baohuoside-i and tocophersolan

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Carriers; Drug Compounding; Flavonoids; Humans; Hyaluronic Acid; Inhibitory Concentration 50; Injections, Intravenous; Lung Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; Micelles; Paclitaxel; Quaternary Ammonium Compounds; Solubility; Surface Properties; Technology, Pharmaceutical; Time Factors; Vitamin E; Xenograft Model Antitumor Assays

The biggest challenge for the treatment of multidrug resistant cancer is to deliver a high concentration of anticancer drugs to cancer cells. Icariside II is a flavonoid from Epimedium koreanum Nakai with remarkable anticancer properties, but poor solubility and significant efflux from cancer cells limited its clinical use. In our previous study, a self-assembled mixture of micelles (TPGS-Icariside II-phospholipid complex) was successfully constructed, which could substantially increase the solubility of Icariside II and inhibit the efflux on Caco-2 cells. In this study, we evaluate the anticancer effect of the mixed micelles encapsulating Icariside II (Icar-MC) on MCF-7/ADR, a multidrug-resistant breast cancer cell line. The cellular uptake of the micelles was confirmed by fluorescent coumarin-6-loaded micelles. The IC50 of Icar-MC in MCF-7/ADR was 2-fold less than the free drug. The in vitro study showed Icar-MC induced more apoptosis and lactate dehydrogenase release. Intravenous injection of Icar-MC into nude mice bearing MCF-7/ADR xenograft resulted in a better antitumor efficacy compared with the administration of free drug, without causing significant body weight changes in mice. The antitumor effect was further verified by magnetic resonance imaging and immunohistochemical assays for Ki-67, a proliferative indicator. Moreover, Icar-MC treatment also elevated Bax/Bcl-2 ratio and the expressions of cleaved caspase-3, -8, -9 and AIFM1 in tumors. This study suggests that phospholipid/TPGS mixed micelles might be a suitable drug delivery system for Icariside II to treat multidrug resistant breast cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Inducing Factor; bcl-2-Associated X Protein; Breast Neoplasms; Caco-2 Cells; Caspases; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Flavonoids; Humans; MCF-7 Cells; Mice; Mice, Nude; Micelles; Phospholipids; Proto-Oncogene Proteins c-bcl-2; Vitamin E

Baohuoside I is an effective anti-cancer drug currently used for a variety of cancers in vitro. Unfortunately, baohuoside I has a very poor solubility in both water and in organic solvents. Besides that, it is subject to significant efflux. This work therefore aimed at evaluating the ability of mixed micelles to solubilize baohuoside I, increase permeability and inhibit efflux of baohuoside I to promote oral absorption. A novel (TPGS-baohuoside I-phospholipid complex) mixed micelles was formed by phospholipid complex and TPGS to increase the solubility, enhance permeability, and inhibit efflux of baohuoside I. Micelle formation was confirmed by differential scanning calorimetry and transmission electron microscopy. The average diameters and efflux ratio of mixed micelles decreased as the ratio of TPGS increased with a respective increase in solubility of baohuoside I. Nevertheless, a slow release of baohuoside I from loaded micelles was noted. The results showed that at a 1:9 ratio for baohuoside I-phospholipid complex: TPGS in mixed micelles, solubility of baohuoside I increased up to 88 fold while the efflux ratio decreased by 85%. Their smaller size and higher zeta potential values indicated that mixed micelles would be easily absorbed and more stable. The relative bioavailability of the micelles (AUC(0-∞)) compared with baohuoside I (AUC(0-∞)) was 533%, demonstrating great potential for clinical application. Hence, the novel micelles formed with phospholipid complex and TPGS considerably increased drug concentration in the media and enhanced absorption.

Topics: Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Biological Availability; Caco-2 Cells; Chemical Phenomena; Drug Carriers; Drug Compounding; Drug Stability; Drugs, Chinese Herbal; Excipients; Flavonoids; Half-Life; Humans; Intestinal Absorption; Male; Micelles; Phospholipids; Polyethylene Glycols; Random Allocation; Rats; Solubility; Vitamin E

In the present study, the Caco-2 monolayer model and a four-site rat intestinal perfusion model were used to investigate the effects of vitamin E tocopherol polyethylene glycol succinate 1000 (TPGS) on the intestinal absorption of icariside II. Icariside II was analyzed by ultra-performance liquid chromatography (UPLC). After that its apparent permeability coefficients (Papp) and effective permeability (P*(eff)) were calculated. In the Caco-2 cell model, Papp values from the apical (AP) to the basolateral (BL) of icariside II were increased and its efflux ratios were markedly reduced in the presence of TPGS. However, either 0.25 mg/mL or 0.5 mg/mL of TPGS had no significant difference in promoting the absorption of icariside II. In four-site rat intestinal perfusion model, P*(eff) of icariside II were significantly increased by 0.5 mg/mL of TPGS in ileum and colon. The results suggest that TPGS could promote the intestinal absorption of icariside II.

Topics: Algorithms; Animals; Caco-2 Cells; Chromatography, High Pressure Liquid; Colon; Electric Impedance; Flavonoids; Humans; Ileum; In Vitro Techniques; Intestinal Absorption; Male; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Vitamin E