Clinical Radiation Research Articles

A pulmonary vein atlas for radiotherapy planning

Background and PurposeCardiac arrhythmia is a recognised potential complication of thoracic radiotherapy, but the responsible cardiac substructures for arrhythmogenesis have not been identified. Arrhythmogenic tissue is commonly located in the pulmonary veins (PVs) of cardiology patients with arrhythmia, however these structures are not currently considered organs-at-risk during radiotherapy planning. A standardised approach to their delineation was developed and evaluated. Materials and MethodsThe gross and radiological anatomy relevant to atrial fibrillation was derived from cardiology and radiology literature by a multidisciplinary team. A region of interest and contouring instructions for radiotherapy computed tomography scans were iteratively developed and subsequently evaluated. Radiation oncologists (n = 5) and radiation technologists (n = 2) contoured the PVs on the four-dimensional planning datasets of five patients with locally advanced lung cancer treated with 1.8–2.75 Gy fractions. Contours were compared to reference contours agreed by the researchers using geometric and dosimetric parameters. ResultsThe mean dose to the PVs was 35% prescription dose. Geometric and dosimetric similarity of the observer contours with reference contours was fair, with an overall mean Dice of 0.80 ± 0.02. The right superior PV (mean DSC 0.83 ± 0.02) had better overlap than the left (mean DSC 0.80 ± 0.03), but the inferior PVs were equivalent (mean DSC of 0.78). The mean difference in mean dose was 0.79 Gy ± 0.71 (1.46% ± 1.25). ConclusionA PV atlas with multidisciplinary approval led to reproducible delineation for radiotherapy planning, supporting the utility of the atlas in future clinical radiotherapy cardiotoxicity research encompassing arrhythmia endpoints.

Osteosarcoma: Current Concepts and Evolutions in Management Principles.

Osteosarcoma is a rare malignancy arising from mesenchymal tissue, and represents the most common bone sarcoma. The management of osteosarcoma is challenging, and requires a multidisciplinary approach. In daily clinical practice, surgery, radiotherapy, and conventional chemotherapy constitute the therapeutic armamentarium against the disease. However, a significant number of patients with initially localized osteosarcoma will experience local or distant recurrence, and the prognosis for metastatic disease remains dismal. There is a pressing need to identify novel therapeutic strategies to better manage osteosarcoma and improve survival outcomes. In this study, we present recent advances in the therapeutic management of osteosarcoma, including surgical and medical advances. The role of immunotherapy (immune checkpoint inhibitors, adoptive cellular therapy, cancer vaccines) and other targeted therapies including tyrosine kinase inhibitors is discussed; however, additional studies are required to delineate their roles in clinical practice.

The Use of Hydrogel-Based Materials for Radioprotection

Major causes of the radiation-induced disease include nuclear accidents, war-related nuclear explosions, and clinical radiotherapy. While certain radioprotective drug or bioactive compounds have been utilized to protect against radiation-induced damage in preclinical and clinical settings, these strategies are hampered by poor efficacy and limited utilization. Hydrogel-based materials are effective carriers capable of enhancing the bioavailability of compounds loaded therein. As they exhibit tunable performance and excellent biocompatibility, hydrogels represent promising tools for the design of novel radioprotective therapeutic strategies. This review provides an overview of common approaches to radioprotective hydrogel preparation, followed by a discussion of the pathogenesis of radiation-induced disease and the current states of research focused on using hydrogels to protect against these diseases. These findings ultimately provide a foundation for discussions of the challenges and future prospects associated with the use of radioprotective hydrogels.

Geometric impact and dose estimation of on-patient placement of a lightweight receiver coil in a clinical magnetic resonance imaging-only radiotherapy workflow for prostate cancer.

