Targeting Endothelium and Its Dynamic Caveolae for Tissue-Specific Transcytosis in vivo: A Pathway to Overcome Cell Barriers to Drug and Gene Delivery

Site-directed pharmacodelivery is a desirable but elusive goal. Endothelium and epithelium create formidable barriers to endogenous molecules as well as targeted therapies in vivo. Caveolae provide a possible, yet unproven, transcellular pathway to overcome such barriers. By using an antibody- and s...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2002-02, Vol.99 (4), p.1996-2001
Main Authors: McIntosh, Deirdre P., Tan, Xiang-Yang, Oh, Phil, Schnitzer, Jan E.
Format: Article
Language:English
Subjects:
Animals
Antibodies
Antibodies, Monoclonal - metabolism
Antigens
Biological Sciences
Biological Transport
Blood
Blotting, Western
Caveolae
Caveolae - metabolism
Cell membranes
Cellular biology
Endothelial cells
Endothelium
Endothelium, Vascular - metabolism
Enzyme-Linked Immunosorbent Assay
Freight
Gene Transfer Techniques
Genetic Vectors
Immunoglobulin G - metabolism
In Situ Hybridization
Lung - metabolism
Lungs
Molecular biology
Perfusion
Rats
Rodents
Time Factors
Tissue Distribution
Transcytosis
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Summary:Site-directed pharmacodelivery is a desirable but elusive goal. Endothelium and epithelium create formidable barriers to endogenous molecules as well as targeted therapies in vivo. Caveolae provide a possible, yet unproven, transcellular pathway to overcome such barriers. By using an antibody- and subfractionationbased strategy, we generated a monoclonal antibody specific for lung caveolae (TX3.833) that targets rat lungs after i.v. injection (up to 89% of dose in 30 min). Unlike control antibodies (nonbinding or to lipid rafts), TX3.833 targets lung caveolae that bud to form free vesicles for selective and quantal transendothelial transport to underlying tissue cells in vivo. Rapid sequential transcytosis can occur to the alveolar air space via epithelial caveolae. Conjugation to TX3.833 increases drug delivery to the lung up to 172-fold and achieves rapid, localized bioefficacy. We conclude that: (i) molecular heterogeneity of the endothelium and its caveolae permits vascular targeting to achieve theoretical expectations of tissue-specific delivery and bioefficacy; (ii) caveolae can mediate selective transcytosis in vivo; and (iii) targeting caveolae may provide a tissue-specific pathway for overcoming key cell barriers to many drug and gene therapies in vivo.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.251662398