Exploiting vegetable oils for the delivery of hydrophilic drugs

The use of oils and fats as pharmaceuticals dates back to biblical times. Through the ages, the science and technology of fats and oils and their chemical derivatives has progressed from traditional products to high-value applications, including lipid-based drug delivery systems. Lipid-based drug delivery is considered a viable strategy for increasing drug efficacy and reducing drug toxicity. Liposomes are among the lipid-based delivery systems which are extensively studied but targeting them to specific tissues, is still problematic. Toward overcoming the limitations of the classical liposomes (made of phospholipids that form bilayer membrane), we are developing lipid-based monolayer cationic vesicles made of bolaamphiphilic compounds containing two hydrophilic head groups at each end of an alkyl chain. The concept is to mimic the high chemical and physical stability of archaebacteria membranes, which is made from bolaamphiphiles. Since it is hard to isolate bolaamphiphiles from araebacteria and their synthesis is also difficult, we took a different approach - synthesizing novel bolaamphiphiles designed to form stable nano vesicles from functional vegetable oils that are excellent renewable resources for the chemical industry. Vernonia oil, a naturally epoxidized triglyceride obtained from the seeds of Vernonia galamensis, is probably the most promising of these functional oils with respect of a facile synthesis of functionalized bolaamphiphiles. Yet, other natural fatty acids, or oleochemicals derived from them, can also serve as a starting material for the synthesis of such bolaamphiphiles.

Here we describe the synthesis of a series of symmetrical and asymmetrical bola¬amphiphilic compounds that form vesicles with unique properties needed for targeted drug delivery. When the head groups are substrates for an enzyme with high activity at the target tissue, the vesicular structure will be disrupted and the vesicles will release the encapsulated drug primarily there. Conjugates between vernonia moiety and polyethylene glycol (PEG) or chitosan, were also prepared and incorporated into the membrane of the cationic vesicles in order to prolonged the circulatory survival of the vesicles and to increase penetrability through the blood-brain barrier (BBB) and the intestinal wall.

Efficacy of these vesicles as a drug delivery system was demonstrated with encapsulated enkephalin (ENK) that was shown to induce analgesia whereas non-encapsulated ENK did not cause any analgesic effect.

In summary, we have demonstrated that cationic vesicles with monolayer membrane made from novel bolaamphiphiles with head groups that are hydrolyzed by specific enzyme with high activity at the target tissue constitute an efficient targeted drug delivery system.