Dose Enhancement Research Articles

X-ray radio-enhancement by Ti3C2Tx MXenes in soft tissue sarcoma.

Radiotherapy is a cornerstone of cancer treatment. However, due to the low tissue specificity of ionizing radiation, damage to the surrounding healthy tissue of the tumor remains a significant challenge. In recent years, radio-enhancers based on inorganic nanomaterials have gained considerable interest. Beyond the widely explored metal and metal oxide nanoparticles, 2D materials, such as MXenes, could present potential benefits because of their inherently large specific surface area. In this study, we highlight the promising radio-enhancement properties of Ti3C2Tx MXenes. We demonstrate that atomically thin layers of titanium carbides (Ti3C2Tx MXenes) are efficiently internalized and well-tolerated by mammalian cells. Contrary to MXenes suspended in aqueous buffers, which fully oxidize within days, yielding rice-grain shaped rutile nanoparticles, the MXenes internalized by cells oxidize at a slower rate. This is consistent with cell-free experiments that have shown slower oxidation rates in cell media and lysosomal buffers compared to dispersants without antioxidants. Importantly, the MXenes exhibit robust radio-enhancement properties, with dose enhancement factors reaching up to 2.5 in human soft tissue sarcoma cells, while showing no toxicity to healthy human fibroblasts. When compared to oxidized MXenes and commercial titanium dioxide nanoparticles, the intact 2D titanium carbide flakes display superior radio-enhancement properties. In summary, our findings offer evidence for the potent radio-enhancement capabilities of Ti3C2Tx MXenes, marking them as a promising candidate for enhancing radiotherapy.

A Monte Carlo study of the dose enhancement effects of high-z foils in proton therapy

AbstractBackground:This investigation quantifies the dose enhancement effect and dose distribution modifications due to the presence of high-z nanospheres in a proton beam.Methods:Various proton pencil beams of therapeutic energies (60–226 MeV) and spatial distribution of 2·7 mm spot size diameter were simulated onto a water phantom utilising the TOPAS Monte Carlo toolkit version 3.6.1. The simulation modelled either water or nanospheres of high-z materials (gold, silver or platinum) at the location of the Bragg Peak (BP) to compare the differences of the resulting dose distributions.Results:The introduction of the nanospheres increases the maximum dose, narrows the BP and shifts the BP location upstream compared to the water phantom with no nanospheres.Conclusions:This work shows that the local dose can be enhanced with the use of high-z nanoparticles in proton therapy, thereby increasing patient safety and decreasing side effects with the same amount of delivered radiation.

Monte Carlo Investigation of Dose Enhancement due to Gold Nanoparticle in Carbon-12, Helium-4, and Proton Beam Therapy

Monte Carlo Investigation of Dose Enhancement due to Gold Nanoparticle in Carbon-12, Helium-4, and Proton Beam Therapy

Dosimetry Effects Due to the Presence of Fe Nanoparticles for Potential Combination of Hyperthermic Cancer Treatment with MRI-Based Image-Guided Radiotherapy

Nanoparticles have proven to be biocompatible and suitable for many biomedical applications. Currently, hyperthermia cancer treatments based on Fe nanoparticle infusion excited by alternating magnetic fields are commonly used. In addition to this, MRI-based image-guided radiotherapy represents, nowadays, one of the most promising accurate radiotherapy modalities. Hence, assessing the feasibility of combining both techniques requires preliminary characterization of the corresponding dosimetry effects. The present work reports on a theoretical and numerical simulation feasibility study aimed at pointing out preliminary dosimetry issues. Spatial dose distributions incorporating magnetic nanoparticles in MRI-based image-guided radiotherapy have been obtained by Monte Carlo simulation approaches accounting for all relevant radiation interaction properties as well as charged particles coupling with strong external magnetic fields, which are representative of typical MRI-LINAC devices. Two main effects have been evidenced: local dose enhancement (up to 60% at local level) within the infused volume, and non-negligible changes in the dose distribution at the interfaces between different tissues, developing to over 70% for low-density anatomical cavities. Moreover, cellular uptakes up to 10% have been modeled by means of considering different Fe nanoparticle concentrations. A theoretical temperature-dependent model for the thermal enhancement ratio (TER) has been used to account for radiosensitization due to hyperthermia. The outcomes demonstrated the reliability of the Monte Carlo approach in accounting for strong magnetic fields and mass distributions from patient-specific anatomy CT scans to assess dose distributions in MRI-based image-guided radiotherapy combined with magnetic nanoparticles, while the hyperthermic radiosensitization provides further and synergic contributions.

