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Frontiers in Oncology 2022Glioblastoma multiforme (GBM) is at present an incurable disease with a 5-year survival rate of 5.5%, despite improvements in treatment modalities such as surgery,...
Glioblastoma multiforme (GBM) is at present an incurable disease with a 5-year survival rate of 5.5%, despite improvements in treatment modalities such as surgery, radiation therapy, chemotherapy [e.g., temozolomide (TMZ)], and targeted therapy [e.g., the antiangiogenic agent bevacizumab (BEV)]. Diffusing alpha-emitters radiation therapy (DaRT) is a new modality that employs radium-224-loaded seeds that disperse alpha-emitting atoms inside the tumor. This treatment was shown to be effective in mice bearing human-derived GBM tumors. Here, the effect of DaRT in combination with standard-of-care therapies such as TMZ or BEV was investigated. In a viability assay, the combination of alpha radiation with TMZ doubled the cytotoxic effect of each of the treatments alone in U87 cultured cells. A colony formation assay demonstrated that the surviving fraction of U87 cells treated by TMZ in combination with alpha irradiation was lower than was achieved by alpha- or x-ray irradiation as monotherapies, or by x-ray combined with TMZ. The treatment of U87-bearing mice with DaRT and TMZ delayed tumor development more than the monotherapies. Unlike other radiation types, alpha radiation did not increase VEGF secretion from U87 cells in culture. BEV treatment introduced several days after DaRT implantation improved tumor control, compared to BEV or DaRT as monotherapies. The combination was also shown to be superior when starting BEV administration prior to DaRT implantation in large tumors relative to the seed size. BEV induced a decrease in CD31 staining under DaRT treatment, increased the diffusive spread of Ra progeny atoms in the tumor tissue, and decreased their clearance from the tumor through the blood. Taken together, the combinations of DaRT with standard-of-care chemotherapy or antiangiogenic therapy are promising approaches, which may improve the treatment of GBM patients.
PubMed: 36237307
DOI: 10.3389/fonc.2022.888100 -
Theranostics 2022Theranostics is an emerging paradigm that combines imaging and therapy in order to personalize patient treatment. In nuclear medicine, this is achieved by using... (Review)
Review
Theranostics is an emerging paradigm that combines imaging and therapy in order to personalize patient treatment. In nuclear medicine, this is achieved by using radiopharmaceuticals that target identical molecular targets for both imaging (using emitted gamma rays) and radiopharmaceutical therapy (using emitted beta, alpha or Auger-electron particles) for the treatment of various diseases, such as cancer. If the therapeutic radiopharmaceutical cannot be imaged quantitatively, a "theranostic pair" imaging surrogate can be used to predict the absorbed radiation doses from the therapeutic radiopharmaceutical. However, theranostic dosimetry assumes that the pharmacokinetics and biodistributions of both radiopharmaceuticals in the pair are identical or very similar, an assumption that still requires further validation for many theranostic pairs. In this review, we consider both same-element and different-element theranostic pairs and attempt to determine if factors exist which may cause inaccurate dose extrapolations in theranostic dosimetry, either intrinsic (e.g. chemical differences) or extrinsic (e.g. injecting different amounts of each radiopharmaceutical) to the radiopharmaceuticals. We discuss the basis behind theranostic dosimetry and present common theranostic pairs and their therapeutic applications in oncology. We investigate general factors that could create alterations in the behavior of the radiopharmaceuticals or the quantitative accuracy of imaging them. Finally, we attempt to determine if there is evidence showing some specific pairs as suitable for theranostic dosimetry. We show that there are a variety of intrinsic and extrinsic factors which can significantly alter the behavior among pairs of radiopharmaceuticals, even if they belong to the same chemical element. More research is needed to determine the impact of these factors on theranostic dosimetry estimates and on patient outcomes, and how to correctly account for them.
Topics: Animals; Humans; Neoplasms; Nuclear Medicine; Radionuclide Imaging; Radiopharmaceuticals; Theranostic Nanomedicine
PubMed: 34987643
DOI: 10.7150/thno.62851 -
Pharmaceutics Jan 2023Gelatin is a biocompatible, biodegradable, cheap, and nontoxic material, which is already used for pharmaceutical applications. Nanoparticles from gelatin (GNPs) are...
