Li Xiaohui, Niu Jiazhen, Deng Lingling, Yu Yunjian, Zhang Liuwei, Chen Qixian, Zhao Jingwen, Wang Bangmao, Gao Hui
State Key Laboratory of Separation Membranes and Membrane Processes, School of Materials Science and Engineering, Tiangong University, Tianjin 300387, China.
School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, China.
Acta Biomater. 2024 Jan 1;173:432-441. doi: 10.1016/j.actbio.2023.11.019. Epub 2023 Nov 19.
Colorectal cancer (CRC) is one of the most prevalent and deadly malignancies that can be influenced by Fusobacterium nucleatum (Fn), a bacterium that promotes tumor development and chemoresistance, resulting in limited therapeutic efficacy. Traditional antibiotics cannot effectively eliminate Fn at tumor site due to issues like biofilm formation, while chemotherapy alone fails to suppress tumor progression. Therefore, the development of new methods to eliminate Fn and promote antitumor efficacy is of great significance for improving the outcome of CRC treatment. Herein, we developed a nanodrug (OPPL) that integrates oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) and an amphiphilic polymer (PPL) to deliver the platinum prodrug and antimicrobial lauric acid (LA) for enhancing the treatment of CRC. We demonstrated that OPPL can synergistically enhance antibacterial and biofilm disruption activities against Fn along with the antimicrobial LA by producing reactive oxygen species (ROS) through its peroxidase-like activity. Furthermore, the OPPL nanodrug can increase intracellular ROS, promote lipid peroxides and deplete glutathione, leading to ferroptosis. By combining chemotherapy and induced ferroptosis, the OPPL nanodrug exhibited high cytotoxicity against CRC cells. In vivo studies showed that the OPPL nanodrug could enhance tumor accumulation, enable magnetic resonance imaging, suppresse tumor growth, and inhibit growth of intratumor Fn. These results suggest that OPPL is an effective and promising candidate for the treatment of Fn-infected CRC. STATEMENT OF SIGNIFICANCE: The enrichment of Fusobacterium nucleatum (Fn) in colorectal cancer is reported to exacerbate tumor malignancy and is particularly responsible for chemoresistance. To this respect, we strategically elaborated multifaceted therapeutics, namely OPPL nanodrug, combining oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) with a polymer containing a platinum prodrug and antimicrobial lauric acid. The O-SPION components exert distinctive peroxidase-like activity, capable of stimulating Fenton reactions selectively in the tumor microenvironment, consequently accounting for the progressive production of reactive oxygen species. Hence, O-SPIONs have been demonstrated to not only supplement the antimicrobial activities of lauric acid in overcoming Fn-induced chemoresistance but also stimulate potent tumor ferroptosis. Our proposed dual antimicrobial and chemotherapeutic nanodrug provides an appreciable strategy for managing challenging Fn-infected colorectal cancer.
结直肠癌（CRC）是最常见且致命的恶性肿瘤之一，可受具核梭杆菌（Fn）影响，该细菌会促进肿瘤发展和化疗耐药性，导致治疗效果有限。由于生物膜形成等问题，传统抗生素无法有效消除肿瘤部位的Fn，而单纯化疗无法抑制肿瘤进展。因此，开发消除Fn并提高抗肿瘤疗效的新方法对于改善CRC治疗结果具有重要意义。在此，我们开发了一种纳米药物（OPPL），它整合了油酸修饰的超顺磁性氧化铁纳米颗粒（O-SPIONs）和两亲聚合物（PPL），用于递送铂前药和抗菌月桂酸（LA），以增强CRC的治疗效果。我们证明，OPPL可通过其类过氧化物酶活性产生活性氧（ROS），协同增强对Fn的抗菌和生物膜破坏活性以及抗菌LA的活性。此外，OPPL纳米药物可增加细胞内ROS，促进脂质过氧化并消耗谷胱甘肽，导致铁死亡。通过结合化疗和诱导铁死亡，OPPL纳米药物对CRC细胞表现出高细胞毒性。体内研究表明，OPPL纳米药物可增强肿瘤蓄积，实现磁共振成像，抑制肿瘤生长，并抑制肿瘤内Fn的生长。这些结果表明，OPPL是治疗Fn感染的CRC的有效且有前景的候选药物。
据报道，具核梭杆菌（Fn）在结直肠癌中的富集加剧了肿瘤恶性程度，尤其导致化疗耐药性。在这方面，我们精心设计了多方面的治疗方法，即OPPL纳米药物，并将油酸修饰的超顺磁性氧化铁纳米颗粒（O-SPIONs）与含有铂前药和抗菌月桂酸的聚合物相结合。O-SPION成分具有独特的类过氧化物酶活性，能够在肿瘤微环境中选择性地刺激芬顿反应，从而导致活性氧的逐步产生。因此，已证明O-SPIONs不仅能补充月桂酸在克服Fn诱导的化疗耐药性方面的抗菌活性，还能刺激有效的肿瘤铁死亡。我们提出的双重抗菌和化疗纳米药物为治疗具有挑战性的Fn感染的结直肠癌提供了一种可行的策略。
