Abstract
The aim of this study was to design and investigate solid lipid nanoparticles (SLN) providing an intestinal alkaline phosphatase (IAP) triggered charge reversion.SLN containing the monophosphate ester bearing surfactant P-PEG-9-lauryl ether and the cationic surfactant benzalkonium chloride were prepared via step-wise hot microemulsion method enabling P-PEG-9-lauryl ether to accumulate the phosphate moiety on the surface of the particles accessible for IAP. Charge reversal SLN were characterized in vitro and ex vivo.SLN containing 10% of P-PEG-9-lauryl ether and 1% of cationic surfactant displayed a z-average of 92 nm and a PDI of 0.33 remaining stable over one year stored at 2–8 °C. An enzyme induced charge reversion from -18.4 mV to +16.5 mV correlated with the cleavage of 82% of the incorporated phosphate. SLN maintained their size during charge reversion, as no significant difference in z-average was observed. Mucin interaction studies revealed a higher interaction between SLN and mucins in the presence of IAP causing an increase in z-average from 190 nm to 2500 nm as well as a decrease in zeta potential from -26 mV to -17 mV. No significant change in z-average and zeta potential was observed when IAP was absent indicating lower mucin interaction of negatively charged particles. In contrast, higher interaction with cell membrane was evidenced by 85% hemolysis when SLN were pretreated with IAP, whereas control SLN without IAP resulted in 16% hemolysis. To investigate the phosphate cleavage by membrane bound IAP, SLN were incubated on excised rat intestinal mucosa and a significant higher release of phosphate was observed in comparison to samples treated with an enzyme inhibitor.Charge reversal SLN might be promising drug delivery systems for alkaline phosphatase bearing membranes that are covered by a mucus gel layer such as the intestine.
Highlights
Solid lipid nanoparticles (SLN) are a promising tool for the delivery of hydrophobic as well as hydrophilic drugs providing several features to overcome the hurdles of oral drug delivery.[1−4] As drugsAbbreviations: benzalkonium chloride (BA), Benzalkonium chloride; DDS, Drug delivery systems; dynamic light scattering (DLS), Dynamic light scattering; HBS, 20 mM HEPES buffered saline pH 7.4; HEPES, 4-(2Hydroxyethyl)-1-piperazineethanesulfonic acid; intestinal alkaline phosphatase (IAP), Intestinal alkaline phosphatase; lactate dehydrogenase (LDH), Lactate dehydrogenase; minimal essential media (MEM), Minimal essential medium; malachite green (MLG), Malachite green assay; OD, Optical density; P, Monophosphate ester; P-PEG, Polyethylene glycol monophosphate ester; phase analysis light scattering (PALS), Phase analysis light scattering; PEG, Polyethylene glycol; phosphatase inhibitor cocktail II (PIC II), Phosphatase inhibitor cocktail II; poly(lactic-co-glycolic) acid (PLGA), Poly(lactic-co-glycolic) acid; solid lipid nanoparticles (SLN), Solid lipid nanoparticles; TBS, 50 mM TRIS buffered saline pH 7.4.(DDS)
47.2 § 0.7 mM of free phosphate after 240 min corresponding to an enzymatic cleavage of 94.4% § 1.34% of P-PEG-9-lauryl ether
Since IAP is known to predominantly cleave monophosphate esters[36,37] and no significant free phosphate could be identified in samples without intestinal alkaline phosphatase (IAP), it can be assumed that purified products contained a high amount of monophosphate esters (Fig. 2)
Summary
Solid lipid nanoparticles (SLN) are a promising tool for the delivery of hydrophobic as well as hydrophilic drugs providing several features to overcome the hurdles of oral drug delivery.[1−4] As drugs(DDS). The surface charge of DDS loaded with surfactants bearing monophosphate esters exhibiting a negative zeta potential can be reversed. To reach this positive surface charge after phosphate cleavage, positively charged surfactants are incorporated into the DDS. Le-Vinh et al took even advantage of this phenomenon and prepared SLN for mucosal drug delivery aggregating after IAP induced phosphate cleavage facilitated by the lower amplitude of the surface charge.[27]. Charge reversal SLN providing a positive zeta-potential after phosphate cleavage by IAP and maintaining their particle size throughout the change could to the best of our knowledge not be developed
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