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

Abstract

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.

Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches

“… 261 Phospholipid-modified Pt(IV) prodrug-loaded iron oxide nanoparticle (IONP)-filled micelles (mIONP-PL-Pt(IV)), which can be used in combination with chemotherapy for antimelanoma treatment. 262 Qingxin Mu et al designed and synthesized a multifunctional nanoparticle containing an iron oxide core. This NP can deliver chemotherapeutic and immunotherapeutic agents to breast cancer and dendritic cells simultaneously, thus enabling simultaneous chemo-immunotherapy and effective inhibition of TNBC growth and metastasis.…”

Progressing nanotechnology to improve targeted cancer treatment: overcoming hurdles in its clinical implementation

“…It leads to the rapid clearance of nanoparticles from the injection site, reducing their retention and bioavailability at the target site. This can be particularly problematic for nanomedicines designed for targeted drug delivery or immunotherapy in lymph nodes [182]. Additionally, if nanomedicines enter the systemic circulation due to lymphatic drainage, there's an increased risk of systemic toxicity and side effects associated with these therapeutic agents [183].…”