scholarly journals The Proton-Boron Reaction Increases the Radiobiological Effectiveness of Clinical Low- and High-Energy Proton Beams: Novel Experimental Evidence and Perspectives

2021 ◽  
Vol 11 ◽  
Author(s):  
Pavel Bláha ◽  
Chiara Feoli ◽  
Stefano Agosteo ◽  
Marco Calvaruso ◽  
Francesco Paolo Cammarata ◽  
...  
Keyword(s):  
Fusion Reaction ◽  
Therapeutic Index ◽  
Clonogenic Survival ◽  
High Energy ◽  
Proton Beams ◽  
Novel Approach ◽  
Nuclear Fusion Reaction ◽  
Biological Effectiveness ◽  
First Time

Protontherapy is a rapidly expanding radiotherapy modality where accelerated proton beams are used to precisely deliver the dose to the tumor target but is generally considered ineffective against radioresistant tumors. Proton-Boron Capture Therapy (PBCT) is a novel approach aimed at enhancing proton biological effectiveness. PBCT exploits a nuclear fusion reaction between low-energy protons and 11B atoms, i.e. p+11B→ 3α (p-B), which is supposed to produce highly-DNA damaging α-particles exclusively across the tumor-conformed Spread-Out Bragg Peak (SOBP), without harming healthy tissues in the beam entrance channel. To confirm previous work on PBCT, here we report new in-vitro data obtained at the 62-MeV ocular melanoma-dedicated proton beamline of the INFN-Laboratori Nazionali del Sud (LNS), Catania, Italy. For the first time, we also tested PBCT at the 250-MeV proton beamline used for deep-seated cancers at the Centro Nazionale di Adroterapia Oncologica (CNAO), Pavia, Italy. We used Sodium Mercaptododecaborate (BSH) as 11B carrier, DU145 prostate cancer cells to assess cell killing and non-cancer epithelial breast MCF-10A cells for quantifying chromosome aberrations (CAs) by FISH painting and DNA repair pathway protein expression by western blotting. Cells were exposed at various depths along the two clinical SOBPs. Compared to exposure in the absence of boron, proton irradiation in the presence of BSH significantly reduced DU145 clonogenic survival and increased both frequency and complexity of CAs in MCF-10A cells at the mid- and distal SOBP positions, but not at the beam entrance. BSH-mediated enhancement of DNA damage response was also found at mid-SOBP. These results corroborate PBCT as a strategy to render protontherapy amenable towards radiotherapy-resilient tumor. If coupled with emerging proton FLASH radiotherapy modalities, PBCT could thus widen the protontherapy therapeutic index.

BIOPHYSICAL SIMULATION TOOL PARTRAC: MODELLING PROTON BEAMS AT THERAPY-RELEVANT ENERGIES

2019 ◽  
Vol 186 (2-3) ◽  
pp. 172-175 ◽  
Author(s):  
Werner Friedland ◽  
Pavel Kundrát ◽  
Janine Becker ◽  
Markus Eidemüller
Keyword(s):  
Dna Damage ◽  
Penetration Depth ◽  
Radiation Effects ◽  
Bragg Peak ◽  
High Energy ◽  
Simulation Tool ◽  
Radiation Physics ◽  
Proton Beams ◽  
Biological Effectiveness ◽  
Penetration Depths

ABSTRACT The biophysical simulation tool PARTRAC has been primarily developed to model radiation physics, chemistry and biology on nanometre to micrometre scales. However, the tool can be applied in simulating radiation effects in an event-by-event manner over macroscopic volumes as well. Benchmark simulations are reported showing that PARTRAC does reproduce the macroscopic Bragg peaks of proton beams, although the penetration depths are underestimated by a few per cent for high-energy beams. PARTRAC also quantifies the increase in DNA damage and its complexity along the beam penetration depth. Enhanced biological effectiveness is predicted in particular within distal Bragg peak parts of therapeutic proton beams.

scholarly journals Gastric inhibitory polypeptide and effects of glycation on glucose transport and metabolism in isolated mouse abdominal muscle

