Desenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de pele

Detalhes bibliográficos
Autor(a) principal: Dias, Marina França
Data de Publicação: 2018
Tipo de documento: Tese
Idioma: por
Título da fonte: Repositório Institucional da UFG
dARK ID: ark:/38995/001300000b9wz
Texto Completo: http://repositorio.bc.ufg.br/tede/handle/tede/8601
Resumo: Skin cancer has the highest incidence among all types of neoplasms and the tendency is the increasing number of new cases in next decades, wich makes necessary new modalities and treatment options. Chemotherapeutic agent imiquimod is used in treatment of disease, but the high occurrence of local and systemic adverse effects associated with its use as well as its low skin permeation impair adherence and therapeutical effectiveness, respectively. The aim of the present work was evaluate the antitumor activity of nanocapsules imiquimod-loaded compared to its commercial product in murine model of skin cancer. Polymeric nanocapsules containing imiquimod, in the absence and presence of chitosan coating, were obtained by the precipitation of preformed polymer technique and characterized by encapsulation efficiency, size, zeta potential, pH, morphology (transmission electron microscopy and scanning), optical scanning spectrophotometry and in vitro release through dialysis membrane in pH 5.6 buffer. Presence of chemical interactions between formulation components was evaluated by thermogravimetric analysis and infrared spectroscopy. Detection of crystalline structures was performed by X-ray diffractometry. The nanocapsules and commercial imiquimod formulation antiagiogenic activity was determined in a chicken embryo chorioallantoic membrane model. Cutaneous permeation of nanocapsules imiquimod-loaded and commercial imiquimod was determined in Swiss albino mice. The chemopreventive activity of colloidal dispersions and the commercial imiquimod was evaluated through the tumoral inhibition promoted by these treatments in a multi- stage model of chemical carcinogenesis in Swiss mice. Encapsulation efficiency, mean diameter, zeta potential and pH of uncoated nanocapsules imiquimod-loaded were 92.5% ± 0.4; 249 ± 22.4 nm; -40.1 mV ± 3.7 and 5.4 ± 0.01 respectively, whereas for nanocapsules with cationic coating the parameters found were: 88.6 ± 2.3%; 287.0 ± 12.6 nm; + 11.3 ± 0.5 mV and 3.7 ± 0.0, respectively. The formulations morphology obtained by scanning and transmission electron microscopy images confirmed the presence of nanocapsules. In the stability analysis by optical scanning spectrophotometry (Turbiscan), all dispersions obtained a backscattering variation less than 2% over 5 weeks and were considered stable. In the in vitro release assay, imiquimod-loaded nanoparticles obtained slower release of the drug compared to free and commercial imiquimod. There were chemical interactions between chitosan and other formulation components evaluated by thermogravimetric and infrared studies. No crystalline structure was detected by the X-ray diffraction technique for the coated and uncoated imiquimod formulation. The dispersion of nanocapsules containing imiquimod presented antiangiogenic activity superior than commercial formulation in chicken embryo chorioallantoic membrane model. Nanocapsules containing imiquimod both uncoated and coated with chitosan presented cutaneous permeation in deep layers of the skin and inhibition in the chemically induced carcinogenicity process superior than tumor control group and groups treated with placebo nanoparticles while the commercial formulation presented retention of the drug in superficial layers of the skin and did not obtain a statistically significant reduction in the number of papillomas formed compared to the carcinogenic control. These results allow to conclude, therefore, that stable nanocarreadores were obtained and the chemopreventive activity and the antiangiogenic effect of these systems represent a promising alternative for the treatment of cutaneous neoplasias.
