Abstract
The interaction of MTX and some aliphatic his(amide) derivatives with synthetic 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) biomembranes was investigated. The drug-membrane model interaction was carried out by differential scanning calorimetry. Anticancer activity of MIX his(amides) was evaluated on cultures of a human leukemic cell line (CCRF-CEM) in comparison with MTX. Compounds were tested at a concentration ranging between 10 nM and 1 μM. The MTX is able to interact with the outer part of the phospholipid bilayers due to its polar nature. Results showed that the amide derivatives of MTX, presenting a marked lipophilic character, are able to interact with the hydrophobic core of the DPPC bilayers, thus perturbing the packing order of the phospholipid bilayers. Particularly, a reduction of the enthalpy values linked to the transition from the gel state to the liquid crystal state of DPPC membranes was observed. This effect is a function of the type and molar fraction of the various compounds. The in vitro antitumor activity on leukemic CCRF-CEM cells was higher for MTX-bis(tetradecylamide) than for the other derivatives. The biological effectiveness of the various MTX derivatives correlates very well with the enthalpy of the transition of drug-loaded DPPC biomembranes.
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