PO.CH01.04 · 化学
由肿瘤靶向青蒿琥酯纳米衍生物放大的铁死亡用于有效治疗结肠癌
Ferroptosis amplified by a tumor-targeted artesunate nano-derivative for effective colon cancer treatment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：青蒿琥酯（ART）是一种已获证实的抗疟药物，颇具前景，但由于其稳定性差、效力低且缺乏肿瘤选择性，抗肿瘤活性有限。虽然其作用与铁死亡（一种由脂质过氧化驱动的铁依赖性细胞死亡形式）相关，但在肿瘤学中的临床转化需要增强药物递送和靶向。我们假设，工程化构建ART前药的肿瘤靶向纳米颗粒可以放大铁死亡的诱导并增强对结直肠癌（CRC）的治疗疗效。
方法：我们系统地设计并合成了六种氨基酸修饰的ART衍生物。将效力最强的偶联物进一步用3-氨基苯硼酸（PBA）功能化，以制成最终前药AAP。AAP通过一步沉淀法自组装成纳米颗粒（AAP NPs）。对NPs的粒径、PDI和形态进行了表征。通过CCK-8试验在多种CRC细胞系（CT26、HCT116、SW480、SW620）和一种肝癌细胞系（Huh7）中评估疗效。通过负载香豆素-6的NPs可视化细胞摄取。在荷CT26肿瘤的BALB/c小鼠模型中全面研究了AAP NPs的抗肿瘤效应、全身安全性、生存获益和机制。
结果：与天然ART相比，AAP展现出更优的体外细胞毒性，在CRC和肝癌细胞中的IC50值低1.77至2.09倍。所得AAP NPs为单分散球体，粒径均匀为174.44 ± 9.97 nm，PDI较低为0.046。与ART或ART-AA（不含PBA）相比，完整的AAP NPs对所有测试的癌细胞表现出显著更强的、剂量和时间依赖性的细胞毒性（P < 0.05），并被CT26细胞有效内化。在体内，AAP NPs实现了最强效的肿瘤生长抑制，将肿瘤体积和重量分别降至531.29 ± 132.20 mm³和483.14 ± 118.91 mg，显著优于对照、ART和ART-AA NP组（P < 0.05）。关键的是，AAP NPs显著延长了小鼠生存期（P < 0.05）。在机制上，AAP NP治疗导致肿瘤组织中ROS的显著蓄积，证实了铁死亡的诱导。
结论：我们开发了一种双靶向ART纳米前药，利用PBA介导的主动靶向和EPR效应。该策略通过触发铁死亡强效抑制CRC生长，并展现出优异的安全性，为将ART重新用于靶向癌症治疗提供了一种引人注目的方法。
查看英文原文 English abstract
Background: Artesunate (ART), a proven antimalarial drug, is promising but has limited antitumor activity because of its poor stability, low potency, and lack of tumor selectivity. While its effect is linked to ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, clinical translation in oncology requires enhanced drug delivery and targeting. We hypothesized that engineering a tumor-targeted nanoparticle of an ART prodrug could amplify ferroptosis induction and therapeutic efficacy against colorectal cancer (CRC).
Methods: We systematically designed and synthesized six amino acid-modified ART derivatives. The most potent conjugate was further functionalized with 3-aminophenylboronic acid (PBA) to create the final prodrug, AAP. AAP self-assembled into nanoparticles (AAP NPs) via a one-step precipitation method. The size, PDI, and morphology of the NPs were characterized. Efficacy was evaluated in multiple CRC cell lines (CT26, HCT116, SW480, SW620) and a hepatoma cell line (Huh7) via CCK-8 assays. Cellular uptake was visualized via coumarin-6-loaded NPs. The antitumor effect, systemic safety, survival benefit, and mechanism of AAP NPs were comprehensively investigated in a BALB/c mouse model bearing CT26 tumors.
Results: AAP demonstrated superior in vitro cytotoxicity compared with native ART, with IC50 values 1.77- to 2.09-fold lower across CRC and hepatoma cells. The resulting AAP NPs were monodisperse spheres with a uniform size of 174.44 ± 9.97 nm and a low PDI of 0.046. Compared with ART or ART-AA (no PBA), the completed AAP NPs exhibited significantly stronger, dose- and time-dependent cytotoxicity against all cancer cells tested (P < 0.05) and were effectively internalized by CT26 cells. In vivo, AAP NPs achieved the most potent tumor growth inhibition, reducing the tumor volume and weight to 531.29 ± 132.20 mm³ and 483.14 ± 118.91 mg, respectively, significantly outperforming the control, ART, and ART-AA NP groups (P < 0.05). Critically, AAP NPs significantly prolonged mouse survival (P < 0.05) . Mechanistically, AAP NP treatment led to significant accumulation of ROS in tumor tissues, confirming the induction of ferroptosis.
Conclusion: We developed a dual-targeted ART nanoprodrug that leverages PBA-mediated active targeting and the EPR effect. This strategy potently inhibits CRC growth by triggering ferroptosis and exhibits an excellent safety profile, offering a compelling approach to repurpose ART for targeted cancer therapy.
利益披露 Disclosure
J. Li, None..
D. Song, None..
Q. Guan, None..
Z. Li, None.