Association of daunorubicin to a lipid nanoemulsion that binds to low-density lipoprotein receptors enhances the antitumour action and decreases the toxicity of the drug in melanoma-bearing mice

Contente, Thaís Costa; Kretzer, Iara Fabrícia; Filippin-Monteiro, Fabíola Branco; Maria, Durvanei Augusto; Maranhão, Raul C.

doi:10.1111/jphp.12296

Cited by 20 publications

(15 citation statements)

References 28 publications

(54 reference statements)

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“…As tested in mice, several formulations developed in our laboratory, such as the association of LDE with carmustine, with etoposide, with paclitaxel (PTX), and with daunorubicin had severalfold less toxicity than the corresponding commercial preparations, as analyzed by classic pharmacological parameters, such as maximum tolerated dose or median lethal dose (LD 50 ). [16][17][18][19][20][21] In pilot clinical trials performed in patients with advanced cancers, LDE-carmustine, LDE-etoposide, and LDE-PTX showed no observable clinical and laboratorial toxicities at doses corresponding to those used in routine cancer treatment. Because it is prepared only with lipids present in the organism, LDE has no immunogenic potential and no safety issues related to materials in the nanoemulsion composition.…”

Section: Introductionmentioning

confidence: 99%

“…[13][14][15] To increase the yield of association with LDEs of those compounds and the stability of the preparations, an oleyl group was added to the molecular structure of the drugs, resulting in more lipophilic derivatives. [16][17][18][19] A prominent aspect of the LDEchemotherapeutic agent formulations is a remarkable reduction in drug toxicity. As tested in mice, several formulations developed in our laboratory, such as the association of LDE with carmustine, with etoposide, with paclitaxel (PTX), and with daunorubicin had severalfold less toxicity than the corresponding commercial preparations, as analyzed by classic pharmacological parameters, such as maximum tolerated dose or median lethal dose (LD 50 ).…”

Section: Introductionmentioning

confidence: 99%

“…As shown here and elsewhere in tumorbearing animals, the use of an LDE system had the ability to increase the effectiveness of carried chemotherapeutic agents, such as carmustine, etoposide, daunorubicin, and PTX, while drastically reducing their toxicity. 17,19,21,84 In pilot clinical trials performed in patients with advanced cancers, LDE-carmustine, LDE-etoposide, and LDE-PTX showed no observable clinical or laboratorial toxicities in doses corresponding to those used in routine cancer treatment. 5,14,23 Therefore, the LDE system and eventually others that explore the LDL-receptor endocytic pathways as drug-delivery gateway are creditable candidates for introduction in clinical oncology practice.…”

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confidence: 99%

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Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice

Kretzer¹,

Maria²,

Guido³

et al. 2016

IJN

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Purpose Lipid nanoemulsions (LDEs) that bind to low-density lipoprotein (LDL) receptors used as carriers of paclitaxel (PTX) can decrease toxicity and increase PTX antitumoral action. The administration of simvastatin (Simva), which lowers LDL-cholesterol, was tested as an adjuvant to commercial PTX and to PTX associated with LDE (LDE-PTX). Materials and methods B16F10 melanoma-bearing mice were treated with saline solution or LDE (controls), Simva, PTX, PTX and Simva, LDE-PTX, and LDE-PTX and Simva: PTX dose 17.5 μmol/kg (three intraperitoneal injections, 3 alternate days): Simva 50 mg/kg/day by gavage, 9 consecutive days. Results Compared with saline controls, 95% tumor-growth inhibition was achieved by LDE-PTX and Simva, 61% by LDE-PTX, 44% by PTX and Simva, and 43% by PTX. Simva alone had no effect. Metastasis developed in only 37% of the LDE-PTX and Simva, 60% in LDE-PTX, and 90% in PTX and Simva groups. Survival rates were higher in LDE-PTX and Simva and in LDE-PTX groups. The LDE-PTX and Simva group presented tumors with reduced cellular density and increased collagen fibers I and III. Tumors from all groups showed reduction in immunohistochemical expression of ICAM, MCP-1, and MMP-9; LDE-PTX and Simva presented the lowest MMP-9 expression. Expression of p21 was increased in the Simva, LDE-PTX, and LDE-PTX and Simva groups. In the Simva and LDE-PTX and Simva groups, expression of cyclin D1, a proliferation and survival promoter of tumor cells, was decreased. Therapy with LDE-PTX and Simva showed negligible toxicity compared with PTX and Simva, which resulted in weight loss and myelosuppression. Conclusion Simva increased the antitumor activity of PTX carried in LDE but not of PTX commercial presentation, possibly because statins increase the expression of LDL receptors that internalize LDE-PTX.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice

