Imran Nazir1, Andrea Fürst2, Noemi Lupo2, Andrea Hupfauf3, Ronald Gust3, Andreas Bernkop-Schnürch4. 1. Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria; Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus, 22060 Abbottabad, Pakistan. 2. Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria. 3. Center for Chemistry and Biomedicine, Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria. 4. Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria. Electronic address: andreas.bernkop@uibk.ac.at.
Abstract
AIM: The aim of the present study was to develop zeta potential changing self-emulsifying drug delivery systems (SEDDS) via a flip-flop mechanism in order to improve their mucus permeating and cellular uptake properties. METHODS: Phosphorylated serine-oleylamine (p-Ser-OA) conjugates were synthesized and incorporated into SEDDS at a concentration of 1% (v/v). Cytotoxic potential of p-Ser-OA and p-Ser-OA loaded SEDDS was investigated on Caco-2 cells. Phosphate release was evaluated using isolated as well as cell-associated intestinal alkaline phosphatase (AP). In parallel, change in zeta potential and amino group concentration on the surface of SEDDS was determined. Furthermore, mucus permeation and cellular uptake studies were performed. RESULTS: p-Ser-OA was synthesized by covalent attachment of serine (Ser) to oleylamine (OA) via a carbodiimide-mediated reaction followed by phosphorylation using phosphorous pentoxide (P2O5) and phosphoric acid (H3PO4). The chemical structure of p-Ser-OA was confirmed via FT-IR, 1H NMR, 13C NMR, 31P NMR and mass spectroscopic analysis. p-Ser-OA loaded SEDDS exhibited a droplet size and zeta potential of 46.42 ± 0.35 nm and -11.53 mV, respectively. A significant amount of phosphate was released after incubation with isolated as well as cell-associated AP within 6 h and zeta potential raised up to -2.04 mV. p-Ser-OA loaded SEDDS showed improved mucus permeation in comparison to p-Ser-OA loaded SEDDS treated with AP. Moreover, cellular uptake increased almost 2-fold after phosphate cleavage using AP. CONCLUSION: Findings of this study show that SEDDS changing their zeta potential via a flip-flop mechanism exhibit both high mucus permeating and high cellular uptake properties.
AIM: The aim of the present study was to develop zeta potential changing self-emulsifying drug delivery systems (SEDDS) via a flip-flop mechanism in order to improve their mucus permeating and cellular uptake properties. METHODS: Phosphorylated serine-oleylamine (p-Ser-OA) conjugates were synthesized and incorporated into SEDDS at a concentration of 1% (v/v). Cytotoxic potential of p-Ser-OA and p-Ser-OA loaded SEDDS was investigated on Caco-2 cells. Phosphate release was evaluated using isolated as well as cell-associated intestinal alkaline phosphatase (AP). In parallel, change in zeta potential and amino group concentration on the surface of SEDDS was determined. Furthermore, mucus permeation and cellular uptake studies were performed. RESULTS:p-Ser-OA was synthesized by covalent attachment of serine (Ser) to oleylamine (OA) via a carbodiimide-mediated reaction followed by phosphorylation using phosphorous pentoxide (P2O5) and phosphoric acid (H3PO4). The chemical structure of p-Ser-OA was confirmed via FT-IR, 1H NMR, 13C NMR, 31P NMR and mass spectroscopic analysis. p-Ser-OA loaded SEDDS exhibited a droplet size and zeta potential of 46.42 ± 0.35 nm and -11.53 mV, respectively. A significant amount of phosphate was released after incubation with isolated as well as cell-associated AP within 6 h and zeta potential raised up to -2.04 mV. p-Ser-OA loaded SEDDS showed improved mucus permeation in comparison to p-Ser-OA loaded SEDDS treated with AP. Moreover, cellular uptake increased almost 2-fold after phosphate cleavage using AP. CONCLUSION: Findings of this study show that SEDDS changing their zeta potential via a flip-flop mechanism exhibit both high mucus permeating and high cellular uptake properties.