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Dosimetry of Brachytherapy Using Radioactive Nanoparticles: in Silico

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Dosimetry of Brachytherapy Using Radioactive Nanoparticles: in Silico ESCOLA DE ENGENHARIA DEPARTAMENTO DE ENGENHARIA NUCLEAR PROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIAS E TÉCNICAS NUCLEARES UNIVERSIDADE FEDERAL DE MINAS GERAIS Baljeet Seniwal Dosimetry of Brachytherapy using Radioactive Nanoparticles: In silico Belo Horizonte May 2021 BALJEET SENIWAL Dosimetry of Brachytherapy using Radioactive Nanoparticles: In silico Thesis presented to the Postgraduate Course in Nuclear Sciences and Techniques at the School of Engineering of the Federal University of Minas Gerais, as a partial requirement to obtain the title of Doctor in Nuclear Sciences and Techniques Concentration area: Radiation Sciences Promoter: Prof. Telma C. F. Fonseca, PhD Co-Promoter: Prof. Jan Schuemann, PhD Line of Research: Applications of Radiation to Biomed- ical Sciences Belo Horizonte 2021 Seniwal, Baljeet. S477d Dosimetry of brachytherapy using radioactive nanoparticles [recurso eletrônico] : in silico / Baljeet Seniwal. - 2021. 1 recurso online (xxiv, 143 f. : il., color.) : pdf. Orientadora: Telma C. F. Fonseca. Coorientador: Jan Schuemann. Tese (doutorado) - Universidade Federal de Minas Gerais, Escola de Engenharia. Anexos: f. 112-143. Bibliografia: f. 104-111. Exigências do sistema: Adobe Acrobat Reader. 1. Engenharia nuclear - Teses. 2. Braquiterapia - Teses. 3. Método de Monte Carlo - Teses. I. Fonseca, Telma Cristina Ferreira. II. Schuemann, Jan. III. Universidade Federal de Minas Gerais. Escola de Engenharia. IV. Título. CDU: 621.039(043) Ficha catalográfica elaborada pelo bibliotecário Reginaldo Cesar Vital dos Santos CRB/6 2165 Biblioteca Prof. Mário Werneck, Escola de Engenharia da UFMG To my Family and my Supervisor Acknowledgements I am indebted to many people who helped me through this journey of Ph.D. research. Without their help, this work would never see light. First and foremost, I would like to thank my research advisor Dr. Telma C.F. Fonseca. I would like to express my sincere gratitude for her support, advice, help, and constant encouragement that has always kept me motivated in my research work and made my Ph.D. experience productive and stimulating. Apart from work she treated me like a friend. I have no idea and no word which can express my thankfulness and the feelings of my heart for warm reception at the airport and hospitality during my stay in Brazil. She went above and beyond, and I am touched and grateful. I also appreciate that she gave me the opportunity to work on the project that I like. She is a dream PhD advisor. I am also thankful to my research co-advisor Prof. Jan Schuemann from Massachusetts General Hospital & Harvard Medical School for giving me opportunity to work with him. Also, providing me constant guidance and feedback, which helped me to improve my research skills. At the personal level, I would like to thank my father Laxman Seniwal, mother Savitri Seniwal, aunt Bimla, brothers Sumit, Manish, sisters Rekha and Sulekha. I am grateful to them for their endless support, encouragement, and trust. I am very grateful to my uncle Ram Chander who was always proud of me and encouraged me to pursue Ph.D. before he passed away. He wished me to get Ph.D. one day, and I hope to fulfill his wish. I am also grateful to my Brazilian family, who acceptedme happily as a family member: Goreti Pereira (My mother) and Felipe Henrique (brother). I would like to express my sincere gratitude for making my stay in Brazil comfortable. This helped me to focus more on research more than other day to day problems. Apart from research I have earned some good friends: Bruno, Jhonny, Lucas, Mazer, Lucas de freitas, Prof. Ademar and Peter. I would like to express my sincere gratitude for their full-time availability, suggestions and positive criticism and guidance, whenever I was in need. I am also thankful to a lot of other friends: Bruno, Mario, Mabel, Carlos, Metheus, Aline, Thales, Joao, and many more for their help and support. I am thankful for everyone who was a part of my journey from the first day of my academic study till my graduation. I would like to thank the Coordination for the Improvement of Higher Education Personnel (CAPES) and the National Council for Scientific and Technological Development (CNPq), for financial support for my doctoral studies. Baljeet Seniwal "I asked him where he had it made, he said he made it himself, & when I asked him where he got his tools said he made them himself & laughing added if I had said for other people to make tools & things for me, I had never made anything......" Sir Isaac Newton Resumo/Abstract Nanopartículas radioativas (radio-NPs) funcionalizadas com biomoléculas específicas do tumor, injetadas de forma intratumoral, têm sido relatadas como uma alternativa à braquiterapia à base de sementes (LDR) de baixa taxa de dose (LDR). Em tratamentos de câncer à base de radiação a estimativa precisa da dose absorvida é crucial para o controle adequado da doença e para minimizar o risco de efeitos colaterais induzidos por