Hydrodynamic Gene Delivery and Its Applications in Pharmaceutical Research

Abstract

Hydrodynamic delivery has emerged as the simplest and most effective method for intracellular delivery of membrane impermeable substances in rodents. The system employs a physical force generated by a rapid injection of large volume of solution into a blood vessel to enhance the permeability of endothelium and the plasma membrane of the parenchyma cells to allow delivery of substance into cells. The procedure was initially established for gene delivery in mice and its applications have been extended to the delivery of proteins, oligo nucleotides, genomic DNA and RNA sequences, and small molecules. The focus of this review is on applications of hydrodynamic delivery in pharmaceutical research. Examples are provided to highlight the use of hydrodynamic delivery for study of transcriptional regulation of CYP enzymes, for establishment of animal model for viral infections, and for gene drug discovery and gene function analysis.

Transient Expression of Proteins by Hydrodynamic Gene Delivery in Mice

“…Generation of transgenic mice using other forms of gene delivery, such as recombinant lentiviral vectors derived from HIV-1 or recombinant adeno-associated viral vectors, require much more specialized expertise. However, their advantage is sustained gene expression, although viral gene expression often causes an inflammatory response due to the host sensing a viral infection and responding [15][16][17][18][19] . Furthermore, the viral vectors have a limited packaging ability and therefore, are limited in gene size, whereas BACs of 150kb have been successfully used in HGD 4 .…”

“…Other types of molecules that have been delivered by a hydrodynamic method include RNA [5][6][7][8][9][10] , morpholinos 11 , proteins 12,13 and other small molecules 12,14 . The advantages and disadvantages of HGD over other delivery methods have been discussed in excellent reviews in the literature [15][16][17][18][19][20] and a number of authors have provided a detailed description of the procedure [21][22][23] .…”

“…For this reason, HGD might be less suitable to study chronic diseases that are a result of long-term exposure to damaging proteins or protein products. With these limitations, HGD is an exceptionally powerful tool for studying the potential role of a gene and the effect of it mutants in vivo, as well as the therapeutic effects and regulation of proteins and for establishing animal models of disease (for review, see 15 ). For example, HGD may be used to assign function to domains and amino acids of proteins by individually introducing various gene constructs into mice that have the respective genes knocked out.…”

Endocrine Delivery System of NK4, an HGF-Antagonist and Anti-Angiogenic Regulator, for Inhibitions of Tumor Growth, Invasion and Metastasis

“…The system employs a physical force generated by the rapid injection of a large volume of solution into a blood vessel to enhance the permeability of endothelium and the plasma membrane of the parenchyma cells, such as hepatocytes, to facilitate a delivery of the substance into cells (Bonamassa et al, 2011). Using this technique in mice, we established an endocrine delivery system for NK4 that leads to an inhibition of the malignant behavior of cancers, as follows.…”

Animal Models for Hydrodynamic Gene Delivery

“…The study of DNA sequences can be achieved with HGD, where promoters, introns, enhancers, suppressors can be delivered intracellular in whole animal. Moreover new animal models are possible to be created for study human diseases, mainly viral due to the fact that they are species specific 5,8,10 . …”