Aim: Evaluation of different polyhydroxy surfaces in SEDDS to overcome the limitations associated with conventional polyethylene glycol (PEG)-based SEDDS surfaces for intracellular drug delivery.

Methods: Anionic, cationic and non-ionic polyglycerol- (PG-) and alkylpolyglucoside- (APG-) surfactant based SEDDS were developed and compared to conventional PEG-SEDDS. Particular emphasis was placed on the impact of SEDDS surface decoration on size and zeta potential, drug loading and protective effect, mucus diffusion, SEDDS-cell interaction and intracellular delivery of the model drug curcumin.

Results: After self-emulsification, SEDDS droplets sizes were within the range of 35-190 nm. SEDDS formulated with high amounts of long PEG-chain surfactants (>10 monomers) a charge-shielding effect was observed. Replacing PEG-surfactants with PG- and an APG-surfactant did not detrimentally affect SEDDS self-emulsification, payloads or the protection of incorporated curcumin towards oxidation. PG- and APG-SEDDS bearing multiple hydroxy functions on the surface demonstrated mucus permeation comparable to PEG-SEDDS. Steric hinderance and charge-shielding of PEG-SEDDS surface substantially reduced cellular uptake up to 50-fold and impeded endosomal escape, yielding in a 20-fold higher association of PEG-SEDDS with lysosomes. In contrast, polyhydroxy-surfaces on SEDDS promoted pronounced cellular internalisation and no lysosomal co-localisation was observed. This improved uptake resulted in an over 3-fold higher inhibition of tumor cell proliferation after cytosolic curcumin delivery.

Conclusion: The replacement of PEG-surfactants by surfactants with polyhydroxy head groups in SEDDS is a promising approach to overcome the limitations for intracellular drug delivery associated with conventional PEGylated SEDDS surfaces.

Keywords: Intracellular drug delivery; PEG-free; Polyglycerol; Polyhydroxy; Saccharide; Surface modification; self-emulsifying drug delivery system (SEDDS).

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