Absorption mechanisms for peptide/protein drugs via lung

描述(由申请人提供)：口服新的生物工程多肽/蛋白质药物通常由于胃和肠道消化酶的降解而无效。作为这类蛋白质/多肽药物全身吸收的替代途径，经肺给药已显示出相当大的潜力。在这项建议中，我们的长期目标是阐明不同类型的肽/蛋白药物通过肺泡上皮(提供广泛的表面积和相对较低的蛋白酶活性)吸收的机制。虽然在动物实验中，蛋白质/多肽药物的肺部给药比口服给药有更好的生物利用度，但到目前为止，吸收机制和途径大多还不清楚。许多与生物工程相关的问题与肺部给药有关，包括特定药物的配方、给药方式和转运机制。其中，我们将使用培养的大鼠和人肺泡上皮细胞单层作为体外模型，研究促进多肽/蛋白质药物跨肺泡上皮吸收的各种转运机制，并将关键的体外研究结果扩展到体内大鼠肺研究。待探索的模型蛋白质/多肽范围从寡肽到具有生物重要性的蛋白质(例如降钙素、胰岛素、粒细胞集落刺激因子和人生长激素)。我们的研究计划细分为三个主要项目：i)研究模型药物通过肺泡上皮屏障吸收的跨细胞转运机制(例如，液体相、受体介导和/或吸附跨细胞作用)，ii)阐明通过旁细胞和/或跨细胞途径促进蛋白质/多肽药物在肺泡上皮细胞吸收的策略(例如，屏障性质的瞬时改变)，以及iii)研究增强受体介导的大分子药物的跨细胞转运(例如，在有反式高尔基干扰物存在的情况下与转铁蛋白结合)。在几个不同的生物医学研究实验室之间，利用不同的实验方法，从细胞生物学到生物工程/生理学，合作研究肺蛋白质/肽药物吸收，有望成功地为推进肺给药的实用方法提供相关信息。

DESCRIPTION (provided by applicant): Oral administration of newly bioengineered peptide/protein drugs is often ineffective due to degradation by gastric and intestinal digestive enzymes. As an alternative route for systemic absorption of such protein/ peptide drugs, transpulmonary delivery has shown considerable potential. In this proposal, our long-term goals are to elucidate the mechanisms for absorption of various classes of peptide/protein drugs across the alveolar epithelium (that affords a vast surface area and relatively low protease activity). Although pulmonary delivery of protein / peptide drugs in animal studies has been shown to yield much better bioavailability compared to oral delivery, absorption mechanisms and pathways are mostly undefined to date. Many bioengineering-related issues are associated with pulmonary drug delivery, including formulation of specific drugs, modes of delivery and transport mechanisms. Of these, we will investigate various transport mechanisms that facilitate absorption of peptide/protein drugs across alveolar epithelium, using cultured rat and human alveolar epithelial cell monolayers as in vitro models, and will extend key in vitro findings to in vivo rat lung studies. Model proteins/peptides to be explored range from oligopeptides to proteins of biological importance (e.g., calcitonin, insulin, granulocyte-colony stimulating factor, and human growth hormone). Our research plan is subdivided into three major projects: i) investigate transcellular transport mechanisms (e.g., fluid-phase, receptor-mediated and/or adsorptive transcytosis) for absorption of model drugs across the alveolar epithelial barrier, ii) elucidate strategies for enhancement of alveolar epithelial absorption of protein/peptide drugs via paracellular and/or transcellular routes (e.g., transient alteration of barrier properties), and iii) study enhanced receptor-mediated transcytosis of macromolecule drugs (e.g., conjugation with transferrin in the presence of trans-Golgi disruptors). The collaborative investigation of pulmonary protein/peptide drug absorption among several different biomedical research laboratories, utilizing different experimental approaches spanning cell biology to bioengineering/physiology, promises success in providing pertinent information on advancing practical approaches to pulmonary drug delivery.