Nanoparticle Drug Delivery in Post-Pneumonectomy Compensatory Lung Growth

描述（由申请方提供）：成年犬的肺切除术（PNX）模拟限制性肺病的后果，是一种稳健的代偿性肺生长（CLG）模型，其特征为早期肺泡细胞增殖-肥大、进行性间隔重塑、腺泡结构逐渐正常化和肺功能在数月内逐渐恢复。后PNX机械信号激活几乎所有的主要稳态途径，下游反应是非常敏感的药理学刺激，但外源性增强肺泡组织生长尚未反映功能增强。这种结构-功能差距是该领域转化进展的关键障碍。差距的潜在原因包括：a）间隔成分的不均匀和/或过度刺激，B）缺乏成比例增强的间隔重塑以优化气体交换、屏障和最小化结构变形，以及c）需要生长促进剂的肺特异性可滴定递送。我们的目标是开发一种平衡增强肺泡生长/重塑的策略，旨在最大限度地减少扭曲并增加功能受益的可能性。我们的假设是，持续低剂量吸入纳米颗粒（NP）输送的补充生长促进剂选择平衡刺激肺泡生长/重塑增强后PNX肺结构和功能。生物相容性生物降解聚将合成（乳酸-共-乙醇酸）或PLGA包封的NP，每个NP含有已知的生长促进剂：全反式视黄酸（RA）、角质形成细胞生长因子（KGF）及其受体（KGFR）的肽或cDNA、或促红细胞生成素（EPO）及其受体（EPOR）组合施用以按比例刺激肺泡上皮、肺泡上皮和内皮，促进/保护有益的间隔重塑，并保持/恢复正常的结构。磁性标签和荧光标记最初可以作为示踪剂掺入NP中，但在最终的治疗制剂中省略。目标1：表征含有单独和组合生长促进剂的NP在人肺细胞中的体外剂量反应、作用持续时间和生物安全性。优化NP配方，以实现持续释放和适度作用。目的2：确定含有生长促进剂组合的NP的体内生物学作用。将悬浮液中的NP雾化吸入成年大鼠和试验犬中，以表征长期给药的生物分布和生物安全性。 目的3：确定NP鸡尾酒对成年犬PNX后CLG和功能的长期影响。将使用非侵入性成像（HRCT和UTE MRI）、生理测试（休息和运动）和详细的结构分析监测治疗反应。这种新型的肺再生多途径范式与癌症化疗中使用的方法相似，结合了最先进的纳米技术、成像和生理技术，并建立了跨学科合作。结果将影响肺再生修复的基本概念，弥合肺生长操作中的关键知识差距，并立即转化为床边。

DESCRIPTION (provided by applicant): Pneumonectomy (PNX) in adult canines mimics the consequences of restrictive lung disease and is a robust model of compensatory lung growth (CLG), characterized by early alveolar cellular proliferation-hypertrophy, progressive septal remodeling, gradual normalization of acinar architecture and incremental restoration of lung function over many months. Post-PNX mechanical signals activate nearly all the major homeostatic pathways; downstream responses are very sensitive to pharmacological stimulation but exogenously enhanced alveolar tissue growth has not been mirrored by functional enhancement. This structure-function gap represents a key obstacle to translational progress in the field. Potential reasons for the gap include: a) uneven and/or over- stimulation of septal components, b) lack of proportionally enhanced septal remodeling to optimize the gas exchange, barrier and minimize architecture distortion, and c) need for lung-specific titratable delivery of growth promoters. Our goal is to develop a strategy of balanced enhancement of alveolar growth/remodeling aimed at minimizing distortion and increasing the likelihood of functional benefit. Our hypothesis is that sustained low-dose inhalational nanoparticle (NP) delivery of complementary growth-promoting agents selected for balanced stimulation of alveolar growth/remodeling enhances post-PNX lung structure and function. Biocompatible biodegradable poly(lactic-co-glycolic acid) or PLGA-encapsulated NPs will be synthesized each containing a known growth promoter: all-trans retinoic acid (RA), peptide or cDNA of keratinocyte growth factor (KGF) and its receptor (KGFR), or erythropoietin (EPO) and its receptor (EPOR), to be administered in combination to proportionally stimulate the alveolar epithelium, interstitium and endothelium, promote/protect beneficial septal remodeling, and preserve/restore normal architecture. Magnetic tag and fluorescent labels may be incorporated into NPs as tracers initially, but omitted in final therapeutic formulations. Aim 1: Characterize i vitro dose-response, duration of action, and biosafety of NPs containing individual and combination growth promoting agent in human lung cells. Optimize NP formulations for sustained release and modest action. Aim 2: Determine in vivo biological action of NPs containing combinations of growth promoting agents. NPs in suspension will be nebulized into adult rats and pilot dogs to characterize bio-distribution and biosafety of chronic administration. Aim 3: Determine the long-term effects of NP cocktails on post-PNX CLG and function in adult canines. Therapeutic response will be monitored using non-invasive imaging (HRCT and UTE MRI), physiological testing (rest and exercise), and detailed structural analysis. This novel multi pathway paradigm for lung regeneration parallels the approach used in cancer chemotherapy, combines state-of-the-art nanotechnology, imaging and physiological techniques, and forges inter-disciplinary collaborations. Results will impact fundamental concepts of lung regeneration-repair, bridge a key knowledge gap in the manipulation of lung growth, and are immediately translatable to the bedside.