Kretzer¹,

Maria²,

Guido³

et al. 2016

IJN

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“…[29][30][31][32][33] We demonstrated earlier that the higher level of LDL receptor expression had been ascribed to the accelerated mitosis rates that are pivotal in cancer pathophysiology. 34 Anticancer complexes with HDL and LDL do not affect the characteristic of the drug. 32,35 Therefore, the higher sensitivity of the Hepa1c1c7 cells to treatment with the liposomal formulation may be correlated to the interaction of the DODAC with lipid receptors of these cells, enabling greater availability of the DODAC/PHO-S in the cell membrane and resulting in a larger action of the PHO-S in these cells.…”

mentioning

confidence: 99%

Potential antitumor activity of novel DODAC/PHO-S liposomes

Luna

Saraiva²,

Filho³

et al. 2016

IJN

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In recent studies, we showed that synthetic phosphoethanolamine (PHO-S) has a great potential for inducing cell death in several tumor cell lines without damage to normal cells. However, its cytotoxic effect and selectivity against tumor cells could increase with encapsulation in cationic liposomes, such as dioctadecyldimethylammonium chloride (DODAC), due to electrostatic interactions between these liposomes and tumor cell membranes. Our aim was to use cationic liposomes to deliver PHO-S and to furthermore maximize the therapeutic effect of this compound. DODAC liposomes containing PHO-S (DODAC/PHO-S), at concentrations of 0.3–2.0 mM, prepared by ultrasonication, were analyzed by scanning electron microscopy (SEM) and dynamic light scattering. The cytotoxic effect of DODAC/PHO-S on B16F10 cells, Hepa1c1c7 cells, and human umbilical vein endothelial cells (HUVECs) was assessed by MTT assay. Cell cycle phases of B16F10 cells were analyzed by flow cytometry and the morphological changes by SEM, after treatment. The liposomes were spherical and polydisperse in solution. The liposomes were stable, presenting an average of ∼50% of PHO-S encapsulation, with a small reduction after 40 days. DODAC demonstrated efficient PHO-S delivery, with the lowest values of IC 50% (concentration that inhibits 50% of the growth of cells) for tumor cells, compared with PHO-S alone, with an IC 50% value of 0.8 mM for B16F10 cells and 0.2 mM for Hepa1c1c7 cells, and without significant effects on endothelial cells. The Hepa1c1c7 cells showed greater sensitivity to the DODAC/PHO-S formulation when compared to B16F10 cells and HUVECs. The use of DODAC/PHO-S on B16F10 cells induced G 2 /M-phase cell cycle arrest, with the proportion significantly greater than that treated with PHO-S alone. The morphological analysis of B16F10 cells by SEM showed changes such as “bleb” formation, cell detachment, cytoplasmic retraction, and apoptotic bodies after DODAC/PHO-S treatment. Cationic liposomal formulation for PHO-S delivery promoted cytotoxicity more selectively and effectively against B16F10 and Hepa1c1c7 cells. Thus, the DODAC/PHO-S liposomal formulation presents great potential for preclinical studies.

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“…Masquelier et al (1986) demonstraram, que antineoplásicos carreados com HDL e LDL são melhor direcionados para as células tumorais, as quais apresentam alta expressão dos receptores de lipoproteínas (Tokui et al 1995;Morille et al, 2008;Moura et al 2011;Kretzer et al, 2012;Mcmahon et al, 2015;Nam et al, 2016). Neste aspecto, níveis elevados de expressão dos receptores de LDL têm sido atribuídos às taxas aceleradas de mitose que são fundamentais na fisiopatologia do câncer (Contente et al, 2014). Portanto, neste trabalho, a maior sensibilidade das células de CHC Hepa1c1c7 ao tratamento com os lipossomas pode estar correlacionada à interação do DODAC com os receptores lipídicos destas células, possibilitando maior disponibilidade do DODAC carreando a FO-S. Reforçando esta hipótese, Oliveira et al (2014) verificaram que formulações lipossomais baseadas na associação da monooleína com lipídios catiônicos da família do dioctadecildimetilamônio são absorvidos, predominante, por um processo ativo, sendo a endocitose a principal via de internalização (Oliveira et al, 2014).…”

