chapter  10
44 Pages

Molecular Modeling of Dendrimers

Figure 10.1 (a) Scheme of the typical structure of a dendrimer, composed of a central core, repetitive branching units and surfacegroups. (b) Example of a triazine dendrimer. (c) Molecular model of the triazine dendrimer. The core of the dendrimeris colored in red, the repetitive units that compose thebranches are colored by element (C: grey, N: blue, O: red, H: white), and the terminal groups in green. (d) Molecular model (starting configuration) of the triazine dendrimer in aqueous solution (Na+ ions in purple, Cl-in orange, water Oxygen atoms in transparent cyan).A multitude of dendrimer variants have been synthesized and tested in the last years.9,10 The most famous examples include poly(propyleneimine) (PPI), poly(amidoamine) (PAMAM), poly(ethyleneimine) (PEI), arborols, poly(lysines), phosphorous-containing dendrimers, triazine dendrimers, aryl ethers, and poly(esters).11-15One of the most interesting characteristics of these macromolecules is that they possess a multivalent surface, where the multiple surface functions at the dendrimer surface can establish strong cooperative binding16 with other molecular targets such as nucleic acids,17-19 proteins,20-22 etc. For example,

cationic PAMAM dendrimers, first synthesized by Tomalia, are known to be able to establish strong binding with the doublestrands of nucleic acids, and to allow for successful gene delivery into cells.23-25 Other molecular variants, such as PEI, possesssimilar properties and are routinely used for gene delivery.26,27Another interesting feature of the dendrimers is that theirstructure can be customized ad hoc, depending on the molecular target they are going to bind-i.e., the surface units can be used to improve the attraction, and the scaffold can be modified to maximize the simultaneous cooperative binding of multiple ligands to the target (scaffold flexibility/rigidity vs. multivalency). Recently, for example, the strong and natural high-affinity ofspermine (natural DNA binder) for DNA has been exploited to produce three-branched spermine-based flexible Newkometype dendrons capable of ultra-high DNA binding affinity.28,29

Several reports in the literature showed that differentparameters in the structure of dendrimers might impact molecular behavior. For example, both the scaffold and the surface are crucialto maximize the interaction between a dendritic binder and a molecular target (this will be discussed in more details later on inthis chapter). However, a deep comprehension of the structural behavior leading to a real rational design of constructs with controlled properties is still awkward. Important efforts recently pointed at putting some order in this multitude of variables. Tomalia recently proposed the critical nanoscale design parameters (CNDPs)—i.e., size, shape, surface chemistry, flexibility/rigidity and architecture-as parameters that should allow, in principle, to control the dendritic behavior.30-32 The CNDPs constitute a first interesting framework to try to understand and predict the dendritic effects on different scales.