Abstract
Recently, nanofibers (NFs) formed from antigenic peptides conjugated to β-sheet-forming peptides have attracted much attention as a new generation of vaccines. However, studies describing how the hydrophilic-hydrophobic balance of NF components affects cellular interactions of NFs are limited. In this report, three different NFs were prepared by self-assembly of β-sheet-forming peptides conjugated with model antigenic peptides (SIINFEKL) from ovalbumin and hydrophilic oligo-ethylene glycol (EG) of differing chain lengths (6-, 12- and 24-mer) to investigate the effect of EG length of antigen-loaded NFs on their cellular uptake, cytotoxicity, and dendritic cell (DC)-stimulation ability. We used an immortal DC line, termed JAWS II, derived from bone marrow-derived DCs of a C57BL/6 p53-knockout mouse. The uptake of NFs, consisting of the EG 12-mer by DCs, was the most effective and activated DC without exhibiting significant cytotoxicity. Increasing the EG chain length significantly reduced cellular entry and DC activation by NFs. Conversely, shortening the EG chain enhanced DC activation but increased toxicity and impaired water-dispersibility, resulting in low cellular uptake. These results show that the interaction of antigen-loaded NFs with cells can be tuned by the EG length, which provides useful design guidelines for the development of effective NF-based vaccines.
Highlights
Peptide-based synthetic vaccines have attracted a significant amount of attention as a new generation of vaccines, because of their safety benefits and ease of production when compared with that of conventional whole pathogen-based vaccines [1,2]
The monomeric peptides exhibited some cytotoxicity but no dendritic cell (DC) activation ability, which is in sharp contrast to the results with NFs (Figure 7a, Figure 8, and Figure 9). These results suggest that monomeric peptides interact with cell membranes, possibly through an N-terminal hydrophobic region, but are not well recognized by receptors involved in DC activation
We demonstrated that the hydrophilic-hydrophobic balance of peptide NFs affects their cellular uptake, cytotoxicity, and DC activation ability
Summary
Peptide-based synthetic vaccines have attracted a significant amount of attention as a new generation of vaccines, because of their safety benefits and ease of production when compared with that of conventional whole pathogen-based vaccines [1,2]. Over the past few decades, various nanocarriers have been developed, including liposomes [3,4,5], polymeric nanoparticles [6,7,8], and polymeric micelles [9] In many of these systems, building block molecules for the construction of nanocarriers are first synthesized and combined with antigenic peptides via several procedures, including nanomaterial formation and loading of antigenic peptides (encapsulation, chemical immobilization or physical adsorption), to give a nano-formulation. The use of antigenic peptides that are pre-conjugated to self-assembly motifs has attracted attention as an easier and simpler procedure to produce nano-formulations [10,11] This self-assembly approach ensures highly efficient drug loading without laborious procedures or the use of synthetic components, which sometimes exhibit toxicity. Because the resulting nanostructures consist of a single component, the physicochemical and structural features of these nanostructures can be tuned by the design of the building block peptide, and variation in drug loading efficiency among different nanostructures can be eliminated
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