radiação. Atualmente, o formalismo da Dose de Radiação Interna Médica (MIRD) usado para fins de dosimetria interna não considera o impacto da absorção e lavagem de radiofarmacêuticos na fração de sobrevivência celular (FS) e estimativa de dose absorvida. A dosimetria celular única (SCD), baseada no formalismo MIRD, é geralmente usada para avaliar as características dosimétricas dos radionuclídeos para aplicações teranósticas. No entanto, existem discrepâncias nos métodos gráficos e na distribuição de energia radial, utilizadas para estimar a distribuição da dose. Além disso, a modelagem precisa do transporte de radiação no meio pelos códigos de Monte Carlo (MC) desempenha um papel fundamental na estimativa da dose absorvida. O núcleo de ponto de dose (DPK) é usado para: (i) testar a precisão de diferentes códigos de Monte Carlo (MC), realizando comparação em termos de DPK; e (ii) estimam a dose absorvida por 3D na medicina nuclear. No entanto, pelo que sabemos, não foram investigadas as diferenças de impacto na DPK na dose absorvida. Este projeto de doutorado tem como objetivo realizar a dosimetria de aplicações LDR BT, utilizando radio-NPs, e preencher as lacunas acima mencionadas na literatura usando métodos de Monte Carlo (MC). Os cálculos dosimétricos foram realizados utilizando-se dois códigos MC amplamente utilizados: Geant4-DNA e EGSnrc. Inicialmente, a comparação em termos de DPK para elétrons na faixa de energia de 1 keV a 3 MeV foram realizadas para testar a precisão de ambos os códigos. Após a validação, utilizou-se a abordagem SCD para avaliar as características dosimétricas de emissão dos radionuclídeos de 12 alfa/beta/auger para aplicações teranósticas. Também foi proposto o conceito de função de dose radial para representação gráfica da distribuição de doses. Além disso, as curvas de sobrevivência celular publicadas na literatura foram replicadas utilizando-se o modelo matemático proposto por Sefl et al. 2016. O nosso trabalho apresenta que, tanto o Geant4-DNA quanto o EGSnrc podem simular com precisão o transporte de elétrons de baixa energia em relação a outros códigos MC. Além disso, as maiores diferenças entre as DPKs foram encontradas para energias eletrônicas abaixo de 10 keV, o que resultou na distribuição de dose homogênea em micrômetros e sem impacto em voxels em tamanhos milimétricos. Os emissores alfas foram encontrados para depositar a dose mais alta absorvida em comparação com os emissores auger e beta. Além disso, replicamos efetivamente as curvas de sobrevivência celular publicadas na literatura sobre o uso de radio-NPs para aplicações LDR BT. Concluiu-se que a precisão dos códigos MC e parâmetros MC deve ser validada e referenciada antes de usá-los para fins de dosimetria. Além disso, o conhecimento preciso da taxa de absorção, taxa de lavagem de NPs, radio-sensibilidade e taxa de repopulação de tumores é importante para o cálculo das curvas de sobrevivência celular. Keywords: Braquiterapia LDR, nanopartículas radioativas, núcleos de ponto de dose, métodos de Monte Carlo. Resumo/Abstract Radioactive nanoparticles (radio-NPs) functionalized with tumor specific biomolecules, injected intratumorally, have been reported as an alternative to low dose rate (LDR) seed based brachytherapy (BT). In radiation based cancer treatments accurate estimation of absorbed dose is crucial for proper disease control and to minimize the risk of radiation induced side effects. Currently, used Medical Internal Radiation Dose (MIRD) formalism for internal dosimetry purposes do not consider the impact of uptake and washout of radiopharmaceutical on the cell survival fraction (SF) and absorbed dose estimation. The single cell dosimetry (SCD), based on MIRD formalism, is generally used to evaluate the dosimetric characteristics of radionuclides for theranostic applications. However, there exists discrepancies in the graphical methods and radial energy distribution, used to estimate the dose distribution. Moreover, precise modeling of radiation transport in the medium by Monte Carlo (MC) codes plays a pivotal role in the estimation of absorbed dose. The dose point kernel (DPK) are used to: (i) test the accuracy of different Monte Carlo (MC) codes, by performing comparison in terms of DPK; and (ii) estimate 3D-absorbed dose in nuclear medicine. However, as per our knowledge the impact differences in DPK on absorbed dose was not investigated. This PhD project aims to perform dosimetry of LDR BT applications, using radio-NPs, and fill the above mentioned gaps in literature using MC methods. The dosimetric calculations were performed using two widely used MC codes: Geant4-DNA and EGSnrc. Initially, the comparison in terms of DPK for electrons in energy range of 1 keV to 3 MeV was made to test the accuracy of both codes. After validation, SCD approach was used to evaluate the dosimetric characteristics of 12 alpha/beta/auger emitting radionuclides for theranostic applications. The concept of radial dose function was also proposed for graphical representation of dose distribution. Further, the cell survival curves published in literature were replicated using the mathematical model proposed by Sefl et al.
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