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spelling Silva Júnior, Armando da Cunhahttp://lattes.cnpq.br/8278273904187275Lima, Eliana MartinsSerakides, RogériaBarros, André Luís Branco dePereira, Bruno Gonçalveshttp://lattes.cnpq.br/1789462070390929Dias, Marina França2018-06-27T11:09:43Z2018-04-11DIAS, Marina França. Desenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de pele. 2018. 102 f. Tese (Doutorado em Nanotecnologia Farmacêutica em Rede) - Universidade Federal de Goiás, Goiânia, 2018.http://repositorio.bc.ufg.br/tede/handle/tede/8601ark:/38995/001300000b9wzSkin cancer has the highest incidence among all types of neoplasms and the tendency is the increasing number of new cases in next decades, wich makes necessary new modalities and treatment options. Chemotherapeutic agent imiquimod is used in treatment of disease, but the high occurrence of local and systemic adverse effects associated with its use as well as its low skin permeation impair adherence and therapeutical effectiveness, respectively. The aim of the present work was evaluate the antitumor activity of nanocapsules imiquimod-loaded compared to its commercial product in murine model of skin cancer. Polymeric nanocapsules containing imiquimod, in the absence and presence of chitosan coating, were obtained by the precipitation of preformed polymer technique and characterized by encapsulation efficiency, size, zeta potential, pH, morphology (transmission electron microscopy and scanning), optical scanning spectrophotometry and in vitro release through dialysis membrane in pH 5.6 buffer. Presence of chemical interactions between formulation components was evaluated by thermogravimetric analysis and infrared spectroscopy. Detection of crystalline structures was performed by X-ray diffractometry. The nanocapsules and commercial imiquimod formulation antiagiogenic activity was determined in a chicken embryo chorioallantoic membrane model. Cutaneous permeation of nanocapsules imiquimod-loaded and commercial imiquimod was determined in Swiss albino mice. The chemopreventive activity of colloidal dispersions and the commercial imiquimod was evaluated through the tumoral inhibition promoted by these treatments in a multi- stage model of chemical carcinogenesis in Swiss mice. Encapsulation efficiency, mean diameter, zeta potential and pH of uncoated nanocapsules imiquimod-loaded were 92.5% ± 0.4; 249 ± 22.4 nm; -40.1 mV ± 3.7 and 5.4 ± 0.01 respectively, whereas for nanocapsules with cationic coating the parameters found were: 88.6 ± 2.3%; 287.0 ± 12.6 nm; + 11.3 ± 0.5 mV and 3.7 ± 0.0, respectively. The formulations morphology obtained by scanning and transmission electron microscopy images confirmed the presence of nanocapsules. In the stability analysis by optical scanning spectrophotometry (Turbiscan), all dispersions obtained a backscattering variation less than 2% over 5 weeks and were considered stable. In the in vitro release assay, imiquimod-loaded nanoparticles obtained slower release of the drug compared to free and commercial imiquimod. There were chemical interactions between chitosan and other formulation components evaluated by thermogravimetric and infrared studies. No crystalline structure was detected by the X-ray diffraction technique for the coated and uncoated imiquimod formulation. The dispersion of nanocapsules containing imiquimod presented antiangiogenic activity superior than commercial formulation in chicken embryo chorioallantoic membrane model. Nanocapsules containing imiquimod both uncoated and coated with chitosan presented cutaneous permeation in deep layers of the skin and inhibition in the chemically induced carcinogenicity process superior than tumor control group and groups treated with placebo nanoparticles while the commercial formulation presented retention of the drug in superficial layers of the skin and did not obtain a statistically significant reduction in the number of papillomas formed compared to the carcinogenic control. These results allow to conclude, therefore, that stable nanocarreadores were obtained and the chemopreventive activity and the antiangiogenic effect of these systems represent a promising alternative for the treatment of cutaneous neoplasias.O câncer de pele é o de maior incidência dentre todos os tipos de neoplasias e a tendência é o aumento crescente do número de novos