Abstract：
Cetuximab (Cet) and oxaliplatin (OXA) are used as first-line drugs for patients with colorectal carcinoma (CRC). In fact, the heterogeneity of CRC, mainly caused by K-ras mutations and drug resistance, undermines the effectiveness of drugs. Recently, a hydrophobic prodrug, (1E,4E)-6-((S)-1-(isopentyloxy)-4-methylpent-3-en-1-yl)-5,8-dimethoxynaphthalene-1,4‑dione dioxime (DMAKO-20), has been shown to undergo tumor-specific CYP1B1-catalyzed bioactivation. This process results in the production of nitric oxide and active naphthoquinone mono-oximes, which exhibit specific antitumor activity against drug-resistant CRC. In this study, a Cet-conjugated bioresponsive DMAKO-20/PCL-PEOz-targeted nanocodelivery system (DMAKO@PCL-PEOz-Cet) was constructed to address the issue of DMAKO-20 dissolution and achieve multitargeted delivery of the cargoes to different subtypes of CRC cells to overcome K-ras mutations and drug resistance in CRC. The experimental results demonstrated that DMAKO@PCL-PEOz-Cet efficiently delivered DMAKO-20 to both K-ras mutant and wild-type CRC cells by targeting the epidermal growth factor receptor (EGFR). It exhibited a higher anticancer effect than OXA in K-ras mutant cells and drug-resistant cells. Additionally, it was observed that DMAKO@PCL-PEOz-Cet reduced the expression of glutathione peroxidase 4 (GPX4) in CRC cells and significantly inhibited the growth of heterogeneous HCT-116 subcutaneous tumors and patient-derived tumor xenografts (PDX) model tumors. This work provides a new strategy for the development of safe and effective approaches for treating CRC. STATEMENT OF SIGNIFICANCE: (1) Significance: This work reports a new approach for the treatment of colorectal carcinoma (CRC) using the bioresponsible Cet-conjugated PCL-PEOz/DMAKO-20 nanodelivery system (DMAKO@PCL-PEOz-Cet) prepared with Cet and PCL-PEOz for the targeted transfer of DMAKO-20, which is an anticancer multitarget drug that can even prevent drug resistance, to wild-type and K-ras mutant CRC cells. DMAKO@PCL-PEOz-Cet, in the form of nanocrystal micelles, maintained stability in peripheral blood and efficiently transported DMAKO-20 to various subtypes of colorectal carcinoma cells, overcoming the challenges posed by K-ras mutations and drug resistance. The system\'s secure and effective delivery capabilities have also been confirmed in organoid and PDX models. (2) This is the first report demonstrating that this approach simultaneously overcomes the K-ras mutation and drug resistance of CRC.
摘要：
西妥昔单抗（Cet）和奥沙利铂（OXA）用作结直肠癌（CRC）患者的一线药物。事实上,CRC的异质性，主要由K-ras突变和耐药性引起,破坏药物的有效性。最近,疏水性前药，(1E,4E)-6-((S)-1-(异戊氧基)-4-甲基戊-3-烯-1-基)-5,8-二甲氧基萘-1,4-二酮二肟(DMAKO-20),已显示经历肿瘤特异性CYP1B1催化的生物活化。此过程导致产生一氧化氮和活性萘醌单肟，对耐药CRC表现出特异性抗肿瘤活性。在这项研究中,构建了Cet缀合的生物响应DMAKO-20/PCL-PEOz靶向纳米共递送系统（DMAKO@PCL-PEOz-Cet），以解决DMAKO-20溶解的问题，并实现了货物向不同亚型的CRC细胞的多靶向递送，以克服CRC中的K-ras突变和耐药性。实验结果表明，DMAKO@PCL-PEOz-Cet通过靶向表皮生长因子受体（EGFR）有效地将DMAKO-20递送至K-ras突变体和野生型CRC细胞。它在K-ras突变细胞和耐药细胞中表现出比OXA更高的抗癌作用。此外,观察到DMAKO@PCL-PEOz-Cet降低了CRC细胞中谷胱甘肽过氧化物酶4（GPX4）的表达，并显着抑制了异质HCT-116皮下肿瘤和患者来源的肿瘤异种移植物（PDX）模型肿瘤的生长。这项工作为开发安全有效的CRC治疗方法提供了新的策略。重要声明：（1）意义：这项工作报道了一种新的治疗结直肠癌（CRC）的方法，使用生物负责的Cet偶联PCL-PEOz/DMAKO-20纳米递送系统（DMAKO@PCL-PEOz-Cet）与Cet和PCL-PEOz一起制备，用于DMAKO-20的靶向转移，甚至可以预防多药野生型和K-ras突变型CRC细胞。DMAKO@PCL-PEOz-Cet,以纳米晶胶束的形式，维持外周血的稳定性，并有效地将DMAKO-20转运至各种亚型的结直肠癌细胞，克服K-ras突变和耐药性带来的挑战。该系统的安全和有效的交付能力也已在类器官和PDX模型中得到证实。（2）这是首次报道，表明该方法同时克服了CRC的K-ras突变和耐药性。
