Colorectal cancer (CRC) occurs in the colorectum and ranks second in the global incidence of all cancers, accounting for one of the highest mortalities. Although the combination chemotherapy regimen of 5-fluorouracil (5-FU) and platinum(IV) oxaliplatin prodrug (OxPt) is an effective strategy for CRC treatment in clinical practice, chemotherapy resistance caused by tumor-resided Fusobacterium nucleatum (Fn) could result in treatment failure. To enhance the efficacy and improve the biocompatibility of combination chemotherapy, we developed an antibacterial-based nanodrug delivery system for Fn-associated CRC treatment. A tumor microenvironment-activated nanomedicine 5-FU-LA@PPL was constructed by the self-assembly of chemotherapeutic drug derivatives 5-FU-LA and polymeric drug carrier PPL. PPL is prepared by conjugating lauric acid (LA) and OxPt to hyperbranched polyglycidyl ether. In principle, LA is used to selectively combat Fn, inhibit autophagy in CRC cells, restore chemosensitivity of 5-FU as well as OxPt, and consequently enhance the combination chemotherapy effects for Fn-associated drug-resistant colorectal tumor. Both in vitro and in vivo studies exhibited that the tailored nanomedicine possessed efficient antibacterial and anti-tumor activities with improved biocompatibility and reduced non-specific toxicity. Hence, this novel anti-tumor strategy has great potential in the combination chemotherapy of CRC, which suggests a clinically relevant valuable option for bacteria-associated drug-resistant cancers.

中文翻译：

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工程化基于月桂酸的纳米药物递送系统，用于恢复化学敏感性并改善 5-FU 和 OxPt 针对 Fn 相关结直肠肿瘤的生物相容性

结直肠癌（CRC）发生于结直肠，在全球所有癌症中发病率位居第二，是死亡率最高的癌症之一。尽管5-氟尿嘧啶（5-FU）和铂（ IV ）奥沙利铂前药（OxPt）的联合化疗方案是临床实践中治疗CRC的有效策略，但肿瘤中的具核梭杆菌（Fn ）引起的化疗耐药可能导致治疗失败。为了增强联合化疗的疗效并改善其生物相容性，我们开发了一种用于Fn相关 CRC 治疗的抗菌纳米药物递送系统。通过化疗药物衍生物5-FU-LA与高分子药物载体PPL自组装，构建了肿瘤微环境激活的纳米药物5-FU -LA@PPL 。 PPL 是通过将月桂酸 (LA) 和 OxPt 与超支化聚缩水甘油醚缀合而制备的。原则上，LA用于选择性对抗Fn，抑制CRC细胞的自噬，恢复5-FU和OxPt的化疗敏感性，从而增强Fn相关耐药结直肠肿瘤的联合化疗效果。体外和体内研究表明，定制的纳米药物具有高效的抗菌和抗肿瘤活性，具有改善的生物相容性和降低的非特异性毒性。因此，这种新颖的抗肿瘤策略在结直肠癌的联合化疗中具有巨大的潜力，这为细菌相关的耐药癌症提供了具有临床意义的有价值的选择。