Structural effects of lipophilic methotrexate conjugates on model phospholipid biomembranes

Citation
R. Pignatello et al., Structural effects of lipophilic methotrexate conjugates on model phospholipid biomembranes, THERMOC ACT, 380(2), 2001, pp. 255-264
Citations number
26
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Spectroscopy /Instrumentation/Analytical Sciences
Journal title
THERMOCHIMICA ACTA
ISSN journal
0040-6031 → ACNP
Volume
380
Issue
2
Year of publication
2001
Pages
255 - 264
Database
ISI
SICI code
0040-6031(200112)380:2<255:SEOLMC>2.0.ZU;2-O
Abstract
Lipophilic conjugates of the antitumor drug methotrexate (MTX) with lipoami no acids (LAAs) have been previously described as a tool to enhance MTX pas sive entrance into cells, overcoming a form of transport resistance which m akes tumour cells insensitive to the antimetabolite. A knowledge of the mec hanisms of interaction of such lipophilic derivatives with cell membranes c ould be useful for planning further lipophilic MTX derivatives with an opti mal antitumour activity. To this aim, a calorimetric study was undertaken u sing a biomembrane model made from synthetic 1,2-dipalmitoyl-glycero-3-phos phocholine (DPPC) multilamellar liposomes. The effects of MTX and conjugate s on the phase transition of liposomes were investigated using differential scanning calorimetry. The interaction of pure MTX with the liposomes was limited to the outer par t of the phospholipid bilayers, due to the polar nature of the drug. Conver sely, its lipophilic conjugates showed a hydrophobic kind of interaction, p erturbing the packing order of DPPC bilayers. In particular, a reduction of the enthalpy of transition from the gel to the liquid crystal phase of DPP C membranes was observed. Such an effect was related to the structure and m ole fraction of the conjugates in the liposomes. The antitumour activity of MTX conjugates was evaluated against cultures of a CCRF-CEM human leukemic T-cell line and a related MTX resistant sub-line . The in vitro cell growth inhibitory activity was higher for bis(tetradecy l) conjugates than for both the other shorter- and longer-chain derivatives . The biological effectiveness of the various MTX derivatives correlated ve ry well with the thermotropic effects observed on the phase transition of D PPC biomembranes. (C), 2001 Elsevier Science B.V All rights reserved.