Abstract
(1) Background: Cytoplasmic delivery of antigens is crucial for the induction of cellular immunity, which is an important immune response for the treatment of cancer and infectious diseases. To date, fusogenic protein-incorporated liposomes and pH-responsive polymer-modified liposomes have been used to achieve cytoplasmic delivery of antigen via membrane rupture or fusion with endosomes. However, a more versatile cytoplasmic delivery system is desired for practical use. For this study, we developed pH-responsive micelles composed of dilauroyl phosphatidylcholine (DLPC) and deoxycholic acid and investigated their cytoplasmic delivery performance and immunity-inducing capability. (2) Methods: Interaction of micelles with fluorescence dye-loaded liposomes, intracellular distribution of micelles, and antigenic proteins were observed. Finally, antigen-specific cellular immune response was evaluated in vivo using ELIspot assay. (3) Results: Micelles induced leakage of contents from liposomes via lipid mixing at low pH. Micelles were taken up by dendritic cells mainly via macropinocytosis and delivered ovalbumin (OVA) into the cytosol. After intradermal injection of micelles and OVA, OVA-specific cellular immunity was induced in the spleen. (4) Conclusions: pH-responsive micelles composed of DLPC and deoxycholic acid are promising as enhancers of cytosol delivery of antigens and the induction capability of cellular immunity for the treatment of cancer immunotherapy and infectious diseases.
Highlights
Cell-mediated immune response plays a crucially important role in the treatment of chronic infectious disease, elimination of virus-infected cells, prophylactic vaccine, and cancer immunotherapy because cytotoxic T lymphocytes (CTLs) can attack tumor cells and virus-infected cells directly [1,2,3,4]
These results indicate that surface of micelles are covered with carboxyl groups derived from deoxycholic acid [25]
Green fluorescence, which signifies the recovery of NBD fluorescence by lipid mixing, was observed clearly within cells (Figure 4c). These results indicate that dilauroyl phosphatidylcholine (DLPC)/deoxycholic acid micelles induced lipid mixing with endo/lysosomes responding to weakly-acidic pH and that subsequent membrane rupture might lead the diffusion of rhodamine B-sulfonyl phosphatidylethanolamine (Rh-PE) molecules to inner spaces of cells
Summary
Cell-mediated immune response (cellular immunity) plays a crucially important role in the treatment of chronic infectious disease, elimination of virus-infected cells, prophylactic vaccine, and cancer immunotherapy because cytotoxic T lymphocytes (CTLs) can attack tumor cells and virus-infected cells directly [1,2,3,4]. For induction of CTL-based cellular immunity, delivery of antigens into the cytosol of antigen-presenting cells, such as macrophages or dendritic cells (DCs), is necessary, which leads to the processing of antigens via proteasome, antigen-loading on major histocompatibility complex (MHC) class I, and antigen presentation to CD8-positive. After an exogenous antigen is taken up by antigen-presenting cells via endocytosis it is processed in endo/lysosomes, which leads to MHC class II-mediated antigen presentation to CD4-positive T lymphocytes [5,6]. Promotion of exogenous antigen transfer into cytosol using endosomolytic reagents or intracellular delivery carriers is necessary to achieve antigen-specific cellular immunity. This process is known as “cross-presentation” [7]. Endosomolytic reagents, such as chloroquine, promote the transfer of antigen into cytosol
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