Microdosimetría de la radioterapia con protones usando nano-partículas de oro como agentes sensibilizadores

ilustraciones, gráficas, tablas

Autores:
Sevilla Moreno, Andrés Camilo
Tipo de recurso:
Fecha de publicación:
2022
Institución:
Universidad Nacional de Colombia
Repositorio:
Universidad Nacional de Colombia
Idioma:
spa
OAI Identifier:
oai:repositorio.unal.edu.co:unal/81476
Acceso en línea:
https://repositorio.unal.edu.co/handle/unal/81476
https://repositorio.unal.edu.co/
Palabra clave:
530 - Física::535 - Luz y radiación relacionada
Radiation - dosage
Radiotherapy
Nanoparticles
Dosimetría (Radiación)
Radioterapia
Nanopartículas
Radioterapia
Protonterapia
Nano-partículas
Simulación computacional
Geant4-DNA
Radiotherapy
Protontherapy
Nano-particles
Computational simulation
Geant4-DNA
Rights
openAccess
License
Atribución-NoComercial-SinDerivadas 4.0 Internacional
id UNACIONAL2_d2f6a687111c5442c5cc398901fb2fc7
oai_identifier_str oai:repositorio.unal.edu.co:unal/81476
network_acronym_str UNACIONAL2
network_name_str Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv Microdosimetría de la radioterapia con protones usando nano-partículas de oro como agentes sensibilizadores
dc.title.translated.eng.fl_str_mv Microdosimetry of proton radiotherapy using gold nanoparticles as sensitizing agents
title Microdosimetría de la radioterapia con protones usando nano-partículas de oro como agentes sensibilizadores
spellingShingle Microdosimetría de la radioterapia con protones usando nano-partículas de oro como agentes sensibilizadores
530 - Física::535 - Luz y radiación relacionada
Radiation - dosage
Radiotherapy
Nanoparticles
Dosimetría (Radiación)
Radioterapia
Nanopartículas
Radioterapia
Protonterapia
Nano-partículas
Simulación computacional
Geant4-DNA
Radiotherapy
Protontherapy
Nano-particles
Computational simulation
Geant4-DNA
title_short Microdosimetría de la radioterapia con protones usando nano-partículas de oro como agentes sensibilizadores
title_full Microdosimetría de la radioterapia con protones usando nano-partículas de oro como agentes sensibilizadores
title_fullStr Microdosimetría de la radioterapia con protones usando nano-partículas de oro como agentes sensibilizadores
title_full_unstemmed Microdosimetría de la radioterapia con protones usando nano-partículas de oro como agentes sensibilizadores
title_sort Microdosimetría de la radioterapia con protones usando nano-partículas de oro como agentes sensibilizadores
dc.creator.fl_str_mv Sevilla Moreno, Andrés Camilo
dc.contributor.advisor.spa.fl_str_mv Castro Serrato, Héctor Fabio
dc.contributor.author.spa.fl_str_mv Sevilla Moreno, Andrés Camilo
dc.contributor.researchgroup.spa.fl_str_mv Fisica de Bajas Temperaturas y Magnetismo Cryomag
dc.subject.ddc.spa.fl_str_mv 530 - Física::535 - Luz y radiación relacionada
topic 530 - Física::535 - Luz y radiación relacionada
Radiation - dosage
Radiotherapy
Nanoparticles
Dosimetría (Radiación)
Radioterapia
Nanopartículas
Radioterapia
Protonterapia
Nano-partículas
Simulación computacional
Geant4-DNA
Radiotherapy
Protontherapy
Nano-particles
Computational simulation
Geant4-DNA
dc.subject.lemb.eng.fl_str_mv Radiation - dosage
Radiotherapy
Nanoparticles
dc.subject.lemb.spa.fl_str_mv Dosimetría (Radiación)
Radioterapia
Nanopartículas
dc.subject.proposal.spa.fl_str_mv Radioterapia
Protonterapia
Nano-partículas
Simulación computacional
Geant4-DNA
dc.subject.proposal.eng.fl_str_mv Radiotherapy
Protontherapy
Nano-particles
Computational simulation
Geant4-DNA
description ilustraciones, gráficas, tablas
publishDate 2022
dc.date.accessioned.none.fl_str_mv 2022-06-01T18:47:52Z
dc.date.available.none.fl_str_mv 2022-06-01T18:47:52Z
dc.date.issued.none.fl_str_mv 2022
dc.type.spa.fl_str_mv Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv Text
dc.type.redcol.spa.fl_str_mv http://purl.org/redcol/resource_type/TM
status_str acceptedVersion
dc.identifier.uri.none.fl_str_mv https://repositorio.unal.edu.co/handle/unal/81476
dc.identifier.instname.spa.fl_str_mv Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv https://repositorio.unal.edu.co/
url https://repositorio.unal.edu.co/handle/unal/81476
https://repositorio.unal.edu.co/
identifier_str_mv Universidad Nacional de Colombia
Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv spa
language spa
dc.relation.indexed.spa.fl_str_mv Bireme
dc.relation.references.spa.fl_str_mv Relative Biological Effectiveness in Ion Beam Therapy. Number 461 in Technical Reports Series. INTERNATIONAL ATOMIC ENERGY AGENCY, Vienna, 2008.