Section: Discussionunclassified

Potencial antitumoral da formulação lipossomal DODAC/fosfoetanolamina sintética no modelo de hepatocarcinoma

Luna¹

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chegar a este momento. Entre as alternâncias de tempestades e dias ensolarados, no mar bravio que é a vida, sempre fostes o meu farol ao norte e, também, os ventos que sopram nas velas da minha embarcação, impulsionando-me.Aos meu pais, Marcos Lima e Norma Luna, por todo incentivo e encorajamento.Agradeço pelos valores e ensinamentos que recebi, aos quais sempre buscarei ser fiel.Aos meus irmãos, Tamires Luna e Lucas Luna, por serem um dos alicerces da minha existência. Em momento de felicidade, vocês compartilharam comigo os sorrisos mais sinceros e a euforia da alegria; nos dias tristes, acalentaram minha alma com palavras brandas e sábias; nas dificuldades, me encorajaram para eu dar o meu melhor e, simplesmente, descansar em Deus. Caminhando percorremos o caminho em direção à "utopia"; sim ela se afastou, eu sei, mas juntos chegamos até aqui e em companhia continuaremos a caminhar.Ao meu tio e sua esposa, Assis Luna e Sueli Luna, pelo apoio concedido para que eu pudesse me estabelecer em São Paulo. Vocês tornaram viável este momento.A Alethéia Lacerda, minha esposa, companheira e amiga. Utilizando as palavras do grande poeta Vinícius de Moraes: "A vida é arte do encontro, embora haja tanto desencontro pela vida". Fui agraciado por ter encontrado você, que inusitadamente veio "escondida" entre os papers, experimentos e pipetas. Você me fez redescobrir o significado da palavra compartilhar, trazendo "novos" sentimentos e momentos para minha existência. Obrigado por todo amor e auxílio, que tantas vezes me trouxeram alento e completude, me trazendo a certeza de que a felicidade só é plena quando partilhada. TE AMO! Ao Dr. Durvanei Augusto Maria, pelas oportunidades, ensinamentos valiosos, confiança e amizade. Agradeço por todo empenho e dedicação com os quais o senhor orientou este trabalho, estando sempre disposto e acessível para ajudar. Obrigado por me receber em seu laboratório e pelo acolhimento.A Dra. Elia Tamaso Espin Garcia Caldini, pela amizade e palavras de incentivo. A Senhora é inspiradora e me faz enxergar a vida acadêmica de uma maneira mais ampla e nobre.A Dra. Marcia Saldanha Kubrusly, por abrir as portas do seu laboratório, possibilitando as análises moleculares deste estudo. Além disto, e mais importante que isto, obrigado pela amizade, ensinamentos, apoio e conversas descontraídas, que sempre trouxeram ao meu rosto um doce e verdadeiro sorriso.A Dra. Juliana Pereira, pelas grandes contribuições para este trabalho. Obrigado por viabilizar as análises de citometria, permitindo a utilização dos equipamentos disponíveis em seu laboratório.A Dra. Greice Kelle Viegas Saraiva, pelo auxílio na preparação dos lipossomas e ensaios bioquímicos.A todos os Professores membros da banca do exame de qualificação, obrigado por todas as sugestões e contribuições. "Apesar das ruínas e da morte, Onde sempre acabou cada ilusão, A força dos meus sonhos é tão forte, Que de tudo renasce a exaltação E nunca as minhas mãos ficam vazias". Sophia de Mello Breyner Andresen"É melhor tentar e falhar, que preocupar-se e ver...

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Association of daunorubicin to a lipid nanoemulsion that binds to low-density lipoprotein receptors enhances the antitumour action and decreases the toxicity of the drug in melanoma-bearing mice

Abstract: Compared with DNR, LDE-oDNR improved tumour growth inhibition and survival rates with pronouncedly less toxicity, and thus may become a new tool for cancer treatment.

Cited by 20 publications

References 28 publications

Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice

Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice

Potential antitumor activity of novel DODAC/PHO-S liposomes

Potencial antitumoral da formulação lipossomal DODAC/fosfoetanolamina sintética no modelo de hepatocarcinoma

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