Redox-Triggered Nanomedicine via Lymphatic Delivery: Inhibition of Melanoma Growth by Ferroptosis Enhancement and a Pt(IV)-Prodrug Chemoimmunotherapy Approach
Redox-Triggered Nanomedicine via Lymphatic Delivery: Inhibition of Melanoma Growth by Ferroptosis Enhancement and a Pt(IV)-Prodrug Chemoimmunotherapy Approach
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DOI：
10.1002/adtp.202200179
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发表时间：
2022-11-14
影响因子：
4.6
通讯作者：
Mareque-Rivas, Juan C.
中科院分区：
文献类型：
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作者：
Bilbao-Asensio, Marc;Ruiz-de-Angulo, Ane;Mareque-Rivas, Juan C.
通过静脉给药获得的肿瘤药物积累有限，以及在靶向和杀死癌细胞方面缺乏选择性，往往阻碍了治疗的效果。利用含铁试剂放大肿瘤氧化还原应激和嗜铁细胞死亡以实现选择性杀伤癌细胞已引起了相当大的兴趣。然而，这些药物需要高剂量和多次注射方案，并且在治疗黑色素瘤等癌症方面的成功有限。黑色素瘤通常通过淋巴管转移，在淋巴管中，转移的细胞经历较少的氧化还原应激，并被保护免于铁下垂。本研究表明，磷脂修饰的Pt（IV）前药负载的氧化铁纳米颗粒（IONP）填充胶束（mionp - plp -Pt(IV)），结合氧化还原反应性和铁催化治疗特性以及有效的纳米颗粒辅助淋巴输送，与基于顺铂的化疗和IONP治疗相比，显著增强了对黑色素瘤肿瘤生长的抑制。过氧化物酶样活性，氧化还原触发的顺铂释放，以及与过氧化氢和抗坏血酸的反应性是诱导基于铁中毒和顺铂联合抗黑色素瘤治疗的因素。使用mIONP-PL-Pt（IV）治疗提供了显著的肿瘤控制，其累积治疗剂量比静脉注射治疗低10-100倍。这项工作证明了利用纳米颗粒淋巴运输来增强化疗和铁基催化纳米药物疗效的潜力。
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.