Abstract
HypothesisSimple zwitterions used as auxiliary agents might have the potential to change the zeta potential of oil-in-water (o/w) nanoemulsions on the mucosa. ExperimentsThe zwitterion phosphorylated tyramine (p-Tyr) was synthesized by phosphorylation of Boc-tyramine (Boc-Tyr) using phosphoryl chloride (POCl3). It was incorporated with 2% (m/v) in a self-emulsifying lipophilic phase comprising Captex 35, Cremophor EL, Capmul MCM and glycerol 85 at a ratio of 30:30:30:10 v/v. Phosphate release and resulting change in zeta potential were evaluated by incubating p-Tyr containing nanoemulsion with isolated intestinal alkaline phosphatase (AP). Mucus permeating behavior was evaluated across mucus obtained from porcine small intestinal mucosa. Subsequently, cellular uptake studies were accomplished on Caco-2 cells. FindingsThe p-Tyr loaded nanoemulsion exhibited a mean droplet size of 43 ± 1.7 nm and zeta potential of −8.40 mV. Phosphate moieties were rapidly cleaved from p-Tyr loaded nanoemulsions after incubation with isolated AP resulting in a shift in zeta potential from −8.40 mV to +1.2 mV. p-Tyr loaded nanoemulsion revealed a significantly (p ≤ 0.001) improved mucus permeation compared to the same nanoemulsion having been pre-treated with AP. Cellular uptake of the zeta potential changing oily droplets was 2.4-fold improved. Phosphorylated zwitterions seem to be an alternative to cationic surfactants and considered as promising auxiliary agents for zeta potential changing nanoemulsions.
Highlights
To overcome the anionically charged mucus gel layer on the one hand and to provide a positive charge on the cell membrane for an improved cellular uptake on the other hand, the approach of zeta potential changing nanocarriers was pioneered [1]
A similar migration of amino groups to the surface of the oily droplets after phosphate cleavage was observed in another study utilizing phosphorylated 12-amino-dodecanol as a zeta potential changing agent [15]. These results provided additional evidence for the accumulation of phosphorylated tyramine (p-Tyr) on the interphase of the nanoemulsion, as an increase in primary amino groups in the aqueous phase due to the addition of alkaline phosphatase (AP) can only be explained by a phosphate cleavage of p-Tyr on the droplet surface followed by a change in orientation of the former zwitterion with its amino group heading towards the aqueous phase
All zeta potential changing nanoemulsions contain a cationic surfactant after phosphate cleavage being responsible for a change to a positive zeta potential [8]
Summary
To overcome the anionically charged mucus gel layer on the one hand and to provide a positive charge on the cell membrane for an improved cellular uptake on the other hand, the approach of zeta potential changing nanocarriers was pioneered [1]. Nanocarriers displaying a negative zeta potential due to phosphate moieties on their surface were shown to rapidly permeate the negatively charged mucus gel layer covering mucosal membranes. When these phosphorylated nanocarriers reach the epithelium, the anionic phosphate moieties are cleaved off by alkaline phosphatase (AP) expressed on the surface of epithelial cells resulting in a shift in zeta potential to positive values and in an improved cellular uptake.
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