For pelvic magnetic resonance imaging (MRI)-only radiotherapy the use of receiver coil bridges (CB) is recommended to avoid deformation of the patient. Development in coil technology has enabled lightweight, flexible coils. In this work we evaluate the effects of a lightweight coil in a pelvic MRI-only radiotherapy workflow. Twenty-one patients, referred to prostate MRI-only radiotherapy, were included. Images were acquired with and without CB. Anatomical deformation from the on-patient coil placement was measured in the anterior-posterior (AP) and left-right (LR) direction. The change in signal-to-noise ratio (SNR) was measured in phantom and in vivo.The clinical treatment plan, created on the image with CB, was transferred and recalculated on the image without the CB. Dose metrics for the targets (planning- and clinical target volume) and organs at risks (OAR) were analyzed. There was a statistically significant increase in SNR in-vivo (median 21%, p=0.002) when removing the CB. Anatomical differences after removing the CB in patients were -1.5mm in AP (median change) and+2.5mm in LR direction. Dosimetric differences for the target structures were clinically negligible, but statistically significant. The difference in target mean doses were 0.2% (both p=0.004) of the prescribed dose. No dosimetric differences were observed for the OAR, except for the penile bulb. We concluded that anatomical change and dosimetric differences, originating from scanning without CB were minor. The CB can thereby be removed from the workflow, enabling easier patient positioning and increased SNR when using lightweight coils.

434 Ionizing radiation acoustic imaging (iRAI) for volumetric mapping the dose deep in the liver during radiation therapy

OBJECTIVES/GOALS: The goal of this study was to develop a clinically applicable technique to increase the precision of in vivo dose monitoring during radiation therapy by mapping the dose deposition and resolving the temporal dose accumulation while the treatment is being delivered in real time. METHODS/STUDY POPULATION: Ironizing radiation acoustic imaging (iRAI) is a novel imaging concept with the potential to map the delivered radiation dose on anatomic structure in real time during external beam radiation therapy without interrupting the clinical workflow. The iRAI system consisted of a custom-designed two-dimensional (2D) matrix transducer array with integrated preamplifier array, driven by a clinic-ready ultrasound imaging platform. The feasibility of iRAI volumetric imaging in mapping dose delivery and real-time monitoring of temporal dose accumulation in a clinical treatment plan were investigated with a phantom, a rabbit model, and a cancer patient. RESULTS/ANTICIPATED RESULTS: The total dose deposition and temporal dose accumulation in 3D space of a clinical C-shape treatment plan in a targeted region were first imaged and optimized in a phantom. Then, semi-quantitative iRAI measurements were achieved in an in vivo rabbit model. Finally, for the first time, real-time visualization of radiation dose delivered deep in a patient with liver metastases was performed with a clinical linear accelerator. These studies demonstrate the potential of iRAI to monitor and quantify the radiation dose deposition during treatment. DISCUSSION/SIGNIFICANCE: Described here is the pioneering role of an iRAI system in mapping the 3D radiation dose deposition of a complex clinical radiotherapy treatment plan. iRAI offers a cost-effective and practical solution for real-time visualization of 3D radiation dose delivery, potentially leading to personalized radiotherapy with optimal efficacy and safety.

Enhanced X-ray Dose Response of Radio-fluorescent Hydrogels Enabled by Persulfate Salts.

Coumarin 3-carboxylic acid (CCA)-loaded radio-fluorescent hydrogels have attracted interest for ionizing radiation dosimeters, but their sensitivity needs to be improved. In this study, we added ammonium persulfate (APS) to a polyacrylamide (PAAm)-CCA hydrogel. The introduction of APS improved the hydrogel dose sensitivity to 336.02Gy- 1, which is 1.8 times that of the counterpart without APS. Our hydrogel can measure the X-ray dose in a range of 0 - 15Gy with a lower limit of detection (LOD) of 0.1Gy. Additionally, the hydrogel can sense X-ray doses within a wide range of the dose rate and temperature, and the dose‒response can be well retained 7 days postirradiation. Therefore, we think this study provides a simple and robust method to improve the sensitivity of CCA hydrogel dosimeters, presenting great potential in clinical radiotherapy.

Microneedles: structure, classification, and application in oral cancer theranostics.

Oral cancer is a malignant tumor that threatens the health of individuals on a global scale. Currently available clinical treatment methods, including surgery, radiotherapy, and chemotherapy, significantly impact the quality of life of patients with systemic side effects. In the treatment of oral cancer, local and efficient delivery of antineoplastic drugs or other substances (like photosensitizers) to improve the therapy effect is a potential way to optimize oral cancer treatments. As an emerging drug delivery system in recent years, microneedles (MNs) can be used for local drug delivery, offering the advantages of high efficiency, convenience, and noninvasiveness. This review briefly introduces the structures and characteristics of various types of MNs and summarizes MN preparation methods. An overview of the current research application of MNs in different cancer treatments is provided. Overall, MNs, as a means of transporting substances, demonstrate great potential in oral cancer treatments, and their promising future applications and perspectives of MNs are outlined in this review.