casos nas próximas décadas, tornando necessárias novas modalidades e opções de tratamento. O agente quimio-terápico imiquimode é utilizado no tratamento da doença, mas a elevada ocorrência de efeitos adversos locais e sistêmicos associados ao seu uso bem como sua baixa permeação cutânea prejudicam a adesão e a efetividade terapêutica, respectiva-mente. O objetivo do presente trabalho foi comparar a atividade quimiopreventiva do imiquimode veiculado em nanocápsulas com a da sua forma comercial, em modelo murino de câncer de pele. Nanocápsulas poliméricas contendo o imiquimode, na ausência e presença de revestimento de quitosana, foram obtidas pela técnica de precipitação do polímero pré-formado e caracterizadas quanto à eficiência de encap-sulação, ao tamanho, ao potencial zeta, ao pH, à morfologia (microscopia eletrônica de transição e varredura), à espectrofotometria de varredura óptica e à liberação in vitro através de membrana de diálise em tampão pH 5,6. A presença de interações entre componentes da formulação foi avaliada por meio de análises termogravimé- tricas e por espectroscopia na região do infravermelho. A detecção de estruturas cristalinas nas formulações foi realizada por difratometria de raios X. A atividade antiangiogênica das nanocápsulas obtidas, bem como da formulação comercial do imiquimode, foi determinada em modelo de membrana corioalantoica de embrião de galinha. A permeação cutânea das nanopartículas e do imiquimode comercial foi determinada em camundongos Swiss. A atividade quimiopreventiva das nanocápsulas obtidas e a do imiquimode comercial foi avaliada por meio da inibição tumoral promovida por esses tratamentos em modelo de carcinogênese química em camundongos Swiss. A eficiência de encapsulação, o diâmetro médio, o potencial zeta e o pH das nanocápsulas não revestidas contendo imiquimode foram respectivamente de 92,5% ± 0,4; 249 ± 22,4 nm; -40,1 mV ± 3,7 e 5,4 ± 0,01. Enquanto que, para as nanocápsulas com recobrimento catiônico os parâmetros encontrados foram 88,6 ± 2,3%; 287,0 ± 12,6 nm; +11,3 ± 0,5 mV e 3,7 ± 0,0, respectivamente. A morfologia das formulações, obtida pelas imagens de microscopia eletrônica de varredura e de transmissão, confirmou a presença de nanocápsulas. Nas análises de estabilidade por espectrofotometria de varredura óptica (Turbiscan), todas as dispersões obtiveram variação de retroespalhamento inferior a 2%, no período de cinco semanas, sendo consideradas estáveis. No ensaio de liberação in vitro, as nanopartículas contendo imiquimode obtiveram liberação mais lenta do fármaco comparativamente ao imiquimode livre (em solução) e ao imiquimode comercial. Foram verificadas interações entre a quitosana e os demais componentes das formulações nos estudos termogravimétricos e na espectroscopia na região do infravermelho. Não foi detectada presença de estrutura cristalina com emprego da técnica de difratometria de raios X para a formulações contendo imiquimode com e sem revestimento. A dispersão de nanocápsulas contendo imiquimode apresentou atividade antiangiogênica superior à da formulação comercial em modelo de membrana corioalantoica de embrião de galinha. As nanocápsulas contendo imi-quimode com e sem revestimento apresentaram permeação cutânea em camadas profundas da pele e inibição no processo de carcinogênese quimicamente induzido superior à do grupo-controle tumoral e à dos grupos tratados com nanopartículas placebo, enquanto a formulação comercial apresentou retenção do fármaco em camadas mais superficiais da pele e não obteve redução estatisticamente significativa no número de papilomas formados em relação ao controle cancerígeno. Esses resultados permitem concluir, portanto, que nanocarreadores estáveis foram obtidos e que a atividade quimiopreventiva e o efeito antiangiogênico desses sistemas representam uma alternativa promissora para o tratamento de neoplasias cutâneas.Submitted by Franciele Moreira (francielemoreyra@gmail.com) on 2018-06-22T19:23:21Z No. of bitstreams: 2 Tese - Marina França Dias - 2018.pdf: 4770115 bytes, checksum: 86e73a57e2ce0a02cb1666dfe5988ce3 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2018-06-27T11:09:43Z (GMT) No. of bitstreams: 2 Tese - Marina França Dias - 2018.pdf: 4770115 bytes, checksum: 86e73a57e2ce0a02cb1666dfe5988ce3 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)Made available in DSpace on 