Gelatin is a biocompatible, biodegradable, cheap, and nontoxic material, which is already used for pharmaceutical applications. Nanoparticles from gelatin (GNPs) are considered a promising delivery system for hydrophilic and macromolecular drugs. Mechanical properties of particles are recognized as an important parameter affecting drug carrier interaction with biological systems. GNPs offer the preparation of particles with different stiffness. GNPs were loaded with Fluorescein isothiocyanate-labeled 150 kDa dextran (FITC-dextran) yielding also different elastic properties. GNPs were visualized using atomic force microscopy (AFM), and force-distance curves from the center of the particles were evaluated for Young's modulus calculation. The prepared GNPs have Young's moduli from 4.12 MPa for soft to 9.8 MPa for stiff particles. Furthermore, cytokine release (IL-6 and TNF-α), cell viability, and cell uptake were determined on macrophage cell lines from mouse (RAW 264.7) and human (dTHP-1 cells, differentiated human monocytic THP-1 cells) origin for soft and stiff GNPs. Both particle types showed good cell compatibility and did not induce IL-6 and TNF-α release from RAW 264.7 and dTHP-1 cells. Stiffer GNPs were internalized into cells faster and to a larger extent.
PubMed: 36678828
DOI: 10.3390/pharmaceutics15010199 -
Journal of Nuclear Medicine : Official... Sep 2023Auger electron (AE) radiopharmaceutical therapy (RPT) may have the same therapeutic efficacy as α-particles for oncologic small disease, with lower risks of... (Review)
Review
Auger electron (AE) radiopharmaceutical therapy (RPT) may have the same therapeutic efficacy as α-particles for oncologic small disease, with lower risks of normal-tissue toxicity. The seeds of using AE emitters for RPT were planted several decades ago. Much knowledge has been gathered about the potency of the biologic effects caused by the intense shower of these low-energy AEs. Given their short range, AEs deposit much of their energy in the immediate vicinity of their site of decay. However, the promise of AE RPT has not yet been realized, with few agents evaluated in clinical trials and none becoming part of routine treatment so far. Instigated by the 2022 "Technical Meeting on Auger Electron Emitters for Radiopharmaceutical Developments" at the International Atomic Energy Agency, this review presents the current status of AE RPT based on the discussions by experts in the field. A scoring system was applied to illustrate hurdles in the development of AE RPT, and we present a selected list of well-studied and emerging AE-emitting radionuclides. Based on the number of AEs and other emissions, physical half-life, radionuclide production, radiochemical approaches, dosimetry, and vector availability, recommendations are put forward to enhance and impact future efforts in AE RPT research.
Topics: Radiopharmaceuticals; Electrons; Alpha Particles; Half-Life; International Agencies
PubMed: 37591544
DOI: 10.2967/jnumed.122.265039 -
The Eurasian Journal of Medicine Jun 2023Radiation is used to treat cancer but causes serious complications, such as liver toxicity. In this study, the protective effects of alpha lipoic acid against the...
OBJECTIVE
Radiation is used to treat cancer but causes serious complications, such as liver toxicity. In this study, the protective effects of alpha lipoic acid against the unwanted effects of radiation used in many cancer treatments which can cause damage after treatment were investigated.
MATERIAL AND METHODS
The sample consisted of 32 Sprague-Dawley male rats randomized equally into 4 groups. The control group received no intervention. The alpha lipoic acid group was administered 50 mg/kg (dissolved in 0.9% NaCl) for 3 days. The ionizing radiation group was exposed to a total of 30 Gy radiation in 10 Gy fractions per day. The ionizing radiation+alpha lipoic acid group was administered 50 mg/kg alpha lipoic acid® prior to exposure to a total of 30 Gy radiation in 10 Gy fractions per day. Rats were sacrificed by cervical dislocation, and the liver was removed for histopathological studies and superoxide dismutase and malondialdehyde assays. Liver tissues were histopathologically assessed using hematoxylin-eosin staining after 4 weeks of the experiment.
RESULTS
The ionizing radiation + alpha lipoic acid group had significantly less severe necrosis than the ionizing radiation group. Compared to the ionizing radiation group and the ionizing radiation + alpha lipoic acid group, superoxide dismutase enzyme activity was decreased with the addition of alpha lipoic acid. In addition, when the amount of malondialdehyde, which is a marker of oxidative stress, was examined, it was determined that the amount of malondialdehyde in the ionizing radiation + alpha lipoic acid group was lower than in the ionizing radiation Group.
CONCLUSION
Alpha lipoic acid® mitigates radiotherapy-induced damage in liver tissue.
