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

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.

Highlights

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.

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.

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Materials

Capmul MCM C8 (glyceryl monocaprylate, G8MD) and Captex 355 (glyceryl tricaprate, MCT) were donated by Abitec (Columbus, USA). Labrasol (PEG8- caprylic/capric glycerides, PEG8-glycerides), Peceol (Glyceryl monooleate, GMO), Gelucire 44/14 (Lauroyl PEG-32 glycerides, LPEG32G) and Gelucire 48/16 (PEG32-stearate) were a gift from Gattefosse (Lyon, France). Curcumin (from Curcuma longa, content >65%), Kolliphor RH40 (PEG40- hydrogenated castor oil, PEG40HCO), Kolliphor EL (PEG35-castor oil, PEG35CO), benzyl alcohol (BA), ethanol (EtOH), glycerol 85%, dimethylsulfoxide (DMSO), dioleyldimethylammonium bromide (DODAB), sulforhodamine B, oleic acid and ethyl oleate were supplied by Sigma-Aldrich (Vienna, Austria). Tegosoft PC41 (PG4-caprate) and Tegosolve 90 (PG6-caprylate/PG4-caprate, PG4/6C) were a gift from Evonik (Hamburg, Germany). Natragem SP140 NP (PG-4 laurate/sebacate and PG-6 caprylate/caprate, PG4LS/PG6CC) and Multitrope 1620 (alkylpolyglucoside, APG) were donated by Croda (Nettetal, Germany). Lumogen Red (LR) and Lumogen Orange (LO) were supplied by Kremer Pigmente (Aichstetten, Germany). Lipoid S 100 (soy phosphatidylcholine, PC) was obtained by Lipoid (Ludwigshafen, Germany). Fasted state simulated intestinal fluid (FasSIF) was purchased by Biorelevant (London, United Kingdom).

Article information: Julian David Friedl, Arne Matteo Jörgensen, Nguyet-Minh Nguyen Le, Christian Steinbring, Andreas Bernkop-Schnürch, Replacing PEG-surfactants in self-emulsifying drug delivery systems: Surfactants with polyhydroxy head groups for advanced cytosolic drug delivery, International Journal of Pharmaceutics, 2022, 121633, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2022.121633.