Avaliação biológica in sílico e in vitro de um organoseleneto inovador e sua associação sinérgica em nanopartículas de PCL ao antitumoral paclitaxel vislumbrando a reversão do fenômeno MDR
Autor(a) principal: | |
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Data de Publicação: | 2024 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
dARK ID: | ark:/26339/001300000g111 |
Texto Completo: | http://repositorio.ufsm.br/handle/1/32142 |
Resumo: | Cancer is characterized by uncontrolled cell proliferation, often resulting from genetic mutations compromising cell cycle regulation. Conventional treatments, such as chemotherapy, while widely utilized, face challenges including lack of specificity and resistance. Nucleoside analogs stand out for their ability to disrupt metabolic and regulatory pathways. However, despite being an intriguing class, they have limitations such as inadequate conversion to the active metabolite and cellular resistance. Concurrently, antimitotic drugs of the taxane class, such as paclitaxel, also have various uses as antineoplastics, known for stabilizing microtubules; however, they encounter significant challenges, including severe side effects and resistance issues. Thus, this study focused on exploring the therapeutic potential of the innovative organoselenium compound AFAT-Se, its synergistic association with paclitaxel, and the incorporation of the combination into pH-sensitive polymeric nanoparticles. Therefore, using in silico and in vitro approaches, the physicochemical properties and biological activity of this compound were investigated. Initial promising results were observed, especially against the sensitive HT-29 tumor cell line (human colorectal adenocarcinoma). Furthermore, the synergistic association with paclitaxel was explored both in free form and after coencapsulation in polymeric nanoparticles. Formulation strategies were employed, including the addition of the amphiphilic copolymer poloxamer and the lysine-derived surfactant with sodium counter-ion (77KS), to add tumor sensitization effect and pH-dependent behavior. The nanoparticles exhibited suitable physicochemical characteristics and encapsulation efficiency. Hemocompatibility and pH-dependent behavior were evidenced by the hemolysis assay. ABTS and DPPH antioxidant assays determined a good free radical scavenging capacity. Evaluation of cytotoxicity profiles in non-tumor cells, 3T3 and PBMCs, provided interesting insights into the probable biological safety of the proposed therapeutic approach. The AFAT-Se + PTX association, especially after co-encapsulation in pH-sensitive nanoparticles, was able to sensitize resistant tumor cells, NCI-ADR/RES (ovarian tumor cell line), in both 2D and 3D cell models, and thus, it can be considered an interesting approach for reversing the multidrug resistence phenomenon (MDR). This study emphasizes the importance of computational tools, in vitro cell culture, and nanotechnology in the pursuit of more specific and safe antitumor therapies. Promising findings from this work suggest a new direction for cancer therapy development, aiming to minimize adverse effects and overcome tumor cell resistance mechanisms. |
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Avaliação biológica in sílico e in vitro de um organoseleneto inovador e sua associação sinérgica em nanopartículas de PCL ao antitumoral paclitaxel vislumbrando a reversão do fenômeno MDRIn silico and in vitro biological evaluation of an innovative organoselenium and its synergistic association in PCL nanoparticles to the antitumoral paclitaxel viewing the reversal of the MDR phenomenonCultivo celularCélulas tumorais resistentes/MDRAtividade antioxidanteCell cultureResistant/MDR tumor cellsAntioxidant activityCNPQ::CIENCIAS DA SAUDE::FARMACIACancer is characterized by uncontrolled cell proliferation, often resulting from genetic mutations compromising cell cycle regulation. Conventional treatments, such as chemotherapy, while widely utilized, face challenges including lack of specificity and resistance. Nucleoside analogs stand out for their ability to disrupt metabolic and