Chemical And Physical Characteristics A General Chemical Structure and Synthesis

Dendrimers are composed of concentric, geometrically progressive layers created through radial amplification from a single, central initiator core molecule containing either three or four reactive sites such as ammonia or ethylene diamine. Like the nucleus of the biotic cell, the core contains the basic information of the dendrimer; it defines the final size, shape, multiplicity, and functionality of the entire structure. Starting from the center, each layer stores information, which is transferred to the next outer layer or generation via covalent connections, determining that layer's physical properties (17). This is accomplished by choosing reactants with additional reactive sites. Then through a series of protection/deprotection strategies, all the reactive sites on the core molecules are converted without reacting with the reactive sites of the additional reactants. As these steps are repeated, new generations are added to the dendrimer. The radial transfer of information distinguishes the synthetic dendrimer from the biotic cell that transmits information in a linear fashion using DNA and RNA.

The dendrimer amplification process can be described by the simplified synthesis of the basic PAMAM dendrimer (7,17). The first step adds methanol to the mixture of ammonia (NH3), the initiator core (I), and methyl acrylate (reactant B), causing a molecule of B to substitute for each of the three hydrogen atoms on I. The second step, ethylene diamine, a primary amine is added to the end of each of the methyl acrylates, completing the first generation of the dendrimer. Each ethylene diamine moiety contains two N-H bonds at the end of each branch of the structure, generating six exposed reactivation sites. The second generation of the dendrimer is created by adding a methyl acrylate moiety at each hydrogen and then an ethylene diamine molecule to the end of the branch, yielding 12 exposed reactive sites (Fig. 1). Thus, with such successive generation, the number of reactive sites increases depending on the substrate added to B. The amplification process can continue for about 9 or 10 generations, when the den-drimer is no longer able to form perfect branches due to steric hindrance (7,17).

Dendrimer molecules can be assembled via two pathways. The original pathway, the divergent process, involves working outward from the initiator molecule with the addition of each generation (17). This method of assembly can create a number of defects within the dendrimer. The defect can be in an individual dendrimer or between dendrimers within the mixture. The intra-

Fig. 1 Schematic drawing of dendrimer structures. Dendrimers are synthesized by two pathways, either the convergent or the divergent pathway. The convergent pathway consists of building the branches prior to addition to the core molecule (A). The divergent pathway consist of building the branches in concentric "layers" (B). Each layer is a generation (G).

Fig. 1 Schematic drawing of dendrimer structures. Dendrimers are synthesized by two pathways, either the convergent or the divergent pathway. The convergent pathway consists of building the branches prior to addition to the core molecule (A). The divergent pathway consist of building the branches in concentric "layers" (B). Each layer is a generation (G).

dendrimer faults are usually in the branching and are caused by incomplete reactions, branch-juncture fragmentation, or abnormal development or sterically induced stoichiometry. The interdendrimer defects usually arise form the incomplete removal of reagents that may function as a core or dendrimer fragmentation, which may act as an initiator species that can act with other dendrimers (Fig. 2). Optimization of the process and synthesis strategies can eliminate these problems (17). In 1989, Hawker and Frechet (18) introduced the second pathway, the convergent process, which builds the branch wedge independently and then adds it to the root molecule (Fig. 1). This method allows for using ideal branches because they can be separated from the defective ones. This method may also allow for the creation of dendrimers that have branches with different functions, such as one branch that targets the dendrimer to a cell and a second branch that contains a drug (18). Although this process can generate sufficient dendrimers for the laboratory, it is not conducive to large-scale production (18).

Fig. 2 Defects within dendrimers. Interdendrimer faults can arise form incomplete reactions creating active sites that interact with other dendrimers. The incomplete branching in the top left dendrimer (intradendrimer) has a reactant B, which can react with z from a second dendrimer to interlink the dendrimer structures, creating a defective molecule.

Fig. 2 Defects within dendrimers. Interdendrimer faults can arise form incomplete reactions creating active sites that interact with other dendrimers. The incomplete branching in the top left dendrimer (intradendrimer) has a reactant B, which can react with z from a second dendrimer to interlink the dendrimer structures, creating a defective molecule.

