For this reason, most of the novel vaccine formulations comprise a combination

of adjuvants. The most common combination of adjuvants with different action mechanism is the use of a vaccine delivery system which contains the antigen and an immune potentiating adjuvant. For instance, combination of PLGA nanoparticles coencapsulating the poorly immunogenic melanoma antigen, tyrosinase-related protein 2 (TRP2), along with Toll-like receptor 4 ligand (TLR4) (7-acyl lipid A) led to a therapeutic antitumor effect against melanoma after the subcutaneous administration to mice [151]. Although they do not contain synthetic peptides, some of the licensed vaccines Inhibitors,research,lifescience,medical are comprised of a mixture of adjuvants, such as Gardasil (composed of VLPs and alum), Fendrix (NLG919 comprising AS04, approved for human use in Europe and USA), or Cervarix (which includes AS04 and VLPs). These vaccines present a high immunogenicity and are safe [26, 152]. 3.2. Targeting Antigens to Dendritic Inhibitors,research,lifescience,medical Cells Vaccine delivery systems can incorporate ligands in order to specifically

Inhibitors,research,lifescience,medical target APCs receptors. It has been shown that ligand grafting can enhance the uptake of microparticles by immune cells. Brandhonneur et al. [153] studied the uptake of different ligand-grafted PLGA microspheres by alveolar macrophages of pigs ex vivo. Three different ligands were used: WGA (lectin weat germ agglutinin, which interacts with lectin receptors), a RGD (arginine-glycine-aspartate) containing peptide (interacting on integrins), and a carbohydrate moiety (manose-PEG3-NH2, interacting on manose receptor). A much higher uptake was observed for mannose-, WGA-, and RGD-grafted microspheres, mainly because of the specific mechanism of phagocytosis.

When other ligands were grafted to the microspheres (peptides Inhibitors,research,lifescience,medical like BSA—bovine serum albumin or RAD—arginine-alanine-aspartame), the uptake was not significantly different from Inhibitors,research,lifescience,medical ungrafted microspheres, due to the nonspecific mechanism of uptake, given the lack of receptors for BSA and RAD into macrophages. Among PRR ligands, TLR ligands have been widely studied. TLR activation leads to upregulation of CD40, CD80, Thiamine-diphosphate kinase CD86, and CD70 costimulatory molecules in the surface of APCs, as well as release of Th1 cytokines such as IL-1, IL-2, IL-6, and TNF. In addition, some ligands are able to trigger cross-presentation. Therefore, TLRs facilitate coordination between innate and adaptive immunities by activating B and T cells as well as memory responses [154]. It has been shown that antigens and TLR ligands can generate more potent immune responses when coencapsulated into the same particle [155]. This can be understood taking into account that endosomal organelles of DCs express some TLRs, in addition to posses machinery to process captured antigens and present them into MHC molecules. Consequently, simultaneous delivery of antigen and TLR-ligands into the cytosol may lead to a better DC activation and subsequent development of immune response.