Monte Carlo simulation of shielding designs for a cabinet form factor preclinical MV-energy photon FLASH radiotherapy system.

A preclinical MV-energy photon FLASH radiotherapy system is being designed at Stanford and SLAC National Accelerator Laboratory. Because of the higher energy and dose rate compared to conventional kV-energy photon laboratory-scale irradiators, adequate shielding in a stand-alone cabinet form factor is more challenging to achieve. We present a Monte Carlo simulation of multilayered shielding for a compact self-shielding system without the need for a radiation therapyvault. A multilayered shielding approach using multiple alternating layers of high-Z and low-Z materials is applied to the self-shielded cabinet to effectively mitigate the secondary radiation produced and to allow the device to be housed in a Controlled Radiation Area outside of a radiation vault. The multilayered shielding approach takes advantage of the properties of high-Z and low-Z radiation shielding materials such as density, cross-section, atomic number of the shielding elements, and products of radiation interactions within each layer. The Monte Carlo radiation transport code, FLUKA, is used to simulate the total effective dose produced by theoperation. The multilayered shielding designs proposed and simulated produced effective dose rates significantly lower than monolayer designs with the same total material thickness at the regulatory boundary; this is accomplished through the manipulation of the locations where secondary radiation is produced and reactions due to material properties such as neutron back reflection in hydrogen. Borated polyethylene at five weight percent significantly increased the shielding performance as compared to regular polyethylene, with the magnitude of the reduction depending upon the order of the shieldingmaterial. The multilayered shielding provides a path for shielding preclinical FLASH systems that deliver MV-energy bremsstrahlung photons. This approach promises to be more efficient with respect to the shielding material mass and space claim as compared to shielded vaults typically required for clinical radiation therapy with MVphotons. This article is protected by copyright. All rights reserved.

An anthropomorphic 3D printed inhomogeneity thorax phantom slab for SBRT commissioning and quality assurance.

Anthropomorphic phantoms with tissue equivalency are required in radiotherapy for quality assurance of imaging and dosimetric processes used in radiotherapy treatments. Commercial phantoms are expensive and provide limited approximation to patient geometry and tissue equivalency. In this study, a 5cm thick anthropomorphic thoracic slab phantom was designed and 3D printed using models exported from a CT dataset to demonstrate the feasibility of manufacturing anthropomorphic 3D printed phantoms onsite in a clinical radiotherapy department. The 3D printed phantom was manufactured with polylactic acid with an in-fill density of 80% to simulate tissue density and 26% to simulate lung density. A common radio-opacifier, barium sulfate (BaSO4), was added 6% w/w to an epoxy resin mixture to simulate similar HU numbers for bone equivalency. A half-cylindrical shape was cropped away from the spine region to allow insertion of the bone equivalent mixture. Two Gafchromic™ EBT3 film strips were inserted into the 3D printed phantom to measure the delivery of two stereotactic radiotherapy plans targeting lung and bone lesions respectively. Results were analysed within SNC Patient with a low dose threshold of 10% and a gamma criterion of 3%/2mm and 5%/1mm. The resulting gamma pass rate across both criterions for lung and bone were ≥ 95% and approximately 85% respectively. Results shows that a cost-effective anthropomorphic 3D printed phantom with realistic heterogeneity simulation can be fabricated in departments with access a suitable 3D printer, which can be used for performing commissioning and quality assurance for stereotactic type radiotherapy to lesions in the presence of heterogeneity.

Cerebral tissue oxygenation response to brain irradiation measured during clinical radiotherapy.

