The use of poly(ethylene glycol)-modified lipids in liposomes : subtitle an immunological perspective

The potential of liposomes as delivery vehicles has long been recognized. In recent years, liposome research was further advanced by the invention of a hydrophilic polymer poly(ethylene glycol) (PEG) which stabilizes liposome surface. This second generation of liposomes exhibit long circulation lifetimes, attributed to the ability of PEG to interfere with liposome removal by the defense mechanism of the host. The long circulation property of PEGylated liposomes has been, in general, claimed to be due to the ability of these liposomes to evade the immune system. However, the finding that PEGylated liposomes can generate immune responses suggests that PEG does not actually limit liposome interaction with the immune system. To date, there is insufficient information in the literature with regard to the role of grafted PEG to alter liposome interaction with the immune system. The research summarized in this thesis has resulted in a better understanding of the implications of using PEG-lipids in liposomes from an immunological perspective. In Chapter 2 and 3 of this thesis, the use of PEG-lipids is discussed in terms of interaction with mechanisms of the immune system for liposome removal. This concerns the development of liposomes with functional groups which are potentially immunogenic. Using biotin as a model ligand, it was found that liposomes can be protected from immune recognition by specific antibodies and the subsequent rapid removal from the circulation. In Chapter 4 and 5, from the perspective of the impact on the immune system, the ability of PEGylatedliposomes to induce immune responses was examined to test the hypothesis that incorporation of PEG-lipids re-directs liposomes from macrophages to more relevant antigen presenting cells. This has important implications for the development of liposomes as vaccine carriers. Using two different types of antigens, namely a T-independent antigen and a tumor antigen, that stimulate different effector functions of the immune system, it is demonstrated that surface-grafted PEG enhances antibody response in both cases. The results presented in this thesis provide a better understanding of the pros and cons of using PEG-lipids in liposomes for various applications.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat