MACROMOLECULAR PRODRUGS INTERACTION WITH MIXED LIPID-MEMBRANE - A CALORIMETRIC STUDY OF NAPROXEN LINKED TO POLYASPARTAMIDE INTERACTING WITH PHOSPHATIDYLCHOLINE AND PHOSPHATIDYLCHOLINE-PHOSPHATIDIC ACID VESICLES

The thermal behavior of pure dipalmitoylphosphatidylcholine (DPPC) liposomes or mixed liposomes of DPPC with charged dipalmitoylphosphatidic acid (DPPA) and interacting with polymeric prodrugs has been investigated by differential scanning calorimetry (DSC). The apolar drug was naproxen (NAP) covalently linked to a water-soluble polymer (alpha,beta-poly(N-hydroxyethyl)-DL-aspartamide (PHEA)). Addition of increasing amounts of NAP to DPPC liposomes causes a decrease in the transition temperature (T(m)) associated to the gel-to-liquid crystal phase transition with a small decrease in the enthalpy values (DELTA-H), whereas a corresponding amount of drug contained in the PHEA-adduct modifies the liposome phase transition by decreasing the DELTA-H and broadening the peak without T(m) variations. These effects have been interpreted as a different interaction of free or polymer-bound drug with the lipid bilayer. The drug effect on mixed liposomes was also investigated, and evidence of improved interaction of the drug-PHEA adduct with two-component bilayers, which better mimic biological membranes, was found. In order to understand the prodrug-lipid interactions, we modulated the surface charge density of the mixed liposomes with Ca2+, which binds strongly to the negatively charged lipid head groups. We observed lateral phase separation, induced by NAP-PHEA adduct and modulated by Ca2+, and the phenomenon was explained in terms of different drug solubility in DPPC-poor and DPPC-rich microdomains. The results are indicative of different interactions of naproxen, either free or bound to a polymeric carrier, with phospholipid membranes and the ability of Ca2+ to influence the adsorption of the drug.