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Gene expression profiles in mouse lung tissue after administration of two cationic polymers used for nonviral gene delivery
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2006 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 23, no 3, 475-482 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: This study compared gene expression profiles in mouse lungs after administration of the cationic polymers polyethyleneimine (PEI) or chitosan alone or formulated with a luciferase reporter plasmid (PEI-pLuc, chitosan-pLuc).

METHODS: The polymers and formulations were administered intratracheally to Balb/c mice at doses judged to be nontoxic according to intracellular dehydrogenase activity and tissue morphology. RNA was isolated from the lungs 24 or 72 h after administration, and a dedicated stress and toxicology cDNA array was used to monitor the in vivo response to the gene delivery system in the lung tissue.

RESULTS: The gene expression profiles differed between the PEI and chitosan groups with regard to both the total number and the type of expressed genes. Chitosan-pLuc upregulated genes that protect the cell from oxidative stress and inflammation, such as heme oxygenase-1 and catalase, whereas PEI-pLuc upregulated genes involved in inflammatory processes, such as the cyclooxygenases 1 and 2, indicating possible involvement in the development of adverse reactions. However, both polymers activated genes involved in reaction to stress, such as DNA damage repair. Furthermore, in the PEI group, chaperone genes and members of the p38 mitogen-activated protein kinase pathway were also upregulated, suggesting a possible explanation for the better performance of PEI in gene delivery systems.

CONCLUSIONS: The results indicate that gene expression profiling is a useful and sensitive tool for the evaluation of tissue responses after administration of polymers or gene delivery systems. The results also suggest a possible explanation for the differences in gene delivery performance between the two polymers in gene delivery systems.

Place, publisher, year, edition, pages
2006. Vol. 23, no 3, 475-482 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93905DOI: 10.1007/s11095-006-9563-7PubMedID: 16463010OAI: oai:DiVA.org:uu-93905DiVA: diva2:167543
Available from: 2005-12-22 Created: 2005-12-22 Last updated: 2013-06-14Bibliographically approved
In thesis
1. Effects of Microparticulate Drug Delivery Systems: Tissue Responses and Transcellular Transport
Open this publication in new window or tab >>Effects of Microparticulate Drug Delivery Systems: Tissue Responses and Transcellular Transport
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Over the past decade, the development of macromolecular drugs based on peptides, proteins and nucleic acids has increased the interest in microparticulate drug delivery, i.e., the delivery of drug systems in the nanometer and micrometer ranges. However, little is known so far about the effect that microparticulate systems have on various tissues after administration. Additionally, the knowledge of mechanisms responsible for the uptake and transport of microparticles across the human intestine is incomplete and requires further investigation to improve both the safety profiles and the efficiency of these drug delivery systems.

This thesis is comprised of two parts. The first one investigates gene expression responses obtained from DNA arrays in local and distal tissues after microparticulate drug delivery. The second part focuses on the mechanisms responsible for the transport of microparticles across epithelial cells lining the intestine.

The results presented in the first part demonstrated that gene expression analysis offers a detailed picture of the tissue responses after intramuscular or pulmonary administration of microparticulate drug delivery systems compared to the traditional techniques used for such evaluations. In addition, DNA arrays provided a useful and sensitive tool for the initial characterization and evaluation of both local and distal tissue responses, making it possible to distinguish between gene expression patterns related to each studied delivery system.

The results presented in the second part demonstrated that the surface properties of the microparticle were important for the extent of transport across an in vitro model of the follicle-associated epithelium (FAE), comprised of intestinal epithelial cells specialized in particle transport (M cells). Another important finding was that the enteropathogen bacterium, Yersinia pseudotuberculosis, induced microparticle transport across the normal intestinal epithelium, represented by Caco-2 cells and excised human ileal tissue. This transport was most probably mediated by an increased capacity for macropinocytosis in the epithelial cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 25
Keyword
Pharmaceutics, microparticles, vaccine, pDNA vaccine, cationic polymer, gene expression analysis (DNA array), Caco-2, follicle-associated epithelium (FAE), M cell, transcytosis, Yersinia pseudotuberculosis, Galenisk farmaci
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-6260 (URN)91-554-6433-5 (ISBN)
Public defence
2006-01-13, Room B21, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2005-12-22 Created: 2005-12-22Bibliographically approved

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