Department of Pulmonary and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China.
J Nanobiotechnology. 2021 Feb 25;19(1):56. doi: 10.1186/s12951-021-00803-w.
Uncontrolled inflammation is a central problem for many respiratory diseases. The development of potent, targeted anti-inflammatory therapies to reduce lung inflammation and re-establish the homeostasis in the respiratory tract is still a challenge. Previously, we developed a unique anti-inflammatory nanodrug, P12 (made of hexapeptides and gold nanoparticles), which can attenuate Toll-like receptor-mediated inflammatory responses in macrophages. However, the effect of the administration route on its therapeutic efficacy and tissue distribution remained to be defined.
In this study, we systematically compared the effects of three different administration routes [the intratracheal (i.t.), intravenous (i.v.) and intraperitoneal (i.p.)] on the therapeutic activity, biodistribution and pulmonary cell targeting features of P12. Using the LPS-induced ALI mouse model, we found that the local administration route via i.t. instillation was superior in reducing lung inflammation than the other two routes even treated with a lower concentration of P12. Further studies on nanoparticle biodistribution showed that the i.t. administration led to more accumulation of P12 in the lungs but less in the liver and other organs; however, the i.v. and i.p. administration resulted in more nanoparticle accumulation in the liver and lymph nodes, respectively, but less in the lungs. Such a lung favorable distribution was also determined by the unique surface chemistry of P12. Furthermore, the inflammatory condition in the lung could decrease the accumulation of nanoparticles in the lung and liver, while increasing their distribution in the spleen and heart. Interestingly, the i.t. administration route helped the nanoparticles specifically target the lung macrophages, whereas the other two administration routes did not.
The i.t. administration is better for treating ALI using nanodevices as it enhances the bioavailability and efficacy of the nanodrugs in the target cells of the lung and reduces the potential systematic side effects.
炎症失控是许多呼吸道疾病的核心问题。开发强效、靶向的抗炎疗法以减轻肺部炎症并重建呼吸道内的稳态仍然是一个挑战。此前，我们开发了一种独特的抗炎纳米药物 P12（由六肽和金纳米颗粒组成），它可以减弱巨噬细胞中 Toll 样受体介导的炎症反应。然而，给药途径对其治疗效果和组织分布的影响仍有待确定。
在这项研究中，我们系统地比较了三种不同给药途径[气管内（i.t.）、静脉内（i.v.）和腹腔内（i.p.）]对 P12 的治疗活性、生物分布和肺细胞靶向特征的影响。使用 LPS 诱导的 ALI 小鼠模型，我们发现局部给药途径经 i.t. 滴注在减轻肺部炎症方面优于其他两种途径，即使使用较低浓度的 P12 也是如此。进一步研究纳米颗粒的生物分布表明，i.t. 给药导致 P12 在肺部的积累更多，而在肝脏和其他器官中的积累更少；然而，i.v. 和 i.p. 给药分别导致更多的纳米颗粒在肝脏和淋巴结中的积累，而在肺部中的积累更少。这种肺部有利的分布也由 P12 的独特表面化学决定。此外，肺部的炎症状况会减少肺部和肝脏中纳米颗粒的积累，同时增加它们在脾脏和心脏中的分布。有趣的是，i.t. 给药途径有助于纳米颗粒特异性地靶向肺巨噬细胞，而其他两种给药途径则没有。
与其他两种给药途径相比，i.t. 给药更有利于使用纳米设备治疗 ALI，因为它可以提高纳米药物在肺部靶细胞中的生物利用度和疗效，并降低潜在的系统副作用。