1998 ◽  
Vol 156 (2) ◽  
pp. 237-243 ◽  
Author(s):  
FP O'Harte ◽  
AM Gray ◽  
PR Flatt
Keyword(s):  
Glucose Uptake ◽  
Glucose Oxidation ◽  
Lactate Production ◽  
Fold Increase ◽  
Gastric Inhibitory Polypeptide ◽  
Abdominal Muscle ◽  
Reducing Conditions ◽  
Biological Effectiveness ◽  
First Time

This study investigates the effects of gastric inhibitory polypeptide (GIP) and glycated GIP (glucitol adduct of GIP) on glucose uptake and metabolism in muscle. Glycated GIP (molecular mass 5147.2 Da) was purified by HPLC following in vitro incubation under hyperglycaemic reducing conditions (24 h at pH 7.4). GIP (10(-10)-10(-8) mol/l) significantly stimulated (1.4- to 1.5-fold, P < 0.001) 2-deoxy-D-[1-3H]glucose uptake in abdominal muscle pieces from 3- to 5-week-old lean mice compared with control incubations (without GIP). This stimulatory effect on glucose uptake at 10(-10)-10(-9) mol/l was decreased by 13-20% following glycation of the peptide (P < 0.05). GIP (10(-9) and 10(-8) mol/l) induced a stepwise 1.4- to 1.7-fold increase (P < 0.01, P < 0.001 respectively) in [14C]glucose oxidation compared with controls. This effect on glucose oxidation was diminished by 32% with 10(-8) mol/l glycated GIP (P < 0.05). GIP (10(-9) and 10(-8) mol/l) induced a 1.4- to 1.8-fold increase in [14C]glucose incorporation into muscle glycogen (glycogenesis) compared with controls. Glycated GIP (10(-8) mol/l) exhibited a 41% decrease in glycogenic activity (P < 0.01). GIP (10(-10)-10(-8) mol/l) stimulated lactate production in isolated abdominal muscle (1.2- to 1.3-fold, P < 0.05); however glycated GIP did not exert a significant effect. This study demonstrates for the first time that GIP promotes glucose uptake, glucose oxidation and glycogenesis in muscle tissue. Furthermore, modification of GIP through glycation diminishes its biological effectiveness.

Calculation of the Depth Dependence of Relative Biological Effectiveness For Clinical Proton Beams

2019 ◽  
pp. 5-10
Author(s):  
А. Белоусов ◽  
A. Belousov ◽  
Р. Бахтиозин ◽  
R. Bahtiosin ◽  
М. Колыва­нова ◽  
...  
Keyword(s):  
Bragg Peak ◽  
Relative Biological Effectiveness ◽  
Complex Function ◽  
Absorbed Dose ◽  
High Energy ◽  
Clinical Value ◽  
Proton Beams ◽  
Depth Dependence ◽  
Biological Effectiveness ◽  
The Impact

Purpose: Accurate establishing the value of relative biological effectiveness (RBE) for high energy protons is one of the main challenges of modern radiotherapy. The purpose of the study is to calculate the depth dependence of RBE for proton beams forming a spread-out Bragg peak. Material and methods: Spatial distributions of absorbed dose and dose-average linear energy transfer (LET) for 50-100 MeV (0.5 MeV energy step) monochromatic proton beams were obtained by Monte-Carlo computer simulation using Geant4 software. A linear dependence of RBE on the dose-average LET was used. Absorbed dose distributions were obtained in a water phantom for monochromatic pencil proton beams of 2.5 mm radius. The absorbed dose and the dose-average LET values were calculated in voxels with dimensions of 2×2×0.2 mm. Results: Calculations of depth dependencies of absorbed dose and dose-average LET for 50–100 MeV monochromatic proton beams were performed. Depth dependencies of RBE for these beams were established. The weighing coefficients values allowing to generate uniformspread-out Bragg peak (SOBP) were determined. Depth distribution of “RBE-weighted” dose and RBE values for SOBP were found. Conclusion: The impact of the initial beam energy step on the degree of homogeneity of the modified Bragg curve was investigated. It was shown that a step up to 1.5 MeV is acceptable for generate a smooth Bragg curve. The depth dependence of the average RBE value is a complex function, which rapidly changes especially at the far end of the SOBP. RBE may vary up to 10-30 % compared to current clinical value. The linear model of RBE-LET dependence shown in the study can be easily used in dosimetric planning systems, that may will significantly improve the quality of proton radiotherapy.

