Cationic micelle delivery of Trp2 peptide for efficient lymphatic draining and enhanced cytotoxic T-lymphocyte responses

Abstract

Neutral particles 20-45 nm in diameter showed potential as tumor antigen vectors because they targeted the draining lymph nodes after subcutaneous injection. However, they were weakly immune-stimulatory and could also spread throughout the body, raising the risk of systemic toxicity. Here we explored whether incorporating positively charged amphiphilic polymers into micelles improves their site specificity and immunogenicity. Cationic polyethylenimine (2k)-stearic acid (PSA) micelles were loaded with the melanoma antigen peptide Trp2; they showed an average size of 28.7±8.2 nm and an encapsulation efficiency of 99.21±5.38%. Empty PSA micelles acted as a robust adjuvant in vitro, promoting maturation, proliferation and migration of bone marrow-derived dendritic cells in a dose-dependent manner. After subcutaneous injection into mice, Trp2-loaded PSA micelles accumulated preferentially in the medulla and paracortex of the draining lymph nodes and were present at negligible levels in the systemic circulation. Mice immunized with Trp2-loaded PSA micelles showed significantly higher Trp2-specific cytotoxic T lymphocyte activity than mice immunized with free Trp2 or a mixture of Trp2 and empty PSA micelles. In a B16-F10 murine melanoma model, Trp2-loaded PSA micelles inhibited tumor growth significantly more than did free Trp2 and PSA micelles caused less systemic toxicity. These findings suggest that cationic PSA micelles loaded with Trp2 may be a potential approach for melanoma immunotherapy.

Keywords: Cationic micelle; Cytotoxic T lymphocytes; Draining lymph node; Polyethylenimine; Trp2 antigen peptide.