Ferroptosis is an
iron-dependent cell death pathway that can eradicate certain apoptosis-insensitive
cancer cells. The ferroptosis-inducing molecules are tailored
lipid peroxides whose efficacy is compromised in hypoxic solid
tumor and lack of
tumor selectivity. It has been demonstrated that ascorbate (Asc) in pharmacological concentrations can selectively kill
cancer cells via accumulating
hydrogen peroxide (H2O2) only in
tumor extracellular fluids. It was hypothesized that Asc-induced, selective enrichment of H2O2 in
tumor coupled with Fe3+ codelivery could simultaneously address the above two problems via boosting the levels of
hydroxyl radicals and
oxygen in the
tumor site to ease peroxidation initiation and propagation, respectively. The aim of this work was to synergize the action of Asc with
lipid-coated
calcium phosphate (CaP) hybrid nanocarrier that can concurrently load polar Fe3+ and nonpolar RSL3, a ferroptosis inducer with the mechanism of inhibiting
lipid peroxide repair
enzyme (GPX4). The hybrid nanocarriers showed accelerated cargo release at acidic conditions (pH 5.0). The combinational approach (Asc plus nanocarrier) produced significantly elevated levels of
hydroxyl radicals,
lipid peroxides, and depleted
glutathione under
hypoxia, which was accompanied with the strong cytotoxicity (IC50 = 1.2 ± 0.2 μM) in the model 4 T1 cells. In the 4 T1
tumor-bearing xenograft mouse model, the intravenous nanocarrier delivery plus intraperitoneal Asc administration resulted in a superior antitumor performance in terms of
tumor suppression, which did not produce supplementary adverse effects to the healthy organs. This work provides a novel approach to enhance the potency of ferroptotic nanomedicine against solid
tumors without inducing additional side effects.