期刊
BIOMEDICINE & PHARMACOTHERAPY
卷 134, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2020.110952
关键词
pH-sensitive liposomes; Doxorubicin; Drug delivery system; Intracellular release
资金
- FAEPEX [3097/17]
- Sao Paulo Research Foundation (FAPESP) [2014/03002-7, 2015/06134-4]
- National Council for Scientific and Technological Development (CNPq) [429703/2018-0]
- Coordination for the Improvement of Higher Education Personnel (CAPES)
- Brazilian Synchrotron Light Laboratory (LNLS)
pH-sensitive liposomes showed fast accumulation and intracellular release of doxorubicin in tumor cells, leading to apoptosis. The cytotoxicity of pH-sensitive liposomes can be enhanced by chloroquine and E64d.
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.
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