Triterpenoid saponin-based supramolecular host-guest injectable hydrogels inhibit the growth of melanoma via ROS-mediated apoptosis

Triterpenoids are natural bioactive compounds that demonstrate cytotoxic and chemopreventive activities by inhibiting various intracellular signals and transcription factors. Despite their efficacy, triterpenoid chemotherapeutics face significant challenges in cancer therapy because of their poor aqueous solubility, which restricts the utilization of potent drug variants. Consequently, there is a pressing need to develop a solubilized form of triterpenoid encapsulated within mechanically robust biomaterials, to facilitate injectable and minimally invasive delivery. In this study, we focused on ginsenoside compound K (CK), a natural pentacyclic triterpenoid. It was conjugated to hyaluronic acid (HA-CK) and employed as a novel guest molecule for binding to β-cyclodextrin-grafted hyaluronic acid (HA-βCD), which is the host polymer. This interaction resulted in the creation of an injectable supramolecular hydrogel (HG-Gel) through a straightforward mixing process involving host–guest interactions between βCD and CK. The physical properties of the hydrogels were easily manipulated by altering the molecular weight of HA and the grafting degree of βCD and CK in HA. Notably, the supramolecular hydrogel precursors exhibited excellent cell viability for normal cells, sparing over 80 % of NIH 3T3 and HaCaT cells. Intriguingly, these hydrogels facilitated effective delivery to CD44-overexpressing cancer cells, suppressing cell proliferation. Enhanced trafficking of CK to cancer cells heightened caspase-dependent apoptosis in B16F10 cells, with the extent of cell death contingent on the expression levels of CD44 in cancer cells. This effect of CK seems to be mediated through the induction of intracellular reactive oxygen species (ROS) and mitochondrial membrane potential loss. In melanoma tumor-bearing mouse models, HG-Gels effectively inhibited tumor growth. Importantly, no side effects were observed on normal tissues, underscoring the safety of naturally derived biomaterials. This study underscores the superiority of HG-Gels as a platform for utilizing triterpenoid saponins in melanoma therapy, suggesting their potential for enhancing the safety and efficacy of triterpenoids in cancer treatment.