Preliminary study on immune mechanisms of pH-sensitive transmembrane peptide modified liposome loaded with α-galactosylceramides / 药学学报

ABSTRACT

In this study, we aim to develop a pH-sensitive transmembrane peptide TH (AGYLLGHINLHH LAHL(Aib)HHIL-Cys) modified liposome loaded with immunoadjuvant α-galactosylceramides (αGC-TH- Lip) and then investigate its effect on the immune function in tumor-bearing mice and its immune mechanism of action. The liposomes were prepared by membrane dispersion-probe ultrasound method and the size and zeta potential of αGC-TH-Lip were also characterized. The uptake of TH modified liposomes (TH-Lip) and polyethylene glycols modified liposomes (PEG-Lip) in DC2.4 cells in vitro were analyzed and the activation of natural killer T (NKT), natural killer (NK) and macrophages in tumor-bearing mice were also measured after systemic administrations of samples. Besides, the degree of maturation of dendritic cell (DC), the number of cytotoxic T lymphocyte (CTL) and the differentiation of helper T cell (Th) were determined. The results showed the particle size of αGC-TH-Lip was about 117.9 nm and the zeta potential was about -8.37 mV under the neutral condition (pH 7.4) and the αGC-TH-Lip had high serum stability in 50% fetal bovine serum. The uptake of TH-Lip in DC2.4 cells in vitro was 1.48 times higher than that of PEG-Lip. After systemic administrations of the samples, the numbers of NKT cells, NK cells and macrophages in tumor-bearing mice were (0.43±0.048)%, (12.80±0.50)% and (3.13±0.26)%, respectively, and the number of mature DCs and CTLs reached (2.30±0.22)% and (32.30±0.80)% separately, which was significantly different from the con-trol group. Finally, we discovered the αGC-TH-Lip had the strongest induction effect on the differentiation of Th1 cells, while barely promote the differentiation of Th2 cells. All the above results demonstrated that the αGC-TH-Lip can improve the immune the activity of mice, enhance the effect of α-galactosylceramide and promote the differentiation of lymphocytes toward the direction of cellular immunity, which consequently achieve a better anti-cancer immune activity.