p-Sulfonatocalixarene-Based Complexation Mitigates Hepatorenal Toxicity of Anticancer Alkaloids without Loss of Efficacy: A Strategy for Selective Detoxification.

p-Sulfonatocalix[n]arenes (SCnA, where n = 6, 8) have emerged as promising supramolecular hosts for encapsulating active pharmaceutical ingredients (APIs) through host-guest complexation, enhancing solubility, stability, and bioavailability. In this study, SCnA was employed to complex hepatotoxic and nephrotoxic alkaloids derived from Traditional Chinese Medicines (TCM), with the objective of reducing hepatorenal toxicity while preserving antitumor efficacy. The cytocompatibility of six alkaloids and their SCnA complexes was evaluated across human embryonic kidney (Hek293), normal liver (L02), breast cancer (MDA-MB-231), and hepatoma (HepG2) cell lines. A high-content assay (HCA) integrated with three fluorescent probes was utilized to simultaneously quantify multiparametric cellular changes, including nucleus number and area, mitochondrial count and area, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) levels. Complexation with SC6A or SC8A significantly reduced the cytotoxicity of tetrandrine, chelerythrine, and dauricine in Hek293 and L02 cells, while antitumor activity against MDA-MB-231 and HepG2 cells was maintained. HCA revealed that the complexes increased nuclei count, nuclear area, mitochondrial number, mitochondrial area, and MMP, while decreasing ROS levels. Notably, the suppression of normal cell proliferation correlated positively with binding constant values, yet complexation did not interfere with antiproliferative effects in tumor cells. We hypothesize that the heightened mitochondrial fission and oxidative stress susceptibility in cancer cells, owing to their reliance on mitochondrial energy production, underlie the differential cytotoxicity. These findings demonstrate that SCnA complexation selectively attenuates alkaloid-induced toxicity in normal cells without diminishing anticancer potency, underscoring its potential as a versatile strategy for safe and effective drug delivery.