Modulation of intrahepatic immune responses through nanoparticle-mediated delivery of drugs, adjuvants, and antigens
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Abstract
Targeted delivery of drugs, antigens, or adjuvants to organs and cells of interest is a promising concept for the development of novel drug or vaccine formulations. Polymeric nanocapsules are particularly suited for the application as vaccine delivery systems, since they facilitate combined delivery of antigens along with adjuvants to antigen-presenting cells (APCs). Intravenous administration of these nanocarriers enables targeting of liver APCs inducing intrahepatic T cellular immune responses essential for eradication of viral infections, e.g. hepatitis C virus (HCV). Aim of the study was the modulation of intrahepatic immune responses using functionalized polymeric nanocapsules (NCs) made of hydroxyethyl starch, dexamethasone, heparin, hyaluronic acid, ovalbumin, and HCV non-structural protein 5A (NS5A). The induction of intrahepatic antigen-specific immune responses was achieved by surface functionalization of NS5A nanocapsules with monophosphoryl lipid A (MPLA). Uptake of these NC formulations by dendritic cells induced vigorous maturation reducing the required equipotent MPLA dosage by more than 15 times. Immunization with MPLA-supplemented NS5A nanocapsules generated robust intrahepatic T cellular immune responses and substantial levels of antigen-specific antibodies. Polymeric nanocapsules, made of immunosuppressive drugs or antigens, represent a novel approach for an effective and targeted treatment of inflammatory and infectious liver diseases such as autoimmune hepatitis or HCV.