Liposomal drug delivery systems: From concept to clinical applications

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Abstract

The first closed bilayer phospholipid systems, called liposomes, were described in 1965 and soon were proposed as drug delivery systems. The pioneering work of countless liposome researchers over almost 5 decades led to the development of important technical advances such as remote drug loading, extrusion for homogeneous size, long-circulating (PEGylated) liposomes, triggered release liposomes, liposomes containing nucleic acid polymers, ligand-targeted liposomes and liposomes containing combinations of drugs. These advances have led to numerous clinical trials in such diverse areas as the delivery of anti-cancer, anti-fungal and antibiotic drugs, the delivery of gene medicines, and the delivery of anesthetics and anti-inflammatory drugs. A number of liposomes (lipidic nanoparticles) are on the market, and many more are in the pipeline. Lipidic nanoparticles are the first nanomedicine delivery system to make the transition from concept to clinical application, and they are now an established technology platform with considerable clinical acceptance. We can look forward to many more clinical products in the future.

Section snippets

Introduction: the pioneers

Since the internet has made literature searches relatively straightforward, there has been a tendency to overlook the early scientific literature and to forget, or fail to cite, the important contributions of the early pioneers in the liposome field. We have made a special effort in this paper to find those early references and give credit to the liposome pioneers — and put their contributions into context.

It is our intent to focus on the early work in the liposome field, especially work done

Drug loading and control of the drug release rate

It soon became clear that there were a number of problems associated with the in vivo use of the 1st generation liposomes, sometimes termed ‘classical’ or conventional liposomes. A very early observation was the difficulty in retaining some types of entrapped molecules in the liposome interior [16], [22], [38]. Drug release was shown to be affected by exposure to serum proteins [39], [40], [41]. Changing the content of the liposome bilayer, in particular by incorporation of cholesterol [40],

Receptor-mediated endocytosis of ligand-targeted liposomes

Early in the history of liposomes it was recognized that a means of increasing the selectivity of the interaction of liposomes with diseased cells was desirable. If this interaction triggered receptor-mediated endocytosis of the liposome and its cargo into the desired cellular target, then so much the better. Antibodies were used in early experiments to mediate their specific attachment target cells [100], [101], and receptor-mediated endocytosis of liposomes was demonstrated [102], [103], [104]

Triggered release

Stability of liposomes in the circulation with retention of their contents has long been recognized as a desirable liposome characteristic for successful drug delivery to diseased tissues. Over two decades ago, it was also recognized that being able to trigger the release of liposomal contents once they reached the target site would lead to improvements in therapeutic outcomes. Two main types of triggers have been explored, remote triggers such as heat, ultrasound and light, and local triggers

Delivery of nucleic acids and DNA

Soon after the first animal experiments began to show improved therapeutic outcomes for small molecule therapeutics, came the realization that liposomes could also be effective delivery systems for DNA [185], [186], and for nucleic acid-based therapeutics such as antisense oligonucleotides (asODN) and siRNA [187]. In vivo delivery of polynucleic acids using lipid-based systems began with an early report that a liposomally encapsulated plasmid for rat insulin could result in gene expression

Combination therapy

The principles of combination chemotherapy, i.e., the combination of therapies with different mechanisms of action and non-overlapping side effects, can be applied to the development of nanomedicines [228], [229], [230], [231], [232], [233], [234]. A variety of different types of combinations have been use in recent years, with at least additive increases in therapeutic outcomes for the combinations compared to individual therapies. Several different types of therapeutic combinations have been

Multi-functional, multi-component formulations

Increasingly, the formulation and use of multi-functional, multi-component liposomal nanoparticles, sometimes referred to as theragnostics, is being explored — formulations that carry within an individual lipidic nanoparticle functions such as site-specific targeting, biomarker and imaging capabilities, delivery of combinations of therapeutics, and response to external or internal triggers to control drug release [242]. As the complexity of lipidic nanoparticles increases, so do the expenses

Clinical development

Both ‘classical’ and ‘Stealth’ liposomes have entered the mainstream as sustained release drug delivery systems [243] for the in vivo delivery of everything from small molecule therapeutics to nucleic acids. Early papers that were important in the clinical development of liposomes include a 1985 paper by Morgan et al. that demonstrated accumulation of liposomes labeled with technetium 111 in sites of infection and inflammation in humans [244], and a subsequent paper that showed accumulation of

Conclusions

In the 40 plus years from the concept of the clinical utility of liposomes to their recognized position in the mainstream of drug delivery systems, the path has been long and winding. They have been explored in the clinic for applications as diverse as imaging tumors and sites of infection, for vaccine and gene medicine delivery, for treatment of infections and for cancer treatment, for lung disease and for skin conditions. In clinical applications, liposomal drugs have been proven to be most

Acknowledgements

The authors would like to acknowledge the outstanding contributions of the staff and trainees of their respective laboratories to the development of liposome technologies. We also thank the following agencies and companies for their funding support: Canadian Institutes for Health Research, Canadian Breast Cancer Association, National Cancer Institute of Canada, National Science and Engineering Research Council of Canada, Canada Foundation for Innovation, Centre for Drug Research and Development

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    This review is part of the Advanced Drug Delivery Reviews theme issue on “25th Anniversary issue — Advanced Drug Delivery: Perspectives and Prospects”.

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