The complement system in liposome clearance: Can complement deposition be inhibited?

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Abstract

The activation of complement results in the opsonization of particles for removal by the reticuloendothelial system. Experimental evidence suggests that complement-mediated clearance of liposomal systems may significantly contribute to liposome biodistribution. Because of the multiplicity of complement activation mechanisms and the large number of proteins in the pathway, there are multiple opportunities to reduce or eliminate the opsonic effects of complement activation. This review addresses the state of our understanding of the interaction of liposomes with complement proteins and suggests some approaches to minimize complement activation.

Introduction

The deposition of activated complement proteins on the surface of liposomes is a critical step in the acceleration of liposome clearance by the reticuloendothelial system. For specific applications, the deposition of complement onto liposomes may assist in targeting liposomes to the RES; however, many potential liposome applications require a minimization of RES clearance with a concomitant increase in circulation residency times. In order to prolong the circulation times of liposomal systems, it is essential to prevent complement-mediated opsonization. To develop strategies to minimize complement activation, it is important to understand the physicochemical characteristics of liposomes that make them activate complement and the precise mechanisms of complement activation. As those working in the field of complement biochemistry identify the nuances of the complement regulatory pathways, new approaches to complement regulation become available to those working in other areas. This article reviews the biochemistry of the complement system and our current understanding of the contribution of complement to liposome removal from the circulation. The mastery of both complement and `liposomology' will be key to understanding the interactions of complement and liposomes and achieving this understanding is the only way to design intelligently specific inhibitors of complement for use in liposomal systems.

Section snippets

The complement system

The complement system evolved as an immediate host defense against invading pathogens. In mammals, complement proteins function not only in host defense but are also crucial for the clearance of circulating immune complexes and particulates such as aggregated proteins, the generation of the inflammatory response and the adequate development of immunological memory [1]. Although the activity of the complement system was identified in the latter part of the last century as an entity in serum that

Complement activation by liposomes

Liposomes have been used extensively as a model system in which to study the biochemistry of complement 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36. These studies have provided information about the physicochemical characteristics that influence in vitro complement activation. In general, the same characteristics have been shown to influence liposome clearance from the circulation 37, 38. Thus, the preponderance of evidence suggests that the activation of complement is an important parameter in

Strategies to minimize complement activation by liposomes

Data collected in both in vitro and in vivo studies suggest that the inhibition of complement-mediated opsonization should result in an increased biological half-life for liposomes and in the alteration of the tissue distribution of certain liposome compositions. The majority of studies to date have focused on the liposomal formulation as a means to reduce complement activation. While this has met with some success, modification of liposome formulation will ultimately be limited by effects on

Conclusion

As can be seen from the above discussion and from the other papers in this issue, the interaction of liposomes with blood plasma proteins, especially the complement proteins, has profound effects on the fate of liposomes in vivo. These interactions ultimately limit the applications of liposome technology for drug delivery or gene therapy. While the addition of polymer grafted phospholipids has achieved the goal of improving circulation residency times for the more conventional formulations,

Acknowledgements

This work was supported by grants in aid from the Medical Research Council of Canada (MT-10933) and the Canadian Red Cross Society Blood Services to DVD.

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