ABSORPTION MECHANISMS FOR PEPTIDE/PROTEIN DRUGS VIA LUNG

生物技术的进步正在导致新的肽/蛋白质药物对人类健康的巨大希望。 不幸的是，口服给药通常不能有效地递送这些药物，这些药物必须胃肠外服用。 最近，经尿道给药作为全身给药的替代途径显示出相当大的潜力。 因此，在本提案中，我们的长期目标是阐明肽类和蛋白质类药物通过肺泡上皮吸收的机制，肺泡上皮是药物从肺气隙吸收的表面。尽管在动物研究中已显示蛋白质/肽类药物的肺部递送导致有希望的生物利用度，但吸收机制和途径实际上是未知的。与肺部给药相关的生物工程问题包括制剂形式、给药途径和经上皮转运。 其中，我们选择描绘特定的机制，可能占主导地位的肽/蛋白质药物吸收肺泡上皮细胞。 我们将利用原代培养的大鼠肺泡上皮细胞单层作为体外模型，并使用二/三肽，粒细胞集落刺激因子和人生长激素作为模型药物。 我们建议i）描述机制和途径（即，细胞旁扩散、液相转胞吞作用、受体介导的和/或吸附性转胞吞作用）用于模型蛋白质药物穿过肺泡上皮屏障的吸收，i i）研究通过穿过肺泡上皮屏障的转胞吞作用刺激蛋白质药物吸收的潜在机制，iii）研究肽药物如何穿过肺泡上皮吸收，和iv）确定物理化学变量对蛋白质/肽药物的肺泡上皮吸收的刺激作用。 通过四个不同的生物医学研究实验室利用实验方法，从细胞生物学到生物（化学）工程的肺蛋白/肽药物吸收的合作调查，这些项目的结果将提供新的信息，推进生物工程方法肺部药物输送，包括开发新的方法，以提高生物利用度通过肺泡上皮屏障。

Biotechnological advances are leading to new peptide/protein drugs of great promise for human health. Unfortunately, oral administration usually is ineffective in delivering such drugs, which must be taken parenterally. Recently, transpulmonary drug delivery has shown considerable potential as an alternative route of systemic delivery. Therefore, in this proposal, our long term goals are to elucidate the mechanisms for absorption of peptide and protein drugs across the alveolar epithelium, the surface across which drug absorption from lung airspaces must occur. Although pulmonary delivery of protein/peptide drugs has been shown in animal studies to lead to promising bioavailabilities, absorption mechanisms and pathways are virtually unknown. Bioengineering related issues pertaining to pulmonary drug delivery include formulation modalities, delivery approaches and transepithelial transport. Of these, we chose to delineate specific mechanisms that may prevail in absorption of peptide / protein drugs across alveolar epithelium. We will utilize primary cultured rat alveolar epithelial cell monolayers as an in vitro model and use di-/tri-peptides, granulocyte-colony stimulating factor and human growth hormone as model drugs. We propose to i) delineate the mechanisms and pathways (i.e., paracellular diffusion, fluid-phase transcytosis, receptor-mediated and/or adsorptive transcytosis) for absorption of model protein drugs across the alveolar epithelial barrier, ii) investigate the mechanisms underlying stimulation of protein drug absorption via transcytosis across the alveolar epithelial barrier, iii) investigate how peptide drugs are absorbed across the alveolar epithelium, and iv) determine the stimulatory effect of physicochemical variables on alveolar epithelial absorption of protein/peptide drugs. Through the collaborative investigation of pulmonary protein/peptide drug absorption among four different biomedical research laboratories utilizing experimental approaches spanning cell biology to bio(chemical)engineering, results from these projects will provide new information for advancing bioengineering approaches to pulmonary drug delivery, including development of new methodologies to improve bioavailability via the alveolar epithelial barrier.