Radiolabeled Gold Nanoseeds Decorated with Substance P Peptides: Synthesis, Characterization and In Vitro Evaluation in Glioblastoma Cellular Models

Despite some progress, the overall survival of patients with glioblastoma (GBM) remains extremely poor. In this context, there is a pressing need to develop innovative therapy strategies for GBM, namely those based on nanomedicine approaches. Towards this goal, we have focused on nanoparticles (AuNP-SP and AuNP-SPTyr8) with a small gold core (ca. 4 nm), carrying DOTA chelators and substance P (SP) peptides. These new SP-containing AuNPs were characterized by a variety of analytical techniques, including TEM and DLS measurements and UV-vis and CD spectroscopy, which proved their high in vitro stability and poor tendency to interact with plasma proteins. Their labeling with diagnostic and therapeutic radionuclides was efficiently performed by DOTA complexation with the trivalent radiometals 67Ga and 177Lu or by electrophilic radioiodination with 125I of the tyrosyl residue in AuNP-SPTyr8. Cellular studies of the resulting radiolabeled AuNPs in NKR1-positive GBM cells (U87, T98G and U373) have shown that the presence of the SP peptides has a crucial and positive impact on their internalization by the tumor cells. Consistently, 177Lu-AuNP-SPTyr8 showed more pronounced radiobiological effects in U373 cells when compared with the non-targeted congener 177Lu-AuNP-TDOTA, as assessed by cell viability and clonogenic assays and corroborated by Monte Carlo microdosimetry simulations.

Charged Particle Irradiation for Pancreatic Cancer: A Systematic Review of In Vitro Studies

PurposeGiven the higher precision accompanied by optimized sparing of normal tissue, charged particle therapy was thought of as a promising treatment for pancreatic cancer. However, systematic preclinical studies were scarce. We aimed to investigate the radiobiological effects of charged particle irradiation on pancreatic cancer cell lines.MethodsA systematic literature search was performed in EMBASE (OVID), Medline (OVID), and Web of Science databases. Included studies were in vitro English publications that reported the radiobiological effects of charged particle irradiation on pancreatic cancer cells.ResultsThirteen carbon ion irradiation and seven proton irradiation in vitro studies were included finally. Relative biological effectiveness (RBE) values of carbon ion irradiation and proton irradiation in different human pancreatic cancer cell lines ranged from 1.29 to 4.5, and 0.6 to 2.1, respectively. The mean of the surviving fraction of 2 Gy (SF2) of carbon ion, proton, and photon irradiation was 0.18 ± 0.11, 0.48 ± 0.11, and 0.57 ± 0.13, respectively. Carbon ion irradiation induced more G2/M arrest and a longer-lasting expression of γH2AX than photon irradiation. Combination therapies enhanced the therapeutic effects of pancreatic cell lines with a mean standard enhancement ratio (SER) of 1.66 ± 0.63 for carbon ion irradiation, 1.55 ± 0.27 for proton irradiation, and 1.52 ± 0.30 for photon irradiation. Carbon ion irradiation was more effective in suppressing the migration and invasion than photon irradiation, except for the PANC-1 cells.ConclusionsCurrent in vitro evidence demonstrates that, compared with photon irradiation, carbon ion irradiation offers superior radiobiological effects in the treatment of pancreatic cancer. Mechanistically, high-LET irradiation may induce complex DNA damage and ultimately promote genomic instability and cell death. Both carbon ion irradiation and proton irradiation confer similar sensitization effects in comparison with photon irradiation when combined with chemotherapy or targeted therapy.

On the 125th anniversary of the discovery of radioactivity: history of development and current state of regulation of the provision of the radiation safety of the public

This paper is focused on the history of development and current state of regulation of the provision of radiation safety of the public. It includes data on the history of discovery of the X-rays, radioactivity and development of the atomic industry in the USSR and in the world as well as the issues of evaluation of the radiobiological effects of the ionizing radiation on the human and history of the development of regulations. It is indicated, that the principles of the radiation safety, norms and approaches to the provision of the radiation protection presented in the Federal state Law № 3-FZ “On the radiation safety of the public” and NRB 99/2009 fully comply with the ICRP Publication 60 (1990) and International Basic Safety Standard (IAEA, 1997). For decades, FZ-3 and NRB 99/2009 have allowed provisioning the high level of radiation safety of the personnel and the public.

