Overcoming Multidrug Resistance via Photodestruction of ABCG2-Rich Extracellular Vesicles Sequestering Photosensitive Chemotherapeutics

Multidrug resistance (MDR) remains a dominant impediment to curative cancer chemotherapy. Efflux transporters of the ATP-binding cassette (ABC) superfamily including ABCG2, ABCB1 and ABCC1 mediate MDR to multiple structurally and functionally distinct antitumor agents. Recently we identified a novel mechanism of MDR in which ABCG2-rich extracellular vesicles (EVs) form in between attached neighbor breast cancer cells and highly concentrate various chemotherapeutics in an ABCG2-dependent manner, thereby sequestering them away from their intracellular targets. Hence, development of novel strategies to overcome MDR modalities is a major goal of cancer research. Towards this end, we here developed a novel approach to selectively target and kill MDR cancer cells. We show that illumination of EVs that accumulated photosensitive cytotoxic drugs including imidazoacridinones (IAs) and topotecan resulted in intravesicular formation of reactive oxygen species (ROS) and severe damage to the EVs membrane that is shared by EVs-forming cells, thereby leading to tumor cell lysis and the overcoming of MDR. Furthermore, consistent with the weak base nature of IAs, MDR cells that are devoid of EVs but contained an increased number of lysosomes, highly accumulated IAs in lysosomes and upon photosensitization were efficiently killed via ROS-dependent lysosomal rupture. Combining targeted lysis of IAs-loaded EVs and lysosomes elicited a synergistic cytotoxic effect resulting in MDR reversal. In contrast, topotecan, a bona fide transport substrate of ABCG2, accumulated exclusively in EVs of MDR cells but was neither detected in lysosomes of normal breast epithelial cells nor in non-MDR breast cancer cells. This exclusive accumulation in EVs enhanced the selectivity of the cytotoxic effect exerted by photodynamic therapy to MDR cells without harming normal cells. Moreover, lysosomal alkalinization with bafilomycin A1 abrogated lysosomal accumulation of IAs, consequently preventing lysosomal photodestruction of normal breast epithelial cells. Thus, MDR modalities including ABCG2-dependent drug sequestration within EVs can be rationally converted to a pharmacologically lethal Trojan horse to selectively eradicate MDR cancer cells

Demonstration of the event identification capabilities of the NEXT-White detector

In experiments searching for neutrinoless double-beta decay, the possibility of identifying the two emitted electrons is a powerful tool in rejecting background events and therefore improving the overall sensitivity of the experiment. In this paper we present the first measurement of the efficiency of a cut based on the different event signatures of double and single electron tracks, using the data of the NEXT-White detector, the first detector of the NEXT experiment operating underground. Using a 228Th calibration source to produce signal-like and background-like events with energies near 1.6 MeV, a signal efficiency of 71.6 ± 1.5 stat± 0.3 sys% for a background acceptance of 20.6 ± 0.4 stat± 0.3 sys% is found, in good agreement with Monte Carlo simulations. An extrapolation to the energy region of the neutrinoless double beta decay by means of Monte Carlo simulations is also carried out, and the results obtained show an improvement in background rejection over those obtained at lower energies. [Figure not available: see fulltext.

Radiogenic backgrounds in the NEXT double beta decay experiment

Natural radioactivity represents one of the main backgrounds in the search for neutrinoless double beta decay. Within the NEXT physics program, the radioactivity- induced backgrounds are measured with the NEXT-White detector. Data from 37.9 days of low-background operations at the Laboratorio Subterráneo de Canfranc with xenon depleted in 136Xe are analyzed to derive a total background rate of (0.84±0.02) mHz above 1000 keV. The comparison of data samples with and without the use of the radon abatement system demonstrates that the contribution of airborne-Rn is negligible. A radiogenic background model is built upon the extensive radiopurity screening campaign conducted by the NEXT collaboration. A spectral fit to this model yields the specific contributions of 60Co, 40K, 214Bi and 208Tl to the total background rate, as well as their location in the detector volumes. The results are used to evaluate the impact of the radiogenic backgrounds in the double beta decay analyses, after the application of topological cuts that reduce the total rate to (0.25±0.01) mHz. Based on the best-fit background model, the NEXT-White median sensitivity to the two-neutrino double beta decay is found to be 3.5σ after 1 year of data taking. The background measurement in a Qββ±100 keV energy window validates the best-fit background model also for the neutrinoless double beta decay search with NEXT-100. Only one event is found, while the model expectation is (0.75±0.12) events. [Figure not available: see fulltext.]