Pedro Andreo, David T. Burns, Alan E. Nahum, Jan Seuntjens, and Frank Herbert Attix. Fundamentals of ionizing radiation dosimetry - Pedro Andreo.
Chafika Belamri, Anis Samy Amine Dib, and Ahmed H. Belbachir. Monte Carlo simulation of proton therapy using bio-nanomaterials. Journal of Radiotherapy in Practice, 15(3):290–295, 2016.
M.J. Berger, J.S. Coursey, M.A. Zucker, and J. Chang. Stopping-Power Range Tables for Electrons, Protons, and Helium Ions. NIST Standard Reference Database 124, 2017.
John C Blasko, Peter D Grimm, John E Sylsvester, and William Cavanagh. The role of external beam radiotherapy with I-125/Pd-103 brachytherapy for prostate carcinoma. Radiotherapy and Oncology, 57(3):273–278, dec 2000.
Göran Borghede, Hans Hedelin, Sten Holmäng, Karl Axel Johansson, Frank Aldenborg, Silas Pettersson, Göran Sernbo, Arne Wallgren, and Claes Mercke. Combined treatment with temporary short-term high dose rate Iridium-192 brachytherapy and external beam radiotherapy for irradiation of localized prostatic carcinoma. Radiotherapy and Oncology, 44(3):237–244, sep 1997.
Mark J. Carvlin. An Introduction to Radiobiology, 1991.
Sang Hyun Cho. Estimation of tumor dose enhancement due to gold nanoparticles during typical radiation treatments: A preliminary Monte Carlo study. Physics in Medicine and Biology, 50(15), 2005.
Leo Y.T. Chou and Warren C.W. Chan. Fluorescence-Tagged Gold Nanoparticles for Rapidly Characterizing the Size-Dependent Biodistribution in Tumor Models. Advanced Healthcare Materials, 1(6):714–721, 2012.
Michael Chuong, Shahed N. Badiyan, Man Yam, Zuofeng Li, Katja Langen, William Regine, Christopher Morris, James Snider, Minesh Mehta, Soon Huh, Michael Rutenberg, and Romaine C. Nichols. Pencil beam scanning versus passively scattered proton therapy for unresectable pancreatic cancer. Journal of Gastrointestinal Oncology, 9(4):687–693, 2018.
Michael Dattoli, Kent Wallner, Richard Sorace, John Koval, Jennifer Cash, Rudolph Acosta, Charles Brown, James Etheridge, Michael Binder, Richard Brunelle, Novelle Kirwan, Servando Sanchez, Douglas Stein, and Stuart Wasserman. 103Pd brachytherapy and external beam irradiation for clinically localized, high-risk prostatic carcinoma. International Journal of Radiation Oncology*Biology*Physics, 35(5):875–879, jul 1996.
Rémi Dendale, Livia Lumbroso-Le Rouic, Georges Noel, Loïc Feuvret, Christine Levy, Sabine Delacroix, Anne Meyer, Catherine Nauraye, Alejandro Mazal, Hamid Mammar, Paul Garcia, François D’Hermies, Eric Frau, Corine Plancher, Bernard Asselain, Pierre Schlienger, Jean Jacques Mazeron, and Laurence Desjardins. Proton beam radiotherapy for uveal melanoma: Results of Curie Institut–Orsay Proton Therapy Center (ICPO). International Journal of Radiation Oncology*Biology*Physics, 65(3):780–787, jul 2006.
Michael Dickson and Jean Paul Gagnon. Key factors in the rising cost of new drug discovery and development. Nature Reviews Drug Discovery, 3(5):417–429, 2004.
Richard P. Feynman. There’s Plenty of Room at the Bottom. In Engineering Science, pages 22–36. 1960.
Jonas Fontenot, Phillip Taddei, Yuanshui Zheng, Dragan Mirkovic, Thomas Jordan, and Wayne Newhauser. Equivalent dose and effective dose from stray radiation during passively scattered proton radiotherapy for prostate cancer. Physics in Medicine and Biology, 53(6):1677–1688, 2008
Evangelos S. Gragoudas. Proton Beam Irradiation of Uveal Melanomas. Archives of Ophthalmology, 100(6):928, jun 1982.
James F. Hainfeld, F. Avraham Dilmanian, Zhong Zhong, Daniel N. Slatkin, John A. Kalef-Ezra, and Henry M. Smilowitz. Gold nanoparticles enhance the radiation therapy of a murine squamous cell carcinoma. Physics in Medicine and Biology, 55(11):3045–3059, jun 2010.
Hooshang Nikjoo, Shuzo Uehara, and Dimitris Emfietzoglou. Interaction of Radiation with Matter. 2012.
R N Kjellberg, W H Sweet, W M Preston, and A M Koehler. The bragg peak of a proton beam in intracranial therapy of tumors. Transactions of the American Neurological Association (U.S.).
R.N. Kjellberg, A.M. Koehler, W.M. Preston, and W.H. Sweet. Stereotaxic Instrument for Use with the Bragg Peak of a Proton Beam. Stereotactic and Functional Neurosurgery, 22(3-5):183–189, 1962.
