Gene delivery dendrimers

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... 

Kukowska-Latallo, J. F., Bielinska, A. U., Chen, C., Rymaszewski, M., Tomalia, D. A. and Baker J. R. Jr. Gene transfer using starburst dendrimers , in Kabanov, A. V., Feigner, P. L. and Seymour, L. W. (eds) Self-Assembling Complexes for Gene Delivery, John Wiley Sons, New York, 1998, pp. 241-253. 

Pan B, Cui D, Sheng Y, Ozkan CS, Gao F, et al. (2007). Dendrimer-modified magnetic nanoparticles enhance efficiency of gene delivery system. Cancer Res. 67 8156-8163. 

Joester D, Losson M, Pugin R et al. (2003) Amphiphilic dendrimers novel self-assembling vectors for efficient gene delivery. Angew Chem Int Ed 42 1486-1490... 

While the dendrimer architecture is the most popular form of polyamidoamine polymers for gene delivery, linear polyamidoamines have also been evaluated for their effectiveness as gene transfer agents to... 

Tang, M.X., Redemann, C.T. and Szoka, F.C. (1996) In vitro gene delivery by degraded polyamidoamine dendrimers. Bioconjug. Chem., 7, 703-714. 

Keywords Cationic lipids Cell delivery Dendrimers Gene therapy... 

The structure of cationic lipids and polymers is readily amenable to chemical modification [35, 36] allowing the exploration of a virtually unlimited number of combinations and strategies at the mercy of chemists creative abilities. Various reviews have been focused on cationic lipids, dendrimers and polymers in terms of their chemical structures and their transfection properties [36—41], in an attempt to shed some light on the chemical requirements necessary to mediate gene delivery. The focus of this chapter will be to explore these carriers from a synthetic perspective, with a description of the chemical strategies used for the preparation via synthetic organic chemistry (excluding polymer synthesis) of cationic lipids and dendrimers. 

From the structural point of view, polyamines used for gene transfection vary widely in their structures, which range between linear [24, 29-35], branched [12, 30, 32], hyperbranched, and perfect branched dendrimers [36]. In this chapter we present a general overview of the research reported so far using dendritic polyamines in gene delivery applications. Particular focus is made on hyperbranched... 

Braun CS, Vetro JA, Tomalia DA et al (2005) Structure/function relationships of polyami-doamine/DNA dendrimers as gene delivery vehicles. J Pharm Sci 94(2)423 136... 

Kim TI, Baek JU, Zhe BC et al (2007) Arginine-conjugated polypropylenimine dendrimer as a non-toxic and efficient gene delivery carrier. Biomaterials 28 2061-2067... 

Lim YB, Kim T, Lee JW et al (2002) Self-assembled ternary complex of cationic dendrimer, cucurbituril, and DNA noncovalent strategy in developing a gene delivery carrier. Bioconjug Chem 13 1181-1185... 

Synthetic polymer. Among the cationic synthetic polymers used for gene delivery are polyethylenimine (PEI), polyamidoamine dendrimers, and poly(2-dimethylaminoethyl methacrylate).161-164 Depending on the flexibility (or rigidity) of the polymers, they form either a small (<100 nm) DNA polyplex or a large (>1 to 10 pm) DNA polyplex.165 More detailed physicochemical properties and their transfection efficacy are to be discussed. 

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