Nanoparticle Drug Delivery in Post-Pneumonectomy Compensatory Lung Growth

描述（由申请人提供）：成年犬的肺切除术（PNX）模拟限制性肺部疾病的后果，是代偿性肺生长（CLG）的稳健模型，其特征是早期肺泡细胞增生-肥大，进行性间隔重塑，腺泡结构逐渐正常化，肺功能在几个月内逐渐恢复。pnx后的机械信号几乎激活了所有主要的稳态通路；下游反应对药物刺激非常敏感，但外源性肺泡组织生长的增强并没有反映在功能增强上。这种结构-功能差距是该领域转化进展的关键障碍。造成间隙的潜在原因包括：a)室间隔成分不均匀和/或过度刺激，b)缺乏比例增强的室间隔重塑来优化气体交换，屏障和最小化结构扭曲，以及c)需要肺特异性可滴定的生长促进剂输送。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获益的可能性。我们的假设是，为平衡刺激肺泡生长/重塑而选择的补充生长促进剂的持续低剂量吸入纳米颗粒（NP）递送可增强pnx后肺结构和功能。将合成生物相容性可生物降解的聚（乳酸-羟基乙酸）或plga封装的NPs，每种NPs含有一种已知的生长促进剂：全反式维甲酸（RA）、角化细胞生长因子（KGF）及其受体（KGFR）或促红细胞生成素（EPO）及其受体（EPOR）的肽或cDNA，联合给药，按比例刺激肺泡上皮、间质和内皮，促进/保护有益的间隔重构，保存/恢复正常结构。磁性标记和荧光标记最初可作为示踪剂加入到NPs中，但在最终的治疗配方中省略。目的1：表征含有单独和联合生长促进剂的NPs在人肺细胞中的体外剂量反应、作用时间和生物安全性。优化NP配方以达到缓释和适度作用。目的2：确定含有促生长剂组合的NPs在体内的生物作用。将悬浊液中的NPs雾化到成年大鼠和导盲犬中，以表征长期给药的生物分布和生物安全性。

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.