regulatory pathways. However, despite being an intriguing class, they have limitations such as inadequate conversion to the active metabolite and cellular resistance. Concurrently, antimitotic drugs of the taxane class, such as paclitaxel, also have various uses as antineoplastics, known for stabilizing microtubules; however, they encounter significant challenges, including severe side effects and resistance issues. Thus, this study focused on exploring the therapeutic potential of the innovative organoselenium compound AFAT-Se, its synergistic association with paclitaxel, and the incorporation of the combination into pH-sensitive polymeric nanoparticles. Therefore, using in silico and in vitro approaches, the physicochemical properties and biological activity of this compound were investigated. Initial promising results were observed, especially against the sensitive HT-29 tumor cell line (human colorectal adenocarcinoma). Furthermore, the synergistic association with paclitaxel was explored both in free form and after coencapsulation in polymeric nanoparticles. Formulation strategies were employed, including the addition of the amphiphilic copolymer poloxamer and the lysine-derived surfactant with sodium counter-ion (77KS), to add tumor sensitization effect and pH-dependent behavior. The nanoparticles exhibited suitable physicochemical characteristics and encapsulation efficiency. Hemocompatibility and pH-dependent behavior were evidenced by the hemolysis assay. ABTS and DPPH antioxidant assays determined a good free radical scavenging capacity. Evaluation of cytotoxicity profiles in non-tumor cells, 3T3 and PBMCs, provided interesting insights into the probable biological safety of the proposed therapeutic approach. The AFAT-Se + PTX association, especially after co-encapsulation in pH-sensitive nanoparticles, was able to sensitize resistant tumor cells, NCI-ADR/RES (ovarian tumor cell line), in both 2D and 3D cell models, and thus, it can be considered an interesting approach for reversing the multidrug resistence phenomenon (MDR). This study emphasizes the importance of computational tools, in vitro cell culture, and nanotechnology in the pursuit of more specific and safe antitumor therapies. Promising findings from this work suggest a new direction for cancer therapy development, aiming to minimize adverse effects and overcome tumor cell resistance mechanisms.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESO câncer é caracterizado por uma proliferação desordenada de células, muitas vezes resultante de mutações genéticas que comprometem a regulação do ciclo celular. Tratamentos convencionais, como a quimioterapia, embora amplamente utilizados, enfrentam desafios, incluindo falta de especificidade e resistência. Análogos de nucleosídeos, destacam-se pela capacidade de perturbar vias metabólicas e regulatórias. No entanto, apesar de ser uma classe interessante, apresentam limitações como conversão inadequada ao metabólito ativo e resistência celular. Paralelamente, fármacos antimitóticos da classe dos taxanos, como o paclitaxel, também apresentam diversos usos como antineoplásicos, conhecidos por estabilizar microtúbulos; todavia, enfrentam desafios importantes incluindo efeitos colaterais graves e problemas relacionados a resistência. Dessa forma, este estudo concentrou-se em explorar o potencial terapêutico do organoseleneto inovador AFAT-Se, sua associação sinérgica com paclitaxel e ainda incorporação da associação em nanopartículas poliméricas pH-sensíveis. Sendo assim, utilizando abordagens in silico e in vitro, investigou-se as propriedades físicoquímicas e a atividade biológica deste composto. Resultados promissores iniciais foram observados, especialmente contra a linhagem tumoral sensível HT-29 (adenocarcinoma colorretal humano). Além disso, a associação sinérgica com o paclitaxel foi explorada tanto na forma livre como após co-encapsulação em nanopartículas poliméricas. Estratégias de formulação foram empregadas, incluindo a adição do copolímero anfifílico poloxamer e do tensoativo derivado de lisina com contra-íon sódio (77KS), para adicionar efeito de