Lipids, curvature stress, and the action of lipid prodrugs: Free fatty acids and lysolipid enhancement of drug transport across liposomal membranes
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Lipids, curvature stress, and the action of lipid prodrugs : Free fatty acids and lysolipid enhancement of drug transport across liposomal membranes. / Jespersen, Henrik; Andersen, Jonas H.; Ditzel, Henrik J.; Mouritsen, Ole G.
In: Biochimie, Vol. 94, No. 1, 2012, p. 2-10.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Lipids, curvature stress, and the action of lipid prodrugs
T2 - Free fatty acids and lysolipid enhancement of drug transport across liposomal membranes
AU - Jespersen, Henrik
AU - Andersen, Jonas H.
AU - Ditzel, Henrik J.
AU - Mouritsen, Ole G.
PY - 2012
Y1 - 2012
N2 - Molecular shape and its impact on bilayer curvature stress are powerful concepts for describing the effects of lipids and fatty acids on fundamental membrane properties, such as passive permeability and derived properties like drug transport across liposomal membranes. We illustrate these relationships by studying the effects of fatty acids and lysolipids on the permeation of a potent anti-cancer drug, doxorubicin, across the bilayer of a liposome in which the drug is encapsulated. Using a simple fluorescence assay, we have systematically studied the passive permeation of doxorubicin across liposomal membranes in different lipid phases: the solid-ordered phase (DPPC bilayers), the liquid-disordered phase (POPC lipid bilayers), and the liquid-ordered phase induced by high levels of cholesterol (DOPC + cholesterol lipid bilayers). The effect of different free fatty acids (FA) and lysolipids (LL), separately and in combination, on permeability was assessed to elucidate the possible mechanism of phospholipase A 2-triggered release in cancer tissue of liposomal doxorubicin formulations. In all cases, FAs applied separately lead to significant enhancement of permeability, most pronounced in liquid-disordered bilayers and less pronounced in solid and solid-ordered bilayers. LLs applied separately had only a marginal effect on permeability. FA and LL applied in combination lead to a synergistic enhancement of permeability in solid bilayers, whereas in liquid-disordered bilayers, the combined effect suppressed the otherwise strong permeability enhancement due to the FAs.
AB - Molecular shape and its impact on bilayer curvature stress are powerful concepts for describing the effects of lipids and fatty acids on fundamental membrane properties, such as passive permeability and derived properties like drug transport across liposomal membranes. We illustrate these relationships by studying the effects of fatty acids and lysolipids on the permeation of a potent anti-cancer drug, doxorubicin, across the bilayer of a liposome in which the drug is encapsulated. Using a simple fluorescence assay, we have systematically studied the passive permeation of doxorubicin across liposomal membranes in different lipid phases: the solid-ordered phase (DPPC bilayers), the liquid-disordered phase (POPC lipid bilayers), and the liquid-ordered phase induced by high levels of cholesterol (DOPC + cholesterol lipid bilayers). The effect of different free fatty acids (FA) and lysolipids (LL), separately and in combination, on permeability was assessed to elucidate the possible mechanism of phospholipase A 2-triggered release in cancer tissue of liposomal doxorubicin formulations. In all cases, FAs applied separately lead to significant enhancement of permeability, most pronounced in liquid-disordered bilayers and less pronounced in solid and solid-ordered bilayers. LLs applied separately had only a marginal effect on permeability. FA and LL applied in combination lead to a synergistic enhancement of permeability in solid bilayers, whereas in liquid-disordered bilayers, the combined effect suppressed the otherwise strong permeability enhancement due to the FAs.
KW - Curvature stress
KW - Doxorubicin
KW - Drug delivery
KW - Free fatty acids
KW - Lipids
KW - Liposome
KW - Lysolipids
KW - Permeability
U2 - 10.1016/j.biochi.2011.07.029
DO - 10.1016/j.biochi.2011.07.029
M3 - Journal article
C2 - 21839138
AN - SCOPUS:80054687304
VL - 94
SP - 2
EP - 10
JO - Biochimie
JF - Biochimie
SN - 0300-9084
IS - 1
ER -
ID: 230975502