Amino-dendrimer

Fig. 1.5 Modification of oxidized CNTs with Newkome-type amino dendrimers.

The use of polycationic moieties in drug delivery has been a subject of considerable interest for the past several decades. One of the earliest demonstrations of the potential value of polycations in chug delivery was a study by Tan in 1977, which demonstrated increased uptake of the SV40 virus when infections were carried out in the presence of polycations.1 Other early efforts involved direct cationization of proteins to enhance cellular uptake.2,3 Simultaneously, extensive investigations of the ability of a variety of polycationic vehicles to enhance the uptake of DNA were made.4 These vehicles include cationic liposomes,5 6 poly-L-lysine,7 polyethe-leneimine,8 amino-dendrimers,9 and a variety of other natural and synthetic polycations. Only in recent years, however, has the surprisingly diverse potential of polycation-based delivery systems been realized. This revelation has come primarily from the discovery and utilization of nonclassical transport-based pathways. 

The field of synthetic enzyme models encompasses attempts to prepare enzymelike functional macromolecules by chemical synthesis [30]. One particularly relevant approach to such enzyme mimics concerns dendrimers, which are treelike synthetic macromolecules with a globular shape similar to a folded protein, and useful in a range of applications including catalysis [31]. Peptide dendrimers, which, like proteins, are composed of amino acids, are particularly well suited as mimics for proteins and enzymes [32]. These dendrimers can be prepared using combinatorial chemistry methods on solid support [33], similar to those used in the context of catalyst and ligand discovery programs in chemistry [34]. Peptide dendrimers used multivalency effects at the dendrimer surface to trigger cooperativity between amino acids, as has been observed in various esterase enzyme models [35]. 

PAMAM dendrimers are synthesized in a multistep process. Starting from a multifunctional amine (for example ammonia, ethylenediamine, or tris(2-amino-ethyl)amine) repeated Michael addition of methylacrylate and reaction of the product with ethylenediamine leads to dendrimers of different generation numbers [1,9]. Two methylacrylate monomers are added to each bifunctional ethylenediamine generating a branch at each cycle. Unreacted ethylenediamine has to be completely removed at each step to prevent the initiation of additional dendrimers of lower generation number. Excess methylacrylate has also to be removed. Bridging between two branches of the same or of two different dendrimers by ethylenediamine can also be a problem, and has to be avoided by choosing appropriate reaction conditions. 

Activated PAMAM dendrimers interact with DNA to form a DNA-dendrimer complex with a toroid-like structure (Fig. 2). Such DNA-dendrimer complexes have diameters of 50-100 nm [10],which means that the DNA molecules are highly condensed in these complexes. A 6-kb plasmid alone, for example, has an extended structure several hundred nanometers in diameter. In transfection experiments, typically an 8- to 12-fold excess of positive amino groups over negatively... 

Regen and Watanabe [158] fabricated multi-layers close to a thickness of 800 A by using fourth or sixth generation PAM AM dendrimers with 16 or 12 cycles, respectively. The construction techniques involved activation with K2PtCl4 on a silicon wafer containing amino groups on the surface, which was followed by deposition of the dendrimer layer. However, elimination of Pt2+ layer resulted in absence of layer growth, as examined by X-ray photoelectron spectroscopy. 

All the experiments are conducted on aldehyde terminal functions. Depending on the solubility of the resulting phosphorylated dendrimers, anchorage of phosphorus moieties has been carried out on generation 1 (6 phosphate or phosphinite groups) and up to generation 5 [(96 aminophosphate (Fig. 6, Scheme 15), amino phosphite or functionalized phosphonate groups)] [17b]. 

Application of the Horner-Wadsworth-Emmons reaction to the functionalization of dendrimers allows one to prepare amino acid terminated macromolecules. Such a reaction conducted with dendrimers 10-[G ], 10-[G 3], lO-fG ] and phosphonates unsubstituted at the carbon a to the phosphoryl group affords in moderate yield dendrimers bearing various a, / unsaturated functional groups on the surface [18]. (Schemes 17 and 18). 

The first example of a grafted dendrimer carrying non-racemic amino acid moieties at the surface has been reported in 1991 byNewkome et al. [20]. A four-directional core molecule, which they prepared from pentaerythrol [21], has been elongated with the branching units fra[carboxyethoxymethyl]amino-... 

The molar ellipticity of these dendrimers was found to increase proportional to the number of chiral end groups. This is to be expected, in the absence of interactions between the terminal tryptophane moieties. No higher-generation dendrimers of this type have been reported. Other amino-acid-containing chiral dendrimers have been described by Meijer et al. who attached various amino acid derivatives to the periphery of poly(propylene imine) dendrimers (see Sect. 3) and more recently by Liskamp et al. (modification of polyamide dendra) [22] and Ritter et al. (synthesis of grafted polymerizable dendrimers containing L-aspartic acid components) [23]. 

Recently, the Okada group described a new class of polymerization systems [43] oligoglycopeptide-type sugar-balls were obtained by a radial growth polymerization (RGP) of a-amino acid AT-carboxyanhydrides with PAMAM dendrimers of different generations. 

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