Mechanistic insights into the intracellular release of doxorubicin from pH-sensitive liposomes - 17/01/21


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Graphical abstract |
Highlights |
• | The release from pH-sensitive liposomes is more complex than only intraluminal pH decreases. |
• | pH-sensitive liposomes released doxorubicin faster than non-pH-sensitive liposomes. |
• | pH-sensitive liposomes have sustained release of doxorubicin compared to free-DOX. |
• | Chloroquine and E64d enhanced the cytotoxicity of doxorubicin pH-sensitive liposomes. |
• | This provides a rational strategy for developing new formulations to be applied in vivo. |
Abstract |
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, intracellular 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.
Le texte complet de cet article est disponible en PDF.Keywords : pH-sensitive liposomes, Doxorubicin, Drug delivery system, Intracellular release
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Vol 134
Article 110952- février 2021 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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