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Structural effects of lipophilic methotrexate conjugates on model phospholipid biomembranes

Abstract

Lipophilic conjugates of the antitumor drug methotrexate (MTX) with lipoamino acids (LAAs) have been previously described as a tool to enhance MTX passive entrance into cells, overcoming a form of transport resistance which makes tumor cells insensitive to the antimetabolite. A knowledge of the mechanisms of interaction of such lipophilic derivs. with cell membranes could be useful for planning further lipophilic MTX derivs. with an optimal antitumor activity. To this aim, a calorimetric study was undertaken using a biomembrane model made from synthetic 1,2-dipalmitoyl-glycero-3-phosphocholine (DPPC) multilamellar liposomes. The effects of MTX and conjugates 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 part of the phospholipid bilayers, due to the polar nature of the drug. Conversely, its lipophilic conjugates showed a hydrophobic kind of interaction, perturbing the packing order of DPPC bilayers. In particular, a redn. of the enthalpy of transition from the gel to the liq. crystal phase of DPPC membranes was obsd. Such an effect was related to the structure and mole fraction of the conjugates in the liposomes. The antitumor 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(tetradecyl) conjugates than for both the other shorter- and longer-chain derivs. The biol. effectiveness of the various MTX derivs. correlated very well with the thermotropic effects obsd. on the phase transition of DPPC biomembranes

Autori

PUGLISI - Giovanni

PIGNATELLO - Rosario

Altri Autori

Toth Istvan