Cancer therapy treatments produce extensive changes in the physiological and morphological properties of tissues, which are also individual dependent. Currently, a key challenge involves developing more tailored cancer therapy, and consequently, individual biological response measurement during therapy, such as tumor hypoxia, is of high interest. This is the first time human cerebral haemodynamics and cerebral tissue oxygenation index (TOI) changes were measured during the irradiation in clinical radiotherapy and functional near-infrared spectroscopy (fNIRS) technique was demonstrated as a feasible technique for clinical use in radiotherapy, based on 34 online patient measurements. Our aim is to develop predictive biomarkers and noninvasive real-time methods to establish the effect of radiotherapy during treatment as well as to optimize radiotherapy dose planning for individual patients. In particular, fNIRS-based technique could offer an effective and clinically feasible online technique for continuous monitoring of brain tissue hypoxia and responses to chemo- and radiotherapy, which involves modulating tumor oxygenation to increase or decrease tumor hypoxia. We aim to show that fNIRS is feasible for repeatability measuring in patient radiotherapy, the temporal alterations of tissue oxygenation induced by radiation. Fiber optics setup using multiwavelength fNIRS was built and combined with a medical linear accelerator to measure cerebral tissue oxygenation changes during the whole-brain radiotherapy treatment, where the radiation dose is given in whole brain area only preventing dosage to eyes. Correlation of temporal alterations in cerebral haemodynamics and TOI response to brain irradiation was quantified. Online fNIRS patient measurement of cerebral haemodynamics during clinical brain radiotherapy is feasible in clinical environment, and results based on 34 patient measurements show strong temporal alterations in cerebral haemodynamics and decrease in TOI during brain irradiation and confirmed the repeatability. Our proof-of-concept study shows evidently that irradiation causes characteristic immediate changes in brain tissue oxygenation. In particular, TOI seems to be a sensitive parameter to observe the tissue effects of radiotherapy. Monitoring the real-time interactions between the subjected radiation dose and corresponding haemodynamic effects may provide important tool for the researchers and clinicians in the field of radiotherapy. Eventually, presented fNIRS technique could be used for improving dose planning and safety control for individual patients.

PyRaDiSe: A Python package for DICOM-RT-based auto-segmentation pipeline construction and DICOM-RT data conversion

Background and objective: Despite fast evolution cycles in deep learning methodologies for medical imaging in radiotherapy, auto-segmentation solutions rarely run in clinics due to the lack of open-source frameworks feasible for processing DICOM RT Structure Sets. Besides this shortage, available open-source DICOM RT Structure Set converters rely exclusively on 2D reconstruction approaches leading to pixelated contours with potentially low acceptance by healthcare professionals. PyRaDiSe, an open-source, deep learning framework independent Python package, addresses these issues by providing a framework for building auto-segmentation solutions feasible to operate directly on DICOM data. In addition, PyRaDiSe provides profound DICOM RT Structure Set conversion and processing capabilities; thus, it applies also to auto-segmentation-related tasks, such as dataset construction for deep learning model training.Methods: The PyRaDiSe package follows a holistic approach and provides DICOM data handling, deep learning model inference, pre-processing, and post-processing functionalities. The DICOM data handling allows for highly automated and flexible handling of DICOM image series, DICOM RT Structure Sets, and DICOM registrations, including 2D-based and 3D-based conversion from and to DICOM RT Structure Sets. For deep learning model inference, extending given skeleton classes is straightforwardly achieved, allowing for employing any deep learning framework. Furthermore, a profound set of pre-processing and post-processing routines is included that incorporate partial invertibility for restoring spatial properties, such as image origin or orientation.Results: The PyRaDiSe package, characterized by its flexibility and automated routines, allows for fast deployment and prototyping, reducing efforts for auto-segmentation pipeline implementation. Furthermore, while deep learning model inference is independent of the deep learning framework, it can easily be integrated into famous deep learning frameworks such as PyTorch or Tensorflow. The developed package has successfully demonstrated its capabilities in a research project at our institution for organs-at-risk segmentation in brain tumor patients. Furthermore, PyRaDiSe has shown its conversion performance for dataset construction.Conclusions: The PyRaDiSe package closes the gap between data science and clinical radiotherapy by enabling deep learning segmentation models to be easily transferred into clinical research practice. PyRaDiSe is available on https://github.com/ubern-mia/pyradise and can be installed directly from the Python Package Index using pip install pyradise.