scholarly journals A New Low-Energy Proton Irradiation Facility to Unveil the Mechanistic Basis of the Proton-Boron Capture Therapy Approach

2021 ◽  
Vol 11 (24) ◽  
pp. 11986
Author(s):  
Valerio Ricciardi ◽  
Pavel Bláha ◽  
Raffaele Buompane ◽  
Giuseppina Crescente ◽  
Giacomo Cuttone ◽  
...  
Keyword(s):  
Cross Section ◽  
Human Cancer ◽  
High Energy ◽  
Reaction Cross ◽  
Tandem Accelerator ◽  
Proton Beams ◽  
Human Cancer Cells ◽  
Energy Proton ◽  
Biological Effectiveness ◽  
Tissue Sparing

Protontherapy (PT) is a fast-growing cancer therapy modality thanks to much-improved normal tissue sparing granted by the charged particles’ inverted dose-depth profile. Protons, however, exhibit a low biological effectiveness at clinically relevant energies. To enhance PT efficacy and counteract cancer radioresistance, Proton–Boron Capture Therapy (PBCT) was recently proposed. PBCT exploits the highly DNA-damaging α-particles generated by the p + 11B→3α (pB) nuclear reaction, whose cross-section peaks for proton energies of 675 keV. Although a significant enhancement of proton biological effectiveness by PBCT has been demonstrated for high-energy proton beams, validation of the PBCT rationale using monochromatic proton beams having energy close to the reaction cross-section maximum is still lacking. To this end, we implemented a novel setup for radiobiology experiments at a 3-MV tandem accelerator; using a scattering chamber equipped with an Au foil scatterer for beam diffusion on the biological sample, uniformity in energy and fluence with uncertainties of 2% and 5%, respectively, was achieved. Human cancer cells were irradiated at this beamline for the first time with 685-keV protons. The measured enhancement in cancer cell killing due to the 11B carrier BSH was the highest among those thus far observed, thereby corroborating the mechanistic bases of PBCT.

scholarly journals Multiparametric radiobiological assays show that variation of X-ray energy strongly impacts relative biological effectiveness: comparison between 220 kV and 4 MV

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Vincent Paget ◽  
Mariam Ben Kacem ◽  
Morgane Dos Santos ◽  
Mohamed A. Benadjaoud ◽  
Frédéric Soysouvanh ◽  
...  
Keyword(s):  
Relative Biological Effectiveness ◽  
Clonogenic Assay ◽  
Umbilical Vein ◽  
High Energy ◽  
X Rays ◽  
X Ray ◽  
Biological Effectiveness ◽  
Umbilical Vein Endothelial Cells ◽  
Interventional Medicine

Abstract Based on classic clonogenic assay, it is accepted by the scientific community that, whatever the energy, the relative biological effectiveness of X-rays is equal to 1. However, although X-ray beams are widely used in diagnosis, interventional medicine and radiotherapy, comparisons of their energies are scarce. We therefore assessed in vitro the effects of low- and high-energy X-rays using Human umbilical vein endothelial cells (HUVECs) by performing clonogenic assay, measuring viability/mortality, counting γ-H2AX foci, studying cell proliferation and cellular senescence by flow cytometry and by performing gene analysis on custom arrays. Taken together, excepted for γ-H2AX foci counts, these experiments systematically show more adverse effects of high energy X-rays, while the relative biological effectiveness of photons is around 1, whatever the quality of the X-ray beam. These results strongly suggest that multiparametric analysis should be considered in support of clonogenic assay.

scholarly journals Topical Nanoemulgel for the Treatment of Skin Cancer: Proof-of-Technology

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 902
Author(s):  
Sreeharsha Nagaraja ◽  
Girish Meravanige Basavarajappa ◽  
Mahesh Attimarad ◽  
Swati Pund
Keyword(s):  
Skin Cancer ◽  
Ex Vivo ◽  
L929 Cell ◽  
Therapeutic Index ◽  
In Vitro Cytotoxicity ◽  
Apparent Permeability ◽  
Efficient Treatment ◽  
Formidable Challenge ◽  
Novel Approach

