Improved Transport And Absorption Through Gastrointestinal Tract By PEGlated Solid Lipid Nanoparticles

Solid lipid nanoparticle (SLN), a colloidal carrier for controlled drug delivery system, has attracted increasing attention in recent years. It has advantages such as good tolerability, low drug leakiness, high oral bioavailability, large scale production by high pressure homogenization and less acute and chronic toxicity. Hence, SLN has been routinely used as a promising vehicle for oral delivery of drug. However, one of the greatest challenges in developing an efficient nanocarrier for oral administration is to overcome the absorption barrier of intestinal mucosa, which consists of intestinal epithelial cells as well as mucus layer. Therefore, active research has focused on the preparation of nanocarrier, which can rapidly penetrate mucus secretions and achieve sustained drug delivery to mucosal tissues. Mucus penetrating particles (MPP) can be actively engineered as a potential nanoparticle carrier by carefully tuning the surface properties and overcoming the low bioavailability of orally administered drugs.In the present study, SLN was prepared by solvent diffusion method in an aqueous system. Monostearin was used as a lipid material, subsequently modified with PEG2000-SA. Otcadecylamine-fluorescein isothiocyanate (ODA-FITC) and doxorubicin (DOX) were used as a fluorescence marker and a model drug, respectively. By measuring the contact angle, we found that the contact angle decreased from45.3°to36.5°, which could contribute to the improvement of surface hydrophilicity after PEG modifying. The diameter and zeta potential of the nanoparticles with the concentration of lmg/mL were measured by Zeta-sizer, the absolute value of which experienced different degrees of decreased with the increasing ratios of PEG. Through the Surface Elemental Analysis, we found the C/O ratios of the particle surface changed after PEG-modified. The results of the stability in vivo showed, the stabilizing effect of the PEG-modifying in the GI tract should be regarded as an important quality for improving the absorption of pSLN. The entrapment efficiency (EE%) of SLN and pSLN had no significant difference. The EE%was about80%. In vitro drug release behavior of SLN was similar with that of pSLN, PEG modifying has been considered to negligibly interfere with the drug release.Mucus-secreting Caco-2/HT29co-culture cell monolayers model which simulated the epithelium were applied for the in vitro evaluations of PEGlated solid lipid nanoparticle (pSLN). HT29was used to provide the ability to examine the effect of mucus gel layer in co-culture cell monolayers model contributed by the mucus-secreting properties. The results showed, the largest amount of drug transport was facilitated by the SLN and PEG modifying appeared to decrease the permeation at different degrees on Caco-2cell monolayer. However, the incorporation of mucus-secreting cells in the culture seemed to alter the transport situation. The apparent permeability coefficient (Papp) of DOX through Caco-2/HT29(75/25) cell monolayer was increased by5-fold when delivered by pSLN-10%, while just3.9-fold by SLN, indicating that appropriate PEG modifying is important to convert nannoparticles from mucoadhesive to mucoinert.For the in vivo studies, male Sprague Dawley rats were used. Firstly, the intestinal absorptive behavior of SLN and pSLN-10%was studied in the gut sac model. The results showed the Papp values of pSLN was significantly enhanced, which were closely related to permeation observed using Caco-2/HT29(75/25) cell monolayer. It’s indicated that the presence of mucus-secreting cells is important in the vitro evaluation of delivery systems. Then, ligated intestinal loops model in vivo was used to get a visualization of the permeation of SLN and pSLN-10%in villi. The tissue-sections were visualized using inverted two-photon confocal microscopy. The results implied that pSLN nanoparticles experience the low viscosity interstitial fluid between mucus mesh elements and, thus, are able to rapidly penetrate the mucus secretion. To further verify the above experiments, the pharmacological effects of SLN/DOX and pSLN/DOX-10%were evaluated. Compared with DOX·HCl, the mean residence time (MRT) of DOX delivered in different nanoparticle formulations was calculated to be5.25h for DOX·HCl and33.02h in case of pSLN. The relative bioavailability of pSLN/DOX-10%were1.99-fold and7.52-fold higher than non-modified SLN and DOX·HCl, which contributed to the improved transport efficiency and prolonged blood circulation times by PEG modification. It’s demonstrated that significant fractions of pSLN was capable of penetrating highly viscoelastic mucus layers in the GI tract while unmodified SLN was strongly trapped and efficiently cleared from the mucosal tissue.