B. Physical Properties

The physical properties of dendrimers depend on the chemical structure/ steric properties of internal and external functional groups. The shape may range from an almost perfect sphere to an ellipsoid to a cylinder-like structure composed of intricately branched "fans" extending out of an elongated base (19). Changes in the core molecule and/or the number of reactive sites present on the core can also influence the shape. Newer dendrimers use phosphorus- or silicone-containing molecules, hydrocarbons, lysine, or thiols as the internal cores (7,17). The dendrimer can also be adjusted based on the selection of reactants. This also can affect the overall size of the dendrimer. Usually size is dependant on the number of generations assembled, but it can also be influenced by the length of the monomers used and the angles between the monomers (7). The average mass of a dendrimer varies from about 500 to 1500 daltons, with the diameter of a spherical dendrimer varying from about 10 A (first generation) to a maximum of about 130 A. Each polymerization step increases the diameter by about 10 A (17).

Dendrimers are relatively stable, covalent macromolecules. They exist independently from each other and from their external environment. As the dendrimer grows, steric congestion eventually prevents further growth. At this point, the dendrimer converts from an open structure to a tight spheroid with open cavities and a dense surface (20). A specific dendrimer's stability depends on the reactivity of the functional groups located on its surface, which can be modified to achieve the necessary level of stability.

C. Dendrimer Core (the ''Guest-in-Box System'')

Naylor et al. (21) were the first to describe the interior dendrimer space and to demonstrate the large carrying capacity of PAMAM dendrimers. Generations 4 through 7 were capable of encapsulating three times their weight in aspirin. Tomalia and Esfand (19) showed that the dendrimer interior also contains recognition properties specific to the shape and functionality of the guest molecule. The dissolving of water-insoluble molecules, such as ibuprofen, increased in the presence of the dendrimer structure. The ability to encapsulate drugs within the cavities of the dendrimers could result in novel delivery methods.

Jansen et al. (22) reported the synthesis of a "dendrimer box" that is based on a chiral shell of protected amino acids on the dendrimer core. During synthesis of the box, "guest" molecules and small amounts of solvent become trapped within the cavities; the molecules dissolve as they become tightly bound to functional groups on the interior "wall" of the box. Compatible guests such as drugs, DNA, or other small molecules cannot be extracted, and their spontaneous outward diffusion is extremely slow due to the close packing of the shell. Only medium- to high-generation dendrimers possess dense enough shells to capture and retain guests (22). The release of guest molecules can be controlled by changing the pH of the reaction mix (23).

D. Dendrimer Surface

The dendrimer surface ultimately determines the structure's interactions with its environment. The surface serves to protect the internal functional groups via steric interactions, which shield these groups from large molecules while retaining their accessibility and reactivity to small molecules. These interactions also maintain an outside versus inside position with ionic (polar) chain ends containing a high density of positively charged amino groups and a hydrophobic (nonpolar) interior (19). Dendrimer surface properties can be subdivided into endo-receptor properties and exo-receptor properties. Endo-receptor properties are the interior dendritic features such as size, chemical composition, flexibility, and topology, which are responsible for the so-called convergent recognition of guest molecules by the internal dendrimer surface (17). Exo-receptor properties encompass the exterior features, such as shape, reactivity, stoichiometry, flexibility, and fractal character, which similarly govern the divergent recognition of external associator molecules by the external dendrimer surface (17).

The dendrimer surface determines its solubility through chemical recognition of different external reagents/solvents and affects the reactivity of the molecule through the number of reactive surface groups (17). The surface can serve as scaffolding for up to thousands of reactive functional groups such as carbohydrate residues and peptidyl epitopes. Functional groups on the surface of dendrimers show higher chemical reactivity than the same groups attached to other polymer molecules (24). This "charging" allows for important covalent coupling reactions with DNA and other molecules. Furthermore, biologically active molecules, when complexed with dendrimers, tend to retain their maximum activity even when surface groups on the dendrimer are activated for a reaction.

Modifications of the dendrimer surface, specifically the addition of functional groups, occur through the addition of either subnanoscopic or nanoscaled reactants (19). Subnanoscopic reactants can be a variety of small molecules, while nanoscaled reactants are composed of larger molecules such as DNA, antibodies, and proteins that can complex with dendrimers. Scott et al. (25) describe the rapid synthesis of a second-generation dendri-

mer with primary alcohol groups at the periphery. (The use of modified dendrimers in bioorganic chemistry is reviewed in Ref. 26.)

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