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.
| Yacobi, Nazanin R; Fazllolahi, Farnoosh; Kim, Yong Ho et al. (2011) Nanomaterial interactions with and trafficking across the lung alveolar epithelial barrier: implications for health effects of air-pollution particles. Air Qual Atmos Health 4:65-78 |
| Kim, Yong Ho; Fazlollahi, Farnoosh; Kennedy, Ian M et al. (2010) Alveolar epithelial cell injury due to zinc oxide nanoparticle exposure. Am J Respir Crit Care Med 182:1398-409 |
| Yacobi, Nazanin R; Malmstadt, Noah; Fazlollahi, Farnoosh et al. (2010) Mechanisms of alveolar epithelial translocation of a defined population of nanoparticles. Am J Respir Cell Mol Biol 42:604-14 |
| Flodby, Per; Borok, Zea; Banfalvi, Agnes et al. (2010) Directed expression of Cre in alveolar epithelial type 1 cells. Am J Respir Cell Mol Biol 43:173-8 |
| Chen, Jo-Lin; Lin, H Helen; Kim, Kwang-Jin et al. (2009) PKC delta signaling: a dual role in regulating hypoxic stress-induced autophagy and apoptosis. Autophagy 5:244-6 |
| Borok, Zea; Crandall, Edward D (2009) More life for a ""terminal"" cell. Am J Physiol Lung Cell Mol Physiol 297:L1042-4 |
| Borok, Zea (2009) Role for alpha3 integrin in EMT and pulmonary fibrosis. J Clin Invest 119:7-10 |
| Demaio, Lucas; Tseng, Wanru; Balverde, Zerlinde et al. (2009) Characterization of mouse alveolar epithelial cell monolayers. Am J Physiol Lung Cell Mol Physiol 296:L1051-8 |
| Zhou, Beiyun; Ann, David K; Flodby, Per et al. (2008) Rat aquaporin-5 4.3-kb 5'-flanking region differentially regulates expression in salivary gland and lung in vivo. Am J Physiol Cell Physiol 295:C111-20 |
| Yacobi, Nazanin R; Phuleria, Harish C; Demaio, Lucas et al. (2007) Nanoparticle effects on rat alveolar epithelial cell monolayer barrier properties. Toxicol In Vitro 21:1373-81 |
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