 MV radiation beam at different depths to explore feasibility of AuNP-assisted prostate cancer RT under clinically relevant conditions. PSMA-targeted AuNPs (PSMA-AuNPs) were synthesized by conjugating PSMA antibodies onto PEGylated AuNPs through EDC/NHS chemistry. Confocal fluorescence microscopy was used to verify the active targeting of the developed PSMA-AuNPs. Transmission electron microscopy (TEM) was used to demonstrate the intracellular biodistribution of PSMA-AuNPs. LNCaP prostate cancer cells treated with PSMA-AuNPs were irradiated on a Varian 6 MV LINAC under varying depths (2.5 cm, 10 cm, 20 cm, 30 cm) of solid water. Clonogenic assays were carried out to determine the in vitro cell survival fractions. A Monte Carlo (MC) model developed on TOPAS platform was then employed to determine the nano-scale radial dose distribution around AuNPs, which was subsequently used to predict the radiation dose response of LNCaP cells treated with AuNPs. Two different cell models, with AuNPs located within the whole cell or only in the cytoplasm, were used to assess how the intracellular PSMA-AuNP biodistribution impacts the prostate cancer radiosensitization. Then, MC-based microdosimetry was combined with the local effect model (LEM) to calculate cell survival fraction, which was benchmarked against the in vitro clonogenic assays at different depths. In vitro clonogenic assay of LNCaP cells demonstrated the depth dependence of AuNP radiosensitization under clinical megavoltage beams, with sensitization enhancement ratio (SER) of 1.14 ± 0.03 and 1.55 ± 0.05 at 2.5 cm depth and 30 cm depth, respectively. The MC microdosimetry model showed the elevated percent of low-energy photons in the MV beams at greater depth, consequently resulting in increased dose enhancement ratio (DER) of AuNPs with depth. The AuNP-induced DER reached ~5.7 and ~8.1 at depths of 2.5 cm and 30 cm, respectively. Microdosimetry based LEM accurately predicted the cell survival under 6 MV beams at different depths, for the cell model with AuNPs placed only in the cell cytoplasm. TEM results demonstrated the distribution of PSMA-AuNPs in the cytoplasm, confirming the accuracy of MC microdosimetry based LEM with modelled AuNPs distributed within the cytoplasm. We conclude that AuNP radiosensitization can be achieved under megavoltage clinical radiotherapy energies with a dependence on tumor depth. Furthermore, the combination of Monte Carlo microdosimetry and LEM will be a valuable tool to assist with developing AuNP-aided radiotherapy paradigm and drive clinical translation. Full article

The quality factor (Q) is formally linked to the stochastic (e.g., carcinogenic) risk of diverse ionizing radiations at low doses and/or low dose rates. Q can be a function of the non-stochastic physical quantity Linear Energy Transfer (LET) or the microdosimetric parameter lineal energy (y). These two physical quantities can be calculated either by Monte Carlo (MC) track-structure simulations or by analytic models. In this work, various generalized analytical models were utilized and combined to determine the proton lineal energy spectra in liquid water spheres of various sizes (i.e., 10–3000 nm diameter) over the proton energy range of 1–250 MeV. The calculated spectra were subsequently used within the Theory of Dual Radiation Action (TDRA) and the ICRU Report 40 microdosimetric methodologies to determine the variation of $\overline{Q}$ with proton energy. The results revealed that the LET-based Q values underestimated the microdosimetric-based $\overline{Q}$ values for protons with energy below ~100 MeV. At energies relevant to the Bragg peak region (<20–30 MeV), the differences were larger than 20–50%, while reaching 200–500% at ~5 MeV. It was further shown that the microdosimetric-based $\overline{Q}$ values for protons below ~100 MeV were sensitive to the sphere size. Finally, condensed-phase effects had a very small (<5%) influence on the calculated microdosimetric-based $\overline{Q}$ over the proton energy range considered here. Full article