Theoretical considerations of RES-avoiding liposomes: Molecular mechanics and chemistry of liposome interactions

The development of long-circulating, RES-avoiding liposomes has become a remarkable milestone in the progress of contemporary pharmacology. Drugs incorporated in such liposomes are protected from fast metabolization and clearance, and can be further targeted to a desired tissue site. Ideally, future developments should result in drug carriers which can identify and act upon their targets with even higher efficiency and selectivity, preferably close to or exceeding that of the natural immune cells. Further increasing carrier 'inertness' with regard to the normal biological milieu is the major requirement for future success. The ability of natural blood components to circulate with blood for several days and weeks presents both the motivation and the challenge for further research. Today, even the best available preparations are inferior to natural proteins and cells with regard to their ability to remain in circulation by approximately two orders of magnitude. In view of the above, it seems vitally important to determine the mechanisms responsible for glycolipid- or polymer-modified liposome protection against RES, and whether any potentially useful mechanisms have been underutilized. Furthermore, identification of quantitative dependencies between liposome structure and pharmacokinetics (and mechanisms underlying such dependencies) would benefit future research and reduce the cost of development. This paper discusses the relationships between liposome structure and circulation with respect to the theoretical mechanistic models of mass transfer, liposome interactions with cells and blood proteins, and boundary effects resulting from surface modification. Special attention is paid to the practical application and limitations of the models. (C) 1998 Elsevier Science B.V.