Dendrimer
Encyclopedia
Greek language
Greek is an independent branch of the Indo-European family of languages. Native to the southern Balkans, it has the longest documented history of any Indo-European language, spanning 34 centuries of written records. Its writing system has been the Greek alphabet for the majority of its history;...
word "δένδρον" , which translates to "tree". Synonymous terms for dendrimer include arborols and cascade molecules. However, dendrimer is currently the internationally accepted term. A dendrimer is typically symmetric around the core, and often adopts 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. The difference between dendrons and dendrimers is illustrated in figure one, but the terms are typically encountered interchangeably.
Jean Frechet
Professor Jean M.J. Fréchet is the Henry Rapoport Chair of Organic Chemistry at the Department of Chemistry, University of California, Berkeley...
. Dendrimer popularity then greatly increased, resulting in more than 5,000 scientific papers and patents by the year 2005.
Properties
Dendritic molecules are characterized by structural perfection. Dendrimers and dendrons are monodisperseMonodisperse
A collection of objects are called monodisperse, or monosized, if they have the same size and shape when discussing particles, and the same mass when discussing polymers...
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
Polymer brush
Polymer brush is a layer of polymers attached with one end to a surface. The brushes may be either in a solvent state, when the dangling chains are submerged into a solvent, or in a melt state, when the dangling chains completely fill up the space available...
.
The properties of dendrimers are dominated by the functional groups on the molecular surface
Molecular surface
Molecular surface may refer to one of the following.* the van der Waals surface*Accessible surface area*any of isosurfaces for a molecule**Connolly surface...
, however, there are examples of dendrimers with internal functionality. Dendritic encapsulation
Molecular encapsulation
Molecular encapsulation in supramolecular chemistry is the confinement of a guest molecule inside the cavity of a supramolecular host molecule...
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
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
, crystallinity
Crystallinity
Crystallinity refers to the degree of structural order in a solid. In a crystal, the atoms or molecules are arranged in a regular, periodic manner. The degree of crystallinity has a big influence on hardness, density, transparency and diffusion. In a gas, the relative positions of the atoms or...
, tecto-dendrimer formation, and chirality
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....
.
Dendrimers are also classified by generation, which refers to the number of repeated branching cycles that are performed during its synthesis. For example if a dendrimer is made by convergent synthesis (see below), and the branching reactions are performed onto the core molecule three times, the resulting dendrimer is considered 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
One of the very first dendrimers, the Newkome dendrimer, was synthesized in 1985. This macromoleculeMacromolecule
A macromolecule is a very large molecule commonly created by some form of polymerization. In biochemistry, the term is applied to the four conventional biopolymers , as well as non-polymeric molecules with large molecular mass such as macrocycles...
is also commonly known by the name arborol. Figure 3 outlines the mechanism of the first two generations of aborol through a divergent route (discussed below). The synthesis is started by nucleophilic substitution
Nucleophilic substitution
In organic and inorganic chemistry, nucleophilic substitution is a fundamental class of reactions in which an electron nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms called the leaving group; the positive or partially positive...
of 1-bromopentane by triethyl sodiomethanetricarboxylate in dimethylformamide
Dimethylformamide
Dimethylformamide is an organic compound with the formula 2NCH. Commonly abbreviated as DMF , this colourless liquid is miscible with water and the majority of organic liquids. DMF is a common solvent for chemical reactions...
and benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....
. The ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
groups were then reduced by lithium aluminium hydride
Lithium aluminium hydride
Lithium aluminium hydride, commonly abbreviated to LAH or known as LithAl, is an inorganic compound with the chemical formula LiAlH4. It was discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic synthesis, especially for the reduction of esters,...
to a triol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
in a deprotection step. Activation of the chain ends was achieved by converting the alcohol groups to tosylate groups with tosyl chloride and pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
. The tosyl group then served as leaving group
Leaving group
In chemistry, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl−, Br−, and I−, and sulfonate esters, such as para-toluenesulfonate...
s in another reaction with the tricarboxylate, forming generation two. Further repetition of the two steps leads to higher generations of arborol.
