Gene delivery systems cationic liposomes

Nonviral vector systems are usually either composed of a plasmid based expression cassette alone ( naked DNA), or are prepared with a synthetic amphipathic DNA-complexing agent (84, 88). Gene delivery systems based on nonviral vectors mainly comprise cationic liposomes, DNA-polymer-protein complexes, and mechanic administration of naked DNA. An idealized/optimized multifunctional nonviral gene delivery system is depicted in Figure 13.4. 

A current theme in plasmid-based delivery approaches is to mimic Nature s methods for nucleic acid delivery. To date, the best system to emulate Nature has been viral vectors. Briefly, most viral vectors escape immune surveillance, interact with cell membranes (e. g., receptor), internalize (via endocytosis), escape from endosomes, migrate to the nuclear envelope, enter the nucleus, and finally take over cellular functions. Plasmid-based systems (cationic liposomes and cationic polymers) can mimic portions of these events. This chapter will explore the barriers facing gene delivery vectors, with an emphasis of the pharmacokinetic behavior of these systems. In order to understand the in-vivo barrier, a brief review of physiology will be provided. 

To develop an efficient gene delivery system, it seems necessary to understand the extra- and intracellular processes involved in the overall transfection mechanism. This will lead to understanding the mechanism, which is necessary for developing novel lipid-based non-viral vectors. For this purpose, cationic liposomes and pDNA are used widely to understand the cellular mechanism involved in the transfection (Fig. 13.3). 

Protamine-based nanoparticles show a very low cytotoxicity in comparison with other gene delivery systems. In addition, when compared with commercially available liposomes (DOTAP, lipofectin), one artificial virus capsoid (polyoma VPl) and two cationic acrylate nanoparticles, the cell transfer efficiency in a mouse fibroblast cell line with protamine nanoparticles was one of the highest [117]. 

Nonviral gene delivery systems currently in use for the development of pulmonary gene therapy have focused on cationic liposomes, with or without DNA-... 

Formation of a complex between DNA and polycationic compounds appears to be the initial and quite possibly a critical parameter for nonviral gene delivery. Several synthetic vector systems, which are generally cationic in nature, including poly(lysines), cationic liposomes or various types of block copolymers and recently dendrimers, have been shown to self-assemble with plasmid DNA [13-15] [16]. Specific physicochemical properties manifested by these DNA complexes depend on the type of cationic agent used however, interesting patterns for such interactions are beginning to evolve [17, 18]. Under certain conditions, the interaction of DNA with polyvalent cations results in... 

Several vectors have been used in an attempt to deliver the cf gene to the airway epithelial cells of sufferers. The most notable systems include adenoviruses and cationic liposomes. Vector delivery to the target cells can be achieved directly by aerosol technology. Delivery of cftr cDNA to airway epithelial cells (and subsequent gene expression) has been demonstrated with the use of both vector types. However, in order to be of therapeutic benefit, it is essential that 5-10% of the target cell population receive and express the cftr gene. This level of integration has not been... 

The therapeutic efficacy of either systemic or local pulmonary delivery of the IFN-y gene was evaluated in a murine allergen-induced airway hyperresponsiveness (AHR) model (Dow et al. 1999) and it was found that a high efficiency of gene transfer could be achieved. Intratracheal administered cationic liposomes were prepared from a mixture of l,2-diacylglycero-3-ethylphosphocholine (EDMPC) and cholesterol. Intravenous injections were prepared from l,2-dioleyl-3-trimethylammo-ninm propane (DOTAP) and cholesterol and compared with pulmonary administered... 

Cullis, P.R., Chonn, A. (1998). Recent advances in liposome technologies and their applications for systemic gene delivery. Adv. Drug Deliv. Rev., 30(1-3), 73-83. Audouy, S.A., de LeiJ, L.F., Hoekstra, D., Molema, G. (2002). In vivo characteristics of cationic liposomes as delivery vectors for gene therapy. Pharm. Res., 19(11), 1599-1605. 

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