Nanoscopic biodosimetry using plasmid DNA in radiotherapy with metallic nanoparticles

Nanoscopic lesions (complex damages), are the most lethal lesions for the cells. As nanoparticles have become increasingly popular in radiation therapy and the importance of analyzing nanoscopic dose enhancement has increased, a reliable tool for nanodosimetry has become indispensable. In this regard, the DNA plasmid is a widely used tool as a nanodosimetry probe in radiobiology and nano-radiosensitization studies. This approach is helpful for unraveling the radiosensitization role of nanoparticles in terms of physical and physicochemical effects and for quantifying radiation-induced biological damage. This review discusses the potential of using plasmid DNA assays for assessing the relative effects of nano-radiosensitizers, which can provide a theoretical basis for the development of nanoscopic biodosimetry and nanoparticle-based radiotherapy.

Preclinical modeling of low energy X-rays radiological burn: Dosimetry study by monte carlo simulations and EPR spectroscopy.

Interventional radiology has grown considerably over the last decades and become an essential tool for treatment or diagnosis. This technique is mostly beneficial and mastered but accidental overexposure can occur and lead to the appearance of deterministic effects. The lack of knowledge about the radiobiological consequences for the low-energy X-rays used for these practices makes the prognosis very uncertain for the different tissues. In order to improve the radiation protection of patients and better predict the risk of complications, we implemented a new preclinical mouse model to mimic radiological burn in interventional radiology and performed a complete characterization of the dose deposition. A new setup and collimator were designed to irradiate the hind legs of 15 mice at 30Gy in air kerma at 80kV. After irradiation, mice tibias were collected to evaluate bone dose by Electron Paramagnetic Resonance (EPR) spectroscopy measurements. Monte Carlo simulations with Geant4 were performed in simplified and voxelized phantoms to characterize the dose deposition in different tissues and evaluate the characteristics of secondary electrons (energy, path, momentum). 30 mice tibias were collected for EPR analysis. An average absorbed dose of 194.0 ± 27.0Gy was measured in bone initially irradiated at 30Gy in air kerma. A bone to air conversion factor of 6.5 ± 0.9 was determined. Inter sample and inter mice variability has been estimated to 13.9%. Monte Carlo simulations shown the heterogeneity of the dose deposition for these low X-rays energies and the dose enhancement in dense tissue. The specificities of the secondary electrons were studied and showed the influence of the tissue density on energies and paths. A good agreement between the experimental and calculated bone to air conversion factor was obtained. A new preclinical model allowing to perform radiological burn in interventional radiology-like conditions was implemented. For the development of new preclinical radiobiological model where the exact knowledge of the dose deposited in the different tissues is essential, the complementarity of Monte Carlo simulations and experimental measurements for the dosimetric characterization has proven to be a considerable asset.

Performance evaluation of buildup bolus during external radiotherapy of mastectomy patients: treatment planning and film dosimetry.

A buildup bolus is used during the post-mastectomy radiotherapy (PMRT) to overcome under-dosage issues in the chest wall. The current study is aimed at evaluating the performance of a bolus in dose enhancement through both film dosimetry and treatment planning approaches. Twenty patients were enrolled in current research. The received dose by the skin at the lateral and medial regions of the chest wall in the presence and absence bolus was evaluated. Film dosimetry results showed that the presence of the bolus can averagely increase the skin dose by about 80% (P value < 0.001) and 92% (P value < 0.001) in lateral and medial regions, respectively. No significant difference was observed between the measured and treatment planning system (TPS)-calculated dose values in the presence of bolus. The presence of the bolus can considerably increase the absorbed dose by superficial chest wall regions. The TPS shows a favorable performance in superficial dose calculations in the presence of the buildup bolus. Hosseini et al.: demonstration of implemented research in the current study.