The present study is a mechanistic validation of ‘proof-of-technology’ for the effective topical delivery of chrysin nanoemulgel for localized, efficient treatment of melanoma-affected skin. Background: Currently available treatments for skin cancer are inefficient due to systemic side effects and poor transcutaneous permeation, thereby presenting a formidable challenge for the development of novel nanocarriers. Methods: We opted for a novel approach and formulated a nanocomplex system composed of hydrophobic chrysin dissolved in a lipid mix, which was further nanoemulsified in Pluronic® F-127 gel to enhance physicochemical and biopharmaceutic characteristics. Chrysin, a flavone extracted from passion flowers, exhibits potential anti-cancer activities; however, it has limited applicability due to its poor solubility. Pseudo-ternary phase diagrams were constructed to identify the best self-nanoemulsifying region by varying the compositions of oil, Caproyl® 90 surfactant, Tween® 80, and co-solvent Transcutol® HP. Chrysin-loaded nanoemulsifying compositions were characterized for various physicochemical properties. Results: This thermodynamically stable, self-emulsifying drug delivery system showed a mean droplet size of 156.9 nm, polydispersity index of 0.26, and viscosity of 9100 cps after dispersion in gel. Mechanical characterization using Texture Analyzer exhibited that the gel had a hardness of 487 g and adhesiveness of 500 g. Ex vivo permeation through rat abdominal skin revealed significant improvement in percutaneous absorption measured as flux, the apparent permeability coefficient, the steady-state diffusion coefficient, and drug deposition. In vitro cytotoxicity on A375 and SK-MEL-2 cell lines showed a significantly improved therapeutic effect, thus ensuring reduction in dose. The safety of the product was established through biocompatibility testing on the L929 cell line. Conclusion: Aqueous, gel-based, topical, nanoemulsified chrysin is a promising technology approach for effective localized transcutaneous delivery that will help reduce the frequency and overall dose usage and ultimately improve the therapeutic index.

Microdosimetric characterization of a clinical proton therapy beam: comparison between simulated lineal energy distributions in spherical water targets and experimental measurements with a silicon detector

2021 ◽  
Author(s):  
Alessio Parisi ◽  
Pawel Olko ◽  
Jan Swakon ◽  
Tomasz Horwacik ◽  
Hubert Jablonski ◽  
...  
Keyword(s):  
Weighting Function ◽  
Silicon Detector ◽  
Clonogenic Survival ◽  
Silicon Detectors ◽  
Energy Distributions ◽  
Mean Values ◽  
Lineal Energy ◽  
Distal Edge ◽  
Biological Effectiveness

Abstract Objective Treatment planning based on computer simulations were proposed to account for the increase in the relative biological effectiveness (RBE) of proton radiotherapy beams near to the edges of the irradiated volume. Since silicon detectors could be used to validate the results of these simulations, it is important to explore the limitations of this comparison. Approach Microdosimetric measurements with a MicroPlus Bridge V2 silicon detector (thickness = 10 µm) were performed along the Bragg peak of a clinical proton beam. The lineal energy distributions, the dose mean values, and the RBE calculated with a biological weighting function were compared with simulations with PHITS (microdosimetric target = 1 µm water sphere), and published clonogenic survival in vitro RBE data for the V79 cell line. The effect of the silicon-to-water conversion was also investigated by comparing three different methodologies (conversion based on a single value, novel bin-to-bin conversions based on SRIM and PSTAR). Main results Mainly due to differences in the microdosimetric targets, the experimental dose-mean lineal energy and RBE values at the distal edge were respectively up to 53% and 28% lower than the simulated ones. Furthermore, the methodology chosen for the silicon-to-water conversion was proven to affect the dose mean lineal energy and the RBE10 up to 32% and 11% respectively. The best methodology to compensate for this underestimation was the bin-to-bin silicon-to-water conversion based on PSTAR. Significance This work represents the first comparison between PHITS-simulated lineal energy distributions in water targets and corresponding experimental spectra measured with silicon detectors. Furthermore, the effect of the silicon-to-water conversion on the RBE was explored for the first time. The proposed methodology based on the PSTAR bin-to-bin conversion appears to provide superior results with respect to commonly used single scaling factors and is recommended for future studies.