Gennadii I. Klenov and Vladimir S. Khoroshkov. Hadron therapy: history, status, prospects. Physics-Uspekhi, 59(8):807–825, aug 2016.
A. M. Koehler, R. J. Schneider, and J. M. Sisterson. Flattening of proton dose distributions for large field radiotherapy. Medical Physics, 4(4):297–301, 1977.
Sophie Laurent, Delphine Forge, Marc Port, Alain Roch, Caroline Robic, Luce Vander Elst, and Robert N. Muller. Magnetic Iron Oxide Nanoparticles: Synthesis, Stabilization, Vectorization, Physicochemical Characterizations, and Biological Applications. Chemical Reviews, 108(6):2064– 2110, jun 2008.
William R. Leo and David G. Haase. Techniques for Nuclear and Particle Physics Experiments , volume 58. 1990.
Michael K.K. Leung, James C.L. Chow, B. Devika Chithrani, Martin J.G. Lee, Barbara Oms, and David A. Jaffray. Irradiation of gold nanoparticles by x-rays: Monte Carlo simulation of dose enhancements and the spatial properties of the secondary electrons production. Medical Physics, 38(2):624–631, 2011.
M. P. Little. Risks associated with ionizing radiation. British Medical Bulletin, 68:259–275, 2003
A. J. Lomax, T. Boehringer, A. Coray, E. Egger, G. Goitein, M. Grossmann, P. Juelke, S. Lin, E. Pedroni, B. Rohrer, W. Roser, B. Rossi, B. Siegenthaler, O. Stadelmann, H. Stauble, C. Vetter, and L. Wisser. Intensity modulated proton therapy: A clinical example. Medical Physics, 28(3):317– 324, 2001.
Anthony John Lomax, Michael Goitein, and Judy Adams. Intensity modulation in radiotherapy: Photons versus protons in the paranasal sinus. Radiotherapy and Oncology, 66(1):11–18, 2003.
Antony J. Lomax, Laura Cella, Damien Weber, John M. Kurtz, and Raymond Miralbell. Potential role of intensity-modulated photons and protons in the treatment of the breast and regional nodes. International Journal of Radiation Oncology*Biology*Physics, 55(3):785–792, mar 2003.
B. Ludewigt, J. Siebers, D. Lesyna, D. Miller, J. Nusbaum, J. Slater, J. Johanning, and J. Miranda. A prototype beam delivery system for the proton medical accelerator at Loma Linda. Medical Physics, 18(6):1093–1099, 1991.
D. M. Herold, I. J. Das, C. C. Stobbe,. Gold microspheres: a selective technique for producing biologically effective dose enhancement. International Journal of Radiation Biology, 76(10):1357– 1364, jan 2000.
Shannon M. MacDonald, Sairos Safai, Alexei Trofimov, John Wolfgang, Barbara Fullerton, Beow Y. Yeap, Thomas Bortfeld, Nancy J. Tarbell, and Torunn Yock. Proton Radiotherapy for Childhood Ependymoma: Initial Clinical Outcomes and Dose Comparisons. International Journal of Radiation Oncology*Biology*Physics, 71(4):979–986, jul 2008.
I. Martínez-Rovira and Y. Prezado. Evaluation of the local dose enhancement in the combination of proton therapy and nanoparticles. Medical Physics, 42(11):6703–6710, 2015.
Priyabrata Mukherjee, Resham Bhattacharya, Ping Wang, Ling Wang, Sujit Basu, Janice A. Nagy, Anthony Atala, Debabrata Mukhopadhyay, and Shay Soker. Antiangiogenic properties of gold nanoparticles. Clinical Cancer Research, 11(9):3530–3534, 2005.
Harald Paganetti. Proton therapy physics. Proton Therapy Physics. Series: Series in Medical Physics and Biomedical Engineering, ISBN: 978-1-4398-3644-6. CRC Press, Edited by Harald Paganetti, 12 2011.
Yu Pan, Annika Leifert, David Ruau, Sabine Neuss, Jörg Bornemann, Günter Schmid, Wolfgang Brandau, Ulrich Simon, and Willi Jahnen-Dechent. Gold nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress and mitochondrial damage. Small, 5(18):2067–2076, 2009.
Steven D. Perrault, Carl Walkey, Travis Jennings, Hans C. Fischer, and Warren C.W. Chan. Mediating tumor targeting efficiency of nanoparticles through design. Nano Letters, 9(5):1909–1915, 2009.
Jerimy C. Polf, Lawrence F. Bronk, Wouter H.P. Driessen, Wadih Arap, Renata Pasqualini, and Michael Gillin. Enhanced relative biological effectiveness of proton radiotherapy in tumor cells with internalized gold nanoparticles. Applied Physics Letters, 98(19):18–21, 2011.
James L. Robar, Silvia A. Riccio, and M. A. Martin. Tumour dose enhancement using modified megavoltage photon beams and contrast media. Physics in Medicine and Biology, 47(14):305, jul 2002.
Macro Schippers. Beam Delivery Systems for Particle Therapy: Current Status and Recent Developments. Proton and Carbon Ion Therapy, 2:29–48, 2012.