In Vivo Studies of Laser-Ablated Gold Nanoparticles as Dose Enhancers for Binary Radiotherapy of Cancer

In Vivo Studies of Laser-Ablated Gold Nanoparticles as Dose Enhancers for Binary Radiotherapy of Cancer

In silico analysis of optimum photon energy spectra and beam parameters for iodine nanoparticle–aided orthovoltage radiation therapy of brain tumors

In this study, the effect of photon energy spectra on the dose enhancement factor (DEF) and other influencing parameters such as skull–tumor dose ratios were estimated for a confined tumor loaded with iodine nanoparticles (INPs). A mathematical brain phantom with a brain tumor was simulated by the MCNP6 Monte Carlo code. A validated commercial computed tomography model consisting of an X-ray tube, Al–Cu filters, and collimators was used to simulate the rotational conformal treatment of the tumor. INPs with a diameter of 20 nm and concentrations of 10–50 mg/g were introduced inside the tumor as homogenously distributed spherical particles. The dose distribution inside the phantom was scored for several orthovoltage beams with the peak voltages of 140, 200, and 320 kVp as well as two 3.5 and 6 MV megavoltage beams. A significant rise of DEF values with nanoparticle (NP) concentration for orthovoltage beams is revealed; no significant dose enhancement was obtained for megavoltage beams. The highest DEF and skull–tumor dose ratio were obtained for the 140 kVp beam which decreased with the number of directional fields. The clinically optimal plan for a brain tumor, with high DEFs of 2.81–2.24 and acceptable skull–tumor dose ratios of 0.61–0.51, would be feasible for treatment using 200 and 320 kVp beams, an iodine concentration of 20 mg/g, and 8–15 fields. Our calculations show that clinically significant radiation dose enhancements can be obtained for tumors loaded with INPs using orthovoltage beams. Optimal treatment regimens are feasible using a proper selection of photon beam spectrum and sufficient numbers of cross-firing beams. The limiting effect of skull bone could be minimized by increasing the number of radiation fields and the use of higher quality of orthovoltage beams.

Variable Relative Biological Effectiveness of Proton Therapy Increases PET-Visible Mucosal Injury in Head and Neck Cancer Patients

Despite dosimetric advantages of proton therapy in head and neck cancers, there is concern for increased end of range relative biologic effectiveness (RBE) and subsequent dose enhancement and mucosal toxicity with proton therapy. Herein, we evaluated differences in mucosal PET avidity on post-treatment scans as a surrogate for mucosal injury between proton and photon therapy patients. We further assessed the relationship between PET changes and RBE. The cohort comprised 9 proton and 10 photon patients who received ≥50 Gy adjuvant radiotherapy to oropharyngeal mucosa who remained loco-regional disease free ≥6 months post-treatment. All patients underwent follow-up fluorodeoxyglucose (FDG) PET-CT scans 3 months post-radiotherapy. PET-CTs were fused to planning CTs using deformable registration. High- and low-uptake regions were auto-contoured using a ≥150% mean liver standard uptake value (SUV) threshold and intersected with mucosal targets with/without a 5mm margin. SUV maximum (SUVMAX) values, linear energy transfer (LET) statistics, and RBE statistics based on McNamara, Jones, and linear LET models were extracted and compared. The mucosal target SUVMAX values on post-treatment PET-CTs for proton patients averaged 6.78 compared to 4.83 for photon patients (p=0.0267). Near maximum (LETd1%) LET for mucosal targets with a 5mm margin averaged 5.232 keV/µm. RBE in high-uptake regions exceeded that of low-uptake regions (p=0.0039), with mean biologic dose exceeding clinical dose by 11.05%, 18.67%, and 15.65%, respectively, using different RBE models. Post-radiotherapy PET avidity was more commonly observed in proton patients. Within proton patient mucosal targets, the location of increased PET avidity corresponded to areas with higher RBE. This is the first report of differential PET findings based on RBE. These results suggest that elevated RBE was associated with PET avidity and mucosal injury.

