Iron ion driven remote loading of galloylated cabazitaxel prodrugs for synergistic ferroptosis and chemotherapy

Liposomes, particularly those designed for remote drug loading, have achieved remarkable success as drug-delivery vehicles in clinical settings. However, the lack of ionizable or coordinative groups prevents many promising drugs from being remotely loaded into liposomes for cancer therapy. Herein, to provide a universal remote loading approach, we chose cabazitaxel (CTX) as a model drug to modify galloyl group bridged by different lengths of alkyl chain. Fortunately, all the synthesized prodrugs could be actively loaded into liposomes via Fe 3+ gradient with high encapsulation efficiency and loading capacity. As the intraliposomal aqueous phase, Fe 3+ was not only served as the driving force of prodrugs remote loading, but also regarded as an exogenous replenishment to strengthen iron-dependent ferroptosis for multimodal therapy. The length of linkage between CTX and galloyl group played a crucial role in the chemical stability of prodrugs, in vitro drug release rate and in vivo pharmacokinetics behavior of prodrug liposomes. Among three prodrug liposomes, only decylene glycol-bridged CTX-gallic acid (CTX-DC-GA) liposomes kept a good balance between drug leakage during circulation and specific drug release under tumor microenvironment. Ultimately, CTX-DC-GA liposomes displayed optimal antitumor efficacy with good safety. We proposed Fe 3+ -based galloylated prodrug liposomes give new horizons for achieving the combination of ferroptosis and chemotherapy.