Replacing PEG-surfactants in self-emulsifying drug delivery systems: Surfactants with polyhydroxy head groups for advanced cytosolic drug delivery

• Published in: International journal of pharmaceutics 2022-04, Vol.618, p.121633-121633, Article 121633
• Main Authors: Friedl, Julian David, Jörgensen, Arne Matteo, Nguyen Le, Nguyet-Minh, Steinbring, Christian, Bernkop-Schnürch, Andreas
• Format: Article
• Language: English
• Subjects: Curcumin; Drug Delivery Systems - methods; Emulsifying Agents - metabolism; Emulsions; Excipients; Intracellular drug delivery; PEG-free; Polyethylene Glycols; Polyglycerol; Polyhydroxy; Saccharide; self-emulsifying drug delivery system (SEDDS); Solubility; Surface modification; Surface-Active Agents
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2022.121633

[Display omitted] •Polyethylene glycol- (PEG-) surfactants in self-emulsifying drug delivery system (SEDDS) can be successfully substituted by surfactants bearing polyhydroxy head groups.•Mucus permeation of SEDDS with polyhydroxy-decorated surfaces was comparable to conventional SEDDS with PEGylated surface.•Long PEG-chains on SEDDS surfaces were identified to impair cellular uptake and increase endosomal and lysosomal entrapment.•Polyhydroxy-decorated surfaces on SEDDS promoted superior cellular internalisation and showed only negligible co-localisation with lysosomes.•Polyhydroxy-decorated SEDDS surfaces outperformed conventional PEGylated SEDDS surfaces in inhibiting tumor cell proliferation after cytosolic delivery of curcumin. Evaluation of different polyhydroxy surfaces in SEDDS to overcome the limitations associated with conventional polyethylene glycol (PEG)-based SEDDS surfaces for intracellular drug delivery. 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. 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. 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 wit