Friday, June 17, 20222:30 PM - 3:30 PM PHSPP01 Presentation Time: 2:30 PM: Dosimetry for Beta Emitting Brachytherapy Sources

<h3>Purpose</h3> Dosimetry for photon-emitting brachytherapy sources is well established, to the point of commercial software for clinical treatment planning to account for material heterogeneities and patient-specific radiation scatter conditions. However, dosimetry standards for beta sources are simpler and have not been recently investigated. While the AAPM TG-149 and ICRU 72 Reports issue clinical guidance and reference data, a modern evaluation of beta-source dosimetry is missing. This investigation strives to identify the potential role for beta-emitting radionuclides as well as to examine theoretical sources for a deeper understanding of beta dosimetry. <h3>Materials and Methods</h3> Available beta-emitting brachytherapy sources include P-32, Sr/Y-90, and Ru/Rh-106 with Y-90 commonly used for selective internal radiation therapy (SIRT) of cancers in the liver. Energy spectra of these sources were taken from ICRU 72 with dose simulations performed using the MCNP v6.2 Monte Carlo radiation transport code. From ICRU 72, the maximum energies for P-32, Sr/Y-90, Y-90, and Ru/Rh-106 were 1.71, 2.28, 2.28, and 3.54 MeV, respectively. Monoenergetic sources of 0.5, 1, 1.5, 2, 3, and 4 MeV were also simulated to extend the energy range and scrutinize dose-distribution dependence on electron energy. Since 2D dose distribution are highly dependent on the design of a source, point sources were simulated to evaluate the depth-dose distribution as a function of radius, <i>r</i>, as well radial dose functions that removed the inverse-square effect. Dose was sampled in 15 cm diameter spheres comprised of water, tissue (ICRU 44 skeletal muscle), or bone (ICRU 44 cortical bone). To mass density effect was quantified in water for 0.5, 1, and 2 g/cm³ with 1 and 2 g/cm³ for tissue and bone, respectively. Observed dose differences were then ascribed to medium differences and not confounded by small differences in mass density. Dose was sampled with radial increments from 0.001 to 0.02 cm for direct comparisons to ICRU 72 results and to evaluate the effect of volume averaging. While only electron sources were considered, dose contributions from bremsstrahlung photons were quantified through comparing results of electron- and electron:photon-transport. Energy deposition was calculated using the MCNP *F8 pulse-height tally, then dividing by the voxel mass to obtain absorbed dose per electron history. With 10⁷ source electrons, statistical uncertainties (<i>k</i>=1) were <0.1% for <i>r</i><0.7 CSDA. When studying bremsstrahlung, 10⁸ source electrons produced 4% statistical uncertainties for <i>r</i>>1.2 CSDA. <h3>Results</h3> In the high dose-gradient region for radionuclide-based beta emitters, the calculated dose distributions in water were within 20% of those from the ICRU 72 Report, which used binned monoenergetic sources to approximate the continuous beta spectra. The radionuclide-based sources exhibited radial dose functions in water that diminished much more steeply than Pd-103, similar to a <0.01 MeV photon source. Sr/Y-90 had a bimodal distribution. Radial dose functions for radionuclide-based sources were inversely proportional to changes in mass density, differing from the scaling-factor models by Cross (1967) and the ICRU 56 Report over the large range of media and densities examined herein. Further, radial dose functions for monoenergetic sources demonstrated a Bragg peak with dose enhancement at <i>r</i>∼0.7 CSDA for all studied energies and media. A sampling of results for radionuclides and monoenergetic sources in water is given in the figure. <h3>Conclusions</h3> Beta dosimetry is largely governed by the mass density with medium composition being a much lesser effect, unlike for low-energy photons where the photoelectric effect is highly sensitive to <i>Z</i>_eff. Unlike for high-energy photon dosimetry, beta dosimetry is negligibly impacted by radiation scatter conditions due to their short range. While Ru/Rh-106 and Sr/Y-90 are proven for shallow plaque brachytherapy and Y-90 for SIRT, beta-emitting radionuclides do not have adequate range for interstitial implants like prostate brachytherapy since dose uniformity is much worse than with HDR Ir-192 or LDR Pd-103 brachytherapy.

