Synthesis of a PEG-bipolar-dimyristoylphosphatidylethanoline

Hacho Bohossian

Document Type Dissertation/Thesis


The problem of drug delivery has been of continuous research interest to the biomedical scientific community. The basic problem of drug delivery is to facilitate the transport of medication via the bloodstream to the target organs. This process can be significantly hampered by the hydrophobic nature of most medications. Pharmaceutical compounds and in particular chemotherapeutics (which are a specific area of research at the Cornell Medical Center and the Sloan-Kettering Institute) tend to be extremely hydrophobic. Blood is a hydrophilic environment, so the hydrophobic drugs simply cannot dissolve in the bloodstream. As a result they cannot be transported successfully to the target tissues. For example, Sloan-Kettering possesses compounds that kill cancer cells 100% in vitro, yet those same compounds are virtually inactive in vivo because of their insolubility in the blood. It was our purpose, therefore, to develop an appropriate and successful drug delivery system. Several approaches have been proposed already in this area. Some researchers have suggested coupling the drug to another compound such that the new complex is rendered soluble in the bloodstream. Even though successful in isolated cases, this approach presents several problems. First, and foremost, the new complexes can be highly toxic. If that is the case, physicians have to balance the problem of toxicity with the enhanced potency of the new complex. A further problem with this approach is that it can work only if the complex is degraded in the cell to its original components. In many cases this does not happen; additionally, degradation can begin before the complex has entered the target cells. Therefore, scientists have decided that the coupling approach is of limited practicality. In recent years, researchers have turned their attention to the liposomes as a possible solution to the drug delivery problem. Ever since their discovery in the 1960s by Alec Bangham.l liposomes have become the perfect model for studying biological membranes. The primary constituents of a liposome are lipids: lollipop-like molecules, consisting of a polar, hydrophilic head attached to a long, nonpolar, hydrophobic tail. The hydrophilic head typically consists of a phosphate group, whereas the hydrophobic tail is made of two long hydrocarbon chains (fatty acids). Because lipid molecules have one part that is water-soluble and one that is not, they tend to aggregate in ordered structures that sequester the hydrophobic tails from the water molecules. The lipids typically form bilayers in which the heads form the surfaces of a sandwich protecting the tails from the water environment. A flat sheet of a lipid bilayer, however, is not stable because the edges are exposed to the water. As a result, the lipid bilayer tends to wrap itself into dosed spherical structures called liposomes. About twenty years ago, scientists started envisioning liposomes as the best solution of the drug delivery problem.' If the medication can be encapsulated in a lipid vesicle such as a liposome, it will be shielded from the water environment of the blood. The liposomes will then circulate in the 2 bloodstream until they successfully deliver the drug to the targeted tissues. Once the liposomes reach the target cells, they would be taken up by endocytosis and their content would be dumped into the cell's cytoplasm. Additionally, liposomes would reduce the drug's possible toxicity because the drug would no longer enter the kidneys.l There is one major problem with liposomes though: they are recognized as foreign bodies. Liposomes are identified by the immune system as foreign and then macrophages, which are specialized cells from the reticuloendothelial system, destroy the liposomes. The immune system is so efficient in this process that liposomes can usually circulate intact only for a few hours. To be effective, though, liposomes have to circulate for at least 2 days so they can deliver the drugs to the tissues. Thus, the major problem of drug delivery has become the synthesis of liposomes that can resist destruction by the immune system for at least 48 hours. When constructing such liposomes, two things should be taken into consideration: the new liposomes should have reduced antigenic properties so they can avoid or delay recognition by the immune system, and they should be able to physically resist destruction by the reticuloendothelial system. Absolute resistance towards the immune systems can, of course, never be achieved nor is it necessary. ]f the liposomes circulate long enough they will have fulfilled their purpose before they are destroyed.