## 3 Some Key Issues on the Use of SLNs and NLCs as Oral Nanovehicles for Nutraceuticals or Bioactives
### Poorly Soluble Bioactive Compounds
#### 4.2.1 Curcuminoids (and Curcumin in Particular)
The curcumin encapsulated in SLN was more readily absorbed by the Caco-2 cells than free curcumin or curcumin in the emulsions [122]. The route of the transport of the SLN across the cells was simple diffusion, and most of the absorbed curcumin (\(\sim\)99%) was metabolized by the cells [122]. [PERSON] et al. [127] further indicated that the transport of curcumin in SLNs through the Caco-2 cell monolayer membrane was passive, and was greatly facilitated by the presence of bile acids and lipases, reflecting that the transfer of encapsulated curcumin in the SLNs to the mixed micelles was favorable for intestinal absorption. Using the same Caco-2 cell absorption model, [PERSON] et al. [55] evaluated the intestinal absorption of micellar curcumin, obtained from NLCs after a simulated gastrointestinal digestion, and showed that the intestinal absorption of micellar curcumin ranged from 26% to 39%, depending on the liquid-lipid (MCT) ratio in total lipid content. Many in vivo animal experiments indicated that the nanoencapsulation of curcumin in SLNs or NLCs remarkably enhanced the oral or intragastric bioavailability of curcumin (compared to free curcumin suspension), but the extent of improvement considerably varied [38; 39; 127; 136]. [PERSON] et al. [130] performed in vivo pharmacokinetics of curcumin in rats after oral administration of curcumin-loaded SLNs, and confirmed a significant improvement in their oral bioavailability (32-155 times) at all doses (1-50 mg/kg dose) as compared to free solubilized curcumin. In a further work, [PERSON] et al. [136] showed that, following per oral administration in mice, curcumin-loaded SLNs had a bioavailability 8.1 times greater than that of free curcumin. They also confirmed that curcumin-loaded SLNs could be effectively delivered across the gut wall and blood brain barrier (BBB) and preferentially distributed in the brain of mice (30 times relative to free curcumin). [PERSON] et al. [136] also confirmed that, via intragastric administration in rats, the curcumin-loaded NLCs exhibited a greatly improved ability to cross the BBB, with an 11.9-fold increase in the curcumin concentration in the brain when compared with curcumin suspension. [PERSON] et al. [127] reported that the curcumin encapsulated in SLNs had a more than 12-fold increase in bioavailability compared to the curcumin solution, in a rat model. [PERSON] et al. [128] developed a novel SLN showing oral bioavailability approximately 70 times higher, with respect to free curcumin, in female Wistar rats. Aside from oral administration, significant improvements of in vivo bioavailability of curcumin using SLNs or NLCs has been demonstrated in animals, e.g., through intravenous administration [137; 138; 139]. Antioxidant and anti-inflammatory activities are one of major health benefits of curcumin, as a polyphenol [61; 118]. However, these beneficial effects are frequently limited by the water-insolubility and unstable nature of curcumin. Some works indicated that the incorporation of curcumin in SLNs or NLCs did not affect--or slightly but significantly increased--its antioxidant potential, e.g., in vitro DPPH radical scavenging capacity [125; 140]. [PERSON] et al. [37] showed that oral administration of curcumin-loaded SLNs provided much greater antioxidant protection in vivo (through increased levels of superoxide dismutase, catalase and glutathione, and improved mitochondrial complex enzyme activities) than free-solubilized curcumin, thus resulting in the improvement of cerebral ischemic reperfusion injury in rats. The significantly-improved in vivo anti-inflammatory activity of curcumin via incorporation in SLNs has also been demonstratedin lipopolysaccharide-induced sepsis of mice, including reduced levels of IL-1\(\beta\) expression and increased anti-inflammatory cytokine IL-10 [141]. The anti-cancer activities of free curcumin in vitro and in vivo have been well recognized [60].