Energy calibration of the NEXT-White detector with 1% resolution near Q ββ of 136Xe

Excellent energy resolution is one of the primary advantages of electroluminescent high-pressure xenon TPCs. These detectors are promising tools in searching for rare physics events, such as neutrinoless double-beta decay (ββ0ν), which require precise energy measurements. Using the NEXT-White detector, developed by the NEXT (Neutrino Experiment with a Xenon TPC) collaboration, we show for the first time that an energy resolution of 1% FWHM can be achieved at 2.6 MeV, establishing the present technology as the one with the best energy resolution of all xenon detectors for ββ0ν searches. [Figure not available: see fulltext.

Sensitivity of a tonne-scale NEXT detector for neutrinoless double beta decay searches

The Neutrino Experiment with a Xenon TPC (NEXT) searches for the neutrinoless double-beta decay of Xe-136 using high-pressure xenon gas TPCs with electroluminescent amplification. A scaled-up version of this technology with about 1 tonne of enriched xenon could reach in less than 5 years of operation a sensitivity to the half-life of neutrinoless double-beta decay decay better than 1E27 years, improving the current limits by at least one order of magnitude. This prediction is based on a well-understood background model dominated by radiogenic sources. The detector concept presented here represents a first step on a compelling path towards sensitivity to the parameter space defined by the inverted ordering of neutrino masses, and beyond.Comment: 22 pages, 11 figure

Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors

Multidrug resistance is often associated with the (over)expression of drug efflux transporters of the ATP-binding cassette (ABC) protein family. This minireview discusses the role of one selected ABC-transporter family member, the breast cancer resistance protein (BCRP/ABCG2), in the (pre)clinical efficacy of novel experimental anticancer drugs, in particular tyrosine kinase inhibitors

Demonstration of the event identification capabilities of the NEXT-White detector