Anti-Hepatitis B Virus Effects of Dehydrocheilanthifoline fromCorydalis saxicola

2013 ◽  
Vol 41 (01) ◽  
pp. 119-130 ◽  
Author(s):  
Fan-Li Zeng ◽  
Yang-Fei Xiang ◽  
Zhen-Ran Liang ◽  
Xiao Wang ◽  
Dan-e Huang ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Therapeutic Index ◽  
Extracellular Dna ◽  
Dependent Manner ◽  
Promising Candidate ◽  
B Virus ◽  
First Time ◽  
Dose Dependent

In this report, the anti-hepatitis B virus (HBV) activity of dehydrocheilanthifoline (DHCH), a quaternary ammonium alkaloid isolated from the traditional Chinese medicine Corydalis saxicola Bunting (Papaveraceae), was determined in vitro. Following six days of treatment, DHCH efficiently suppressed the secretions of HBsAg and HBeAg in HepG2.2.15 cell cultures, with a half-maximal inhibitory concentration (IC50) of 15.84 and 17.12 μM, and with a therapeutic index (TI) of 7.32 and 6.77, respectively. Further studies revealed that DHCH reduced the levels of extracellular DNA, intracellular DNA and covalently closed circular DNA (cccDNA) of HBV in a dose-dependent and time-dependent manner, with IC50values of 15.08, 7.62 and 8.25 μM, respectively after six days of treatment. In contrast, the level of viral pre-genomic RNA (pgRNA) increased 6.13-fold after treatment with DHCH. Together, it was demonstrated for the first time that DHCH could significantly inhibit the replication of HBV, which warrants further studies on the antiviral mechanisms of DHCH, and suggests that it may be a promising candidate in the therapy of HBV infection.

scholarly journals Enantiomers of Chloroquine and Hydroxychloroquine Exhibit Different Activities Against SARS-CoV-2 in vitro, Evidencing S-Hydroxychloroquine as a Potentially Superior Drug for COVID-19

2020 ◽  
Author(s):  
Guanguan Li ◽  
Jing Sun ◽  
Yi-You Huang ◽  
Yingjun Li ◽  
Yongjie Shi ◽  
...  
Keyword(s):  
Therapeutic Index ◽  
Racemic Mixture ◽  
Significant Finding ◽  
Pronounced Difference ◽  
Toxicity Potential ◽  
Pharmacokinetic Properties ◽  
Level 3 ◽  
First Time ◽  
Transcription And Replication

ABSTRACTIn all of the clinical trials for COVID-19 conducted thus far and among those ongoing involving chloroquine or hydroxychloroquine, the drug substance used has invariably been chloroquine (CQ) diphosphate or hydroxychloroquine (HCQ) sulfate, i.e., the phosphoric or sulfuric acid salt of a racemic mixture of R- and S-enantiomer (50/50), respectively. As a result, the clinical outcome from previous CQ or HCQ trials were, in fact, the collective manifestation of both R and S- enantiomers with inherent different pharmacodynamic and pharmacokinetic properties, and toxicity liabilities. Our data for the first time demonstrated the stereoselective difference of CQ and HCQ against live SARS-CoV-2 virus in a Biosafety Level 3 laboratory. S-chloroquine (S-CQ) and S-hydroxychloroquine (S-HCQ) significantly more active against SARS-CoV-2, as compared to R-CQ and R-HCQ, respectively. In addition, Mpro, as one of the critical enzymes for viral transcription and replication, also exhibited an enantioselective binding affinity toward the S-enantiomers. The most significant finding from this study is the pronounced difference of the two enantiomers of CQ and HCQ observed in hERG inhibition assay. The IC50 value of S-HCQ was higher than 20 μM against hERG channel, which was much less active over all tested CQ and HCQ compounds. Moreover, S-HCQ alone did not prolong QT interval in guinea pigs after 3 days and 6 days of administration, indicating a much lower cardiac toxicity potential. With these and previous findings on the enantio-differentiated metabolism, we recommend that future clinical studies should employ S-HCQ, substantially free of the R-enantiomer, to potentially improve the therapeutic index for the treatment of COVID-19 over the racemic CQ and HCQ.

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