Raloxifene (RXF) is a hormone-like medication used for treating postmenopausal osteoporosis and estrogen-dependent breast cancer, yet associated with bad low bioavailability due to poor solubility. This study was intended to develop cyclodextrin/chitosan nanoparticles (ccNPs) for oral delivery of RXF in order to enhance the oral bioavailability. RXF-loaded ccNPs (RXF-ccNPs) were prepared by cyclodextrin inclusion followed by complexation with chitosan. RXF-ccNPs were fully characterized by particle size, morphology and in vitro drug release. The oral delivery efficacy and transepithelial transport potential were evaluated by pharmacokinetics, in situ single-pass intestinal perfusion, cellular uptake and ex vivo imaging. The resulting RXF-ccNPs were around 165 nm in particle size with a narrow distribution. The oral bioavailability of RXF was enhanced by 2.6 folds through ccNPs compared to RXF suspensions in rats. It was shown that RXF-ccNPs could improve the intestinal permeability of RXF, increase the cellular uptake of RXF and facilitate its transport across the absorptive epithelia. The results indicate that our developed ccNPs based on sulfobutylether-β-cyclodextrin and oligochitosan are a promising vehicle to orally deliver poorly water-soluble drugs over and above RXF.

Raloxifene (RLX) is a second-generation selective estrogen receptor modulator used to treat osteoporosis in postmenopausal women. RLX fails to be developed into injectable dosage forms due to poor solubility. Although oral formulations are clinically available, the lower bioavailability (<2%) embarrasses the pharmaceutists. This work reported a bioadhesive nanosystem intended for oral delivery of RLX to enhance its oral bioavailability and address the formulation challenge. The bioadhesive nanosystem refers to polymer–lipid hybrid nanoparticles made up of Carbopol 940, glyceryl distearate, and TGPS. RLX was solidly encapsulated into bioadhesive nanoparticles (bNPs) through a nanoprecipitation technique along with synchronous desalting of RLX·HCl. The resultant RLX-loaded bNPs (RLX-bNPs) were characterized by particle size, ζ potential, morphology, and entrapment efficiency. The in vitro release and in vivo oral bioavailability of RLX-bNPs in rats were comparatively investigated with RLX-loaded common lipid nanoparticles (RLX-cNPs). The preferred formulation possesses a particle size of 150 nm around with a polydispersity index (PDI) of 0.282. RLX-bNPs exhibited slower drug release than RLX-cNPs owing to the presence of an adhesive layer. After oral administration, RLX-bNPs resulted in significant enhancement in the bioavailability of RLX, up to 556.9% relative to RLX suspensions, while it was merely 244.7% for RLX-cNPs. Cellular testing and ex vivo transport imaging demonstrated that bNPs were endowed with excellent intestinal epithelial affinity and absorbability. Our study affords an alternative option for designing a suitable oral delivery system specific to amphiphobic drugs like RLX·HCl.

Background: Aloperine (ALO), a novel active alkaloid extracted from S. alopecuroide, has been reported to possess anti-tumor effect. However, its potential effect on bladder cancer remains unknown. Therefore, the objective of this study was to investigate the effect of ALO bladder cancer cells under hypoxia condition.Methods: Human bladder cancer cell line T24 cells were treated with different concentrations of ALO and maintained in hypoxic condition for 12, 24, or 48 h. MTT assay was performed to detect cell viability. Transwell assay was performed to detect cell migration and invasion. Epithelial-mesenchymal transition (EMT) was evaluated by detecting the expression levels of E-cadherin, N-cadherin, and vimentin using western blot. The mRNA and protein levels of HIF-1α, snail, slug, and twist1 were measured using qRT-PCR and western blot. The expression levels of mTOR/p70S6K/4E-BP1 pathway-related proteins were detected using western blot.Results: Our results showed that ALO inhibited the cell viability of T24 cells cultured in hypoxia condition. ALO also attenuated hypoxia-induced migration and invasion of T24 cells. We also found that ALO treatment caused a significant increase in E-cadherin expression and decreases in N-cadherin and vimentin expressions. Besides, ALO dose-dependently inhibited the expressions of EMT inducers including snail, slug, and twist1 both in mRNA and protein levels in T24 cells induced by hypoxia. Furthermore, ALO significantly inhibited HIF-1α protein synthesis and phosphorylation of mTOR, as well 4E-BP1 and p70S6K in hypoxia-induced T24 cells.Conclusion: These results indicated that ALO exerted anti-tumor effect on bladder cancer in vitro via inhibiting the activation of mTOR/p70S6K/4E-BP1 pathway.