In vitro biological evaluation of a water-soluble hyperbranched β-cyclodextrin nanocarrier for co-delivery of doxorubicin and curcumin

Conventional chemotherapy is often limited by poor aqueous solubility, systemic toxicity, and low bioavailability. To address these limitations, a water-dispersible hyperbranched β-cyclodextrin (HBCD) crosslinked with 1,2,3,4-butanetetracarboxylic acid (BTCA) was developed as a nanocarrier for the co-delivery of doxorubicin (DOX) and curcumin (CUR). HBCD was synthesized under optimized conditions and characterized using complementary physicochemical techniques. DOX and CUR were loaded individually and in combination, and drug release kinetics were evaluated. Biological performance was assessed by hemolysis, cytocompatibility, cellular uptake assessment, apoptosis analyses, anticancer activity, and concentration-dependent drug interaction analysis using SynergyFinder+. The optimized HBCD exhibited favorable physicochemical properties and excellent water solubility. Encapsulation efficiencies in the co-loaded formulation reached 50.8% for DOX and 45.7% for CUR. Drug release showed an initial burst followed by sustained release over 96 h, with kinetics best described by the Korsmeyer–Peppas model. HBCD demonstrated excellent hemocompatibility (<2% hemolysis) and high cytocompatibility toward HDF cells. Drug-loaded formulations produced concentration-dependent cytotoxicity in cancer cell lines. Cellular association and apoptosis analyses confirmed the biological activity of the formulations, while SynergyFinder+ indicated predominantly additive drug interactions with localized concentration-dependent positive interaction regions rather than uniform synergism. BTCA-crosslinked water-dispersible HBCD provides an effective platform for the co-delivery of hydrophilic and hydrophobic anticancer agents, combining efficient drug loading, sustained release, hemocompatibility, and encouraging in vitro biological performance. These findings establish a foundation for future mechanistic, pharmacokinetic, and in vivo studies to further evaluate the translational potential of this delivery system.