Jan Schuemann, Ross Berbeco, Devika B. Chithrani, Sang Hyun Cho, Rajiv Kumar, Stephen J. McMahon, Srinivas Sridhar, and Sunil Krishnan. Roadmap to clinical use of gold nanoparticles for radiation sensitization. International Journal of Radiation Oncology Biology Physics, 94(1):189– 205, 2016.
Antonio Brosed Serreta. Fundamentos de Física Médica.
W. H. St. Clair, J. A. Adams, M. Bues, B. C. Fullerton, Sean La Shell, H. M. Kooy, J. S. Loeffler, and N. J. Tarbell. Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. International Journal of Radiation Oncology Biology Physics, 58(3):727–734, 2004.
Marloes Steneker, Antony Lomax, and Uwe Schneider. Intensity modulated photon and proton therapy for the treatment of head and neck tumors. Radiotherapy and Oncology, 80(2):263–267, aug 2006.
Edward A. Sykes, Juan Chen, Gang Zheng, and Warren C.W. Chan. Investigating the impact of nanoparticle size on active and passive tumor targeting efficiency. ACS Nano, 8(6):5696–5706, 2014.
C. A. Tobias, J. H. Lawrence, J. L. Born, R. K. Mccombs, J. E. Roberts, H. O. Anger, B. V.A. Low-Beer, and C. B. Huggins. Pituitary Irradiation with High-Energy Proton Beams A Preliminary Report. Cancer Research, 18(2):121–134, 1958.
H. N. Tran, M. Karamitros, V. N. Ivanchenko, S. Guatelli, S. McKinnon, K. Murakami, T. Sasaki, S. Okada, M. C. Bordage, Z. Francis, Z. El Bitar, M. A. Bernal, J. I. Shin, S. B. Lee, Ph Barberet, T. T. Tran, J. M.C. Brown, T. V. Nhan Hao, and S. Incerti. Geant4 Monte Carlo simulation of absorbed dose and radiolysis yields enhancement from a gold nanoparticle under MeV proton irradiation. Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms, 373:126–139, 2016.
Alexei Trofimov, Paul L. Nguyen, John J. Coen, Karen P. Doppke, Robert J. Schneider, Judith A. Adams, Thomas R. Bortfeld, Anthony L. Zietman, Thomas F. DeLaney, and William U. Shipley. Radiotherapy Treatment of Early-Stage Prostate Cancer with IMRT and Protons: A Treatment Planning Comparison. International Journal of Radiation Oncology*Biology*Physics, 69(2):444– 453, oct 2007.
Dongxu Wang, Blake Dirksen, Daniel E. Hyer, John M. Buatti, Arshin Sheybani, Eric Dinges, Nicole Felderman, Mindi Tennapel, John E. Bayouth, and Ryan T. Flynn. Impact of spot size on plan quality of spot scanning proton radiosurgery for peripheral brain lesions. Medical Physics, 41(12):1–10, 2014.
Liming Wang, Ying Liu, Wei Li, Xiumei Jiang, Yinglu Ji, Xiaochun Wu, Ligeng Xu, Yang Qiu, Kai Zhao, Taotao Wei, Yufeng Li, Yuliang Zhao, and Chunying Chen. Selective targeting of gold nanorods at the mitochondria of cancer cells: Implications for cancer therapy. Nano Letters, 11(2):772–780, 2011.
R. R. WILSON. Radiological use of fast protons. Radiology, 47(5):487–491, 1946.
dc.rights.coar.fl_str_mv http://purl.org/coar/access_right/c_abf2
dc.rights.license.spa.fl_str_mv Atribución-NoComercial-SinDerivadas 4.0 Internacional
dc.rights.uri.spa.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.accessrights.spa.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv Atribución-NoComercial-SinDerivadas 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.extent.spa.fl_str_mv xiv, 55 páginas
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv Universidad Nacional de Colombia
dc.publisher.program.spa.fl_str_mv Bogotá - Ciencias - Maestría en Física Médica
dc.publisher.department.spa.fl_str_mv Departamento de Física
dc.publisher.faculty.spa.fl_str_mv Facultad de Ciencias
dc.publisher.place.spa.fl_str_mv Bogotá, Colombia
dc.publisher.branch.spa.fl_str_mv Universidad Nacional de Colombia - Sede Bogotá
institution Universidad Nacional de Colombia
bitstream.url.fl_str_mv https://repositorio.unal.edu.co/bitstream/unal/81476/1/Trabajo%20final%20de%20Maestri%cc%81a%20en%20Fi%cc%81sica%20Me%cc%81dica%20ACSM.pdf
https://repositorio.unal.edu.co/bitstream/unal/81476/2/license.txt
https://repositorio.unal.edu.co/bitstream/unal/81476/3/Trabajo%20final%20de%20Maestri%cc%81a%20en%20Fi%cc%81sica%20Me%cc%81dica%20ACSM.pdf.jpg
bitstream.checksum.fl_str_mv 535ebd3e5f860575f8391760bb285446
8153f7789df02f0a4c9e079953658ab2
472c76d20ca6a9ae9c35e6c8dbb7d91a
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
repository.name.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
repository.mail.fl_str_mv repositorio_nal@unal.edu.co
_version_ 1806886593612480512
