Nanonscale drug carriers for the treatment of acute respiratory distress syndrome

项目总结/摘要 急性呼吸窘迫综合征（ARDS）是一种急性、弥漫性、炎性肺损伤， 通路已经被坚定地牵连，但药物治疗在几十个大型临床试验中普遍失败。 为什么这么多合理选择的药物在ARDS中失败了？从药理学的角度来看， 是药物输送不良，只有很少的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）。PEL只是 载药脂质体（~100纳米球形脂质双层），静脉注射时浓缩 在肺里很强烈。在这项提案中，我们将研究一种有前途的新型肺部靶向治疗策略， 我们最近发明了一种叫"RBC搭便车"的方法在RH中，PEL被动地离体吸附到红细胞上， 血细胞（RBC），然后在IV注射时，RBC挤压通过肺毛细血管， 将脂质体转移至毛细血管内皮。RH PELs在小鼠肺中浓缩药物 > 300倍于"免费药物"（无靶向药物）。此外，RH在肺中浓缩了PEL “抗体靶向”药物甚至超过了过去20年靶向药物输送的“黄金标准” 载体，在这种情况下是包被有结合表位的抗体的PEL（例如，PECAM）在 肺内皮6，7. RH的主要优点是，强肺靶向不需要PEL 涂上靶向抗体，这使得临床翻译更加容易。在本提案中，我们将 侧重于PEL的RH靶向，但也将RH与"抗体靶向PEL"进行比较， 一个黄金标准和一个后备目标策略 在本提案中，我们将以3种方式测试PEL：在目标1中，我们将确定PEL在 小鼠肺，在体内，测量在健康与发炎区域和各种细胞类型中的PEL积累。我们 假设RH和抗体靶向都将使PEL集中在肺中，但肺内 定位将由目标定位策略的细节来确定。在目标2中，我们将评估 载药PEL的作用，假设PEL将减少所需的药物质量， 改善ARDS小鼠模型。最后，在目标3中，我们将确定PELs如何在前 体内人肺，从肺因ARDS而被拒绝移植的器官供体获得。 这些研究将使我们的药物输送技术更接近ARDS患者，同时提供机械的 深入了解靶向药物输送的原理 该提案还概述了候选人在肺部靶向药物输送这一独特领域的培训计划。

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.