Emerging non-antibody‒drug conjugates (non-ADCs) therapeutics of toxins for cancer treatment.

The non-selective cytotoxicity of toxins limits the clinical relevance of the toxins. In recent years, toxins have been widely used as warheads for antibody‒drug conjugates (ADCs) due to their efficient killing activity against various cancer cells. Although ADCs confer certain targeting properties to the toxins, low drug loading capacity, possible immunogenicity, and other drawbacks also limit the potential application of ADCs. Recently, non-ADC delivery strategies for toxins have been extensively investigated. To further understand the application of toxins in anti-tumor, this paper provided an overview of prodrugs, nanodrug delivery systems, and biomimetic drug delivery systems. In addition, toxins and their combination strategies with other therapies were discussed. Finally, the prospect and challenge of toxins in cancer treatment were also summarized.

Combination of resveratrol and luteolin ameliorates α-naphthylisothiocyanate-induced cholestasis by regulating the bile acid homeostasis and suppressing oxidative stress.

Cholestasis is a common liver injury without any effective therapeutic drugs so far. Resveratrol (RES) and luteolin (LUT) are natural polyphenols that exert protective effects on multiple liver injuries. Coadministration of RES and LUT could significantly improve the bioavailability of LUT and increase the systemic exposure to RES, and the combined treatment could also benefit from their multi-component and multi-target characteristics. Our current aim is to study the protective effects of coadministration of RES and LUT on α-naphthylisothiocyanate (ANIT)-induced cholestasis. Serum biochemical indices and liver histopathology in rats indicated that coadministration of RES and LUT could improve liver function by suppressing oxidative stress. Dysregulated bile acid (BA) homeostasis is a significant pathological feature of cholestasis, which was determined to explore the potential biomarkers and to clarify the protection mechanism of coadministration of RES and LUT. The levels of cholic acid, chenodeoxycholic acid, taurine conjugates and glycine conjugates, and the ratios of taurine conjugates to their free forms could be used as diagnosis indicators for cholestasis in rats. Furthermore, the coadministration of RES and LUT could restore the BA levels and exert better protective effects than administration alone. This study suggested that the coadministration of RES and LUT could protect against ANIT-induced cholestasis and the mechanism was closely related to regulating BA homeostasis and suppressing oxidative stress.

A rapid HPLC-MS/MS method for the simultaneous determination of luteolin, resveratrol and their metabolites in rat plasma and its application to pharmacokinetic interaction studies.

Both luteolin (LUT) and resveratrol (RES) are natural polyphenols that exert therapeutic effects on liver injuries. Extensive glucuronidation by uridine diphosphate-glucuronosyltransferases 1As (UGT1As) results in poor bioavailability of LUT, which limits its clinical application. As an inhibitor of UGT1A1 and UGT1A9, RES may affect the bioavailability of LUT. The purpose of this study was to develop and validate an HPLC-MS/MS method for the simultaneous determination of LUT, luteolin-3'-O-glucuronide (LUT-3'-G), RES and resveratrol-3-O-glucuronide (RES-3-G) in rat plasma to investigate the effects of RES on the bioavailability and metabolism of LUT after coadministration. The samples were extracted by protein precipitation with methanol using daidzein and naringenin as the internal standards. Separation was achieved on an XBridgeTM C18 column by isocratic elution using 88% methanol-12% water with 2 mM ammonium acetate and 0.01% formic acid. Multiple reaction monitoring mode with a negative electrospray ionization interface was used for quantification of the analytes. The calibration curves were linear over the concentration ranges of 1-1000 (r > 0.995), 2-2000 (r > 0.999), 5-5000 (r > 0.998) and 10-40000 ng/mL (r > 0.996) for LUT, LUT-3'-G, RES and RES-3-G, respectively. The method was fully validated in terms of accuracy, precision, matrix effect, recovery and stability. The validated data met the acceptance criteria in FDA guidelines. The method was successfully applied in a pharmacokinetic interaction study of LUT and RES. The results indicated that RES had a significant effect on the enhanced bioavailability of LUT by reducing the major glucuronidation metabolite in rats, which provides a reference for the combination of LUT and RES in liver diseases.