spelling Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Castro Serrato, Héctor Fabio8746f6e67a0c6080ae1924c0c256d0a8Sevilla Moreno, Andrés Camilo527b63f00e1ff4d5007995614a0697ff600Fisica de Bajas Temperaturas y Magnetismo Cryomag2022-06-01T18:47:52Z2022-06-01T18:47:52Z2022https://repositorio.unal.edu.co/handle/unal/81476Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, gráficas, tablasLa radioterapia con protones es uno de los enfoques más prometedores para el tratamiento del cáncer. En comparación con las técnicas modernas de radioterapia con fotones, como lo son la radioterapia de intensidad modulada (IMRT) y la arcoterapia volumétrica (VMAT), con esta técnica se alcanza una mejor conformación de la dosis en el tejido tumoral al mismo tiempo que se disminuye la dosis en estructuras a riesgo cercanas y tejido sano circundante. De forma semejante, desde principios de los años 2000, experimentos de irradiación de líneas celulares (in-vitro) y tumores en pequeños animales (in-vivo), han demostrado el potencial de las nano-partículas de oro (GNP) para ser utilizadas como agentes sensibilizadores en tratamientos de radioterapia con fotones. Al respecto, durante los años recientes la comunidad científica ha dirigido su interés hacia una tercera opción potencial para el mejoramiento de la radioterapia, en donde las dos alternativas anteriores convergen, ahora se estudia el incremento del efecto biológico resultado del uso de las GNP en la irradiación con protones. Investigaciones pioneras en las que se irradian lineas celulares (in-vitro) han reportado incrementos hasta del 20 % en la efectividad de la protonterapia para producir la muerte de células tumorales cuando en el medio se encuentran GNP. En este trabajo se estudia la dosimetría de un haz de protones interactuando en un medio acuoso con nano-partículas de oro (GNP), y se analiza tanto el incremento local de dosis, y el incremento del LET como factores que contribuyen significativamente a esta mejora. Para este fin, fue construida una simulación, usando el código Montecarlo Geant4-DNA, por medio de la cual se modela un haz de protones de uso clínico que interactúa con un maniquí de agua y diferentes concentraciones de GNP de forma esférica. Como resultado se cuantifica la energía depositada, la longitud de la trayectoria recorrida y el LET promedio de los protones en agua, se comparan los resultados variando los valores de diámetro de las GNP en el rango de 1 - 20 nm y las concentraciones de oro en el rango de 5 - 25 mg/ml. Se encuentra que las nano-partículas de oro en el medio acuoso actúan como moderadores del haz de protones, de manera tal que se alcanza la región de dosis máxima (Pico de Bragg) en una trayectoria más corta de los protones. Se estiman incrementos en el LET, al final del recorrido, de entre 7 % y 38 % para concentraciones de oro de 5 y 25 mg/ml respectivamente, como consecuencia se evidencian incrementos de la dosis absorbida hasta del 10 %. (Texto tomado de la fuente).Proton radiation therapy is one of the most promising approaches to treating cancer. Compared to modern photon radiotherapy techniques, such as intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT), this technique achieves better dose conformation in the tumor tissue, at the same time, the dose in nearby structures at risk and surrounding healthy tissue is reduced. Similarly, since the early 2000s, in irradiation experiments of cell lines (in-vitro) and tumors in small animals (in-vivo), the potential of gold nanoparticles (GNP) has been demonstrated to be used as sensitizing agents in photon radiotherapy treatments. In this regard, during recent years the scientific community has focused its interest towards a third potential option for the radiotherapy improvement, where the two previous alternatives converge, the increase in the biological effect resulting from the use of GNP in proton irradiation is now being studied. Pioneering researchs in which cell lines are irradiated (in-vitro) have reported increases of up to 20 % in the effectiveness of proton therapy to produce tumor cell death when GNP is deposited in the medium. In this work, the dosimetry of a proton beam interacting in an aqueous medium with gold nanoparticles (GNP) is studied, and both the local dose and the LET increases in the Bragg peak region are analyzed as contributing factors to this improvement. For this purpose, a simulation was built, using the Montecarlo Geant4-DNA code, by means of which a beam of protons for clinical use is modeled that interacts with a phantom of water and different concentrations of spherical GNP. As results, the energy deposited, path length and LET average of protons in water are estimated. The results are compared by varying the diameter values