Liposome research in drug delivery: The early days

Arguably, the first rational attempts to deliver drugs in a specific manner were made in the 1950s with the use of polyclonal antibodies. This work, although intellectually attractive, was unremarkable in terms of results (O’Neil 1979). In the ensuing years, drug delivery and targeting evolved into system versions of considerable sophistication and wider scope. They include an array of receptor-specific ligands, humanized monoclonal antibodies, a variety of designer polymers and a multitude of microspheres. Effective delivery of drugs via such systems in the treatment or prevention of disease is now the aim of numerous research groups worldwide. It covers therapies such as those for cancer, microbial infections, hormone and enzyme deficiencies, gene deficiency or malfunction, as well as vaccines. Intimate knowledge of the structure and physical properties of these systems, and of the ways such properties influence system behaviour within the biological milieu, is central to their success. The significance of the relationship between these two aspects (structure and behaviour in vivo) in the design of pharmacologically optimal constructs was fully realized and systematically explored with the advent of liposomes. The discovery of liposomes in the mid1960s (Bangham et al. 1965) and their similarity to cell membranes presented cell biologists with a unique tool for the study of a number of cell membrane functions including cell fusion, membrane pumps and antigen presentation. It was not until several years later that liposomes were considered as a candidate carrier for the delivery of pharmacologically active agents in the treatment of disease (Gregoriadis et al. 1971; Gregoriadis and Ryman 1972a, b). Liposome research in drug delivery and targeting is often discussed in the context of decades marked by significant milestones. For instance, the 1970s are noted for the initial understanding of the system’s behaviour in vivo, namely its interaction with the biological milieu in the living animal and, as a result, the proposition of an array of therapeutic applications. Following a period of ‘disillusionment’ of those with expectations unjustified by the degree to which liposomes had been developed at that time, the 1980s were a period of reflection and consolidation. This was also a period of advancements in improving liposomal stability in biological fluids (e.g. blood; Lasic and Martin 1996), in liposome technology (Gregoriadis 1992) in terms of developing techniques for high-yield drug entrapment and the preservation of intact liposomes under storage. Importantly, the founding in 1981 of three liposome-based companies in the USA ensured a systematic transition of some of the earlier concepts (Gregoriadis 1976; Gregoriadis 1977; Papahadjopoulos 1978) to realistic goals, backed by significant progress in large-scale technology. The 1990s were clearly the decade of clinical trials, approved injectable products (e.g. AmBisome, Doxil), and of new horizons. As the present decade approaches its end, nearly 40 years after work on the use of liposomes in drug delivery commenced, enthusiasm is still prevailing. The old guard of liposomologists who were ‘there’ from the very beginning, but are gradually retiring into new pastures, are being replaced by worthy successors. Below I discuss early developments which are thought to have helped shape the future of the field. My audience includes young liposomologists entrapped in the maize of a myriad of publications of varying clarity, insight, accuracy and, perhaps, bias. My affair with liposomes, described in more detail elsewhere (Gregoriadis 1995), begun with a chance event. In 1969, while in New York, I came across a