Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences , Washington State University , Spokane , Washington 99210 , United States.
School of Chemical Engineering and Light Industry , Guangdong University of Technology , Guangzhou 510006 , China.
ACS Appl Mater Interfaces. 2019 May 8;11(18):16380-16390. doi: 10.1021/acsami.9b04051. Epub 2019 Apr 24.
Dysregulated vascular inflammation is the underlying cause of acute lung inflammation/injury (ALI). Bacterial infections and trauma cause ALI that may rapidly lead to acute respiratory distress syndrome (ARDS). There are no pharmacological therapies available to patients with ALI/ARDS, partially as drugs cannot specifically target the lungs. Herein, we developed a stimuli-responsive nanoparticle (NP) to target inflammatory lungs for ALI therapies. The NP is composed of a sharp acid-sensitive segment poly(β-amino esters) as a core for drug loading and controlled release and a polyethylene glycol-biotin on the particle surface available for bioconjugation, enabling lung targeting and extended circulation. The studies on dissipative particle dynamics simulation and characteristics of NPs suggest that anti-ICAM-1 antibodies can be coated to the particle surface and this coating is required to enhance lung targeting of NPs. A model drug of anti-inflammatory agent TPCA-1 is encapsulated in NPs with a high drug-loading content at 24% (w/w). In the mouse ALI model, our TPCA-1-loaded NPs coated with anti-ICAM-1 can target inflamed lungs after intravenous injection, followed by drug release triggered by the acid environment, thus mitigating lung inflammation and injury. Our studies reveal the rational design of nanotherapeutics for improved therapy of ALI, which may be applied to treating a wide range of vascular inflammation.
血管炎症失调是急性肺炎症/损伤 (ALI) 的根本原因。细菌感染和创伤会导致 ALI，这可能会迅速导致急性呼吸窘迫综合征 (ARDS)。ALI/ARDS 患者没有可用的药物治疗方法，部分原因是药物不能专门针对肺部。在此，我们开发了一种对炎症肺部具有靶向作用的响应性纳米颗粒 (NP)，用于 ALI 治疗。该 NP 由尖锐的酸敏感段聚（β-氨基酯）作为药物负载和控制释放的核心，以及粒子表面上的聚乙二醇-生物素组成，可用于生物缀合，实现肺部靶向和延长循环。耗散粒子动力学模拟和 NPs 的特性研究表明，可以将抗 ICAM-1 抗体涂覆到粒子表面，并且这种涂层对于增强 NPs 的肺部靶向性是必需的。具有 24%（w/w）高载药含量的抗炎剂 TPCA-1 被包封在 NPs 中。在小鼠 ALI 模型中，我们载有 TPCA-1 的 NPs 经静脉注射后可靶向发炎的肺部，然后在酸性环境下触发药物释放，从而减轻肺部炎症和损伤。我们的研究揭示了用于改善 ALI 治疗的纳米治疗学的合理设计，这可能适用于治疗广泛的血管炎症。
