Size Shifting of Solid Lipid Nanoparticle System Triggered by Alkaline Phosphatase for Site Specific Mucosal Drug Delivery

We aim to prepare a size-shifting nanocarrier for site-targeting mucosal drug delivery that can penetrate through mucus gel layer and remain close to the absorption membrane. As nanocarriers can be engineered to penetrate mucus but they can also back diffuse into outer mucus regions, a size shifting to micron range once they have reached the absorption membrane would prevent back-diffusion effect and extend drug release over a long period of time.

For this purpose, we loaded solid lipid nanoparticles (SLN) with a phosphate ester surfactant and octadecylamine. Alkaline phosphatase (AP), a membrane bound enzyme was for the first time utilized as an in situ partner for triggering the size conversion at epithelial cell surface. Having the size of ∼120 nm, SLN with hydrophilic and phosphate-decorated shells were shown to penetrate through mucus gel and form aggregates above cell layer surface.

Aggregates of 5-8 µm were formed due to interparticle interactions induced by enzymatic phosphate removal after ∼30 min in contact with isolated AP. The developed SLN system could be a potential tool for mucosal drug delivery to AP-expressing tissues like colon, lung, cervix, vagina and some mucus-secreting tumors.

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Article information: Bao Le-Vinh, Christian Steinbring, Richard Wibel, Julian David Friedl, Andreas Bernkop-Schnürch. European Journal of Pharmaceutics and Biopharmaceutics, 2021. https://doi.org/10.1016/j.ejpb.2021.03.012.

Materials: Lanphos TE43 (phosphorylated PEG surfactant) was kindly provided by Lankem, UK. This is a phosphate ester (C12-15 + 3EO) in acid form, mainly monoester, and dispersible in water. Geleol^TM (glyceryl monostearate) melting range 54-64 ^oC was kindly provided by Gattefossé, Germany. Lutrol® F68 (poloxamer 188) was obtained from BASF, Germany. Span® 60 (sorbitan monostearate), 1-butanol, octadecylamine, malachite green (MLG), ammonium molypdate, minimum essential medium (MEM), MEM Eagle powder, HEPES, isolated AP from bovine intestinal mucosa (≥2,000 DEA units/mg protein) and phosphatase inhibitor cocktail 2 (PIC2) were purchased from Sigma-Aldrich, Austria. Fetal bovine serum FBS superior was purchased from Biochrom GmbH, Germany. Penicillin-Streptomycin solution (Penicillin 10 000 U/mL and Streptomycin 10 mg/mL) was obtained from Pan Biotech, Germany.