Treatment planning with a 2.5MV photon beam for radiation therapy.

The shallow depth of maximum dose and higher dose fall-off gradient of a 2.5MV beam along the central axis that is available for imaging on linear accelerators is investigated for treatment of shallow tumors and sparing the organs at risk (OARs) beyond it. In addition, the 2.5MV beam has an energy bridging the gap between kilo-voltage (kV) and mega-voltage (MV) beams for applications of dose enhancement with high atomic number (Z) nanoparticles. We have commissioned and utilized a MATLAB-based, open-source treatment planning software (TPS), matRad, for intensity-modulated radiation therapy (IMRT) dose calculations. Treatment plans for prostate, liver, and head and neck (H&N), nasal cavity, two orbit cases, and glioblastoma multiforme (GBM) were performed and compared to a conventional 6MV beam. Additional Monte Carlo calculations were also used for benchmarking the central axis dose. Both beams had similar planning target volume (PTV) dose coverage for all cases. However, the 2.5MV beam deposited 6%-19% less integral doses to the nasal cavity, orbit, and GBM cases than 6MV photons. The mean dose to the heart in the liver plan was 10.5% lower for 2.5MV beam. The difference between the doses to OARs of H&N for two beams was under 3%. Brain mean dose, brainstem, and optic chiasm max doses were, respectively, 7.5%-14.9%, 2.2%-8.1%, and 2.5%-19.0% lower for the 2.5MV beam in the nasal cavity, orbit, and GBM plans. This study demonstrates that the 2.5MV beam can produce clinically relevant treatment plans, motivating future efforts for design of single-energy LINACs. Such a machine will be capable of producing beams at this energy beneficial for low- and middle-income countries, and investigations on dose enhancement from high-Z nanoparticles.

Trial in Progress: 2019-1001 A Phase I Study of NBTXR3 Activated by Radiotherapy for Locally Advanced or Borderline Resectable Pancreatic Ductal Adenocarcinoma (LAPC or BRPC)

<h3>Purpose/Objective(s)</h3> Patients with pancreatic ductal adenocarcinoma (PDAC), who are not eligible for surgery after induction chemotherapy often receive radiation. Although radiation therapy (RT) improves local disease control, the placement of the pancreas proves to be difficult when safely delivering therapeutic doses. NBTXR3 is a novel, potentially first-in-class radio enhancer, composed of functionalized hafnium oxide nanoparticles that is administered via one-time intratumoral injection and activated by RT. Pre-clinical testing suggests up to a 9-fold enhancement of the RT dose delivered within tumor cells. In this phase 1 trial-in-progress, the primary objective is to determine the recommended phase II dose (RP2D) of NBTXR3 for LAPC and BRPC patients undergoing RT. The secondary objectives are to evaluate the safety, feasibility, and anti-tumor response of NBTXR3 intratumoral injection on PDAC patients as well as time-to-event outcomes of subjects. <h3>Materials/Methods</h3> For the dose-finding part 1 of the study, patients with LAPC and no metastatic disease after at least 2-6 months of chemotherapy will be eligible. For part 2, the expansion at RP2D, patients with BRPC or LAPC and no metastatic disease after chemotherapy will be eligible. The statistical design of the trial uses a Bayesian optimal interval (BOIN) design. A maximum of 24 patients will be enrolled. For baseline and follow-up, imaging and blood biomarkers will be collected. Patients enrolled will receive NBTXR3, once, through intratumoral injection via endoscopic ultrasound (Day 1). Pre-treatment biopsy will be collected. Post NBTXR3 injection, blood samples will be collected at 4 time points (0,5,30, and 120 minutes). Two urine voids will be collected post injection for hafnium quantification as well. At least three days later, patients will undergo imaging for RT dosimetry and planning where NBTXR3 can be visualized. Patients will then receive 45 Gy in 15 fractions with IMRT, with regional nodal basins receiving 37.5 Gy. Follow-up period will begin 4 weeks after end of treatment and continue every 3 months for a year. Patients will be evaluated for surgery 4-12 weeks post RT. At 11-13 weeks after end of RT, if the patient is not eligible for surgery, an endoscopic ultrasound procedure will be performed. In both events, a post-treatment biopsy will be obtained. The imaging collected of pancreatic target lesion will be used to determine tumor response as per RECIST v1.1 criteria. <h3>Results</h3> Trial is open and accruing, with 8 patients enrolled so far. <h3>Conclusion</h3> We expect to determine the RP2D, safety, and preliminary efficacy of NBTXR3 in pancreatic cancer with this study with blood, tissue, and imaging correlates in 2022.