2018-06-27T11:09:43Z (GMT). No. of bitstreams: 2 Tese - Marina França Dias - 2018.pdf: 4770115 bytes, checksum: 86e73a57e2ce0a02cb1666dfe5988ce3 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-04-11Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqapplication/pdfporUniversidade Federal de GoiásPrograma de Pós-graduação em Nanotecnologia Farmacêutica em Rede (FF)UFGBrasilFaculdade Farmácia - FF (RG)http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessCâncer de peleNanopartículasImiquimodeAtividade antiangiogênicaQuimioprevençãoSkin câncerNanoparticlesImiquimodAntiangiogenic activityChemopreventionFARMACIA::FARMACOTECNIADesenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de peleDevelopment and evaluation of the chemopreventive activity of nanoparticles containing imiquimod in murine model of skin cancerinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesis-89454519598569253156006006006006010281161524209375-1498234366838932019-2555911436985713659reponame:Repositório Institucional da UFGinstname:Universidade Federal de Goiás (UFG)instacron:UFGLICENSElicense.txtlicense.txttext/plain; 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dc.title.eng.fl_str_mv Desenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de pele
dc.title.alternative.eng.fl_str_mv Development and evaluation of the chemopreventive activity of nanoparticles containing imiquimod in murine model of skin cancer
title Desenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de pele
spellingShingle Desenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de pele
Dias, Marina França
Câncer de pele
Nanopartículas
Imiquimode
Atividade antiangiogênica
Quimioprevenção
Skin câncer
Nanoparticles
Imiquimod
Antiangiogenic activity
Chemoprevention
FARMACIA::FARMACOTECNIA
title_short Desenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de pele
title_full Desenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de pele
title_fullStr Desenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de pele
title_full_unstemmed Desenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de pele
title_sort Desenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de pele
author Dias, Marina França
author_facet Dias, Marina França
author_role author
dc.contributor.advisor1.fl_str_mv Silva Júnior, Armando da Cunha
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/8278273904187275
dc.contributor.referee1.fl_str_mv Lima, Eliana Martins
dc.contributor.referee2.fl_str_mv Serakides, Rogéria
dc.contributor.referee3.fl_str_mv Barros, André Luís Branco de
dc.contributor.referee4.fl_str_mv Pereira, Bruno Gonçalves
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/1789462070390929
dc.contributor.author.fl_str_mv Dias, Marina França
contributor_str_mv Silva Júnior, Armando da Cunha
Lima, Eliana Martins
Serakides, Rogéria
Barros, André Luís Branco de
Pereira, Bruno Gonçalves
dc.subject.por.fl_str_mv Câncer de pele
Nanopartículas
Imiquimode
Atividade antiangiogênica
Quimioprevenção
topic Câncer de pele
Nanopartículas
Imiquimode
Atividade antiangiogênica
Quimioprevenção
Skin câncer
Nanoparticles
Imiquimod
Antiangiogenic activity
Chemoprevention
FARMACIA::FARMACOTECNIA
dc.subject.eng.fl_str_mv Skin câncer
Nanoparticles
Imiquimod
Antiangiogenic activity
Chemoprevention
dc.subject.cnpq.fl_str_mv FARMACIA::FARMACOTECNIA
description Skin cancer has the highest incidence among all types of neoplasms and the tendency is the increasing number of new cases in next decades, wich makes necessary new modalities and treatment options. Chemotherapeutic agent imiquimod is used in treatment of disease, but the high occurrence of local and systemic adverse effects associated with its use as well as its low skin permeation impair adherence and therapeutical effectiveness, respectively. The aim of the present work was evaluate the antitumor activity of nanocapsules imiquimod-loaded compared to its commercial product in murine model of skin cancer. Polymeric nanocapsules containing imiquimod, in the absence and presence of chitosan coating, were obtained by the precipitation of preformed polymer technique and characterized by encapsulation efficiency, size, zeta potential, pH, morphology (transmission electron microscopy and scanning), optical scanning spectrophotometry and in vitro release through dialysis membrane in pH 5.6 buffer. Presence of chemical interactions