Towards personalised dosimetry in patients with liver malignancy treated with 90Y-SIRT using in vivo-driven radiobiological parameters.

BACKGROUND: The prediction of response is one of the major challenges in radiation-based therapies. Although the selection of accurate linear-quadratic model parameters is essential for the estimation of radiation response and treatment outcome, there is a limited knowledge about these radiobiological parameters for liver tumours using radionuclide treatments. METHODS: The "clinical radiobiological" parameters ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]) for twenty-five patients were derived using the generalised linear-quadratic model, the diagnostic ([18F] FDG PET/CT) and therapeutic ([90Y]-SIR-Spheres PET/CT) images to compute the biological effective dose and tumour control probability (TCP) for each patient. RESULTS: It was estimated that the values for [Formula: see text] and [Formula: see text] parameters range in ≈ 0.001-1 Gy-1 and ≈ 1-49 Gy, respectively. We have demonstrated that the time factors, [Formula: see text], [Formula: see text] and [Formula: see text] are the key parameters when evaluating liver malignancy lesional response to [90Y]SIR-Spheres treatment. Patients with cholangiocarcinoma have been shown to have the longest average [Formula: see text] (≈ 236 ± 67 d), highest TCP (≈ 53 ± 17%) and total liver lesion glycolysis response ([Formula: see text] ≈ 64%), while patients with metastatic colorectal cancer tumours have the shortest average [Formula: see text] (≈ 129 ± 19 d), lowest TCP (≈ 28 ± 13%) and [Formula: see text] ≈ 8%, respectively. CONCLUSIONS: Tumours with shorter [Formula: see text] have shown a shorter [Formula: see text] and thus poorer TCP and [Formula: see text]. Therefore, these results suggest for such tumours the [90Y]SIR-Spheres will be only effective at higher initial dose rate (e.g. > 50 Gy/day).

Overlooked potential of positrons in cancer therapy.

Positron (ß+) emitting radionuclides have been used for positron emission tomography (PET) imaging in diagnostic medicine since its development in the 1950s. Development of a fluorinated glucose analog, fluorodeoxyglucose, labelled with a ß+ emitter fluorine-18 (18F-FDG), made it possible to image cellular targets with high glycolytic metabolism. These targets include cancer cells based on increased aerobic metabolism due to the Warburg effect, and thus, 18F-FDG is a staple in nuclear medicine clinics globally. However, due to its attention in the diagnostic setting, the therapeutic potential of ß+ emitters have been overlooked in cancer medicine. Here we show the first in vitro evidence of ß+ emitter cytotoxicity on prostate cancer cell line LNCaP C4-2B when treated with 20 Gy of 18F. Monte Carlo simulation revealed thermalized positrons (sub-keV) traversing DNA can be lethal due to highly localized energy deposition during the thermalization and annihilation processes. The computed single and double strand breakages were ~ 55% and 117% respectively, when compared to electrons at 400 eV. Our in vitro and in silico data imply an unexplored therapeutic potential for ß+ emitters. These results may also have implications for emerging cancer theranostic strategies, where ß+ emitting radionuclides could be utilized as a therapeutic as well as a diagnostic agent once the challenges in radiation safety and protection after patient administration of a radioactive compound are overcome.

Positron annihilation localization by nanoscale magnetization.

In positron emission tomography (PET), the finite range over which positrons travel before annihilating with an electron places a fundamental physical limit on the spatial resolution of PET images. After annihilation, the photon pair detected by the PET instrumentation is emitted from a location that is different from the positron-emitting source, resulting in image blurring. Here, we report on the localization of positron range, and hence annihilation quanta, by strong nanoscale magnetization of superparamagnetic iron oxide nanoparticles (SPIONs) in PET-MRI. We found that positron annihilations localize within a region of interest by up to 60% more when SPIONs are present (with [Fe] = 3 mM) compared to when they are not. The resulting full width at half maximum of the PET scans showed the spatial resolution improved by up to [Formula: see text] 30%. We also found evidence suggesting that the radiolabeled SPIONs produced up to a six-fold increase in ortho-positronium. These results may also have implications for emerging cancer theranostic strategies, where charged particles are used as therapeutic as well as diagnostic agents and improved dose localization within a tumor is a determinant of better treatment outcomes.

Roadmap for metal nanoparticles in radiation therapy: current status, translational challenges, and future directions.

This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z = 22, to Bismuth, Z = 83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation dose enhancers, hyperthermia inducers, drug delivery vehicles, vaccine adjuvants, photosensitizers, enhancers of immunotherapy) and theranostic (combining both diagnostic and therapeutic), are being fabricated and evaluated. This roadmap covers contributions from experts in these topics summarizing their view of the current status and challenges, as well as expected advancements in technology to address these challenges.

A Chelate-Free Nano-Platform for Incorporation of Diagnostic and Therapeutic Isotopes.