sensibilização do tumor e comportamento pH-dependente. As nanopartículas apresentaram características físico-químicas e eficiência de encapsulamento adequadas. A hemocompatibilidade e o comportamento pH-dependente foram evidenciados pelo ensaio de hemólise. Ensaios antioxidantes ABTS e DPPH determinaram boa capacidade sequestrante de radicais livres. A avaliação do perfil de citotoxicidade em células não-tumorais, 3T3 e PBMCs, forneceu informações interessantes sobre a provável segurança biológica da abordagem terapêutica proposta. A associação AFAT-Se + PTX, especialmente após co-encapsulação em nanopartículas pH-sensíveis, foi capaz de sensibilizar as células tumorais resistentes, NCIADR/RES (linhagem celular de tumor de ovário), tanto no modelo celular 2D como no 3D e, portanto, pode ser considerada uma abordagem interessante para a reversão do fenômeno de resistência a múltiplos fármacos (MDR). Este estudo destaca a importância das ferramentas computacionais, da cultura celular in vitro e da nanotecnologia na busca por terapias antitumorais mais específicas e seguras. Descobertas promissoras evidenciadas neste trabalho sugerem uma nova direção para o desenvolvimento de terapias contra o câncer, buscando minimizar efeitos adversos e contornar mecanismos de resistência da célula tumoral.Universidade Federal de Santa MariaBrasilDesenvolvimento e Avaliação de Produtos FarmacêuticosUFSMPrograma de Pós-Graduação em Ciências FarmacêuticasCentro de Ciências da SaúdeLibrelotto, Daniele Rubert Nogueirahttp://lattes.cnpq.br/1940490517223751Rolim, Clarice Madalena BuenoSilva, Cristiane de Bona daReolon, Jéssica BrandãoMathes, Daniela2024-07-03T18:53:33Z2024-07-03T18:53:33Z2024-03-27info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/32142ark:/26339/001300000g111porAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSM2024-07-03T18:53:33Zoai:repositorio.ufsm.br:1/32142Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2024-07-03T18:53:33Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Avaliação biológica in sílico e in vitro de um organoseleneto inovador e sua associação sinérgica em nanopartículas de PCL ao antitumoral paclitaxel vislumbrando a reversão do fenômeno MDR In silico and in vitro biological evaluation of an innovative organoselenium and its synergistic association in PCL nanoparticles to the antitumoral paclitaxel viewing the reversal of the MDR phenomenon |
title |
Avaliação biológica in sílico e in vitro de um organoseleneto inovador e sua associação sinérgica em nanopartículas de PCL ao antitumoral paclitaxel vislumbrando a reversão do fenômeno MDR |
spellingShingle |
Avaliação biológica in sílico e in vitro de um organoseleneto inovador e sua associação sinérgica em nanopartículas de PCL ao antitumoral paclitaxel vislumbrando a reversão do fenômeno MDR Mathes, Daniela Cultivo celular Células tumorais resistentes/MDR Atividade antioxidante Cell culture Resistant/MDR tumor cells Antioxidant activity CNPQ::CIENCIAS DA SAUDE::FARMACIA |
title_short |
Avaliação biológica in sílico e in vitro de um organoseleneto inovador e sua associação sinérgica em nanopartículas de PCL ao antitumoral paclitaxel vislumbrando a reversão do fenômeno MDR |
title_full |
Avaliação biológica in sílico e in vitro de um organoseleneto inovador e sua associação sinérgica em nanopartículas de PCL ao antitumoral paclitaxel vislumbrando a reversão do fenômeno MDR |
title_fullStr |
Avaliação biológica in sílico e in vitro de um organoseleneto inovador e sua associação sinérgica em nanopartículas de PCL ao antitumoral paclitaxel vislumbrando a reversão do fenômeno MDR |
title_full_unstemmed |
Avaliação biológica in sílico e in vitro de um organoseleneto inovador e sua associação sinérgica em nanopartículas de PCL ao antitumoral paclitaxel vislumbrando a reversão do fenômeno MDR |
title_sort |
Avaliação biológica in sílico e in vitro de um organoseleneto inovador e sua associação sinérgica em nanopartículas de PCL ao antitumoral paclitaxel vislumbrando a reversão do fenômeno MDR |
author |
Mathes, Daniela |
author_facet |
Mathes, Daniela |
author_role |
author |
dc.contributor.none.fl_str_mv |
