Enhanced water solubility, antioxidant activity, and oral absorption of hesperetin by D-α-tocopheryl polyethylene glycol 1000 succinate and phosphatidylcholine / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Hesperetin, an abundant bioactive component of citrus fruits, is poorly water-soluble, resulting in low oral bioavailability. We developed new formulations to improve the water solubility, antioxidant activity, and oral absorption of hesperetin. Two nano-based formulations were developed, namely hesperetin-TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) micelles and hesperetin-phosphatidylcholine (PC) complexes. These two formulations were prepared by a simple technique called solvent dispersion, using US Food and Drug Administration (FDA)-approved excipients for drugs. Differential scanning calorimetry (DSC) and dynamic light scattering (DLS) were used to characterize the formulations' physical properties. Cytotoxicity analysis, cellular antioxidant activity assay, and a pharmacokinetic study were performed to evaluate the biological properties of these two formulations. The final weight ratios of both hesperetin to TPGS and hesperetin to PC were 1:12 based on their water solubility, which increased to 21.5- and 20.7-fold, respectively. The hesperetin-TPGS micelles had a small particle size of 26.19 nm, whereas the hesperetin-PC complexes exhibited a larger particle size of 219.15 nm. In addition, the cellular antioxidant activity assay indicated that both hesperetin-TPGS micelles and hesperetin-PC complexes increased the antioxidant activity of hesperetin to 4.2- and 3.9-fold, respectively. Importantly, the in vivo oral absorption study on rats indicated that the micelles and complexes significantly increased the peak plasma concentration (Cmax) from 2.64 μg/mL to 20.67 and 33.09 μg/mL and also increased the area under the concentration-time curve of hesperetin after oral administration to 16.2- and 18.0-fold, respectively. The micelles and complexes increased the solubility and remarkably improved the in vitro antioxidant activity and in vivo oral absorption of hesperetin, indicating these formulations' potential applications in drugs and healthcare products.

Advances in the study of tumor pH-responsive polymeric micelles for cancer drug targeting delivery / 药学学报

This review presents the state of the art of pH-responsive polymeric micelles for cancer drug delivery. Solid tumors have a weakly acidic extracellular pH (pH < 7), and cancer cells have even more acidic pH in endosomes and lysosomes (pH 4-6). The pH-gradients in tumor can be explored for tumor targeting and drug release in cancer drug delivery by applying pH-responsive polymeric micelles. The pH-responsive polymeric micelles consist of a corona and a core, and are made of amphiphilic copolymers, in which there are pH-responsive polymeric blocks. Two types of pH-responsive polymers-protonizable polymers and acid-labile polymers have been mainly used to make pH-responsive micelles for drug delivery. The protonizable polymers are polybases or polyacids, and their water-soluble/insoluble or charge states undergo changes with the protonation or deprotonation stimulated by external acidity, while the acid-labile polymers change their physical properties by chemical reaction stimulated by the acidity. Polymeric micelles whose core or coronas respond to the tumor extracellular acidity can be explored for triggering the fast release of the carried drug, activating the targeting group and accelerating the endocytosis of drug-loaded polymeric micelles, and those whose core or coronas respond to the tumor lysosomal acidity can be used for facilitating their escape from the lysosomes and targeting the nucleus. Various in vivo and in vitro experiments demonstrated that pH-responsive polymeric micelles are effective for cellular targeting, internalization, fast drug release and nuclear localization, and hence enhancing the therapeutic efficacy and reducing the side effect of cancer chemical therapy.