Nonviral gene delivery

Green JJ, Langer R, Anderson DG (2008) A combinatorial polymer library approach yields insight into nonviral gene delivery. Acc Chem Res 41 749-759... 

Tomlinson, E., and Rolland, A.P., Controllable gene therapy pharmaceutics of nonviral gene delivery systems, Journal of Controlled Release, 1995, 39, 357-372. 

Rudolph C, Schillinger U, Plank C, Gessner A, Nicklaus P, Muller R, Rosenecker J (2002) Nonviral gene delivery to the lung with copolymer-protected and transferrin-modified polyethylenimine 1. Biochim Biophys Acta 1573 75... 

Elfinger M, Maucksch C, Rudolph C (2007) Characterization of lactoferrin as a targeting ligand for nonviral gene delivery to airway epithelial cells. Biomaterials 28 3448-3455... 

D. Luo and W. M. Saltzman, Nonviral gene delivery thinking of silica, Gene Ther., 2006, 13, 585. 

Interest in dendritic polymers (dendrimers) has grown steadily over the past decade due to use of these molecules in numerous industrial and biomedical applications. One particular class of dendrimers, Starburst polyamidoamine (PAMAM) polymers, a new class of nanoscopic, spherical polymers that appears safe and nonimmunogenic for potential use in a variety of therapeutic applications for human diseases. This chapter will focus on investigations into PAMAM dendrimers for in vitro and in vivo nonviral gene delivery as these studies have progressed from initial discoveries to recent animal trials. In addition, we will review other applications of dendrimers where the polymers are surface modified. This allows the opportunity to target-deliver therapeutics or act as competitive inhibitors of viral or toxin attachment to cells. 

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... 

Isobe H, Nakanishi W, Tomita N, Jinno S, Okayama H, Nakamura E (2006b) Nonviral gene delivery by tetraamino fullerene. Mol. Pharm. 3 124-134. 

Anchordoquy, TJ. 1999. Nonviral gene delivery systems, Part 1 Physical stability. Biop harm 12 42-48. 

Wagner E. Application of membrane-active peptides for nonviral gene delivery. Adv Drug Deliv Rev 1999 38 279-289. 

Keller M, Harbottle RP, Perouzel E, et al. Nuclear localisation sequence tern-plated nonviral gene delivery vectors investigation of intracellular trafficking events of LMD and LD vector systems. Chembiochem 2003 4(4) 286-298. 

Leong KW (2006) Polymer design for nonviral gene delivery. BioMEMS Biomed Nanotech-nol 1 239-263... 

This section will describe the features and clinical applications for each gene delivery system. The description will start with a common feature of both viral and nonviral gene delivery systems, the expression cassette for the therapeutic protein. 

TABLE 15.2. Key features of viral and nonviral gene delivery systems... 

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. 

Several major barriers need to be overcome for the development of nonviral gene delivery systems into true therapeutic products for use in humans. These barriers fall into three classes manufacturing, formulation, and stability (extracellular barriers and intracellular barriers) (85). Cationic lipids and cationic polymers self-assemble with DNA to form small particles that are suitable for cellular uptake. At the therapeutic doses positively charged particles readily aggregate as their concentration increases, and are quickly precipitated above their critical flocculation concentration. 

FIGURE 13.4 An optimized/ideal multifunctional nonviral gene delivery system. 

Boletta, A., Benigni, A., Lutz, J., Remuzzi, G., Soria, M.R., Monaco, L. (1997). Nonviral gene delivery to the rat kidney with polyethylenimine. Hum. Gene Then, 8, 1243-1251. 

Modification of depolymerization kinetics and release Endosomal escape Nonviral gene delivery Boron neutron capture therapy Fusogenic liposomes, increase transfection efficiency... 

Ogris M, Carlisle RC, et al. Melittin enables efficient vesicular escape and enhanced nuclear access of nonviral gene delivery vectors. J Biol Chem 2001 276(50) 47550-47555. 

Lin, A.J., Slack, N.L., Ahmad, A., Koltover, I., George, C.X., Samuel, C.E. and Safinya, C.R. (2000) Structure-function studies of lipid-DNA nonviral gene delivery systems. J. Drug Target., 8, 13-27. 

Byk, G., Wetzer, B., Frederic, M., Dubertret, C., Pitard, B., Jaslin, G. etal. (2000) Reduction-sensitive lipopolyamines as a novel nonviral gene delivery system for modulated release of DNA with improved transgene expression. J. Med. Chem., 43,4377M387. 

McKenzie, D.L., Smiley, E., Kwok, K.Y. and Rice, K.G. (2000b) Low molecular weight disulfide cross-linking peptides as nonviral gene delivery carriers. Bioconjug. Chem., 11, 901-909. 

Rolland, A.P. (1998) From genes to gene medicines recent advances in nonviral gene delivery. Crit. Rev. Ther. Drug Carrier Syst., 15, 143-198. 

Van de Wetering, P., Moret, E.E., Schuurmans-Nieuwenbroek, N.M.E., Van Steenbergen, M.J. and Hennink, W.E. (1999a) Structure-activity relationships of water-soluble cationic methacrylate/methacrylamide polymers for nonviral gene delivery. Bioconjug. Chem., 10, 589-597. 

Wiethoff CM, Middaugh CR (2003) Barriers to nonviral gene delivery. J Pharm Sci 92... 

Kraemer M (2004) Dendritic polyamines simple access to new materials with defined treelike structures for application in nonviral gene delivery. ChemBioChem 5(8) 1081... 

Onishi Y, Eshita Y, Murashita A et al (2005) Synthesis and characterization of 2-diethyl-aminoethyl-dextran-methyl methacrylate graft copolymer for nonviral gene delivery vector. J Appl Polym Sci 98 9-14... 

Koping-Hoggard M, Tubulekas I, Guan H, Edwards K, Nilsson M, Varum KM, Artursson P (2001) Chitosan as a nonviral gene delivery system. Structure-property relationships and characteristics compared with polyethylenimine in vitro and after lung administration in vivo. Gene Ther 8 1108-1121... 

Lou Y-L, Peng Y-S, Chen B-H et al (2009) Poly(ethylene imine)-g-chitosan using EX-810 as a spacer for nonviral gene delivery vectors. J Biomed Mater Res A 88A(4) 1058-1068... 

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