Enhanced solubility, stability, permeation and anti-cancer efficacy of Celastrol-β-cyclodextrin inclusion complex

Celastrol (Cela), a pentacyclic triterpenoid, has been explored widely due to its broad therapeutic activity such as antioxidant, chemotherapeutic, neuroprotective etc. However, poor aqueous solubility, limited permeability, and instability in physiological conditions result in reduced therapeutic efficacy of Cela and thereby hinder its potential clinical translation. In this exploration, we demonstrate the impact of FDA approved β-cyclodextrin (βCD) derivatives complexation with Cela in overcoming its existing limitations. In-silico molecular modeling studies and phase solubility results indicated superior activity of sulfobutyl-βCD (SBE-βCD; Dexolve®) in improving the aqueous solubility of Cela. Formation of inclusion complex was confirmed using spectroscopic and solid-state characterization studies. In-vitro permeability was assessed using EpiIntestinal® 3D small intestine tissue model and the results demonstrated improved permeability of Cela-SBE-βCD complex across the intestinal tissue. The stability of Cela was found to be greatly increased in phosphate buffer saline (pH 7.4) and biological matrices; rat plasma and human plasma upon complexation with SBE-βCD. In-vitro EpiIntestinal® tissue permeability results demonstrated improved permeability of Cela-SBE-βCD inclusion complex. Moreover, the in-vitro anti-cancer studies on human lung cancer cells showed that SBE-βCD complexation of Cela resulted into enhanced cytotoxic efficacy as compared to free Cela with significant reduction in IC50 values (p < 0.0001). Our results provide valuable insights on the effectiveness of SBE-βCD complexation as a potential strategy to improve the characteristics of Cela for its extended clinical application.