of the GNP in the range of 1 - 20 nm and the concentrations of gold in the range of 5 - 25 mg/ml. Gold nanoparticles in the aqueous medium are found to moderate the proton beam, such that the region of maximum dose (Bragg peak) is reached in a shorter proton path. Increases in the LET, at the end of the run, between 7 % and 38 % are estimated for gold concentrations of 5 and 25 mg/ml respectively, as a consequence, increases in the absorbed dose of up to 10 % are evidenced.MaestríaMagíster en Física MédicaRadioterapiaxiv, 55 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Ciencias - Maestría en Física MédicaDepartamento de FísicaFacultad de CienciasBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá530 - Física::535 - Luz y radiación relacionadaRadiation - dosageRadiotherapyNanoparticlesDosimetría (Radiación)RadioterapiaNanopartículasRadioterapiaProtonterapiaNano-partículasSimulación computacionalGeant4-DNARadiotherapyProtontherapyNano-particlesComputational simulationGeant4-DNAMicrodosimetría de la radioterapia con protones usando nano-partículas de oro como agentes sensibilizadoresMicrodosimetry of proton radiotherapy using gold nanoparticles as sensitizing agentsTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMBiremeRelative Biological Effectiveness in Ion Beam Therapy. Number 461 in Technical Reports Series. INTERNATIONAL ATOMIC ENERGY AGENCY, Vienna, 2008.Pedro Andreo, David T. Burns, Alan E. Nahum, Jan Seuntjens, and Frank Herbert Attix. Fundamentals of ionizing radiation dosimetry - Pedro Andreo.Chafika Belamri, Anis Samy Amine Dib, and Ahmed H. Belbachir. Monte Carlo simulation of proton therapy using bio-nanomaterials. Journal of Radiotherapy in Practice, 15(3):290–295, 2016.M.J. Berger, J.S. Coursey, M.A. Zucker, and J. Chang. Stopping-Power Range Tables for Electrons, Protons, and Helium Ions. NIST Standard Reference Database 124, 2017.John C Blasko, Peter D Grimm, John E Sylsvester, and William Cavanagh. The role of external beam radiotherapy with I-125/Pd-103 brachytherapy for prostate carcinoma. Radiotherapy and Oncology, 57(3):273–278, dec 2000.Göran Borghede, Hans Hedelin, Sten Holmäng, Karl Axel Johansson, Frank Aldenborg, Silas Pettersson, Göran Sernbo, Arne Wallgren, and Claes Mercke. Combined treatment with temporary short-term high dose rate Iridium-192 brachytherapy and external beam radiotherapy for irradiation of localized prostatic carcinoma. Radiotherapy and Oncology, 44(3):237–244, sep 1997.Mark J. Carvlin. An Introduction to Radiobiology, 1991.Sang Hyun Cho. Estimation of tumor dose enhancement due to gold nanoparticles during typical radiation treatments: A preliminary Monte Carlo study. Physics in Medicine and Biology, 50(15), 2005.Leo Y.T. Chou and Warren C.W. Chan. Fluorescence-Tagged Gold Nanoparticles for Rapidly Characterizing the Size-Dependent Biodistribution in Tumor Models. Advanced Healthcare Materials, 1(6):714–721, 2012.Michael Chuong, Shahed N. Badiyan, Man Yam, Zuofeng Li, Katja Langen, William Regine, Christopher Morris, James Snider, Minesh Mehta, Soon Huh, Michael Rutenberg, and Romaine C. Nichols. Pencil beam scanning versus passively scattered proton therapy for unresectable pancreatic cancer. Journal of Gastrointestinal Oncology, 9(4):687–693, 2018.Michael Dattoli, Kent Wallner, Richard Sorace, John Koval, Jennifer Cash, Rudolph Acosta, Charles Brown, James Etheridge, Michael Binder, Richard Brunelle, Novelle Kirwan, Servando Sanchez, Douglas Stein, and Stuart Wasserman. 103Pd brachytherapy and external beam irradiation for clinically localized, high-risk prostatic carcinoma. International Journal of Radiation Oncology*Biology*Physics, 35(5):875–879, jul 1996.Rémi Dendale, Livia Lumbroso-Le Rouic, Georges Noel, Loïc Feuvret, Christine Levy, Sabine Delacroix, Anne Meyer, Catherine Nauraye, Alejandro Mazal, Hamid Mammar, Paul Garcia, François D’Hermies, Eric Frau, Corine Plancher, Bernard Asselain, Pierre Schlienger, Jean Jacques Mazeron, and Laurence Desjardins. Proton beam radiotherapy for uveal melanoma: Results of Curie Institut–Orsay Proton Therapy Center (ICPO). International Journal of Radiation Oncology*Biology*Physics, 65(3):780–787, jul 2006.Michael Dickson and Jean Paul Gagnon. Key factors in the rising cost of new drug discovery and development. Nature Reviews Drug Discovery, 3(5):417–429, 2004.Richard P. Feynman. There’s Plenty of Room at the Bottom. In Engineering Science, pages 22–36. 