Dendrimers are highly ordered, branched polymeric molecules.Vögtle, Fritz / Richardt, Gabriele / Werner, Nicole Dendrimer Chemistry Concepts, Syntheses, Properties, Applications 2009 Synonymous terms for dendrimer include arborols and cascade molecules. Typically, dendrimers are symmetric about the core, and often adopt a spherical three-dimensional morphology. The word dendron is also encountered frequently. A dendron usually contains a single chemically addressable group called the focal point or core. The difference between dendrons and dendrimers is illustrated in the top figure, but the terms are typically encountered interchangeably.
The first dendrimers were made by divergent synthesis approaches by Fritz Vögtle in 1978, R.G. Denkewalter at Allied Corporation in 1981, Denkewalter, Robert G., Kolc, Jaroslav, Lukasavage, William J.Denkewalter, Robert G. et al. (1981) "Macromolecular highly branched homogeneous compound" Donald Tomalia at Dow Chemical in 1983Tomalia, Donald A. and Dewald, James R. (1983) "Dense star polymers having core, core branches, terminal groups" and in 1985, and by George R. Newkome in 1985. In 1990 a convergent synthetic approach was introduced by Craig Hawker and Jean Fréchet. Dendrimer popularity then greatly increased, resulting in more than 5,000 scientific papers and patents by the year 2005.
Etymology The name comes from two Greek words: "dendron" meaning 'tree' and "meros" meaning 'part'.
Properties
Dendritic molecules are characterized by structural perfection. Dendrimers and dendrons are monodisperse and usually highly symmetric, spherical compounds. The field of dendritic molecules can be roughly divided into low-molecular weight and high-molecular weight species. The first category includes dendrimers and dendrons, and the latter includes dendronized polymers, hyperbranched polymers, and the polymer brush.
A hyperbranched polymer is similar to a dendrimer, but more randomly structured. A hyperbranched polymer has a number of randomly distributed linear constitutional repeating units.
The properties of dendrimers are dominated by the functional groups on the molecular surface. Dendrimers may have a single surface functional group, or may be modified to allow for multiple functional groups on the surface. But some dendrimers have functional groups inside, not on the surface. Dendritic encapsulation of functional molecules allows for the isolation of the active site, a structure that mimics that of active sites in biomaterials. Also, it is possible to make dendrimers water-soluble, unlike most polymers, by functionalizing their outer shell with charged species or other hydrophilic groups. Other controllable properties of dendrimers include toxicity, crystallinity, tecto-dendrimer formation, and chirality.
Generation In a dendrimer, the monomers are arranged in generations. The monomers in the "core" are generation 0, written as G0. The monomers attached to G0 are generation 1, written as G1, etc. A dendrimer is called a "first-generation dendrimer" if it has monomers of G0 and G1, but not G2. Similarly for "second-generation dendrimer" and so on.
In general, an n-th generation dendrimer is synthesized by n repeated branching cycles. For example, if a dendrimer is made by convergent synthesis, and the branching reactions are performed onto the core molecule three times, the resulting dendrimer is a third-generation dendrimer.
Each successive generation results in a dendrimer roughly twice the molecular weight of the previous generation. Higher generation dendrimers also have more exposed functional groups on the surface, which can later be used to customize the dendrimer for a given application.
Synthesis A dendrimer has three major components: a core, an inner shell, and an outer shell. Ideally, an experimenter can design a synthesis process, to obtain a dendrimer with different designated functionalities in each of these portions. This allows the experimenter to finely control properties of the final dendrimer, such as solubility, thermal stability, and attachment of compounds for particular applications. The experimenter can also design the synthesis processes to precisely control the size and number of branches on the dendrimer.
There are two defined methods of dendrimer synthesis, divergent synthesis and convergent synthesis. However, because the actual reactions consist of many steps needed to protect the active site, it is difficult to synthesize dendrimers using either method. This makes dendrimers hard to make and very expensive to purchase.
Divergent methods
The dendrimer is assembled from a multifunctional core, which is extended outward by a series of reactions, commonly a Michael reaction. Each step of the reaction must be driven to full completion to prevent mistakes in the dendrimer, which can cause trailing generations (some branches are shorter than the others). Such impurities can impact the functionality and symmetry of the dendrimer, but are extremely difficult to purify out because the relative size difference between perfect and imperfect dendrimers is very small.
Convergent methods
Dendrimers are built from small molecules that end up at the surface of the sphere, and reactions proceed inward building inward and are eventually attached to a core. This method makes it much easier to remove impurities and shorter branches along the way, so that the final dendrimer is more monodisperse. However dendrimers made this way are not as large as those made by divergent methods because crowding due to steric effects along the core is limiting.
Click chemistry
Dendrimers have been prepared via click chemistry, employing Diels-Alder reactions, thiol-ene and thiol-yne reactions and azide-alkyne reactions.
