Interaction of lipophilic gemcitabine prodrugs with biomembrane models studied by Langmuir–Blodgett technique

Abstract

The stability and bioavailability of anticancer agents, such as gemcitabine, can be increased by forming prodrugs. Gemcitabine is rapidly deaminated to the inactive metabolite (2 ,2 -difluorodeoxyuridine), thus to improve its stability a series of increasingly lipophilic gemcitabine prodrugs linked through the 4-amino group to valeroyl, lauroyl, and stearoyl acyl chains were synthesized. Studies of monolayer properties are important to improve understanding of biological phenomena involving lipid/gemcitabine or lipid/gemcitabine derivative interactions. The interfacial behavior of monolayers constituted by DMPC plus gemcitabine or lipophilic gemcitabine prodrugs at increasing molar fractions was studied at the air/water interface at temperatures below (10 • C) and above (37 • C) the lipid phase transition. The effect of the hydrophobic chain length of gemcitabine derivatives on the isotherm of pure DMPC was investigated by surface tension measurement, and the results are reported as molar fractions as a function of mean molecular area per molecule. The results show that the compounds interact with DMPC producing mixed monolayers that are subject to an expansion effect, depending on the prodrug chain length. The results give useful hints of the interaction of these prodrugs with biological membranes and increase knowledge on the incorporation site of such compounds, as a function of their lipophilicity, in a lipid carrier; they may lead to improved liposomal formulation design.

Lipophilic prodrug of paclitaxel: Interaction with a dimyristoylphosphatidylcholine monolayer

“…From these results a possible localization of SQ-COOH, paclitaxel and SQ-paclitaxel in the DMPC monolayer can be hypothesized. SQ-COOH caused small deviation from the straight line; then, as already suggested (Castelli et al, 2007b), it could lie parallel to the DMPC chains with the À ÀCOOH residue immersed in the aqueous subphase. Paclitaxel caused positive deviation from the ideal line.…”

Solid Lipid Microparticles for the Stability Enhancement of a Dopamine Prodrug

“…16 The employment of valeroyl prodrugs has been also proposed with the aim to improve liposome incorporation of hydrophilic drugs like ara-C or gemcitabine. 17,18 Stability analysis of DVD in human plasma demonstrated that it is a suitable dopamine prodrug and it was therefore employed for encapsulation studies. Incorporation of DVD in tristearin-based LMs achieved release modulation (Fig.…”

Monolayers of mixture of alkylaminomethyl rutin and lecithin at the air/water interface

“…This is different from the case of cholesterol/lecithin which is in the form of a condensed structure only [15,16]. The phase transition of the mixture of nitrogen-containing drug/phospholipid, depending on both the molar fraction of the composition and the length of hydrophobic side chain, is proposed to be attributed to hydrophobic force or Van der Waals force [17,18]. For nitrogencontaining flavonoids, their surface behavior is still unknown.…”