Review of the Geant4-DNA Simulation Toolkit for Radiobiological Applications at the Cellular and DNA Level

The Geant4-DNA low energy extension of the Geant4 Monte Carlo (MC) toolkit is a continuously evolving MC simulation code permitting mechanistic studies of cellular radiobiological effects. Geant4-DNA considers the physical, chemical, and biological stages of the action of ionizing radiation (in the form of x- and γ-ray photons, electrons and β±-rays, hadrons, α-particles, and a set of heavier ions) in living cells towards a variety of applications ranging from predicting radiotherapy outcomes to radiation protection both on earth and in space. In this work, we provide a brief, yet concise, overview of the progress that has been achieved so far concerning the different physical, physicochemical, chemical, and biological models implemented into Geant4-DNA, highlighting the latest developments. Specifically, the “dnadamage1” and “molecularDNA” applications which enable, for the first time within an open-source platform, quantitative predictions of early DNA damage in terms of single-strand-breaks (SSBs), double-strand-breaks (DSBs), and more complex clustered lesions for different DNA structures ranging from the nucleotide level to the entire genome. These developments are critically presented and discussed along with key benchmarking results. The Geant4-DNA toolkit, through its different set of models and functionalities, offers unique capabilities for elucidating the problem of radiation quality or the relative biological effectiveness (RBE) of different ionizing radiations which underlines nearly the whole spectrum of radiotherapeutic modalities, from external high-energy hadron beams to internal low-energy gamma and beta emitters that are used in brachytherapy sources and radiopharmaceuticals, respectively.

Microdosimetry and Dose-Averaged LET Calculations of Protons in Liquid Water: A Novel Geant4-DNA Application

The spatial distribution of energy deposition events is an essential aspect in the determination of the radiobiological effects of ionizing radiation at the cellular level. Microdosimetry provides a theoretical framework for the description of these events, and has been used in several studies to address problems such as the characterization of Linear Energy Transfer (LET) and Relative Biological Effectiveness (RBE) of ion beams for proton therapy applications. Microdosimetry quantities and their distributions can be obtained by means of Monte Carlo simulations. In this work, we present a track structure Monte Carlo (MC) application, based on Geant4-DNA, for the computation of microdosimetric distributions of protons in liquid water. This application provides two sampling methods uniform and weighted, for the scoring of the quantities of interest in spherical sites, with diameters ranging from 1 to 10 μm. As an element of novelty, the work shows the approach followed to calculate, without resorting to dedicated simulations, the distribution of energy imparted to the site per electronic collision of the proton, which can be used to obtain the macroscopic dose-averaged LET as proposed by Kellerer. Furthermore, in this work the concept of effective mean chord length is proposed to take into account δ-ray influx and escape in the calculation of macroscopic dose-averaged LET for proton track segments and retrieve the agreement predicted by Kellerer’s formula. Finally, the results obtained demonstrate that our MC application is reliable and computational-efficient to perform calculations of microdosimetric distributions and dose-averaged LET of proton track segments in liquid water.

Establishment and Validation of CyberKnife Irradiation in a Syngeneic Glioblastoma Mouse Model

CyberKnife stereotactic radiosurgery (CK-SRS) precisely delivers radiation to intracranial tumors. However, the underlying radiobiological mechanisms at high single doses are not yet fully understood. Here, we established and evaluated the early radiobiological effects of CK-SRS treatment at a single dose of 20 Gy after 15 days of tumor growth in a syngeneic glioblastoma-mouse model. Exact positioning was ensured using a custom-made, non-invasive, and trackable frame. One superimposed target volume for the CK-SRS planning was created from the fused tumor volumes obtained from MRIs prior to irradiation. Dose calculation and delivery were planned using a single-reference CT scan. Six days after irradiation, tumor volumes were measured using MRI scans, and radiobiological effects were assessed using immunofluorescence staining. We found that CK-SRS treatment reduced tumor volume by approximately 75%, impaired cell proliferation, diminished tumor vasculature, and increased immune response. The accuracy of the delivered dose was demonstrated by staining of DNA double-strand breaks in accordance with the planned dose distribution. Overall, we confirmed that our proposed setup enables the precise irradiation of intracranial tumors in mice using only one reference CT and superimposed MRI volumes. Thus, our proposed mouse model for reproducible CK-SRS can be used to investigate radiobiological effects and develop novel therapeutic approaches.