There are ample avenues that can be opened by exploring this chemistry in dendrimer synthesis.
Examples
Arborol
One of the first dendrimers, the Newkome dendrimer, was synthesized in 1985. This macromolecule is also commonly known by the name arborol. The figure outlines the mechanism of the first two generations of arborol through a divergent route (discussed below). The synthesis is started by nucleophilic substitution of 1-bromopentane by triethyl sodiomethanetricarboxylate in dimethylformamide and benzene. The ester groups were then reduced by lithium aluminium hydride to a triol in a deprotection step. Activation of the chain ends was achieved by converting the alcohol groups to tosylate groups with tosyl chloride and pyridine. The tosyl group then served as leaving groups in another reaction with the tricarboxylate, forming generation two. Further repetition of the two steps leads to higher generations of arborol.
PAMAM Poly(amidoamine), or PAMAM, is perhaps the most well known dendrimer. The core of PAMAM is a diamine (commonly ethylenediamine), which is reacted with methyl acrylate, and then another ethylenediamine to make the generation-0 (G-0) PAMAM. Successive reactions create higher generations, which tend to have different properties. Lower generations can be thought of as flexible molecules with no appreciable inner regions, while medium-sized (G-3 or G-4) do have internal space that is essentially separated from the outer shell of the dendrimer. Very large (G-7 and greater) dendrimers can be thought of more like solid particles with very dense surfaces due to the structure of their outer shell. The functional group on the surface of PAMAM dendrimers is ideal for click chemistry, which gives rise to many potential applications.
Commercial supply Dendrimer synthesis is still difficult and expensive. At this time, there are only a few companies that sell dendrimers; Polymer Factory Sweden ABPolymer Factory AB, Stockholm, Sweden.Polymer Factory commercializes biocompatible bis-MPA dendrimers and DendritechDendritech Inc., from Midland, Michigan, USA.Dendritech. is the only kilogram-scale producers of PAMAM dendrimers. NanoSynthons, LLCHome. NanoSynthons. Retrieved on 2015-09-29. from Mount Pleasant, Michigan, USA produces PAMAM dendrimers and other proprietary dendrimers.
Applications
Applications of dendrimers typically involve conjugating other chemical species to the dendrimer surface that can function as detecting agents (such as a dye molecule), affinity ligands, targeting components, radioligands, imaging agents, or pharmaceutically active compounds. Dendrimers have very strong potential for these applications because their structure can lead to multivalent systems. In other words, one dendrimer molecule has hundreds of possible sites to couple to an active species. Researchers aimed to utilize the hydrophobic environments of the dendritic media to conduct photochemical reactions that generate the products that are synthetically challenged. Carboxylic acid and phenol-terminated water-soluble dendrimers were synthesized to establish their utility in drug delivery as well as conducting chemical reactions in their interiors. This might allow researchers to attach both targeting molecules and drug molecules to the same dendrimer, which could reduce negative side effects of medications on healthy cells.
Dendrimers can also be used as a solubilizing agent. Since their introduction in the mid-1980s, this novel class of dendrimer architecture has been a prime candidate for host–guest chemistry. Dendrimers with hydrophobic core and hydrophilic periphery have shown to exhibit micelle-like behavior and have container properties in solution. The use of dendrimers as unimolecular micelles was proposed by Newkome in 1985. This analogy highlighted the utility of dendrimers as solubilizing agents. The majority of drugs available in pharmaceutical industry are hydrophobic in nature and this property in particular creates major formulation problems. This drawback of drugs can be ameliorated by dendrimeric scaffolding, which can be used to encapsulate as well as to solubilize the drugs because of the capability of such scaffolds to participate in extensive hydrogen bonding with water. Dendrimer labs are trying to manipulate dendrimer's solubilizing trait, to explore dendrimers for drug delivery and to target specific carriers.
For dendrimers to be able to be used in pharmaceutical applications, they must surmount the required regulatory hurdles to reach market. One dendrimer scaffold designed to achieve this is the polyethoxyethylglycinamide (PEE-G) dendrimer. This dendrimer scaffold has been designed and shown to have high HPLC purity, stability, aqueous solubility and low inherent toxicity.
Drug delivery
Approaches for delivering unaltered natural products using polymeric carriers is of widespread interest. Dendrimers have been explored for the encapsulation of hydrophobic compounds and for the delivery of anticancer drugs. The physical characteristics of dendrimers, including their monodispersity, water solubility, encapsulation ability, and large number of functionalizable peripheral groups make these macromolecules appropriate candidates for drug delivery vehicles.
Role of dendrimer chemical modifications in drug delivery Dendrimers are particularly versatile drug delivery devices due to the wide range of chemical modifications that can be made to increase in vivo suitability and allow for site-specific targeted drug delivery.