Dendrimer
Dendrimers are highly ordered, branched polymeric molecules. 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.
Image:Dendrimer ChemEurJ 2002 3858.jpg|thumb|Crystal structure of a first-generation polyphenylene dendrimer reported by Müllen et al
The first dendrimers were made by [|divergent synthesis approaches] by Fritz Vögtle in 1978, R.G. Denkewalter at Allied Corporation in 1981, Donald Tomalia at Dow Chemical in 1983 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.The properties of dendrimers are dominated by the functional groups on the molecular surface, however, there are examples of dendrimers with internal functionality. 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.
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, 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. Dendrimers may have a single surface functional group, or may be modified to allow for multiple functional groups on the surface.
Synthesis
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. 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.Poly, or PAMAM, is perhaps the most well known dendrimer. The core of PAMAM is a diamine, which is reacted with methyl acrylate, and then another ethylenediamine to make the generation-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 do have internal space that is essentially separated from the outer shell of the dendrimer. Very large 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.
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 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. At this time, there are only a few companies that sell dendrimers; Polymer Factory Sweden AB commercializes biocompatible bis-MPA dendrimers and Dendritech is the only kilogram-scale producers of PAMAM dendrimers. NanoSynthons, LLC 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 reaction. Each step of the reaction must be driven to full completion to prevent mistakes in the dendrimer, which can cause trailing generations. 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.
Applications
Applications of dendrimers typically involve conjugating other chemical species to the dendrimer surface that can function as detecting agents, 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 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.Drug attachment to the dendrimer may be accomplished by a covalent attachment or conjugation to the external surface of the dendrimer forming a dendrimer prodrug, ionic coordination to charged outer functional groups, or micelle-like encapsulation of a drug via a dendrimer-drug supramolecular assembly. In the case of a dendrimer prodrug structure, linking of a drug to a dendrimer may be direct or linker-mediated depending on desired release kinetics. Such a linker may be pH-sensitive, enzyme catalyzed, or a disulfide bridge. The wide range of terminal functional groups available for dendrimers allows for many different types of linker chemistries, providing yet another tunable component on the system. Key parameters to consider for linker chemistry are release mechanism upon arrival to the target site, whether that be within the cell or in a certain organ system, drug-dendrimer spacing so as to prevent lipophilic drugs from folding into the dendrimer, and linker degradability and post-release trace modifications on drugs.
Polyethylene glycol is a common modification for dendrimers to modify their surface charge and circulation time. Surface charge can influence the interactions of dendrimers with biological systems, such as amine-terminal modified dendrimers which have a propensity to interact with cell membranes with anionic charge. Certain in vivo studies have shown polycationic dendrimers to be cytotoxic through membrane permeabilization, a phenomenon that could be partially mitigated via addition of PEGylation caps on amine groups, resulting in lower cytotoxicity and lower red blood cell hemolysis. Additionally, studies have found that PEGylation of dendrimers results in higher drug loading, slower drug release, longer circulation times in vivo, and lower toxicity in comparison to counterparts without PEG modifications.
Numerous targeting moieties have been used to modify dendrimer biodistribution and allow for targeting to specific organs. For example, folate receptors are overexpressed in tumor cells and are therefore promising targets for localized drug delivery of chemotherapeutics. Folic acid conjugation to PAMAM dendrimers has been shown to increase targeting and decrease off-target toxicity while maintaining on-target cytotoxicity of chemotherapeutics such as methotrexate, in mouse models of cancer.
Antibody-mediated targeting of dendrimers to cell targets has also shown promise for targeted drug delivery. As epidermal growth factor receptors are often overexpressed in brain tumors, EGFRs are a convenient target for site-specific drug delivery. The delivery of boron to cancerous cells is important for effective neutron capture therapy, a cancer treatment which requires a large concentration of boron in cancerous cells and a low concentration in healthy cells. A boronated dendrimer conjugated with a monoclonal antibody drug that targets EGFRs was used in rats to successfully deliver boron to cancerous cells.
Modifying nanoparticle dendrimers with peptides has also been successful for targeted destruction of colorectal cancer cells in a co-culture scenario. Targeting peptides can be used to achieve site- or cell-specific delivery, and it has been shown that these peptides increase in targeting specificity when paired with dendrimers. Specifically, gemcitabine-loaded YIGSR-CMCht/PAMAM, a unique kind of dendrimer nanoparticle, induces a targeted mortality on these cancer cells. This is performed via selective interaction of the dendrimer with laminin receptors. Peptide dendrimers may be employed in the future to precisely target cancer cells and deliver chemotherapeutic agents.
The cellular uptake mechanism of dendrimers can also be tuned using chemical targeting modifications. Non-modified PAMAM-G4 dendrimer is taken up into activated microglia by fluid phase endocytosis. Conversely, mannose modification of hydroxyl PAMAM-G4 dendrimers was able to change the mechanism of internalization to mannose-receptor mediated endocytosis. Additionally, mannose modification was able to change the biodistribution in the rest of the body in rabbits.