Librelotto, Daniele Rubert Nogueira http://lattes.cnpq.br/1940490517223751 Rolim, Clarice Madalena Bueno Silva, Cristiane de Bona da Reolon, Jéssica Brandão |
dc.contributor.author.fl_str_mv |
Mathes, Daniela |
dc.subject.por.fl_str_mv |
Cultivo celular Células tumorais resistentes/MDR Atividade antioxidante Cell culture Resistant/MDR tumor cells Antioxidant activity CNPQ::CIENCIAS DA SAUDE::FARMACIA |
topic |
Cultivo celular Células tumorais resistentes/MDR Atividade antioxidante Cell culture Resistant/MDR tumor cells Antioxidant activity CNPQ::CIENCIAS DA SAUDE::FARMACIA |
description |
Cancer is characterized by uncontrolled cell proliferation, often resulting from genetic mutations compromising cell cycle regulation. Conventional treatments, such as chemotherapy, while widely utilized, face challenges including lack of specificity and resistance. Nucleoside analogs stand out for their ability to disrupt metabolic and regulatory pathways. However, despite being an intriguing class, they have limitations such as inadequate conversion to the active metabolite and cellular resistance. Concurrently, antimitotic drugs of the taxane class, such as paclitaxel, also have various uses as antineoplastics, known for stabilizing microtubules; however, they encounter significant challenges, including severe side effects and resistance issues. Thus, this study focused on exploring the therapeutic potential of the innovative organoselenium compound AFAT-Se, its synergistic association with paclitaxel, and the incorporation of the combination into pH-sensitive polymeric nanoparticles. Therefore, using in silico and in vitro approaches, the physicochemical properties and biological activity of this compound were investigated. Initial promising results were observed, especially against the sensitive HT-29 tumor cell line (human colorectal adenocarcinoma). Furthermore, the synergistic association with paclitaxel was explored both in free form and after coencapsulation in polymeric nanoparticles. Formulation strategies were employed, including the addition of the amphiphilic copolymer poloxamer and the lysine-derived surfactant with sodium counter-ion (77KS), to add tumor sensitization effect and pH-dependent behavior. The nanoparticles exhibited suitable physicochemical characteristics and encapsulation efficiency. Hemocompatibility and pH-dependent behavior were evidenced by the hemolysis assay. ABTS and DPPH antioxidant assays determined a good free radical scavenging capacity. Evaluation of cytotoxicity profiles in non-tumor cells, 3T3 and PBMCs, provided interesting insights into the probable biological safety of the proposed therapeutic approach. The AFAT-Se + PTX association, especially after co-encapsulation in pH-sensitive nanoparticles, was able to sensitize resistant tumor cells, NCI-ADR/RES (ovarian tumor cell line), in both 2D and 3D cell models, and thus, it can be considered an interesting approach for reversing the multidrug resistence phenomenon (MDR). This study emphasizes the importance of computational tools, in vitro cell culture, and nanotechnology in the pursuit of more specific and safe antitumor therapies. Promising findings from this work suggest a new direction for cancer therapy development, aiming to minimize adverse effects and overcome tumor cell resistance mechanisms. |
publishDate |
2024 |
dc.date.none.fl_str_mv |
2024-07-03T18:53:33Z 2024-07-03T18:53:33Z 2024-03-27 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/32142 |
dc.identifier.dark.fl_str_mv |
ark:/26339/001300000g111 |
url |
http://repositorio.ufsm.br/handle/1/32142 |
identifier_str_mv |
ark:/26339/001300000g111 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Desenvolvimento e Avaliação de Produtos Farmacêuticos UFSM Programa de Pós-Graduação em Ciências Farmacêuticas Centro de Ciências da Saúde |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Desenvolvimento e Avaliação de Produtos Farmacêuticos UFSM Programa de Pós-Graduação em Ciências Farmacêuticas Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
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1815172336780836864 |