Interaction of Alkylphospholipid Formulations with Breast Cancer Cells in the Context of Anticancer Drug Development

Koklic, Tilen; Podlipec, Rok; Mravljak, Janez; Šentjurc, Marjeta; Zeisig, Reiner

doi:10.5772/20584

Cited by 1 publication

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References 84 publications

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“…One of key properties of perifosine containing liposomal formulations, which is unusual for liposomes composed of bilayer forming lipids, is presence of high amounts of micelles in liposomal samples [ 26 , 27 ]. The content of micelles in perifosine liposomal formulations decreases with increasing cholesterol concentration, disappearing roughly at below 1:1 ratio of perifosine to cholesterol [ 26 , 28 ], similarly as capacity of perifosine liposomal formulations for transendothelial delivery. Presence of micelles in perifosine liposomal formulations could be expected, taking into account lipid monolayer experiments, which showed that alkyl phospholipids, below the critical micellar concentration (CMC), insert progressively into lipid monolayers as monomers from the aqueous medium, but above CMC, not only monomers but also groups of monomers (micelles) are transferred into the monolayers [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Lysolipid containing liposomes for transendothelial drug delivery

Koklic

trancar

2012

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BackgroundDesigning efficient 'vectors', to deliver therapeutics across endothelial barriers, in a controlled manner, remains one of the key goals of drug development. Recently, transcytosis of liposome encapsulated fluorescence marker calcein across a tight cell barrier was studied. The most efficient liposomes were found to be liposomes containing sufficient amount of alkyl phospholipid (APL) perifosine. APLs have similar structure as lysophosphatidyl choline (LPC), since APLs were synthesized as metabolically stable analogues of LPC, which increases endothelial permeability directly by inducing endothelial cell contraction, resulting in formation of gaps between endothelial cells. Since one of the unique properties of lysolipid, containing liposomal formulations is dynamic equilibrium of lysolipids, which are distributed among liposomes, micelles, and free form, such liposomes represent a reservoir of free lysolipids. On the other hand lysolipid containing liposomes also represent a reservoir of an encapsulated hydrophilic drug.Presentation of the hypothesisWe hypothesize that free lysolipids, with highest concentration in vicinity of drug carrying liposomes, compromise endothelial integrity, primarily where concentrations of liposomes is the highest, in a similar manner as LPC, by formation of gaps between endothelial cells. Liposome encapsulated drug, which leaks from liposomes, due to liposome destabilization, caused by lysolipid depletion, can therefore be efficiently transported across the locally compromised endothelial barrier.Testing the hypothesisThis hypothesis could be verified: by measuring binding of perifosine and other lysolipids to albumin and to lysophospholipid receptor (LPL-R) group; formation of stress fibers and subsequent cell contraction; activation of RhoA, and endothelial barrier dysfunction; by a synthesis of other LPC analogues with high critical micellar concentration and measuring their effect on transendothelial permeability in presence and absence of albumin.Implications of the hypothesisWe propose that lysolipid containing liposomal formulations might be used as nonspecific transendothelial transport vector, since leakage of liposome encapsulated active drug occurs simultaneously with the release of the lysolipids. The concentration of the active drug is therefore expected to be the highest at the site of compromised endothelial barrier. By appropriate choice of the lysolipids an endothelial barrier would stay open only for a short time. Use of such liposomes would potentially maximize the delivery of the drug while limiting the passage of toxic substances and pathogens across the endothelial barrier. Combining lysolipid containing liposomes with superparamagnetic iron oxide nanoparticles or a targeting ligand might be required to efficiently localize drug delivery to a disease affected tissue and to avoid endothelial disruption over the entire body.

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