Absorption mechanisms for peptide/protein drugs via lung - NIH Grant Award Recipients

Absorption mechanisms for peptide/protein drugs via lung
CRISP (Computer Retrieval of Information on Scientific Projects)
Abstract
Grant Number: 5R01HL064365-08
PI Name: CRANDALL, EDWARD D.
PI Email: ecrandal@usc.edu
PI Title: PROFESSOR
Project Title: Absorption mechanisms for peptide/protein drugs via lung
Abstract: 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.
Thesaurus Terms:
diffusion, drug administration route, drug delivery system, lung alveolus, peptide, protein transport, respiratory epithelium, transcytosis
receptor mediated endocytosis, somatotropin
bioengineering /biomedical engineering, clinical research, electron microscopy, human tissue, laboratory rat, northern blotting, radiotracer, tissue /cell culture, western blotting
Institution: UNIVERSITY OF SOUTHERN CALIFORNIA
DEPARTMENT OF CONTRACTS AND GRANTS
LOS ANGELES, CA 90033
Fiscal Year: 2006
Department: MEDICINE
Project Start: 30-SEP-1999
Project End: 31-JUL-2009
ICD: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
IRG: ZRG1