Mechanistic insights into the intracellular release of doxorubicin from pH-sensitive liposomes
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Universidade Federal de Minas Gerais
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Artigo de periódico
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Membros da banca
Resumo
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.
Abstract
Assunto
Lipossomos, Doxorrubicina, Sistemas de distribuição de medicamentos
Palavras-chave
PH-sensitive liposome, Doxorubicin, Drug delivery system, Intracellular release
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Endereço externo
https://www.sciencedirect.com/science/article/pii/S0753332220311446