Sulfonated azocalix[4]arene-Tanshinone IIA supramolecular drug delivery system based on hypoxic reduction response for treatment of ischemic heart disease: Enhance the solubility, stability and bioavailability of drugs

Ischemic heart disease (IHD) is a serious threat to human health due to its high incidence, high mortality and difficult treatment. Tanshinone IIA (Tan IIA), a significant traditional Chinese medicine monomer that has been shown to have remarkable protective effects against IHD. However, the poor solubility and stability resulted in its low oral bioavailability. In this paper, sulfonated azocalix [4]arene (SAC4A), a deep cavitand calixarene that can bind to hydrophobic drugs, is introduced as a new synthetic material to bind to traditional Chinese medicine monomer Tan IIA. Thus, a SAC4A-Tan IIA supramolecular drug delivery system with hypoxia reactivity (SAC4A-Tan IIA) was constructed. The complexation of inclusion complexes was confirmed by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Moreover, in vitro drug release and cell experiments indicated that SAC4A-Tan IIA had good reductive and hypoxic reaction ability. In vivo pharmacokinetic study showed that AUC (0-∞) of supramolecular drug delivery system was 2.68 times that of control group (P < 0.01). Tissue distribution showed that the AUC (0-∞) of heart, lung and liver in SAC4A-Tan IIA was 5.85 times, 3.69 times and 2.19 times of that in Tan IIA, respectively (P < 0.01). In conclusion, the supramolecular delivery system showed excellent physicochemical properties and improved oral bioavailability. It provides the basis for supramolecular delivery system in the treatment of IHD.