Starburst molecules Dendrimers

Beginning with the work of Thomalia [17] in 1986, starburst molecules (dendrimers) have achieved enormous interest within the last years. Dendrimers are highly branched regular molecules, which are usually prepared by stepwise reactions. In many cases the behaviour of dendritic macromolecules are different from that of linear polymers, e. g. the former... 

Molecular Recognition and Chemistry in Restricted Reaction Spaces. Photophysics and Photoinduced Electron Transfer on the Surfaces of Micelles, Dendrimers and DNA [N. J. Turro, J. K. Barton, D. A. Tomalia, Acc. Chem. Res. 1991, 24, 332], Self-Assembly in Synthetic Routes to Molecular Devices. Biological Principles and Chemical Perspectives A Review [J. S. Lindsey, New J. Chem. 1991,15, 153], Amorphous molecular materials synthesis and properties of a novel starburst molecule, 4,4, 4 -tri(N-phenothiazinyl)triphenylamine [A. Higuchi, H. Inada, T. Kobata, Y. Shirota, Adv. Mat. (Weinheim, Ger.) 1991, 3(11), 549-550],... 

Dendrimers (sometimes called arbor, cascade, or starburst molecules) share some characteristics with polymers but also manifest critical differences. Whereas linear polymers like polystyrene are polydisperse (have a range of molecular weights and character), dendrimers, synthesized in a stepwise manner, are monodisperse (have uniform molecular mass). Unlike polymers, their growth becomes at some stage self-limiting as the molecule folds into itself. Unlike linear polymers, which present countless rapidly interconverting shapes, dendrimers are nearly spherical in shape with diameters typically between 2 and 10 nm. 

Dendritic molecule, dendrimer A multibranched meso-molecule prepared by either an iterative or a convergent methodology. Typically such structures are very highly branched and have been described as multiarmed . Dendritic molecules may be perfectly monodisperse, or may contain structural defects. A variety of synonyms are in use cascade molecule, dendrimer, arborol, cascadol, molecular fractal, starburst dendrimer, etc. 

Polyamidoamine (PAMAM) systems are perhaps the most studied in the area of electrochemistry in the presence of dendrimers. The uptake of by coordination to amine sites followed by reduction to Cu yielded clusters that have potential use for catalysis [38]. The stabiUty of the small clusters suggested that they reside in the cavities of these starburst molecules. Because PAMAM is a nonspecific ligand, the use of this method of preparing clusters is applicable to a wide range of metals. Moreover, the geometry of dendrimers and the variation of size that is available by controlling the generation number allow the prediction that they can be immobilized by a variety of methods at electrode surfaces. 

The sequential growth and branching involved in the preparation of dendrimers had been considered by Flory many years before they were actually prepared. Flory developed a sound understanding of the kind of processes that would occur in the self-polymerization of a molecule of the type ABj most of which have been shown to be correct by the relatively recent experimental studies. In particular, the existence of a limit to growth was predicted. This limit has become known as the starburst limit, and is the reason for the highly monodisperse nature of fully developed dendrimers. 

The first true dendrimers were the polyamidoamines (PAMAMs). They are also known as starburst dendrimers, and the term starburst is a trademark of the Dow Chemical Company, who have commercialized these materials for a range of applications. These dendrimers use ammonia as the core molecule, and this is reacted with methyl acrylate in the presence of methanol, after which ethylenediamine is added. This is shown in Scheme 9.2. 

The addition of ammonia to excess methyl acrylate (a linear monomer), followed by amidation with excess ethylenediamine afforded the resultant cascade molecule, and thus Tomalia [37] created the commercially available PAMAM starburst series of dendrimers (2, Fig. 2). Related core molecules such as ethylenediamine and aminoalcohols and other functionalizable groups such as thiol moieties were used to prepare similar dendrimers [38]. This methodology is applicable to most primary amines, resulting in a 1 —> 2 branching pattern. Recently, examples of related Si-, [39] P-, [40] and metallo systems [41], which follow this linear monomer protocol have been reported. 

In 1994 we published the first chiral dendrimers built from chiral cores and achiral branches [ 1,89], see for instance dendrimer 57 with a core from hydroxy-butanoic acid and diphenyl-acetaldehyde and with twelve nitro-groups at the periphery (Fig. 21). As had already been observed with starburst dendrimers, compound 57 formed stable clathrates with many polar solvent molecules, and it could actually only be isolated and characterized as a complex [2 (57- EtO-Ac (8 H20))]. Because no enantioselective guest-host complex formation could be found, and since compounds of type 57 were poorly soluble, and could thus not be easily handled, we have moved on and developed other systems to investigate how the chirality of the core might be influencing the structure of achiral dendritic elongation units. 

Roberts, J.C., Adams, Y.E., Tomalia, D., Mercer-Smith, J.A., and Lavallee, D.K. (1990) Using starburst dendrimers as linker molecules to radiolabel antibodies. Bioconjugate Chem. 1(5), 305-308. 

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. 

Our results have shown that the use of STARBURST dendrimers for the covalent coupling of the molecules of biological interest can lead to a reproduc-ibly performing product with very little impact on the biological activity of the immobilized protein. By careful optimization of the reaction parameters, it has... 

Up to now, the equilibrium structure of flexible dendrimers in solution has been treated in several exhaustive theoretical studies [6-13]. Shortly after the first experimental reports on the synthesis of dendrimers their spatial structure was considered by de Gennes and Hervet [6]. These authors derived a density profile which has a minimum at the center of the starburst and increased monotonically to the outer edge. It must be noted that de Gennes and Hervet assumed that all subsequent bonds point to the periphery of the molecule. A structure complying with this assumption may be given by the fully aromatic dendrimers as displayed in Fig. 2. In consequence, the dense-shell picture" deriving from this theory is built into the model. It should not be regarded as its result. 

Another approach to controlled molecular morphogenesis is provided by the generation of globular molecules such as the starburst dendrimers and the arborols , based on highly branched structures formed via cascade processes and growing from a central core [7.55-7.60]. Most such molecular scaffolding hase been produced by repetitive processes the use of sequences of different reactions is expected to give access to an even richer variety of non-repetitive branched architectures. 

Dendrimers are molecules with regularly placed branched repeat units. They are also known as Starburst, Cascade or Arborols. These names describe aspects of their molecular architecture. Dendrimers consist of different parts (see Fig. 1). Each dendrimer has a core or focal point. The core is the central unit of the den-drimer and can formally be regarded as the center of symmetry for the entire molecule. The core has its characteristic branching functionality, i.e. the number of chemical bond by which it is connected to the rest of the molecule (Fig. la). The focal point plays the same role as the core. Moreover,it has a chemical functional group not found elsewhere in the dendrimer. 

Barth et alJ30 have reported the preparation of boronated starburst dendrimer— monoclonal antibodies immunoconjugates as a potential delivery system for boron neutron capture therapy. 31 32 Starburst dendrimers have also been employed as linker molecules for the covalent connection of synthetic porphyrins to antibodies J33 ... 

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