Discovery of a Novel Driver of Radioresistance in Pancreatic Cancer (PC) Using Genome-Wide RNA-Seq

<h3>Purpose/Objective(s)</h3> Discovery of genetic drivers of radioresistance in PC is critical for developing novel therapeutic strategies to combine with radiation in this radioresistant disease. In this study, we used genome-wide RNA-seq to identify genes upregulated in radioresistant (RR) generated PC cell lines and discovered the Inhibitor of DNA Binding 1 (ID1) gene as a promising radiosensitizing target. <h3>Materials/Methods</h3> RR PC cell lines MIA PaCa-2 and PANC-1 were generated by delivering daily ionizing irradiation (IR) (2 Gy/day) <i>in vitro</i> over two weeks (total 20 Gy) followed by standard clonogenic assays to calculate the dose enhancement ratio (DER) following one week from the end of IR. Parental and RR cell lines were submitted for RNA-seq analysis to identify differentially expressed genes. The Limma R package was used to calculate differential expression among genes. Log2 fold change values were calculated for each sample compared to control. Genes with an absolute fold change > 1 were considered significant. Knockdown of target genes via small interfering RNA (siRNA) was confirmed through immunoblotting. Luciferase expressing RR PANC-1 and MIA PaCa-2 with or without shRNA stable knockdown of ID1 were implanted orthotopically in the pancreas of athymic nude mice, and tumors were treated with external beam radiation using a Small Animal Radiation Research Platform to a dose of 20 Gy in 5 daily fractions. Tumor growth was measured weekly via bioluminescence. <h3>Results</h3> Following exposure to two weeks of 2 Gy daily IR <i>in vitro</i>, the two PC cell lines showed significantly greater clonogenic cell survival than parental cell lines (DER 0.4 and 0.5), indicating enhanced RR in these cells. RNA-seq analysis comparing parental and RR cell lines found upregulated seven genes (TNS4, ZDHHC8P1, APLNR, AQP3, SPP1, ID1, ID2) and seven genes downregulated (PTX3, ITGB2, EPS8L1, ALDH1L2, KCNT2, ARHGAP9, IFI16) in both RR cell lines. Western blotting confirmed either increased or decreased expression of these 14 genes in the RR cell lines compared to their parental. siRNA knockdown of each of the seven most significant upregulated genes in the RR MIA PaCa-2 and PANC-1 cells revealed ID1 as the most potent radiosensitizer in the RR cell lines (DER 1.5 and 1.6, respectively). ID1 protein expression was higher in 6 different human PC cell lines than both non-malignant pancreatic and intestinal cell lines. Orthotopic RR tumors with stable knockdown of ID1 showed significantly decreased tumor growth following <i>in vivo IR</i> than the wild-type ID1 tumors (2.5-fold decrease, p<0.001). After the last dose of IR, expression of the DNA damage marker yH2aX in tumors was significantly higher in the ID1 knockdown tumors compared to controls indicating reduced DNA repair in tumors deficient in ID1. <h3>Conclusion</h3> Our analysis indicates a novel role of ID1 in PC radioresistance. Targeting ID1 prior to IR is a promising strategy to overcome the RR of PC, and pre-clinical studies using ID1 inhibitors are ongoing.

