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

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Marc Bilbao-Asensio, Ane Ruiz-de-Angulo, Amaia G. Arguinzoniz, James Cronin, Jordi Llop, Aintzane Zabaleta, Saul Michue-Seijas, Dominika Sosnowska, James N. Arnold, Juan C. Mareque-Rivas

Original languageEnglish
JournalAdvanced Therapeutics
DOIs
Published14 Nov 2022

Bibliographical note

Funding Information: J.C. and J.C.M.‐R. thank an MRC Confidence in Concept award (MC_PC_19053). M.B.‐A. was supported by an EPSRC Ph.D. Studentship (project reference 2105067). J.N.A. was funded by a grant from Cancer Research UK (DCRPGF∖100009) and is the recipient of a Cancer Research Institute/Wade F.B. Thompson CLIP grant (CRI3645). Publisher Copyright: © 2022 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.

Documents

  • Bilbao-Asensio et al 2022

    Bilbao_Asensio_et_al_2022.docx, 21.8 MB, application/vnd.openxmlformats-officedocument.wordprocessingml.document

    Uploaded date:15 Nov 2022

    Licence:CC BY

King's Authors

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.

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