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Current Drug Delivery

Editor-in-Chief

ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

Advances in Noninvasive Pulmonary Gene Therapy

Author(s): Charles L. Densmore

Volume 3, Issue 1, 2006

Page: [55 - 63] Pages: 9

DOI: 10.2174/156720106775197547

Price: $65

Abstract

One of the most noninvasive approaches to drug delivery is via inhalation. The delivery of genes via aerosol holds promise for the treatment of a broad spectrum of pulmonary disorders and offers numerous advantages over more invasive modes of delivery. Delivery of genes expressing secretory therapeutic proteins or peptides may even have application to a number of nonpulmonary diseases. After the cloning of the cystic fibrosis gene, there was great interest in the delivery of genes directly to the lung surfaces via inhalation and most early efforts focused on the use of nonviral vectors, particularly cationic lipids. Early on, nebulization shear forces, inefficient penetration of mucous barriers and inhibitory effects of surfactant and other lung specific features generally resulted in a lack of therapeutic effect. But in recent years, a number of other nonviral and even viral vectors have been delivered successfully in this manner. Polyethyleneimine (PEI)-based formulations have proven stable during nebulization and result in transfection of a very large proportion of epithelial cells throughout the airways (though the level of transgene expression per cell may be relatively low), as well as significant, though lower levels of transfection throughout the lung parenchyma. Most importantly, therapeutic responses have been obtained in several animal lung tumor models when PEI-based complexes of p53 and IL-12 genes were delivered by aerosol. This approach may also prove useful as a means of localized genetic immunization. In addition, inhalation delivery of some formulations seems to be associated with surprisingly low toxicity and has resulted in little or no immunostimulatory response to the unmethylated CpG sequences in bacterially-produced plasmid DNA, which has presented a challenge to repeated gene therapy via many other modes of delivery.

Keywords: Polyethyleneimine, aerosol, noninvasive, gene therapy, non-viral delivery, cancer, toxicity, inhalation


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