Impact of Treatment Modality on Post-Radiation Imaging in Post-Operative Head and Neck Cancers

<h3>Purpose/Objective(s)</h3> Despite frequent dosimetric advantages to proton therapy over photon therapy in head and neck (H&N) cancers, there is concern for end of range biologic dose enhancement and subsequent increased mucosal toxicity with proton therapy. Herein, we evaluated differences in mucosal FDG avidity on post-treatment FDG PET-CTs between proton and photon therapy patients, as persistent activity is a surrogate for residual mucosal toxicity. <h3>Materials/Methods</h3> The cohort comprised ten proton and ten photon patients who received ≥40 Gy to a mucosal oropharyngeal site with curative intent after initial surgery and who remained loco-regional disease free ≥6 months post-treatment. All patients underwent follow-up PET-CT scans 3 months post-radiotherapy. Images centered over the treated primary were acquired 60 minutes after intravenous administration of 10 mCi of FDG. CT-based attenuation correction was applied to the data sets. The PET-CTs were fused to the planning CT using deformable registration using a commercial treatment planning system (TPS). Contours were generated in the deformed PET datasets using a 1.5 × Liver_SUV threshold, i.e., 50% above background; these uptake areas were later intersected with the mucosal CTV plus a 5 mm margin to create the region of interest (ROI). SUV maximum (SUV_MAX) values based on lean body mass were extracted for this ROI. <h3>Results</h3> The SUV_MAX values found in the post-treatment PET-CTs in the intersected ROI for the proton group ranged between 7.08 and 9.38, whereas in the photon group, SUV_MAX values ranged from 3.89 and 6.49. The likelihood of having SUV_MAX values above the 1.5 × Liver_SUV threshold was higher in the proton group (4 of 10 patients) compared to the photon group (2 of 10 patients). Clinically, an ulcer was visible in one proton patient at the area of FDG avidity. <h3>Conclusion</h3> Our results indicate that post-radiotherapy FDG avidity was more commonly observed in proton patients, which correlated with clinical mucosal toxicity.

Monte Carlo Simulation-Guided Design of a Thorium-Based Metal-Organic Framework for Efficient Radiotherapy-Radiodynamic Therapy.

High-Z metal-based nanoscale metal-organic frameworks (nMOFs) with photosensitizing ligands can enhance radiation damage to tumors via a unique radiotherapy-radiodynamic therapy (RT-RDT) process. Here we report Monte Carlo (MC) simulation-guided design of a Th-based nMOF built from Th6 -oxo secondary building units and 5,15-di(p-benzoato)porphyrin (DBP) ligands, Th-DBP, for enhanced RT-RDT. MC simulations revealed that the Th-lattice outperformed the Hf-lattice in radiation dose enhancement owing to its higher mass attenuation coefficient. Upon X-ray or γ-ray radiation, Th-DBP enhanced energy deposition, generated more reactive oxygen species, and induced significantly higher cytotoxicity to cancer cells over the previously reported Hf-DBP nMOF. With low-dose X-ray irradiation, Th-DBP suppressed tumor growth by 88 % in a colon cancer and 97 % in a pancreatic cancer mouse model.

Quantifying Radiosensitization of PSMA-Targeted Gold Nanoparticles on Prostate Cancer Cells at Megavoltage Radiation Energies by Monte Carlo Simulation and Local Effect Model.

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.

Monte Carlo Simulation‐Guided Design of a Thorium‐Based Metal–Organic Framework for Efficient Radiotherapy‐Radiodynamic Therapy

AbstractHigh‐Z metal‐based nanoscale metal–organic frameworks (nMOFs) with photosensitizing ligands can enhance radiation damage to tumors via a unique radiotherapy‐radiodynamic therapy (RT‐RDT) process. Here we report Monte Carlo (MC) simulation‐guided design of a Th‐based nMOF built from Th6‐oxo secondary building units and 5,15‐di(p‐benzoato)porphyrin (DBP) ligands, Th‐DBP, for enhanced RT‐RDT. MC simulations revealed that the Th‐lattice outperformed the Hf‐lattice in radiation dose enhancement owing to its higher mass attenuation coefficient. Upon X‐ray or γ‐ray radiation, Th‐DBP enhanced energy deposition, generated more reactive oxygen species, and induced significantly higher cytotoxicity to cancer cells over the previously reported Hf‐DBP nMOF. With low‐dose X‐ray irradiation, Th‐DBP suppressed tumor growth by 88 % in a colon cancer and 97 % in a pancreatic cancer mouse model.