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
Methyl acrylate
Methyl acrylate is a volatile chemical compound classified as a methyl ester. It has a characteristic acrid odor used in the preparation of polyamidoamine dendrimers typically by Michael addition with a primary amine....
, 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
Click chemistry
Click chemistry is a chemical philosophy introduced by K. Barry Sharpless of The Scripps Research Institute, in 2001 and describes chemistry tailored to generate substances quickly and reliably by joining small units together...
, which gives rise to many potential applications.
Dendrimers can be considered to have three major portions: a core, an inner shell, and an outer shell. Ideally, a dendrimer can be synthesized to have different functionality in each of these portions to control properties such as solubility, thermal stability, and attachment of compounds for particular applications. Synthetic processes can also precisely control the size and number of branches on the dendrimer. There are two defined methods of dendrimer synthesis, divergent synthesis
Divergent synthesis
In chemistry a divergent synthesis is a strategy with the aim to improve the efficiency of chemical synthesis. It is often an alternative to convergent synthesis or linear synthesis....
and convergent synthesis
Convergent synthesis
In chemistry a convergent synthesis is a strategy that aims to improve the efficiency of multi-step chemical synthesis, most often in organic synthesis...
. However, because the actual reactions consist of many steps needed to protect the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
, it is difficult to synthesize dendrimers using either method. This makes dendrimers hard to make and very expensive to purchase. At this time, there are only a few companies that sell dendrimers; Polymer Factory Sweden AB
Polymer Factory Sweden AB
Polymer Factory Sweden AB is creating advance dendritic macromolecules for the future.Established in 2005, Polymer Factory concentrates on developing well defined dendrimers and dendron based on 2,2-bispropionic acid where the company has the exclusive right to the production, marketing, and sales...
commercializes biocompatible bis-MPA dendrimers and Dendritech is the only kilogram-scale producers of PAMAM dendrimers. Dendritic Nanotechnologies Inc., from Mount Pleasant, Michigan, USA produces PAMAM dendrimers and other proprietary dendrimers.
Divergent Methods
The dendrimer is assembled from a multifunctional core, which is extended outward by a series of reactions, commonly a Michael reactionMichael reaction
The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an alpha, beta unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C-C bonds...
. 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 effectsSteric effects
Steric effects arise from the fact that each atom within a molecule occupies a certain amount of space. If atoms are brought too close together, there is an associated cost in energy due to overlapping electron clouds , and this may affect the molecule's preferred shape and reactivity.-Steric...
along the core is limiting.
Click chemistry
Click chemistry
Click chemistry is a chemical philosophy introduced by K. Barry Sharpless of The Scripps Research Institute, in 2001 and describes chemistry tailored to generate substances quickly and reliably by joining small units together...
, employing Diels-Alder reaction
Diels-Alder reaction
The Diels–Alder reaction is an organic chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. The reaction can proceed even if some of the atoms in the newly formed ring are not carbon...
s, thiol-yne reactions
Thiol-yne reaction
The Thiol-yne reaction is an organic reaction between a thiol and an alkyne. The reaction product is an alkenyl sulfide...
and azide-alkyne reactions
Azide alkyne Huisgen cycloaddition
The Azide-Alkyne Huisgen Cycloaddition is a 1,3-dipolar cycloaddition between an azide and a terminal or internal alkyne to give a 1,2,3-triazole. Rolf Huisgen was the first to understand the scope of this organic reaction. American chemist K...
. An example is the synthesis of certain polyphenylene dendrimers can be seen in figure 6.
There are ample avenues that can be opened by exploring this chemistry in dendrimer synthesis.
Applications
Applications of dendrimers typically involve conjugating other chemical species to the dendrimer surface that can function as detecting agents (such as a dyeDye
A dye is a colored substance that has an affinity to the substrate to which it is being applied. The dye is generally applied in an aqueous solution, and requires a mordant to improve the fastness of the dye on the fiber....
molecule), affinity ligands, targeting components, radioligand
Radioligand
A radioligand is a radioactive biochemical substance that is used for diagnosis or for research-oriented study of the receptor systems of the body....
s, imaging agent
Imaging agent
Imaging agents are chemicals designed to allow clinicians to determine whether a mass is benign or malignant and locate metastatic cancer sites in the body....
s, 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 hosts 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 throughout the planet are persistently trying to manipulate dendrimer’s solubilizing trait, in their way to explore dendrimer as drug delivery and target specific carrier.