Prioritizing clinical trial quality assurance for photons and protons: A failure modes and effects analysis (FMEA) comparison

Background and PurposeThe Global Clinical Trials RTQA Harmonization Group (GHG) set out to evaluate and prioritize clinical trial quality assurance. MethodsThe GHG compiled a list of radiotherapy quality assurance (QA) tests performed for proton and photon therapy clinical trials. These tests were compared between modalities to assess whether there was a need for different types of assessments per modality. A failure modes and effects analysis (FMEA) was performed to assess the risk of each QA failure. ResultsThe risk analysis showed that proton and photon therapy shared four out of five of their highest-risk failures (end-to-end anthropomorphic phantom test, phantom tests using respiratory motion, pre-treatment patient plan review of contouring/outlining, and on-treatment/post-treatment patient plan review of dosimetric coverage). While similar trends were observed, proton therapy had higher risk failures, driven by higher severity scores. A sub-analysis of occurrence × severity scores identified high-risk scores to prioritize for improvements in RTQA detectability. A novel severity scaler was introduced to account for the number of patients affected by each failure. This scaler did not substantially alter the ranking of tests, but it elevated the QA program evaluation to the top 20th percentile. This is the first FMEA performed for clinical trial quality assurance. ConclusionThe identification of high-risk errors associated with clinical trials is valuable to prioritize and reduce errors in radiotherapy and improve the quality of trial data and outcomes, and can be applied to optimize clinical radiotherapy QA.

X‐Ray‐Responsive Zeolitic Imidazolate Framework‐Capped Nanotherapeutics for Cervical Cancer‐Targeting Radiosensitization

AbstractDeveloping radiosensitizers based on the characteristics of the tumor microenvironment can improve the effectiveness and overcome the bottleneck of cervical cancer radiotherapy. Herein, an in situ synthesis strategy is demonstrated by using a highly bioactive zeolitic imidazolate framework to cap Mn3O4 and folic acid as targeting molecules (FA‐Mn3O4@ZIF‐8) to achieve enhanced radiosensitization against cervical cancer. As expected, the ZIF‐8 cap on the surface of Mn3O4 responds more effectively to X‐rays. Meanwhile, by facilitating the presence of oxygen vacancies and valence transition of manganese on the surface of Mn3O4, the ZIF‐8 cap on Mn3O4 can increase the catalytic capacity for hydrogen peroxide (H2O2) and glutathione as well as produce more singlet oxygen under X‐ray, alleviate hypoxia within the tumor microenvironment, and increase reactive oxygen species production. Moreover, FA‐Mn3O4@ZIF‐8 shows excellent radiotherapy‐sensitizing properties in vitro and in vivo by promoting DNA damage and apoptosis. Collectively, this study suggests that designing and construction of X‐ray responsive nanoradiosensitizers could be a good way for future clinical radiotherapy of malignant cervical cancer.

The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis

BackgroundHeat shock protein 27 (HSP27) is overexpressed during pulmonary fibrosis (PF) and exacerbates PF; however, the upregulation of HSP27 during PF and the therapeutic strategy of HSP27 inhibition is not well elucidated.MethodsWe have developed a mouse model simulating clinical stereotactic body radiotherapy (SBRT) with focal irradiation and validated the induction of RIPF. HSP25 (murine form of HSP27) transgenic (TG) and LLC1-derived orthotropic lung tumor models were also used. Lung tissues of patients with RIPF and idiopathic pulmonary fibrosis, and lung tissues from various fibrotic mouse models, as well as appropriated cell line systems were used. Public available gene expression datasets were used for therapeutic response rate analysis. A synthetic small molecule HSP27 inhibitor, J2 was also used.ResultsHSP27 expression with its phosphorylated form (pHSP27) increased during PF. Decreased mRNA expression of SMAD-specific E3 ubiquitin-protein ligase 2 (Smurf2), which is involved in ubiquitin degradation of HSP27, was responsible for the increased expression of pHSP27. In addition, increased expression of miRNA15b was identified with decreased expression of Smurf2 mRNA in PF models. Inverse correlation between pHSP27 and Smurf2 was observed in the lung tissues of PF animals, an irradiated orthotropic lung cancer models, and PF tissues from patients. Moreover, a HSP27 inhibitor cross-linked with HSP27 protein to ameliorate PF, which was more effective when targeting the epithelial to mesenchymal transition (EMT) stage of PF.ConclusionsOur findings identify upregulation mechanisms of HSP27 during PF and provide a therapeutic strategy for HSP27 inhibition for overcoming PF.

Real-time, volumetric imaging of radiation dose delivery deep into the liver during cancer treatment.

