Purpose: The present study was to formulate curcumin solid lipid nanoparticles (Cur-SLNs) with P-gp modulator excipients, TPGS and Brij78, to enhance the solubility and bioavailability of curcumin. Methods: The formulation was optimized by Plackett-Burman screening design and Box-Behnken experiment design. Then physiochemical properties, entrapment efficiency and in vitro release of Cur-SLNs were characterized. In vivo pharmacokinetics study and in situ single-pass intestinal perfusion were performed to investigate the effects of Cur-SLNs on the bioavailability and intestinal absorption of curcumin. Results: The optimized formulations showed an average size of 135.3 ± 1.5 nm with a zeta potential value of À24.7 ± 2.1 mV and 91.09% ± 1.23% drug entrapment efficiency, meanwhile displayed a sustained release profile. In vivo pharmacokinetic study showed AUC 0!t for Cur-SLNs was 12.27-folds greater than curcumin suspension and the relative bioavailability of Cur-SLNs was 942.53%. Meanwhile, T max and t 1/2 of curcumin for Cur-SLNs were both delayed comparing to the suspensions (p50.01). The in situ intestinal absorption study revealed that the effective permeability (P eff ) value of curcumin for SLNs was significantly improved (p50.01) comparing to curcumin solution. Conclusion: Cur-SLNs with TPGS and Brij78 could improve the oral bioavailability and intestinal absorption of curcumin effectively. KeywordsCurcumin, in situ intestinal absorption, oral bioavailability, P-glycoprotein, solid lipid nanoparticles History

Abstract. Multidrug resistance (MDR) is a main clinical hurdle for chemotherapy of cancer, and overexpression of P-glycoprotein (P-gp) is a key factor. In the present study, a new co-delivery system for reversing MDR was designed and developed. The system was composed of curcumin (Cur) and piperine (Pip) encapsulated in solid lipid nanoparticles (SLNs) with tocopheryl polyethylene glycol succinate (TPGS) and Brij 78 [(Cur+Pip)-SLNs]. TPGS and Brij 78 could sensitize MDR tumors by inhibiting the P-gp drug efflux system. The combination of Cur and Pip, when administered in SLNs formulations, resulted in a significant enhancement in cytotoxicity and allowed efficient intracellular delivery of the drugs in drug-resistant A2780/Taxol cells. This dual inhibitory strategy may have significant potential in the clinical management of MDR in cancer.

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Background Dipeptidyl peptidase-4 inhibitors (DPP-4i) decrease glucose levels by regulating incretin peptides in type 2 diabetes mellitus (T2DM). This study aimed to determine the modulatory effect of DPP-4i on brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in patients with T2DM. Methods PubMed, Embase and the Cochrane Library were systematically searched to identify randomized controlled trials (RCTs) evaluating the impact of DPP-4i on BNP or NT-pro-BNP. A fixed- or random-effects model was used for quantitative analysis, according to the heterogeneity. Sensitivity analysis and publication bias were performed using standard methods. Results Nine trials with 3056 patients with T2DM were included. Meta-analysis revealed that DPP-4i did not significantly modulate the BNP (0.21 pg/mL, 95% CI − 2.36–2.79) or NT-pro-BNP level (− 7.34 pg/mL, 95% CI − 24.27–9.59). DPP-4i demonstrated no stronger effect on modulating BNP (5.17 pg/mL, 95% CI − 7.48–17.82) or NT-pro-BNP (− 9.95 pg/mL, 95% CI − 44.61–24.71) than active comparators. Pooled analysis was robust and stable after sensitivity analysis. Conclusions DPP-4i exhibits no significant effect on modulating BNP or NT-pro-BNP and shows no stronger effect than traditional antidiabetic agents in T2DM.