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 macromoleculeMacromolecule
A macromolecule is a very large molecule commonly created by some form of polymerization. In biochemistry, the term is applied to the four conventional biopolymers , as well as non-polymeric molecules with large molecular mass such as macrocycles...
s appropriate candidates for evaluation as drug delivery vehicles. There are three methods for using dendrimers in drug delivery: first, the drug is covalently attached to the periphery of the dendrimer to form dendrimer prodrugs, second the drug is coordinated to the outer functional groups via ionic interactions, or third the dendrimer acts as a unimolecular micelle
Micelle
A micelle is an aggregate of surfactant molecules dispersed in a liquid colloid. A typical micelle in aqueous solution forms an aggregate with the hydrophilic "head" regions in contact with surrounding solvent, sequestering the hydrophobic single tail regions in the micelle centre. This phase is...
by encapsulating a pharmaceutical through the formation of a dendrimer-drug supramolecular assembly. The use of dendrimers as drug carriers by encapsulating hydrophobic drugs is a potential method for delivering highly active pharmaceutical compounds that may not be in clinical use due to their limited water solubility and resulting suboptimal pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
. Dendrimers have been widely explored for controlled delivery of antiretroviral bioactives The inherent antiretroviral activity of dendrimers enhances their efficacy as carriers for antiretroviral drugs The dendrimer enhances both the uptake and retention of compounds within cancer cells, a finding that was not anticipated at the onset of studies. The encapsulation increases with dendrimer generation and this method may be useful to entrap drugs with a relatively high therapeutic dose. Studies based on this dendritic polymer also open up new avenues of research into the further development of drug-dendrimer complexes specific for a cancer and/or targeted organ system. These encouraging results provide further impetus to design, synthesize, and evaluate dendritic polymers for use in basic drug delivery studies and eventually in the clinic.
Gene Delivery
The ability to deliver pieces of DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
to the required parts of a cell includes many challenges. Current research is being performed to find ways to use dendrimers to traffic genes into cells without damaging or deactivating the DNA. To maintain the activity of DNA during dehydration, the dendrimer/DNA complexes were encapsulated in a water soluble polymer, and then deposited on or sandwiched in functional polymer films with a fast degradation rate to mediate gene transfection
Transfection
Transfection is the process of deliberately introducing nucleic acids into cells. The term is used notably for non-viral methods in eukaryotic cells...
. Based on this method, PAMAM dendrimer/DNA complexes were used to encapsulate functional biodegradable polymer films for substratemediated gene delivery. Research has shown that the fast degrading functional polymer has great potential for localized transfection.
Sensors
Scientists have also studied dendrimers for use in sensorSensor
A sensor is a device that measures a physical quantity and converts it into a signal which can be read by an observer or by an instrument. For example, a mercury-in-glass thermometer converts the measured temperature into expansion and contraction of a liquid which can be read on a calibrated...
technologies. Studied systems include proton
Proton
The proton is a subatomic particle with the symbol or and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number....
or pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
sensors using poly(propylene imine), cadmium-sulfide/polypropylenimine tetrahexacontaamine dendrimer composites to detect fluorescence
Fluorescence
Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation of a different wavelength. It is a form of luminescence. In most cases, emitted light has a longer wavelength, and therefore lower energy, than the absorbed radiation...
signal quenching, and poly(propylenamine) first and second generation dendrimers for metal cation photodetection
Photodetection
In his historic paper, entitled " The Quantum Theory of Optical Coherence," Roy J. Glauber set a solid foundation for the quantum electronics/quantum optics enterprise. The experimental development of the optical maser and later laser at that time had made the classical concept of optical...
amongst others. Research in this field is vast and ongoing due to the potential for multiple detection and binding sites in dendritic structures.