Radiobiological risks following dentomaxillofacial imaging: should we be concerned?

Objectives: This review aimed to present studies that prospectively investigated biological effects in patients following diagnostic dentomaxillofacial radiology (DMFR). Methods: Literature was systematically searched to retrieve all studies assessing radiobiological effects of using X-ray imaging in the dentomaxillofacial area, with reference to radiobiological outcomes for other imaging modalities and fields. Results: There is a lot of variability in the reported radiobiological assessment methods and radiation dose measures, making comparisons of radiobiological studies challenging. Most radiological DMFR studies are focusing on genotoxicity and cytotoxicity, data for 2D dentomaxillofacial radiographs, albeit with some methodological weakness biasing the results. For CBCT, available evidence is limited and few studies include comparative data on both adults and children. Conclusions In the future, one will have to strive towards patient-specific measures by considering age, gender and other individual radiation sensitivity-related factors. Ultimately, future radioprotection strategies should build further on the concept of personalized medicine, with patient-specific optimization of the imaging protocol, based on radiobiological variables.

Biomarker of buccal mucosa cells damaged after exposure to panoramic radiography: a literature review

Objectives: This review aimed to understand the effect of exposure to panoramic radiographs on exfoliated buccal mucosal cells at the cellular level. Review: The dose of radiation exposure in dentistry, both intraoral and extraoral, has been regulated by The National Radiological Protection Board (NRPB). However, even though it is given in small doses, x-ray radiation due to intraoral and extraoral radiographs still has a radiobiological effect on the exposed tissue. The radiobiological effects of X-ray exposure can cause changes in biological molecules, either directly or indirectly, within hours or days. There are two classification of this radiobiological effect, called deterministic and stochastic effect. The deterministic effect occurs when the dose given exceeds the recommended dose by the NRPB, whereas the stochastic effect does not have any threshold that needs to be exceeded to give some adverse impact to the exposed tissue One method used as a predictor or biomarker of genetic damage due to exposure to physical or chemical mutagenic agents in humans is micronucleus (MN). The biomarker for the cell damaged is the change of nucleus shape and outline, called pycnosis, karyolysis, karyorrhexis. Conclusion: The exposed to x-ray from panoramic could induce cell and genetic damaged. Prescription for panoramic radiographic examination in patients should be as effectively as possible according to the principles of ALADA (as low as diagnostically acceptable) to avoid adverse effects on the exposed tissue.

On the Equivalence of the Biological Effect Induced by Irradiation of Clusters of Heavy Atom Nanoparticles and Homogeneous Heavy Atom-Water Mixtures

A multiscale local effect model (LEM)-based framework was implemented to study the cell damage caused by the irradiation of clusters of gold nanoparticles (GNPs) under clinically relevant conditions. The results were compared with those obtained by a homogeneous mixture of water and gold (MixNP) irradiated under similar conditions. To that end, Monte Carlo simulations were performed for the irradiation of GNP clusters of different sizes and MixNPs with a 6 MV Linac spectrum to calculate the dose enhancement factor in water. The capabilities of our framework for the prediction of cell damage trends are examined and discussed. We found that the difference of the main parameter driving the cell damage between a cluster of GNPs and the MixNP was less than 1.6% for all cluster sizes. Our results demonstrate for the first time a simple route to intuit the radiobiological effects of clusters of nanoparticles through the consideration of an equivalent homogenous gold/water mixture. Furthermore, the negligible difference on cell damage between a cluster of GNPs and MixNP simplifies the modelling for the complex geometries of nanoparticle aggregations and saves computational resources.