Redox‐Triggered Nanomedicine via Lymphatic Delivery: Inhibition of Melanoma Growth by Ferroptosis Enhancement and a Pt(IV)‐Prodrug Chemoimmunotherapy Approach

The efficacy of therapies is often hampered by limited tumor drug accumulation achieved through their intravenous administration, and by the lack of selectivity in targeting and killing cancer cells. Amplification of tumor redox stress and ferroptotic cell death to achieve selective killing of cancer cells using iron‐containing agents has attracted considerable interest. However, these agents need high doses and multiple injection regimens and have limited success in the treatment of cancers such as melanoma. Melanoma often metastasizes via lymphatic vessels, where the metastasizing cells experience less redox stress and are protected from ferroptosis. Here it is shown that phospholipid‐modified Pt(IV) prodrug‐loaded iron oxide nanoparticle (IONP)‐filled micelles (mIONP‐PL‐Pt(IV)), which integrate redox reactivity and iron‐enabled catalytic therapeutic features with effective nanoparticle‐assisted lymphatic delivery, provide significantly enhanced suppression of melanoma tumor growth compared to cisplatin‐based chemotherapy and IONP treatments. Peroxidase‐like activity, redox‐triggered release of cisplatin, and reactivity with hydrogen peroxide and ascorbic acid are contributors toward the induction of a combined ferroptosis‐based and cisplatin anti‐melanoma treatment. Treatment with mIONP‐PL‐Pt(IV) provides significant tumor control using cumulative treatment doses 10–100‐fold lower than reported in intravenously administered treatments. This work demonstrates the potential of enhancing chemotherapeutic and iron‐based catalytic nanomedicine efficacy exploiting nanoparticle‐enabled lymphatic trafficking. This article describes phospholipid‐modified Pt(IV) prodrug‐loaded iron oxide‐filled micelles (mIONP‐PL‐Pt(IV)), which are designed and shown to take advantage of the lymphatic system/transport process to deliver redox‐triggered therapy, providing greatly enhanced suppression of melanoma tumor growth compared to cisplatin‐based chemotherapy and iron oxide nanoparticle treatments.