Polycationic dendrimer

Most of the methods of synthesis reported above present some limitations and constraints lack of solubility for polycationic phosphorus-containing dendrimers from generation 3 [2], dendrimers of weak molecular weight [4], difficulties to overcome cross Unking reactions [6], possibility only to incorporate phosphorus groups on the surface of dendrimers [3], etc. 

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... 

One of the earliest reports on the use of dendrimers in catalysis is the unimolecu-lar decarboxylation of 6-nitro-benzisoxazole-3-carboxylate in the presence of a dendrimer comprising ether dendrons which are functionalized at their periphery with tetra-alkylammonium cations (e.g. 20, Scheme 21) [30]. In aqueous media, the quaternary ammonium groupings promote the reactivity of organic anions which presumably bind in high concentration to the polycationic periphery of the dendrimer. The latter species enhances the rate of the bimolecular hydrolysis of p-nitrophenyl diphenyl phosphate catalyzed by o-iodosobenzoate ion. 

The first family of polycationic cobaltocenium dendrimers reported in the literature is constituted by four generations of the diaminobutane-based polypropylene amine) dendrimers containing 4, 8, 16, and 32 (compound 7 in Fig. 6.7a) cobaltocenium peripheral units, respectively.41... 

Polyamidoamine (PAMAM) dendrimers are non-linear polycationic cascade polymers that can bind plasmid DNA [43]. The interaction of activated PAMAM-dendrimers and plasmid DNA induces condensation of the nucleic acid. The compact transfection complexes can subsequently adhere to the cell surface and be taken up by endocytosis. 

Abstract In the late 1980s independent work by Feigner and Behr pioneered the use of cationic materials to complex and deliver nucleic acids into eukaryotic cells. Since this time, a vast number of synthetic transfection vectors, which are typically divided into two main transfectors , have been developed namely (1) cationic lipids and (2) polycationic polymers. In this chapter the main synthetic approaches used for the synthesis of these compounds will be reviewed with particular attention paid to cationic lipids and dendrimers. This review is aimed primarily at the younger audience of doctoral students and non-specialist readers. 

Fig. 25 Solid-phase synthesis of polycationic peptoid dendrimers...

Stoddart et al. developed a convergent route to polycationic dendrimers based on mesitylene units [65]. Positively charged dendrons obtained by the Menschut-kin reaction are attached as branching units around the l,3,5-tris(diethylamino-methyl)benzene core unit (3) (Fig. 4.36). (Anion) exchange of bromide with hex-afluorophosphate ions provides better solubility. 

Fig. 4.36 Convergent synthesis of polycationic dendrimers (according to Stoddart et al.)...

Fig. 4.37 Dendrimer with polycationic core shell (shown in grey according to van Koten et al.)...

Alternatively, Michael reaction of the nonaol with acrylonitrile yields a nonanitrile, which can be reduced to the nonaamine. This nonaamine was allowed to react with chloro-carbonylmetallocenes and other chlorocarbonyl sandwich complexes to yield nonaamido-metallocenes [61-63] and nonaamido-sandwich compounds [63] (Scheme 20). These metallodendrimers also give rise to only one cyclic voltammetry wave, the intensity of which corresponds to approximately nine electrons using the technique indicated above (the solvent was CH2CI2 for the nonaamidoferrocene and MeCN for the polycationic dendrimers). Chemical reversibility was observed at room temperature, although some adsorption was noted. 

Parekh, H. S., et al. (2006), Synthesis of a library of polycationic lipid core dendrimers and their evaluation in the delivery of an oligonucleotide with hVEGF inhibition, Bioorg. Med. Chem., 14(14), 4775 1780. 

Wimmer, N., Marano, R. J., Kearns, P. S., Rakaczy, E. P., and Toth, I. (2002) Syntheses of polycationic dendrimers on lipophilic peptide core for complexation and transport of oligonucleotides. Biorg. Med. Chem. Lett. 12, 2635-2631. 

A new type of core is used in dendrimer 19 functionalized with 24 [FeCp( -arene)]+ units, thus obtaining a 24+ polycationic species. Cyclic voltammetry in DMF features a single reversible 24-electron reduction wave [61 j. FI NMR spectroscopy indicates that 19 recognizes CC and Br ions, whereas electrochemistry was in this case an ineffective technique. 

Dendrimers with up to 96 redox-active TTF moieties on the periphery, which allow the generation of polycationic species bearing up to 192 positive charges on the surface, were incorporated into electrodes. These dendrimer-modified electrodes find application in electrochemical sensing of metal cations (i.e., Ba ), thanks to the grafting of crown ether/TTF units on the periphery of dendrimers < 2001AGE224>. 

Preparation and possible applications of polycationic dendrimers (120a -120c) have been patented. ... 

Zhang, Z.Y. Smith, B.D. High-generation polycationic dendrimers are unusually effective at disrupting anionic vesicles membrane bending model. Bioconjug. Chem. 2000, 11, 805-814. 

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. 

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