Superior Therapeutic Efficacy and Reduced Systemic Toxicity of a Cucurbit[7]uril-Camptothecin Supramolecular Complex in Colorectal Cancer

Abstract The clinical application of camptothecin (CPT) is limited by poor solubility and severe toxicity. This study compares the therapeutic performance of a cucurbit[7]uril-based CPT complex (CB[7]-CPT) with free CPT and β-cyclodextrin-CPT (β-CD-CPT) in colorectal cancer models. In vitro, free CPT, β-CD-CPT, and CB[7]-CPT were tested on normal LO2 and cancerous HCT116 cells. CB[7] encapsulation reduced toxicity toward normal LO2 cells (IC50: 0.47 μM, ∼25-fold higher than the IC50 of free CPT) while improving potency against HCT116 cells (CB[7]-CPT IC50: 0.24 μM; free CPT IC50: 0.55 μM, ∼2-fold more potent than free CPT). The selectivity index improved from 0.034 (CPT) to 1.976 (CB[7]-CPT), indicating a wide safety margin. Apoptosis assays confirmed that CB[7]-CPT induced significantly greater apoptotic cell death at equivalent concentrations than either free CPT or β-CD-CPT. In HCT116 xenograft models, CB[7]-CPT achieved a tumor inhibition rate of 76%, markedly outperforming free CPT (46%) and β-CD-CPT (62%). This enhanced efficacy was accompanied by increased intratumoral apoptosis, reduced proliferation, and decreased microvessel density. Importantly, CB[7]-CPT markedly attenuated liver, kidney, and gastrointestinal toxicity typically associated with CPT exposure. Pharmacokinetically, CB[7]-CPT displayed a 1.94-fold higher AUC and a 1.59-fold prolonged elimination half-life relative to free CPT, reflecting extended circulation and improved systemic exposure. These findings collectively establish CB[7]-CPT as a highly effective and safer alternative not only to free CPT but also to conventional cyclodextrin-based formulations, demonstrating enhanced selectivity, robust pro-apoptotic activity, and a superior safety profile.