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Drug release from liposomes in the endosome-lysosomal organelles into cytoplasm is critical to cytotoxicity and anticancer effects. Chloroquine is a lysosomotropic agent that has been reported to enhance in vitro cytotoxicity of basic anticancer drugs. To investigate the mechanism of chloroquine triggering basic anticancer drugs release from liposomes and the potential to treat solid tumors in clinic, daunorubicin was loaded into folate-targeted liposomes by ammonium sulfate remote loading method. In vitro triggered release profiles showed that chloroquine can instantly expel about 11% daunorubicin out of liposomes. In vitro cytotoxicity of folate-targeted liposomal daunorubicin on L1210JF(FR+) was enhanced by chloroquine, which was further confirmed by confocal micrographs. Intraliposomal pH was increased by adding chloroquine into 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS) liposomes with ammonium sulfate gradient, but was not higher than 5.5. Ion exchange and pH rising are the most plausible mechanisms of chloroquine triggering daunorubicin release from liposomes. In vivo anticancer effects on a murine solid tumor model with L1210JF indicated that chloroquine induced daunorubicin release from liposomes as well. Overall, these results support the potential application of chloroquine to trigger the release of liposomal drugs and ultimately to improve the therapeutic efficacy. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:5011-5018, 2010 [ABSTRACT FROM AUTHOR]

Phospholipids have been extensively evaluated as an anchor for both PEGylation and receptor-targeting in liposomal formulations. However, cholesterol, another important component in biomembranes, has not been fully investigated as an alternative anchor. In this study, the potential role of cholesterol for anchoring PEG and folate was investigated. Cholesterol derivatives were synthesized for PEGylation (mPEG-cholesterol) and folate receptor (FR) targeting (folate-PEG-cholesterol) and incorporated into the bilayer of FR-targeted liposomal doxorubicin. The colloidal stability of these cholesterol derivative-containing liposomes was superior to non-PEGylated liposomes, indicating that steric barrier provided by mPEG-cholesterol can efficiently inhibit aggregation of liposomes. FR-targeting activity of these liposomes was demonstrated by in vitro cell-binding studies on FR-overexpressing KB cells. In addition, in vivo circulation of cholesterol-anchored liposomes was prolonged compared to non-PEGylated liposomes. These studies suggest that cholesterol is a viable bilayer anchor for synthesis of PEGylated and FR-targeted liposomes. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2424–2435, 2007 [ABSTRACT FROM AUTHOR]