Dosimetric Impact on the Flattening Filter and Addition of Gold Nanoparticles in Radiotherapy: A Monte Carlo Study on Depth Dose Using the 6 and 10 MV FFF Photon Beams.

Purpose: This phantom study investigated through Monte Carlo simulation how the dose enhancement varied with depth, when gold nanoparticles (NPs) were added using the flattening filter-free (FFF) photon beams in gold NP-enhanced radiotherapy. Method: A phantom with materials varying from pure water to a mixture of water and gold NPs at different concentrations (3–40 mg/mL) were irradiated by the 6 and 10 MV flattening filter (FF) and FFF photon beams. Monte Carlo simulations were carried out to determine the depth doses along the central beam axis of the phantom up to a depth of 40 cm. The dose enhancement ratio (DER) and FFF enhancement ratio (FFFER) were calculated based on the Monte Carlo results. Results: The DER values were found decreased with an increase of depth and increase of NP concentration in the phantom. For the maximum NP concentration of 40 mg/mL, the DER values decreased 6.9, 12, 4.6 and 7.2% at a phantom depth from 2 to 40 cm, using the 6 MV FF, 6 MV FFF, 10 MV FF and 10 MV FFF photon beams, respectively. The maximum DER values for the 6 MV beams were 1.08 (FF) and 1.14 (FFF), while those for the 10 MV beams were 1.04 (FF) and 1.07 (FFF). When the FF was removed from the linear accelerator head, the FFFER showed a more significant increase of dose enhancement for the 6 MV beams (1.057) than the 10 MV (1.031). Conclusion: From the DER and FFFER values based on the Monte Carlo results, it is concluded that the dose enhancement with depth was dependent on the NP and beam variables, namely, NP concentration, presence of FF in the beam and beam energy. Dose enhancement was more significant when using the lower photon beam energy (i.e., 6 MV), FFF photon beam and higher NP concentration in the study.

Monte Carlo model for evaluation of concentration of gold nanoparticle clusters as predictor of effective dose in proton therapy of microscopic tumors

Radio-sensitization with gold nanoparticles (GNPs) is a relatively recent advancement of radiotherapy that is determined to increase radiation in the target tumor region. Monte Carlo (MC) simulation is a well-known method that has gained popularity by assisting in determining the effective dose in various tumors. Assessing the concentration of particles during proton therapy can provide the key to evaluating the efficiency of the performed treatment. Therefore, this study aimed to investigate the interconnection between the concentration of gold nanoparticle clusters and the dose enhancement in microscopic tumors by using the MC Model. A single cell tumor model with a size of 5 μm that was exposed to 100 MeV protons in a region resembling the human brain was investigated by using an MC simulation employing the Geant4 toolkit. With each nanoparticle having a diameter of 15 nm, a three-dimensional model of the random distribution of gold nanoparticle clusters was developed. Then, the dose enhancement for various concentrations of the GNPs accumulated around the tumor was estimated according to the dose enhancement factor (DEF), while the dose was concentrated on the surface of each GNP in the clusters. The results showed that the dose enhancement located at the Bragg-peak in the tumor region depended on the different concentrations of the GNPs. DEF values were found to be 1.016, 1.022, 1.026, 1.035, 1.013, 1.000, and 0.984 for the 1, 2, 3, 5, 10, 30, and 50 mg/ml concentration levels in water, respectively. The findings also revealed that large GNP clusters with high concentration levels yield larger DEFs than clusters with lower concentration levels, which may have an impact on radiation therapy. Specifically, at a concentration higher than 10 mg/ml, the estimated dose was significantly lower than those for a concentration of 5 mg/ml by about ∼100 mGy. As the benefit of the increased total dose must be balanced against the effect of the accumulation of nanoparticles, the current study detected dose reduction in regions that accumulate GNPs at high concentrations. As a result, the potential efficiency of the radiotherapeutic treatment can be reduced.