Enantiospecific adjuvant activity of cationic lipid DOTAP in cancer vaccine

Abstract

Commercially available DOTAP is a racemic mixture of two enantiomers. The adjuvanticity of each isomer was examined using a peptide/lipid complex as a therapeutic vaccine in an established murine cervical cancer model. This simple vaccine consists of a cationic lipid (DOTAP) and a major histocompatibility complex (MHC) class I–restricted epitope of the Human Papillomavirus (HPV) 16 protein E7. Dose-dependent tumor regression experiments have been completed for racemic DOTAP/E7, (R)-DOTAP/E7 and (S)-DOTAP/E7. Tumor-bearing mice treated with (R)-DOTAP/E7 complexes have shown tumor regression in a dose-dependent manner comparable to those mice treated with a racemic DOTAP with E7 peptide. These data are supported by IFN-γ production by CD8+ splenocytes, in vivo cytotoxic T-lymphocytes (CTL) response, CD8+ tumor-infiltrating lymphocytes (TIL), and IFN-γ production by CD8+ TIL in (R)-DOTAP/E7-vaccinated mice. When (S)-DOTAP/E7 is delivered, tumor progression is delayed. While IFN-γ production is absent from CD8+ splenocytes in mice vaccinated with (S)-DOTAP/E7, IFN-γ production by CD8+ TIL is present, supporting our hypothesis that (S)-DOTAP has limited activity. Activation of bone marrow-derived dendritic cells by the enantiomeric formulations has also been evaluated, as well as cytokine production and toxicity with no considerable differences between the groups. The results show the DOTAP enantiomers act differently as adjuvants in vivo, with (R)-DOTAP being more effective at stimulating a CD8+ anti-tumor response.

The potential of antigen and TriMix sonoporation using mRNA-loaded microbubbles for ultrasound-triggered cancer immunotherapy

“…Another possibility is direct triggering of innate immune responses by the cationic lipids (in this case DOTAP) within the mRNA lipoplexes, via TLR4 ligation. This, charge-related TLR activation was previously reported for DOTAP-containing lipoplexes as well as for various cationic polymers that are routinely used as transfection reagents [32,33]. Likely, the observed effects are caused by a combination of these different mechanisms.…”

Current understanding of interactions between nanoparticles and the immune system

“…Furthermore, lipid nanocarriers were shown to contribute to the drug's immunostimulation (Abrams et al, 2010). Examples of immunostimulatory lipids used to prepare nanocarriers for therapeutic nucleic acids include 2-(4-[(3β)-cholest-5-en-3-yloxy]butoxy)-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-1-amine (CLinDMA) and PEG-dimyristoylglycerol (Abrams et al, 2010), protamine (Li et al, 1999), trimethyl ammonium propane-cholesterol (Kim et al, 2007), and 1,3-dioleoyl-3-trimethylammonium propane (DOTAP) (Li et al, 1999; Vasievich et al, 2011). Clinical studies investigating the safety of such formulations are often designed to prevent adverse reactions by premedicating patients with immunosuppressive cocktails containing immunosuppressive agents (e.g dexamethasone), antipyretic agents (e.g acetaminophen), histamine H1 receptor blockers (e.g.…”

Selection of Adjuvants for Enhanced Vaccine Potency

“…The type and degree of immunogenicity enhancement by liposomes depends on liposome's composition, size, the type of antigens [185], and interestingly, the chirality of lipids [186] Liposomes made of S. cerevisiae membrane lipids are more effective than egg PC liposomes in inducing IgG2a, IFN-, and IL-4 cytokine [170]. Cationic lipid vesicles (comprising a cationic cholesterol derivative, DC-Chol) bind strongly split influenza vaccine antigens and induced robust anti-influenza immune responses while neutral cholesterol/DOPC liposomes displayed virtually no stable antigen binding and no adjuvant effect in mice [187].…”