Shanghai Key Laboratory of Advanced Polymeric Materials, Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China.
Department of Endodontics and Operative Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Disease, Shanghai Key Laboratory of Stomatology, Shanghai, China.
Acta Biomater. 2024 Sep 1;185:323-335. doi: 10.1016/j.actbio.2024.06.042. Epub 2024 Jul 2.
Intratumor microbes have attracted great attention in cancer research due to its influence on the tumorigenesis, progression and metastasis of cancer. However, the therapeutic strategies targeting intratumoral microbes are still in their infancy. Specific microorganisms, such as Fusobacterium nucleatum (F. nucleatum), are abundant in various cancer and always result in the CRC progression and chemotherapy resistance. Here, a combined anticancer and antibacterial therapeutic strategy is proposed to deliver antitumor drug to the tumors containing intratumor microbiota by the antibacerial polymeric drug carriers. We construct oral tellurium-containing drug carriers using a complex of tellurium-containing polycarbonate with cisplatin (PTE@CDDP). The results show that the particle size of the prepared nanoparticles could be maintained at about 105 nm in the digestive system environment, which is in line with the optimal particle size of oral nanomedicine. In vitro mechanism study indicates that the tellurium-containing polymers are highly effective in killing F.nucleatum through a membrane disruption mechanism. The pharmacokinetic experiments confirmed that PTE@CDDP has the potential function of enhancing the oral bioavailability of cisplatin. Both in vitro and in vivo studies show that PTE@CDDP could inhibit intratumor F.nucleatum and lead to a reduction in cell proliferation and inflammation in the tumor site. Together, the study identifies that the CDDP-loaded tellurium-containing nanoparticles have great potential for treating the F.nucleatum-promoted colorectal cancer (CRC) by combining intratumor microbiota modulation and chemotherapy. The synergistic therapeutic strategy provide new insight into treating various cancers combined with bacterial infection. STATEMENT OF SIGNIFICANCE: The synthesized antibacterial polymer was first employed to remodel the intratumor microbes in tumor microenvironment (TME). Moreover, it was the first report of tellurium-containing polymers against F.nucleatum and employed for treatment of the CRC. A convenient oral dosage form of cisplatin (CDDP)-loaded tellurium-containing nanoparticles (PTE@CDDP) was adopted here, and the synergistic antibacterial/chemotherapy effect occurred. The PTE@CDDP could quickly and completely eliminate F.nucleatum in a safe dose. In the CRC model, PTE@CDDP effectively reversed the inflammation level and even restored the intestinal barrier damaged by F.nucleatum. The ultrasensitive ROS-responsiveness of PTE@CDDP triggered the fast oxidation and efficient drug release of CDDP and thus a highly efficient apoptosis of the tumors. Therefore, the tellurium-containing polymers are expected to serve as novel antibacterial agents in vivo and have great potential in the F.nucleatum-associated cancers. The achievements provided new insight into treating CRC and other cancers combined with bacterial infection.
肿瘤内微生物因其对癌症的发生、进展和转移的影响而在癌症研究中引起了极大的关注。然而,针对肿瘤内微生物的治疗策略仍处于起步阶段。特定的微生物,如具核梭杆菌(Fusobacterium nucleatum,F. nucleatum),在各种癌症中大量存在,并且总是导致 CRC 的进展和化疗耐药。在这里,我们提出了一种联合抗癌和抗菌的治疗策略,通过抗菌聚合物药物载体将抗肿瘤药物递送到含有肿瘤内微生物群的肿瘤中。我们使用含有碲的聚碳酸酯与顺铂(PTE@CDDP)的复合物构建口服含碲药物载体。结果表明,在消化系统环境中,制备的纳米粒子的粒径可保持在约 105nm,符合口服纳米药物的最佳粒径。体外机制研究表明,含碲聚合物通过破坏膜的机制对 F.nucleatum 具有高效的杀灭作用。药代动力学实验证实,PTE@CDDP 具有增强顺铂口服生物利用度的潜力。体外和体内研究均表明,PTE@CDDP 可抑制肿瘤内 F.nucleatum,并导致肿瘤部位细胞增殖和炎症减少。综上所述,该研究表明,载顺铂的含碲纳米粒子通过调节肿瘤内微生物群和化疗相结合,具有治疗 F.nucleatum 促进的结直肠癌(CRC)的巨大潜力。协同治疗策略为治疗各种合并细菌感染的癌症提供了新的思路。
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