Epidermal growth factor receptor-responsive supramolecular curcumin/carboxymethyl β-cyclodextrin self-assemblies enable improved treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) remains one of the most aggressive and therapeutically challenging breast cancer subtypes due to the lack of effective treatments, high recurrence rates, and poor clinical outcomes. Curcumin (Cur) is a natural anticancer agent; however, its clinical translation is limited by poor aqueous solubility, low stability, and insufficient tumor selectivity. In this study, Cur/carboxymethyl-β-cyclodextrin (CM-βCD) supramolecular assemblies were developed using different formulation approaches. Then, GE11 was covalently coupled to the carboxyl groups of CM-βCD via post-assembly functionalization. For this purpose, the formulation exhibiting the highest Cur loading (16.95%) was selected to construct EGFR-targeted supramolecular delivery systems. GE11-functionalized Cur/CM-βCD supramolecular assemblies significantly enhanced Cur cytotoxicity, reducing IC50 values by ~1.7-fold in MCF-7 cells and up to 2.2-fold in MDA-MB-231 TNBC cells compared to free Cur at 48 h. Quantitative uptake studies revealed a ~3.25-fold higher cellular internalization in MDA-MB-231 cells relative to MCF-7 cells. Moreover, GE11-Cur/CM-βCD markedly suppressed proliferation, evidenced by a 3.29-fold reduction in PCNA-positive cells, and induced apoptosis, with a 5.1-fold increase in TUNEL-positive cells. Overall, the findings suggest that GE11-functionalized Cur/CM-βCD is a promising targeted strategy to overcome Cur limitations and address TNBC therapy needs.