Pharmacokinetics and bioavailability in vivo
The mean plasma concentration–time profiles of NUC after both the IV administration of NUC and the oral administration of n-NUC and NUC-PLGA-NPs are presented in ; the calculated pharmacokinetic parameters are summarized in as well. After oral administration, the plasma concentrations of NUC-loaded NPs were all higher than that of the plain drug at nearly every time point. The t1/2 and tmax for NUC-PLGA-NPs was found to be 1.8 ± 0.2 and 1.3 ± 0.3 h, respectively, which was higher than n-NUC for which t1/2 was 0.8 ± 0.4 h and tmax was 0.6 ± 0.2 h. Moreover, the AUCt for NUC-PLGA-NPs was extremely higher than n-NUC (**p < 0.01). The result showed that our NUC-PLGA-NPs had higher plasma concentration, lower clearance, and longer half-life as compared with NUC in rats. The lesser Cmax for plain drug was due to self-aggregation, poor permeability and extensive metabolism mediated by P-glycoprotein (P-gp) efflux pump, while the improvement in Cmax and AUCt for NPs could be attributed to a decrease in first pass metabolism, as NPs reaches systemic circulation through gut-associated lymphatic tissue (Ahmad et al., Citation2015). The absolute bioavailability of NUC was a significant increase from 4.2 ± 1.3 to 13.5 ± 1.9. The relative bioavailability was increased by 3.3 ± 0.61-fold in NUC-PLGA-NPs as compared to corresponding n-NUC.
Figure 4. Mean plasma concentration–time curves of NUC (mean ± SD, n = 6).
Table 1. Pharmacokinetic parameters of NUC (mean ± SD, n = 6).
Serum biochemical parameters
The serum biochemical parameters after 2, 4, 6 and 8 weeks’ treatment are listed in . The HC group exhibited significantly increased serum levels of TC, TG and LDL-C, as well as lower concentration of HDL-C, compared with that of NC group. These results demonstrated that the HC group exhibited dyslipidemia to some extent. However, the abnormal serum lipid levels were prevented by NUC and the treatment of NUC-PLGA-NPs was better than n-NUC. The administration of NUC-PLGA-NPs reduced serum TC and HDL-C levels compared with that of HC group after 2 weeks (**p < 0.01), and even more significantly after 6 weeks (***p < 0.001). n-NUC also showed significant effects on HDL-C levels after 2 weeks (**p < 0.01) and TC levels after 6 weeks (*p <0.05). In addition, the level of TG and LDL-C decreased only when rats treated NUC-PLGA-NPs after 8 weeks (*p <0.05). In this research, the intervention of both NUC and NUC-PLGA-NPs might prevent hyperlipidemia from HFD rats, and NUC-PLGA-NP treatment plays a significant role in regulating blood lipids due to the improved bioavailability, sustained and controlled release. As a broad term containing various lipid and/or lipoprotein disorder, the primary manifestations of dyslipidemia are the increased serum lipid concentrations of TC, TG and LDL-C, as well as the low concentrations of HDL-C. TC and TG are the dominating lipids circulating in the blood. The danger of increased TC was clear. The role of TC levels in various diseases was controversial, while high levels of TC are often related to metabolic syndrome and always accompanied with low levels of good cholesterol named HDL-C, which induced vascular disease (Zhou et al., Citation2016). The excessive LDL-C, bad cholesterol, will initiate the formation of atherosclerotic plaques (Gao et al., Citation2014). Therefore, high levels of TC, TG and LDL-C, as well as low levels of HDL-C in the blood could be regarded as a danger sign.
Table 2. Serum indexes for male Sprague Dawley rats after 2, 4, 6 and 8 weeks of treatment (mean ± SD, n = 6).
Conclusion
In summary, the s/o/w emulsion technique selected in this research allowed the reproducible and momentary formation of nanometric (∼150 nm), homogeneous and spherical nanocomposites, which exhibited a remarkable loading capacity for NUC with an adjustable dosage ratio. The oral bioavailability of NUC-PLGA-NPs was significantly increased to 3.3 ± 0.61-fold when compared to that of n-NUC in rats. In addition, NUC-PLGA-NPs are more efficient in alleviating lipogenesis in both in vitro and in vivo evaluation due to the improved water solubility and prolonged incubation time. These findings indicated that NUC-PLGA-NPs hold great promise for sustained and controlled drug delivery with improved bioavailability to alleviating lipogenesis.
Declaration of interest
The authors report no conflicts of interest in this work.
This research work was supported by the Crossing Program between Medicine and Industry of Shanghai Jiao Tong University (Grant No. YG2014MS32), and the Doctoral Program of Higher Education of China (Grant No. 20110073120097).
Related Research Data
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