1960.Jonas Fontenot, Phillip Taddei, Yuanshui Zheng, Dragan Mirkovic, Thomas Jordan, and Wayne Newhauser. Equivalent dose and effective dose from stray radiation during passively scattered proton radiotherapy for prostate cancer. Physics in Medicine and Biology, 53(6):1677–1688, 2008Evangelos S. Gragoudas. Proton Beam Irradiation of Uveal Melanomas. Archives of Ophthalmology, 100(6):928, jun 1982.James F. Hainfeld, F. Avraham Dilmanian, Zhong Zhong, Daniel N. Slatkin, John A. Kalef-Ezra, and Henry M. Smilowitz. Gold nanoparticles enhance the radiation therapy of a murine squamous cell carcinoma. Physics in Medicine and Biology, 55(11):3045–3059, jun 2010.Hooshang Nikjoo, Shuzo Uehara, and Dimitris Emfietzoglou. Interaction of Radiation with Matter. 2012.R N Kjellberg, W H Sweet, W M Preston, and A M Koehler. The bragg peak of a proton beam in intracranial therapy of tumors. Transactions of the American Neurological Association (U.S.).R.N. Kjellberg, A.M. Koehler, W.M. Preston, and W.H. Sweet. Stereotaxic Instrument for Use with the Bragg Peak of a Proton Beam. Stereotactic and Functional Neurosurgery, 22(3-5):183–189, 1962.Gennadii I. Klenov and Vladimir S. Khoroshkov. Hadron therapy: history, status, prospects. Physics-Uspekhi, 59(8):807–825, aug 2016.A. M. Koehler, R. J. Schneider, and J. M. Sisterson. Flattening of proton dose distributions for large field radiotherapy. Medical Physics, 4(4):297–301, 1977.Sophie Laurent, Delphine Forge, Marc Port, Alain Roch, Caroline Robic, Luce Vander Elst, and Robert N. Muller. Magnetic Iron Oxide Nanoparticles: Synthesis, Stabilization, Vectorization, Physicochemical Characterizations, and Biological Applications. Chemical Reviews, 108(6):2064– 2110, jun 2008.William R. Leo and David G. Haase. Techniques for Nuclear and Particle Physics Experiments , volume 58. 1990.Michael K.K. Leung, James C.L. Chow, B. Devika Chithrani, Martin J.G. Lee, Barbara Oms, and David A. Jaffray. Irradiation of gold nanoparticles by x-rays: Monte Carlo simulation of dose enhancements and the spatial properties of the secondary electrons production. Medical Physics, 38(2):624–631, 2011.M. P. Little. Risks associated with ionizing radiation. British Medical Bulletin, 68:259–275, 2003A. J. Lomax, T. Boehringer, A. Coray, E. Egger, G. Goitein, M. Grossmann, P. Juelke, S. Lin, E. Pedroni, B. Rohrer, W. Roser, B. Rossi, B. Siegenthaler, O. Stadelmann, H. Stauble, C. Vetter, and L. Wisser. Intensity modulated proton therapy: A clinical example. Medical Physics, 28(3):317– 324, 2001.Anthony John Lomax, Michael Goitein, and Judy Adams. Intensity modulation in radiotherapy: Photons versus protons in the paranasal sinus. Radiotherapy and Oncology, 66(1):11–18, 2003.Antony J. Lomax, Laura Cella, Damien Weber, John M. Kurtz, and Raymond Miralbell. Potential role of intensity-modulated photons and protons in the treatment of the breast and regional nodes. International Journal of Radiation Oncology*Biology*Physics, 55(3):785–792, mar 2003.B. Ludewigt, J. Siebers, D. Lesyna, D. Miller, J. Nusbaum, J. Slater, J. Johanning, and J. Miranda. A prototype beam delivery system for the proton medical accelerator at Loma Linda. Medical Physics, 18(6):1093–1099, 1991.D. M. Herold, I. J. Das, C. C. Stobbe,. Gold microspheres: a selective technique for producing biologically effective dose enhancement. International Journal of Radiation Biology, 76(10):1357– 1364, jan 2000.Shannon M. MacDonald, Sairos Safai, Alexei Trofimov, John Wolfgang, Barbara Fullerton, Beow Y. Yeap, Thomas Bortfeld, Nancy J. Tarbell, and Torunn Yock. Proton Radiotherapy for Childhood Ependymoma: Initial Clinical Outcomes and Dose Comparisons. International Journal of Radiation Oncology*Biology*Physics, 71(4):979–986, jul 2008.I. Martínez-Rovira and Y. Prezado. Evaluation of the local dose enhancement in the combination of proton therapy and nanoparticles. Medical Physics, 42(11):6703–6710, 2015.Priyabrata Mukherjee, Resham Bhattacharya, Ping Wang, Ling Wang, Sujit Basu, Janice A. Nagy, Anthony Atala, Debabrata Mukhopadhyay, and Shay Soker. Antiangiogenic properties of gold nanoparticles. Clinical Cancer Research, 11(9):3530–3534, 2005.Harald Paganetti. Proton therapy physics. Proton Therapy Physics. Series: Series in Medical Physics and Biomedical Engineering, ISBN: 978-1-4398-3644-6. CRC Press, Edited by Harald Paganetti, 12 2011.Yu Pan, Annika Leifert, David Ruau, Sabine Neuss, Jörg Bornemann, Günter Schmid, Wolfgang Brandau, Ulrich Simon, and Willi Jahnen-Dechent. Gold nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress and mitochondrial damage. Small, 5(18):2067–2076, 2009.Steven D. Perrault, Carl Walkey, Travis