DEFAR - Departamento de Farmácia

URI permanente desta comunidadehttp://www.hml.repositorio.ufop.br/handle/123456789/530

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20211

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Autor: search.filters.author.Jesus, Marcelo Bispo deAssunto: search.filters.subject.Drug delivery system

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    Mechanistic insights into the intracellular release of doxorubicin from pH-sensitive liposomes.
    (2021) Reis, Samara Bonesso dos; Silva, Juliana de Oliveira; Fossa, Fernanda Garcia; Leite, Elaine Amaral; Souza, Angelo Malachias de; Lana, Gwenaelle Elza Nathalie Pound; Mosqueira, Vanessa Carla Furtado; Oliveira, Mônica Cristina de; Barros, André Luís Branco de; Jesus, Marcelo Bispo de
    pH-sensitive liposomes are interesting carriers for drug-delivery, undertaking rapid bilayer destabilization in response to pH changes, allied to tumor accumulation, a desirable behavior in the treatment of cancer cells. Previously, we have shown that pH-sensitive liposomes accumulate in tumor tissues of mice, in which an acidic environment accelerates drug delivery. Ultimately, these formulations can be internalized by tumor cells and take the endosome-lysosomal route. However, the mechanism of doxorubicin release and intracellular traffic of pH-sensitive liposomes remains unclear. To investigate the molecular mechanisms underlying the intracellular release of doxorubicin from pH-sensitive liposomes, we followed HeLa cells viability, internalization, intracel lular trafficking, and doxorubicin’s intracellular delivery mechanisms from pH-sensitive (SpHL-DOX) and non pH-sensitive (nSpHL-DOX) formulations. We found that SpHL-DOX has faster internalization kinetics and intracellular release of doxorubicin, followed by strong nuclear accumulation compared to nSpHL-DOX. The increased nuclear accumulation led to the activation of cleaved caspase-3, which efficiently induced apoptosis. Remarkably, we found that chloroquine and E64d enhanced the cytotoxicity of SpHL-DOX. This knowledge is paramount to improve the efficiency of pH-sensitive liposomes or to be used as a rational strategy for developing new formulations to be applied in vivo.