PURPOSE: Using our chelate-free, heat-induced radiolabeling (HIR) method, we show that a wide range of metals, including those with radioactive isotopologues used for diagnostic imaging and radionuclide therapy, bind to the Feraheme (FH) nanoparticle (NP), a drug approved for the treatment of iron anemia. MATERIAL AND METHODS: FH NPs were heated (120°C) with nonradioactive metals, the resulting metal-FH NPs were characterized by inductively coupled plasma mass spectrometry (ICP-MS), dynamic light scattering (DLS), and r1 and r2 relaxivities obtained by nuclear magnetic relaxation spectrometry (NMRS). In addition, the HIR method was performed with [90Y]Y3+, [177Lu]Lu3+, and [64Cu]Cu2+, the latter with an HIR technique optimized for this isotope. Optimization included modifying reaction time, temperature, and vortex technique. Radiochemical yield (RCY) and purity (RCP) were measured using size exclusion chromatography (SEC) and thin-layer chromatography (TLC). RESULTS: With ICP-MS, metals incorporated into FH at high efficiency were bismuth, indium, yttrium, lutetium, samarium, terbium and europium (>75% @ 120 oC). Incorporation occurred with a small (less than 20%) but statistically significant increases in size and the r2 relaxivity. An improved HIR technique (faster heating rate and improved vortexing) was developed specifically for copper and used with the HIR technique and [64Cu]Cu2+. Using SEC and TLC analyses with [90Y]Y3+, [177Lu]Lu3+ and [64Cu]Cu2+, RCYs were greater than 85% and RCPs were greater than 95% in all cases. CONCLUSION: The chelate-free HIR technique for binding metals to FH NPs has been extended to a range of metals with radioisotopes used in therapeutic and diagnostic applications. Cations with f-orbital electrons, more empty d-orbitals, larger radii, and higher positive charges achieved higher values of RCY and RCP in the HIR reaction. The ability to use a simple heating step to bind a wide range of metals to the FH NP, a widely available approved drug, may allow this NP to become a platform for obtaining radiolabeled nanoparticles in many settings.

Comparison of radiobiological parameters for 90Y radionuclide therapy (RNT) and external beam radiotherapy (EBRT) in vitro.

BACKGROUND: Dose rate variation is a critical factor affecting radionuclide therapy (RNT) efficacy. Relatively few studies to date have investigated the dose rate effect in RNT. Therefore, the aim of this study was to benchmark 90Y RNT (at different dose rates) against external beam radiotherapy (EBRT) in vitro and compare cell kill responses between the two irradiation processes. RESULTS: Three human colorectal carcinoma (CRC) cell lines (HT29, HCT116, SW48) were exposed to 90Y doses in the ranges 1-10.4 and 6.2-62.3 Gy with initial dose rates of 0.013-0.13 Gy/hr (low dose rate, LDR) and 0.077-0.77 Gy/hr (high dose rate, HDR), respectively. Results were compared to a 6-MV photon beam doses in the range from 1-9 Gy with constant dose rate of 277 Gy/hr. The cell survival parameters from the linear quadratic (LQ) model were determined. Additionally, Monte Carlo simulations were performed to calculate the average dose, dose rate and the number of hits in the cell nucleus. For the HT29 cell line, which was the most radioresistant, the α/ß ratio was found to be ≈ 31 for HDR-90Y and ≈ 3.5 for EBRT. LDR-90Y resulting in insignificant cell death compared to HDR-90Y and EBRT. Simulation results also showed for LDR-90Y, for doses ≲ 3 Gy, the average number of hits per cell nucleus is ≲ 2 indicating insufficiently delivered lethal dose. For 90Y doses [Formula: see text] 3 Gy the number of hits per nucleus decreases rapidly and falls below ≈ 2 after ≈ 5 days of incubation time. Therefore, our results demonstrate that LDR-90Y is radiobiologically less effective than EBRT. However, HDR-90Y at ≈ 56 Gy was found to be radiobiologically as effective as acute ≈ 8 Gy EBRT. CONCLUSION: These results demonstrate that the efficacy of RNT is dependent on the initial dose rate at which radiation is delivered. Therefore, for a relatively long half-life radionuclide such as 90Y, a higher initial activity is required to achieve an outcome as effective as EBRT.

A unique alpha dosimetry technique using Gafchromic EBT3(®) film and feasibility study for an activity calibrator for alpha-emitting radiopharmaceuticals.

OBJECTIVE: To develop an alpha dosimetry technique for activity calibration of alpha-emitting radiopharmaceuticals using the Gafchromic(®) EBT3 (Gaf-EBT3) radiochromic film (International Speciality product, Wayne, NJ). METHODS: The Gaf-EBT3 has a tissue equivalent radiosensitive layer (approximately 28 µm) sandwiched between two 100-µm thick polyester sheaths, thereby making it insensitive to alpha particles. We have split a Gaf-EBT3 sheet using a surgical scalpel to remove one of the polyester protective layers and covered the radiosensitive layer with thin Mylar(®) foil (Goodfellow Cambridge Limited, Huntingdon, UK) (2.5 µm). Small pieces of modified film were exposed at contact with a 560-Bq thin (241)Am source for 5, 10, 24 and 94 h. The optical density of the films was evaluated using an optical densitometer. The alpha energy spectra of the (241)Am source were recorded using a Si(Li) surface barrier detector. RESULTS: Time-integrated specific alpha surface activity (kBq cm(-2) h) was represented as a function of optical density. CONCLUSION: By removing one of the 100 µm thick polyester protective layers, the authors have modified the Gaf-EBT3 film to a sensitive alpha dosemeter. The calibration function relevant to a (241)Am reference source was evaluated from the optical densities of the dosemeter foils. Furthermore, calibration functions for important alpha emitters such as (223)Ra, (225)Ac or (210)Bi were parameterized from the (241)Am reference data. ADVANCES IN KNOWLEDGE: The authors have developed and tested the principle of a clinical alpha dosemeter using Gaf-EBT3 radiochromic films originally developed for photon dosimetry. This novel, user-friendly technique could be implemented in quality assurance and calibration procedures of important alpha-emitting radiopharmaceuticals prior to their clinical applications.