ENCAPSULATION OF THIOGUANINE IN LIPOSOMES

Thioguanine, a chemotherapeutic drug employed in the treatment of leuk emia, was encapsulated in three kinds of liposomes: extrusion, ethanol injection and dehydration-rehydration vesicles. The degree of entrapm ent was examined at three different concentrations, 1, 0.1 and 0.01 mM , and three pH values, 4.7, 7.4 and 9.2. Thioguanine had a considerabl e ability to cross the lipid bilayer, especially if the molecule prese nted a net charge. Like the amphiphilic drugs it was very permeant. Co ncerning the kind of liposomes, dehydration-rehydration of vesicles wa s found to be the optimal method for encapsulation of thioguanine irre spective of the pH. At pH 4.7 an encapsulation efficiency of 12 mmol/m ol of lipid was elicited. The other methods never entrapped more than 3 mmol/mol of lipid. This behaviour can be explained by the formation in the drug of intermolecular bonds by hydrogen bridges during the pro cess of lyophilization. The product formed might encounter greater dif ficulty in escaping from the vesicle than the non-bonded thioguanine. On the other hand, pH 4.7 also afforded more efficient encapsulation t han the other pH values. Furthermore, this pH corresponds to the maxim al apparent partition coefficient, and, consequently, to the maximal n eutrality of the molecule. At this point, thioguanine is present as a neutral or as zwitterionic species. From these findings it can be infe rred that entrapped thioguanine, as a zwitterionic form, is associated with the membrane lipids by means of electrostatic interactions with the zwitterionic phospholipid.