PubMed: 37403907
DOI: 10.5152/eurasianjmed.2023.0148 -
International Journal of Environmental... Nov 2020Alpha-emitting radioisotopes are the most toxic among all radionuclides. In particular, medium to long-lived isotopes of the heavier metals are of the greatest concern... (Review)
Review
Alpha-emitting radioisotopes are the most toxic among all radionuclides. In particular, medium to long-lived isotopes of the heavier metals are of the greatest concern to human health and radiological safety. This review focuses on the most common alpha-emitting radionuclides of natural and anthropogenic origin in wild mushrooms from around the world. Mushrooms bio-accumulate a range of mineral ionic constituents and radioactive elements to different extents, and are therefore considered as suitable bio-indicators of environmental pollution. The available literature indicates that the natural radionuclide Po is accumulated at the highest levels (up to 22 kBq/kg dry weight (dw) in wild mushrooms from Finland), while among synthetic nuclides, the highest levels of up to 53.8 Bq/kg dw of Pu were reported in Ukrainian mushrooms. The capacity to retain the activity of individual nuclides varies between mushrooms, which is of particular interest for edible species that are consumed either locally or, in some cases, also traded on an international scale. The effective radiation dose from the ingestion of this food can reportedly range from 0.033 µSv/kg dw to 26.8 mSv/kg and varies depending on the country. Following pollution events, such consumption may expose consumers to highly radiotoxic decay particles produced by alpha emitters.
Topics: Adult; Agaricales; Alpha Particles; Humans; Radiation Monitoring; Radioisotopes; Soil Pollutants, Radioactive
PubMed: 33172165
DOI: 10.3390/ijerph17218220 -
Biomacromolecules Jul 2019Glycogen, a randomly branched glucose polymer, provides energy storage in organisms. It forms small β particles which in animals bind to form composite α particles,...
Glycogen, a randomly branched glucose polymer, provides energy storage in organisms. It forms small β particles which in animals bind to form composite α particles, which give better glucose release. Simulations imply β particle size is controlled only by activities and sizes of glycogen biosynthetic enzymes and sizes of polymer chains. Thus, storing more glucose requires forming more β particles, which are expected to sometimes form α particles. No α particles have been reported in bacteria, but the extraction techniques might have caused degradation. Using milder glycogen extraction techniques on Escherichia coli, transmission electron microscopy and size-exclusion chromatography showed α particles, consistent with this hypothesis for α-particle formation. Molecular density and size distributions show similarities with animal glycogen, despite very different metabolic processes. These general polymer constraints are such that any organism which needs to store and then release glucose will have similar α and β particle structures: a type of convergent evolution.
Topics: Alpha Particles; Beta Particles; Energy Metabolism; Escherichia coli; Glucose; Glycogen; Microscopy, Electron, Transmission; Polymers
PubMed: 31244022
DOI: 10.1021/acs.biomac.9b00586 -
Nature Reviews. Urology Dec 2019The targeted alpha therapy radium-223 (Ra) can prolong survival in men with castration-resistant prostate cancer (CRPC) who have symptomatic bone metastases and no known... (Review)
Review
The targeted alpha therapy radium-223 (Ra) can prolong survival in men with castration-resistant prostate cancer (CRPC) who have symptomatic bone metastases and no known visceral metastases. Preclinical studies demonstrate that Ra preferentially incorporates into newly formed bone matrix within osteoblastic metastatic lesions. The emitted high-energy alpha particles induce DNA double-strand breaks that might be irreparable and lead to cell death in nearby exposed tumour cells, osteoblasts and osteoclasts. Consequently, tumour growth and abnormal bone formation are inhibited by these direct effects and by the disruption of positive-feedback loops between tumour cells and the bone microenvironment. Ra might also modulate immune responses within the bone. The clinical utility of Ra has encouraged the development of other anticancer targeted alpha therapies. A thorough understanding of the mechanism of action could inform the design of new combinatorial treatment strategies that might be more efficacious than monotherapy. On the basis of the current mechanistic knowledge and potential clinical benefits, combination therapies of Ra with microtubule-stabilizing cytotoxic drugs and agents targeting the androgen receptor axis, immune checkpoint receptors or DNA damage response proteins are being explored in patients with CRPC and metastatic bone disease.
