Nanonscale drug carriers for the treatment of acute respiratory distress syndrome

项目摘要/摘要 急性呼吸窘迫综合征(ARDS)是一种急性、弥漫性、炎症性肺损伤，其中许多 这些途径被明确地牵连在一起，但药物疗法在数十项大型临床试验中普遍失败。 为什么这么多理性选择的药物在ARDS中失败了？从药理学的角度来看，一个明确的原因 是药物输送不畅，几乎没有药物到达发炎的肺泡。 为了解决这个问题，我们开发了肺内皮靶向脂质体(PELS)。贝尔斯只是简单地 载药脂质体(~100纳米球形脂质双层)，静脉注射时浓缩 在肺部有很强的冲击力。在这项提案中，我们将研究一种有前景的、新颖的肺靶向PEL策略，该策略 我们最近发明了“RBC搭便车”(RH)。在RH中，PEL在体外被被动地吸附在RED上 血细胞(RBC)，然后在静脉注射时，RBC挤过肺毛细血管， 将脂质体转移到毛细血管内皮细胞。Rh-PEL在小鼠肺内浓缩药物 &gt；是“免费药品”(无靶向投放的药品)的300倍。此外，RH将PEL浓缩在肺部 甚至超过了过去20年靶向给药的“黄金标准”--“抗体靶向”药物 载体，在这种情况下是包被抗体的PEL，这些抗体结合表位(例如，PECAM) 肺内皮细胞6，7.RH的主要优势是，强大的肺靶向不需要PEL 包被靶向抗体，这使得临床翻译变得容易得多。在这项提案中，我们将 重点关注RH靶向PEL，但也将RH与“抗体靶向PEL”进行比较，提供与 黄金标准和后备目标战略。 在本提案中，我们将通过三种方式测试PEL：在目标1中，我们将确定PEL在 小鼠的肺部，在活体内，测量PEL在健康和炎症区域以及各种细胞类型中的积聚。我们的 假设RH和抗体靶向都会在肺内浓缩PEL，但肺内 本地化将由目标战略的细节决定。在目标2中，我们将评估治疗 载药PELS的作用，假设PELS将减少所需药物的质量 ARDS小鼠模型的改进。最后，在目标3中，我们将确定PEL如何在EX中分配药物 活体人肺，来自因ARDS而肺被排斥进行移植的器官捐赠者。 这些研究将使我们的药物输送技术更接近ARDS患者，同时提供机械 对靶向药物传递实际工作原理的洞察。 该提案还概述了候选人在独特的肺部靶向药物输送领域的培训计划。

Project Summary / Abstract Acute respiratory distress syndrome (ARDS) is an acute, diffuse, inflammatory lung injury in which many pathways have been firmly implicated, but drug therapy has universally failed in dozens of large clinical trials. Why have so many rationally chosen drugs failed in ARDS? From a pharmacology perspective, a clear reason is that of poor drug delivery, with very little drug reaching the inflamed alveoli. To solve this problem, we developed pulmonary endothelium-targeted liposomes (PELs). PELs are simply drug-loaded liposomes (~100 nanometer spherical lipid bilayers), that when injected intravenously concentrate strongly in the lungs. In this proposal, we will study a promising and novel lung-targeting strategy for PELs that we recently invented, called “RBC-hitchhiking” (RH). In RH, PELs are passively adsorbed ex vivo onto red blood cells (RBCs) and then, upon IV injection, the RBCs squeeze through the pulmonary capillaries, transferring the liposomes to the capillary endothelium. RH PELs concentrate drugs in the lungs of mice >300x more than “free drugs” (drugs delivered without targeting). Further, RH concentrates PELs in the lungs even more than the “gold standard” in targeted drug delivery for the last 20 years, “antibody-targeted” drug carriers, which in this case are PELs coated with antibodies that bind epitopes (e.g., PECAM) on the pulmonary endothelium6,7. RH has the major advantage that strong lung targeting does not require the PELs to be coated with targeting antibodies, which makes clinical translation much easier. In this proposal, we will focus on RH targeting of PELs, but will also compare RH to “antibody-targeted PELs”, providing comparison to a gold standard, and a back-up targeting strategy. In this proposal, we will test PELs in 3 ways: In Aim 1, we will determine the localization of PELs within the lungs of mice, in vivo, measuring PEL accumulation in healthy vs inflamed regions and various cell types. Our hypothesis is that both RH and antibody-targeting will concentrate PELs in the lungs, but the intra-pulmonary localization will be determined by details of the targeting strategy. In Aim 2 we will assess the therapeutic effects of drug-loaded PELs, with the hypothesis that PELs will decrease the mass of drug required to ameliorate mouse models of ARDS. Finally, in Aim 3 we will determine how PELs distribute drugs within ex vivo human lungs, obtained from organ donors whose lungs were rejected for transplantation due to ARDS. These studies will move our drug delivery technologies closer to ARDS patients, while providing mechanistic insights into how targeted drug delivery actually works. The proposal also outlines the candidate's training plan in the unique field of pulmonary targeted drug delivery.