[EN] In experiments searching for neutrinoless double-beta decay, the possibility of identifying the two emitted electrons is a powerful tool in rejecting background events and therefore improving the overall sensitivity of the experiment. In this paper we present the first measurement of the efficiency of a cut based on the different event signatures of double and single electron tracks, using the data of the NEXT-White detector, the first detector of the NEXT experiment operating underground. Using a 228Th calibration source to produce signal-like and background-like events with energies near 1.6 MeV, a signal efficiency of 71.6 ± 1.5 stat ± 0.3 sys% for a background acceptance of 20.6 ± 0.4 stat ± 0.3 sys% is found, in good agreement with Monte Carlo simulations. An extrapolation to the energy region of the neutrinoless double beta decay by means of Monte Carlo simulations is also carried out, and the results obtained show an improvement in background rejection over those obtained at lower energies.The NEXT Collaboration acknowledges support from the following agencies and institutions: the European Research Council (ERC) under the Advanced Grant 339787NEXT; the European Union's Framework Programme for Research and Innovation Horizon 2020 (2014-2020) under the Marie Sklodowska-Curie Grant Agreements No. 674896, 690575 and 740055; the Ministerio de Economia y Competitividad and the Ministerio de Ciencia, Innovacion y Universidades of Spain under grants FIS2014-53371-C04, RTI2018-095979, the Severo Ochoa Program SEV-2014-0398 and the Maria de Maetzu Program MDM-2016-0692; the GVA of Spain under grants PROMETEO/2016/120 and SEJI/2017/011; the Portuguese FCT under project PTDC/FIS-NUC/2525/2014, under project UID/FIS/04559/2013 to fund the activities of LIBPhys, and under grants PD/BD/FBD/105921/2014, SFRH/BPD/109180/2015 and SFRH/BPD/76842/2011; the U.S. Department of Energy under contracts number DE-AC02-06CH11357 (Argonne National Laboratory), DE-AC02-07CH11359 (Fermi National Accelerator Laboratory), DE-FG02-13ER42020 (Texas A&M) and DE-SC0019223/DE-SC0019054 (University of Texas at Arlington); and the University of Texas at Arlington. DGD acknowledges Ramon y Cajal program (Spain) under contract number RYC-2015-18820. We also warmly acknowledge the Laboratori Nazionali del Gran Sasso (LNGS) and the Dark Side collaboration for their help with TPB coating of various parts of the NEXT-White TPC. Finally, we are grateful to the Laboratorio Subterraneo de Canfranc for hosting and supporting the NEXT experiment.Ferrario, P.; Benlloch-Rodríguez, J.; Díaz López, G.; Hernando Morata, J.; Kekic, M.; Renner, J.; Usón, A.... (2019). Demonstration of the event identification capabilities of the NEXT-White detector. Journal of High Energy Physics (Online). (10):1-17. https://doi.org/10.1007/JHEP10(2019)052S11710M. Fukugita and T. Yanagida, Baryogenesis without grand unification, Phys. Lett.B 174 (1986) 45 [ INSPIRE ].EXO-200 collaboration, Improved measurement of the 2νββ half-life of136Xe with the EXO-200 detector, Phys. Rev.C 89 (2014) 015502 [ arXiv:1306.6106 ] [ INSPIRE ].XENON collaboration, Dark matter search results from a one ton-year exposure of XENON1T, Phys. Rev. Lett.121 (2018) 111302 [ arXiv:1805.12562 ] [ INSPIRE ].Caltech-Neuchâtel-PSI collaboration, Search for ββ decay in136Xe: new results from the Gotthard experiment, Phys. Lett.B 434 (1998) 407 [ INSPIRE ].NEXT collaboration, First proof of topological signature in the high pressure xenon gas TPC with electroluminescence amplification for the NEXT experiment, JHEP01 (2016) 104 [ arXiv:1507.05902 ] [ INSPIRE ].NEXT collaboration, The Next White (NEW) detector, 2018 JINST13 P12010 [ arXiv:1804.02409 ] [ INSPIRE ].M. Redshaw, E. Wingfield, J. McDaniel and E.G. Myers, Mass and double-beta-decay Q value of136Xe, Phys. Rev. Lett.98 (2007) 053003 [ INSPIRE ].NEXT collaboration, Initial results on energy resolution of the NEXT-White detector, 2018 JINST13 P10020 [ arXiv:1808.01804 ] [ INSPIRE ].NEXT collaboration, Energy calibration of the NEXT-White detector with 1% resolution near Qββ of136Xe, arXiv:1905.13110 [ INSPIRE ].NEXT collaboration, Electron drift properties in high pressure gaseous xenon, 2018 JINST13 P07013 [ arXiv:1804.01680 ] [ INSPIRE ].T.H. Cormen, C. Stein, R.L. Rivest and C.E. Leiserson, Introduction to algorithms, 2nd ed., McGraw-Hill Higher Education, U.S.A. (2001).NEXT collaboration, Calibration of the NEXT-White detector using83mKr decays, 2018 JINST13 P10014 [ arXiv:1804.01780 ] [ INSPIRE ].J. Martín-Albo, The NEXT experiment for neutrinoless double beta decay searches, Ph.D. thesis, Valencia U., IFIC, Valencia, Spain (2015).GEANT4 collaboration, GEANT4: a simulation toolkit, Nucl. Instrum. Meth.A 506 (2003) 250 [ INSPIRE ].J.J. Gomez-Cadenas et al., Sense and sensitivity of double beta decay experiments, JCAP06 (2011) 007 [ arXiv:1010.5112 ] [ INSPIRE ].NEXT collaboration, Radiogenic backgrounds in the NEXT double beta decay experiment, arXiv:1905.13625 [ INSPIRE ].NEXT collaboration, Background rejection in NEXT using deep neural networks, 2017 JINST12 T01004 [ arXiv:1609.06202 ] [ INSPIRE ].NEXT collaboration, Application and performance of an ML-EM algorithm in NEXT, 2017 JINST12 P08009 [ arXiv:1705.10270 ] [ INSPIRE ].NEXT collaboration, Secondary scintillation yield of xenon with sub-percent levels of CO2 additive for rare-event detection, Phys. Lett.B 773 (2017) 663 [ arXiv:1704.01623 ] [ INSPIRE ].NEXT collaboration, Electroluminescence TPCs at the thermal diffusion limit, JHEP01 (2019) 027 [ arXiv:1806.05891 ] [ INSPIRE ].R. Felkai et al., Helium-xenon mixtures to improve the topological signature in high pressure gas xenon TPCs, Nucl. Instrum. Meth.A 905 (2018) 82 [ arXiv:1710.05600 ] [ INSPIRE ].NEXT collaboration, Electron drift and longitudinal diffusion in high pressure xenon-helium gas mixtures, 2019 JINST14 P08009 [ arXiv:1902.05544 ] [ INSPIRE ].NEXT collaboration, Sensitivity of NEXT-100 to neutrinoless double beta decay, JHEP05 (2016) 159 [ arXiv:1511.09246 ] [ INSPIRE ].J. Muñoz Vidal, The NEXT path to neutrino inverse hierarchy, Ph.D. thesis, Valencia U., IFIC, Valencia, Spain (2018)

Dependence of polytetrafluoroethylene reflectance on thickness at visible and ultraviolet wavelengths in air

Polytetrafluoroethylene (PTFE) is an excellent diffuse reflector widely used in light collection systems for particle physics experiments. However, the reflectance of PTFE is a function of its thickness. In this work, we investigate this dependence in air for light of wavelengths 260 nm and 450 nm using two complementary methods. We find that PTFE reflectance for thicknesses from 5 mm to 10 mm ranges from 92.5% to 94.5% at 450 nm, and from 90.0% to 92.0% at 260 nm. We also see that the reflectance of PTFE of a given thickness can vary by as much as 2.7% within the same piece of material. Finally, we show that placing a specular reflector behind the PTFE can recover the loss of reflectance in the visible without introducing a specular component in the reflectance