Ionizing radiation acoustic imaging (iRAI) allows online monitoring of radiation's interactions with tissues during radiation therapy, providing real-time, adaptive feedback for cancer treatments. We describe an iRAI volumetric imaging system that enables mapping of the three-dimensional (3D) radiation dose distribution in a complex clinical radiotherapy treatment. The method relies on a two-dimensional matrix array transducer and a matching multi-channel preamplifier board. The feasibility of imaging temporal 3D dose accumulation was first validated in a tissue-mimicking phantom. Next, semiquantitative iRAI relative dose measurements were verified in vivo in a rabbit model. Finally, real-time visualization of the 3D radiation dose delivered to a patient with liver metastases was accomplished with a clinical linear accelerator. These studies demonstrate the potential of iRAI to monitor and quantify the 3D radiation dose deposition during treatment, potentially improving radiotherapy treatment efficacy using real-time adaptive treatment.

Accuracy and Feasibility of Synthetic CT for Lung Adaptive Radiotherapy: A Phantom Study.

The respiratory variations will lead to inconsistency between the actual delivery dose and the planning dose. How the minor interfractional amplitude changes affect the geometry and dose delivery accuracy remains to be investigated in the context of lung adaptive radiotherapy. Planning 4-dimensional-computed tomography and kV-cone beam computed tomography were scanned based on the Computerized Imaging Reference Systems phantom, which was employed to simulate the minor interfractional amplitude variations. The corresponding synthetic computed tomography for a particular motion pattern can be generated from Velocity program. Then a clinically meaningful synthetic computed tomography was analyzed through the geometrical and dosimetric assessment. The image quality of synthetic computed tomography was improved obviously compared with cone beam computed tomography. Mean absolute error was minimized when no significant interfractional motion occurs and Velocity can be qualified for dealing with the regular breathing motion patterns. The mean percent hounsfield unit difference of the synthetic hounsfield unit values per organ relative to the planning 4-dimensional-computed tomography image was 22.3%. Under the same conditions, the mean percent hounsfield unit difference of the cone beam computed tomography hounsfield unit values per organ, relative to the planning 4-dimensional-computed tomography image was 83.9%. Overall, the accuracy of hounsfield unit in synthetic computed tomography was improved obviously and the variability of the synthetic image correlates with the planning 4-dimensional-computed tomography image variability. Meanwhile, the dose-volume histograms between planning 4-dimensional-computed tomography and synthetic computed tomography almost coincided each other, which indicates that Velocity program can qualify lung adaptive radiotherapy well when there were no interfractional respiratory variations. However, for cases with obvious interfractional amplitude change, the volume covered at least by 100% of the prescription dose was only 59.6% for that synthetic image. The synthetic computed tomography images generated from Velocity were close to the real images in anatomy and dosimetry, which can make clinical lung adaptive radiotherapy possible based on the actual patient anatomy during treatment.

Monte-Carlo techniques for radiotherapy applications I: introduction and overview of the different Monte-Carlo codes

Abstract Introduction: The dose calculation plays a crucial role in many aspects of contemporary clinical radiotherapy treatment planning process. It therefore goes without saying that the accuracy of the dose calculation is of very high importance. The gold standard for absorbed dose calculation is the Monte-Carlo algorithm. Methods: This first of two papers gives an overview of the main openly available and supported codes that have been widely used for radiotherapy simulations. Results: The paper aims to provide an overview of Monte-Carlo in the field of radiotherapy and point the reader in the right direction of work that could help them get started or develop their existing understanding and use of Monte-Carlo algorithms in their practice. Conclusions: It also serves as a useful companion to a curated collection of papers on Monte-Carlo that have been published in this journal.

Radiation-induced salivary gland damage/dysfunction in head and neck cancer: Nano-bioengineering strategies and artificial intelligence for prevention, therapy and reparation