between formulation components was evaluated by thermogravimetric analysis and infrared spectroscopy. Detection of crystalline structures was performed by X-ray diffractometry. The nanocapsules and commercial imiquimod formulation antiagiogenic activity was determined in a chicken embryo chorioallantoic membrane model. Cutaneous permeation of nanocapsules imiquimod-loaded and commercial imiquimod was determined in Swiss albino mice. The chemopreventive activity of colloidal dispersions and the commercial imiquimod was evaluated through the tumoral inhibition promoted by these treatments in a multi- stage model of chemical carcinogenesis in Swiss mice. Encapsulation efficiency, mean diameter, zeta potential and pH of uncoated nanocapsules imiquimod-loaded were 92.5% ± 0.4; 249 ± 22.4 nm; -40.1 mV ± 3.7 and 5.4 ± 0.01 respectively, whereas for nanocapsules with cationic coating the parameters found were: 88.6 ± 2.3%; 287.0 ± 12.6 nm; + 11.3 ± 0.5 mV and 3.7 ± 0.0, respectively. The formulations morphology obtained by scanning and transmission electron microscopy images confirmed the presence of nanocapsules. In the stability analysis by optical scanning spectrophotometry (Turbiscan), all dispersions obtained a backscattering variation less than 2% over 5 weeks and were considered stable. In the in vitro release assay, imiquimod-loaded nanoparticles obtained slower release of the drug compared to free and commercial imiquimod. There were chemical interactions between chitosan and other formulation components evaluated by thermogravimetric and infrared studies. No crystalline structure was detected by the X-ray diffraction technique for the coated and uncoated imiquimod formulation. The dispersion of nanocapsules containing imiquimod presented antiangiogenic activity superior than commercial formulation in chicken embryo chorioallantoic membrane model. Nanocapsules containing imiquimod both uncoated and coated with chitosan presented cutaneous permeation in deep layers of the skin and inhibition in the chemically induced carcinogenicity process superior than tumor control group and groups treated with placebo nanoparticles while the commercial formulation presented retention of the drug in superficial layers of the skin and did not obtain a statistically significant reduction in the number of papillomas formed compared to the carcinogenic control. These results allow to conclude, therefore, that stable nanocarreadores were obtained and the chemopreventive activity and the antiangiogenic effect of these systems represent a promising alternative for the treatment of cutaneous neoplasias.
publishDate 2018
dc.date.accessioned.fl_str_mv 2018-06-27T11:09:43Z
dc.date.issued.fl_str_mv 2018-04-11
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/doctoralThesis
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dc.identifier.citation.fl_str_mv DIAS, Marina França. Desenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de pele. 2018. 102 f. Tese (Doutorado em Nanotecnologia Farmacêutica em Rede) - Universidade Federal de Goiás, Goiânia, 2018.
dc.identifier.uri.fl_str_mv http://repositorio.bc.ufg.br/tede/handle/tede/8601
dc.identifier.dark.fl_str_mv ark:/38995/001300000b9wz
identifier_str_mv DIAS, Marina França. Desenvolvimento e avaliação da atividade quimiopreventiva de nanopartículas contendo imiquimode em modelo murino de câncer de pele. 2018. 102 f. Tese (Doutorado em Nanotecnologia Farmacêutica em Rede) - Universidade Federal de Goiás, Goiânia, 2018.
ark:/38995/001300000b9wz
url http://repositorio.bc.ufg.br/tede/handle/tede/8601
dc.language.iso.fl_str_mv por
language por
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dc.relation.sponsorship.fl_str_mv -2555911436985713659
dc.rights.driver.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
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rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
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dc.publisher.none.fl_str_mv Universidade Federal de Goiás
dc.publisher.program.fl_str_mv Programa de Pós-graduação em Nanotecnologia Farmacêutica em Rede (FF)
dc.publisher.initials.fl_str_mv UFG
dc.publisher.country.fl_str_mv Brasil
dc.publisher.department.fl_str_mv Faculdade Farmácia - FF (RG)
publisher.none.fl_str_mv Universidade Federal de Goiás
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