School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816, People's Republic of China.
School of Pharmacy, Hainan Medical University, Haikou, Hainan, 571199, People's Republic of China.
Int J Nanomedicine. 2024 Nov 21;19:12205-12219. doi: 10.2147/IJN.S477278. eCollection 2024.
Compared to conventional photodynamic therapy (PDT), oxygen-affording PDT represents a promising strategy for treating multidrug-resistant (MDR) gram-negative bacterial infections due to its enhanced sensitization ability towards bacteria and amplified therapeutic efficacy. Over the last decade, various nanoplatforms for the co-delivery of oxygen and photosensitizers have been developed. However, their application in the treatment of infectious diseases is hampered by their poor stability and easy clearance by the reticuloendothelial system (RES).
To address these obstacles, we reported an erythrocyte membrane (EM) camouflaged nanoemulsion containing chlorin e6 (Ce6) and perfluorocarbon (FDC), named ECF, showing good colloidal stability and long-circulating potential, making it suitable for fighting against MDR Gram-negative bacterial infections. The nanoemulsion was fabricated and characterized. The oxygen loading and release performance, photodynamic activity, and bactericidal performance of ECF against () were evaluated. Furthermore, the antiphagocytosis profile was tested in vitro using Raw 264.7 cells. In addition, the pharmacokinetic behavior and therapeutic efficiency of ECF were studied in vivo.
ECF exhibited superior oxygen loading and release behavior, potent photodynamic activity, and negligible toxicity to mammalian cells. Upon light irradiation, the antibacterial rate of preoxygenated-ECF reached 98% at 40 μg mL of Ce6 and the bactericidal activity of preoxygenated-ECF and Gen was 3.3 folds higher than that of Gen. Furthermore, ECF could effectively inhibit uptake by phagocytes and circulate in the blood 1.5-fold longer than that of nanoemulsion without EM modification (CF) following intravenous administration. In addition, preoxygenated-ECF combined with antibiotic plus light irradiation showed prominent therapeutic efficacy in treating -induced acute peritonitis, accompanied by good biocompatibility in vivo.
Our results provide a novel paradigm for evading immune clearance, prolonging retention time and improving synergetic bactericidal capacity in combination with PDT and antibiotic therapy against planktonic bacteria and gram-negative bacterial infections.
与传统光动力疗法（PDT）相比，供氧 PDT 由于其对细菌的增强敏感性和放大的治疗效果，代表了治疗多药耐药（MDR）革兰氏阴性细菌感染的有前途的策略。在过去的十年中，已经开发了各种用于共递送氧气和光敏剂的纳米平台。然而，由于其较差的稳定性和容易被网状内皮系统（RES）清除，它们在治疗传染病方面的应用受到阻碍。
为了解决这些障碍，我们报道了一种含有氯己定（Ce6）和全氟碳（FDC）的红细胞膜（EM）伪装纳米乳液，命名为 ECF，具有良好的胶体稳定性和长循环潜力，适用于对抗 MDR 革兰氏阴性细菌感染。制备并表征了纳米乳液。评估了 ECF 对 （）的氧负载和释放性能、光动力活性和杀菌性能。此外，在体外使用 Raw 264.7 细胞测试了抗吞噬作用。此外，在体内研究了 ECF 的药代动力学行为和治疗效率。
ECF 表现出优异的氧负载和释放行为、强大的光动力活性和对哺乳动物细胞的低毒性。在光照射下，预充氧-ECF 的抗菌率在 40 μg mL 的 Ce6 时达到 98%，预充氧-ECF 和 Gen 的杀菌活性比 Gen 高 3.3 倍。此外，与没有 EM 修饰的纳米乳液（CF）相比，ECF 经静脉注射后能够有效地抑制吞噬细胞的摄取并在血液中循环 1.5 倍更长时间。此外，预充氧-ECF 结合抗生素加光照射在治疗 -诱导的急性腹膜炎方面显示出显著的治疗效果，同时具有良好的体内生物相容性。
我们的结果为逃避免疫清除、延长保留时间和提高与 PDT 和抗生素治疗联合对浮游细菌和革兰氏阴性细菌感染的协同杀菌能力提供了一种新的范例。