Saliva is produced by and secreted from salivary glands. It is an extra-cellular fluid, 98% water, plus electrolytes, mucus, white blood cells, epithelial cells, enzymes, and anti-microbial agents. Saliva serves a critical role in the maintenance of oral, dental, and general health and well-being. Hence, alteration(s) in the amount/quantity and/or quality of secreted saliva may induce the development of several oro-dental variations, thereby the negatively-impacting overall quality of life. Diverse factors may affect the process of saliva production and quantity/quality of secretion, including medications, systemic or local pathologies and/or reversible/irreversible damage. Herein, chemo- and/or radio-therapy, particularly, in cases of head and neck cancer, for example, are well-documented to induce serious damage and dysfunction to the radio-sensitive salivary gland tissue, resulting in hypo-salivation, xerostomia (dry mouth) as well as numerous other adverse Intra-/extra-oral, medical and quality-of-life issues. Indeed, radio-therapy inevitably causes damage to the normal head and neck tissues including nerve structures (brain stem, spinal cord, and brachial plexus), mucous membranes, and swallowing muscles. Current commercially-available remedies as well as therapeutic interventions provide only temporary symptom relief, hence, do not address irreversible glandular damage. Further, despite salivary gland-sparing techniques and modified dosing strategies, long-term hypo-function remains a significant problem. Although a single governing mechanism of radiation-induced salivary gland tissue damage and dysfunction has not been yet elucidated, the potential for synergy in radio-protection (mainly, and possibly -reparation) via a combinatorial approach of mechanistically distinct strategies, has been suggested and explored over the years. This is, undoubtfully, in parallel to the ongoing efforts in improving the precision, safety, delivery, and efficacy of clinical radiotherapy protocols/outcomes, and in designing, developing, evaluating and optimizing (for translation) new artificial intelligence, technological and bio-pharmaceutical alternatives, topics covered in this review.

Prodrug Nanosensitizer Overcomes the Radiation Resistance of Hypoxic Tumor.

Clinical radiation therapy (RT) is often hindered by the low radiation energy absorption coefficient and the hypoxic features of tumor tissues. Among the tremendous efforts devoted to overcoming the barriers to efficient RT, the application of hypoxic radiosensitizers and cell-cycle-specific chemotherapeutics has shown great potential. However, their effectiveness is often compromised by their limited bioavailability, especially in the hypoxic region, which plays a major role in radioresistance. Herein, to simultaneously improve the delivery efficacy of both hypoxic radiosensitizer and cell-cycle-specific drug, a gambogic acid (GA) metronidazole (MN) prodrug (GM) was designed and synthesized based on GA, a naturally occurring chemotherapeutic and multiple pathway inhibitor, and MN, a typical hypoxic radiosensitizer. In combination with MN-containing block copolymers, the prodrug nanosensitizer (NS) of GM was obtained. Owing to the bioreduction of MN, the as-designed prodrug could be efficiently delivered to hypoxic cells and act on mitochondria to cause the accumulation of reactive oxygen species. The strong G2/M phase arrest caused by the prodrug NS could further sensitize treated cells to external radiation under hypoxic conditions by increasing DNA damage and delaying DNA repair. After coadministration of the NS with a well-established tissue-penetrating peptide, efficient tumor accumulation, deep tumor penetration, and highly potent chemoradiotherapy could be achieved.

Monophosphoryl lipid A ameliorates radiation-induced lung injury by promoting the polarization of macrophages to the M1 phenotype

BackgroundRadiation-induced lung injury (RILI) often occurs during clinical chest radiotherapy and acute irradiation from accidental nuclear leakage. This study explored the role of monophosphoryl lipid A (MPLA) in RILI.Materials and MethodsThe entire thoracic cavity of C57BL/6N mice was irradiated at 20 Gy with or without pre-intragastric administration of MPLA. HE staining, Masson trichrome staining, and TUNEL assay were used to assess lung tissue injury after treatment. The effect of irradiation on the proliferation of MLE-12 cells was analyzed using the Clonogenic assay. The effect of MPLA on the apoptosis of MLE-12 cells was analyzed using flow cytometry. Expression of γ-H2AX and epithelial-mesenchymal transition (EMT) markers in MLE-12 cells was detected by immunofluorescence and Western blot, respectively.ResultsMPLA attenuated early pneumonitis and late pulmonary fibrosis after thoracic irradiation and reversed radiation-induced EMT in C57 mice. MPLA further promoted proliferation and inhibited apoptosis of irradiated MLE-12 cells in vitro. Mechanistically, the radioprotective effect of MPLA was mediated by exosomes secreted by stimulated macrophages. Macrophage-derived exosomes modulated DNA damage in MLE-12 cells after irradiation. MPLA promoted the polarization of RAW 264.7 cells to the M1 phenotype. The exosomes secreted by M1 macrophages suppressed EMT in MLE-12 cells after irradiation.ConclusionMPLA is a novel treatment strategy for RILI. Exosomes derived from macrophages are key to the radioprotective role of MPLA in RILI.