Topics: Animals; Bone Neoplasms; Combined Modality Therapy; Disease Models, Animal; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Radium
PubMed: 31712765
DOI: 10.1038/s41585-019-0251-x -
Particle and Fibre Toxicology Aug 2023Traffic-derived particles are important contributors to the adverse health effects of ambient particulate matter (PM). In Nordic countries, mineral particles from road...
BACKGROUND
Traffic-derived particles are important contributors to the adverse health effects of ambient particulate matter (PM). In Nordic countries, mineral particles from road pavement and diesel exhaust particles (DEP) are important constituents of traffic-derived PM. In the present study we compared the pro-inflammatory responses of mineral particles and DEP to PM from two road tunnels, and examined the mechanisms involved.
METHODS
The pro-inflammatory potential of 100 µg/mL coarse (PM), fine (PM and ultrafine PM (PM) sampled in two road tunnels paved with different stone materials was assessed in human bronchial epithelial cells (HBEC3-KT), and compared to DEP and particles derived from the respective stone materials. Release of pro-inflammatory cytokines (CXCL8, IL-1α, IL-1β) was measured by ELISA, while the expression of genes related to inflammation (COX2, CXCL8, IL-1α, IL-1β, TNF-α), redox responses (HO-1) and metabolism (CYP1A1, CYP1B1, PAI-2) was determined by qPCR. The roles of the aryl hydrocarbon receptor (AhR) and reactive oxygen species (ROS) were examined by treatment with the AhR-inhibitor CH223191 and the anti-oxidant N-acetyl cysteine (NAC).
RESULTS
Road tunnel PM caused time-dependent increases in expression of CXCL8, COX2, IL-1α, IL-1β, TNF-α, COX2, PAI-2, CYP1A1, CYP1B1 and HO-1, with fine PM as more potent than coarse PM at early time-points. The stone particle samples and DEP induced lower cytokine release than all size-fractionated PM samples for one tunnel, and versus fine PM for the other tunnel. CH223191 partially reduced release and expression of IL-1α and CXCL8, and expression of COX2, for fine and coarse PM, depending on tunnel, response and time-point. Whereas expression of CYP1A1 was markedly reduced by CH223191, HO-1 expression was not affected. NAC reduced the release and expression of IL-1α and CXCL8, and COX2 expression, but augmented expression of CYP1A1 and HO-1.
CONCLUSIONS
The results indicate that the pro-inflammatory responses of road tunnel PM in HBEC3-KT cells are not attributed to the mineral particles or DEP alone. The pro-inflammatory responses seem to involve AhR-dependent mechanisms, suggesting a role for organic constituents. ROS-mediated mechanisms were also involved, probably through AhR-independent pathways. DEP may be a contributor to the AhR-dependent responses, although other sources may be of importance.
Topics: Humans; Particulate Matter; Reactive Oxygen Species; Tumor Necrosis Factor-alpha; Cyclooxygenase 2; Cytochrome P-450 CYP1A1; Plasminogen Activator Inhibitor 2; Cytokines; Epithelial Cells; Vehicle Emissions; Air Pollutants
PubMed: 37537647
DOI: 10.1186/s12989-023-00542-w -
Molecules (Basel, Switzerland) Aug 2022Advances in the field of molecular biology have had an impact on biomedical applications, which provide greater hope for both imaging and therapeutics. Work has been... (Review)
Review
Advances in the field of molecular biology have had an impact on biomedical applications, which provide greater hope for both imaging and therapeutics. Work has been intensified on the development of radionuclides and their application in radiopharmaceuticals (RP) which will certainly influence and expand therapeutic approaches in the future treatment of patients. Alpha or beta particles and Auger electrons are used for therapy purposes, and each has advantages and disadvantages. The radionuclides labeled drug delivery system will deliver the particles to the specific targeting cell. Different radioligands can be chosen to uniquely target molecular receptors or intracellular components, making them suitable for personal patient-tailored therapy in modern cancer therapy management. Advances in nanotechnology have enabled nanoparticle drug delivery systems that can allow for specific multivalent attachment of targeted molecules of antibodies, peptides, or ligands to the surface of nanoparticles for therapy and imaging purposes. This review presents fundamental radionuclide properties with particular reference to tumor biology and receptor characteristic of radiopharmaceutical targeted therapy development.
Topics: Beta Particles; Diagnostic Imaging; Humans; Neoplasms; Radioisotopes; Radiopharmaceuticals
PubMed: 36014472
DOI: 10.3390/molecules27165231