Jennings, Hans C. Fischer, and Warren C.W. Chan. Mediating tumor targeting efficiency of nanoparticles through design. Nano Letters, 9(5):1909–1915, 2009.Jerimy C. Polf, Lawrence F. Bronk, Wouter H.P. Driessen, Wadih Arap, Renata Pasqualini, and Michael Gillin. Enhanced relative biological effectiveness of proton radiotherapy in tumor cells with internalized gold nanoparticles. Applied Physics Letters, 98(19):18–21, 2011.James L. Robar, Silvia A. Riccio, and M. A. Martin. Tumour dose enhancement using modified megavoltage photon beams and contrast media. Physics in Medicine and Biology, 47(14):305, jul 2002.Macro Schippers. Beam Delivery Systems for Particle Therapy: Current Status and Recent Developments. Proton and Carbon Ion Therapy, 2:29–48, 2012.Jan Schuemann, Ross Berbeco, Devika B. Chithrani, Sang Hyun Cho, Rajiv Kumar, Stephen J. McMahon, Srinivas Sridhar, and Sunil Krishnan. Roadmap to clinical use of gold nanoparticles for radiation sensitization. International Journal of Radiation Oncology Biology Physics, 94(1):189– 205, 2016.Antonio Brosed Serreta. Fundamentos de Física Médica.W. H. St. Clair, J. A. Adams, M. Bues, B. C. Fullerton, Sean La Shell, H. M. Kooy, J. S. Loeffler, and N. J. Tarbell. Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. International Journal of Radiation Oncology Biology Physics, 58(3):727–734, 2004.Marloes Steneker, Antony Lomax, and Uwe Schneider. Intensity modulated photon and proton therapy for the treatment of head and neck tumors. Radiotherapy and Oncology, 80(2):263–267, aug 2006.Edward A. Sykes, Juan Chen, Gang Zheng, and Warren C.W. Chan. Investigating the impact of nanoparticle size on active and passive tumor targeting efficiency. ACS Nano, 8(6):5696–5706, 2014.C. A. Tobias, J. H. Lawrence, J. L. Born, R. K. Mccombs, J. E. Roberts, H. O. Anger, B. V.A. Low-Beer, and C. B. Huggins. Pituitary Irradiation with High-Energy Proton Beams A Preliminary Report. Cancer Research, 18(2):121–134, 1958.H. N. Tran, M. Karamitros, V. N. Ivanchenko, S. Guatelli, S. McKinnon, K. Murakami, T. Sasaki, S. Okada, M. C. Bordage, Z. Francis, Z. El Bitar, M. A. Bernal, J. I. Shin, S. B. Lee, Ph Barberet, T. T. Tran, J. M.C. Brown, T. V. Nhan Hao, and S. Incerti. Geant4 Monte Carlo simulation of absorbed dose and radiolysis yields enhancement from a gold nanoparticle under MeV proton irradiation. Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms, 373:126–139, 2016.Alexei Trofimov, Paul L. Nguyen, John J. Coen, Karen P. Doppke, Robert J. Schneider, Judith A. Adams, Thomas R. Bortfeld, Anthony L. Zietman, Thomas F. DeLaney, and William U. Shipley. Radiotherapy Treatment of Early-Stage Prostate Cancer with IMRT and Protons: A Treatment Planning Comparison. International Journal of Radiation Oncology*Biology*Physics, 69(2):444– 453, oct 2007.Dongxu Wang, Blake Dirksen, Daniel E. Hyer, John M. Buatti, Arshin Sheybani, Eric Dinges, Nicole Felderman, Mindi Tennapel, John E. Bayouth, and Ryan T. Flynn. Impact of spot size on plan quality of spot scanning proton radiosurgery for peripheral brain lesions. Medical Physics, 41(12):1–10, 2014.Liming Wang, Ying Liu, Wei Li, Xiumei Jiang, Yinglu Ji, Xiaochun Wu, Ligeng Xu, Yang Qiu, Kai Zhao, Taotao Wei, Yufeng Li, Yuliang Zhao, and Chunying Chen. Selective targeting of gold nanorods at the mitochondria of cancer cells: Implications for cancer therapy. Nano Letters, 11(2):772–780, 2011.R. R. WILSON. Radiological use of fast protons. Radiology, 47(5):487–491, 1946.EstudiantesORIGINALTrabajo final de Maestría en Física Médica ACSM.pdfTrabajo final de Maestría en Física Médica ACSM.pdfTesis de Maestría en Física Médicaapplication/pdf5374341https://repositorio.unal.edu.co/bitstream/unal/81476/1/Trabajo%20final%20de%20Maestri%cc%81a%20en%20Fi%cc%81sica%20Me%cc%81dica%20ACSM.pdf535ebd3e5f860575f8391760bb285446MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-84074https://repositorio.unal.edu.co/bitstream/unal/81476/2/license.txt8153f7789df02f0a4c9e079953658ab2MD52THUMBNAILTrabajo final de Maestría en Física Médica ACSM.pdf.jpgTrabajo final de Maestría en Física Médica ACSM.pdf.jpgGenerated Thumbnailimage/jpeg4004https://repositorio.unal.edu.co/bitstream/unal/81476/3/Trabajo%20final%20de%20Maestri%cc%81a%20en%20Fi%cc%81sica%20Me%cc%81dica%20ACSM.pdf.jpg472c76d20ca6a9ae9c35e6c8dbb7d91aMD53unal/81476oai:repositorio.unal.edu.co:unal/814762024-08-06 23:09:50.274Repositorio Institucional Universidad Nacional de Colombiarepositorio_nal@unal.edu.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

Publicaciones similares