Dendrimers : Polymers of 21 st Century

Hitesh V. Chavda

A dendrimer is generally described as a macromolecule, which is characterized by its highly branched 3D structure that provides a high degree of surface functionality and versatility. During the past couple of years, there has been an intensifying interest in dendrimer chemistry.

The word “ dendrimer ” originated from two words, the Greek word dendron , meaning tree, and meros , meaning part. Dendrimer chemistry was first introduced in 1978 by Fritz Vogtle and coworkers ¹ . He synthesized the first “cascade molecules”, today known as dendritic molecules. In 1985, Donald A. Tomalia, working in the field of polymer chemistry, synthesized the first family of dendrimers ² . These contributions to the field have paved the way for continuing research in this promising area. The term ‘dendrimer’ refers only to an architectural motif and not a particular compound. To date greater than 160 various polymers with dendritic structures are reported in the literatures. The surface groups of dendrimers are amenable to modification and can be tailored for specific applications. The dendrimer architecture therefore permits control over properties such as shape, size, density, polarity, reactivity and solubility. They are produced in an iterative sequence of reaction steps, in which each reaction results in a new so called generation. Dendrimer density functions and starburst limits can be easily modeled mathematically. These features are related to core multiplicity, the branching multiplicity of the monomer units, and the branch lengths, as well as the core and branch volumes ³ . Due to their multivalent and monodisperse character, dendrimers have stimulated wide interest in the field of chemistry and biology, especially in applications like drug delivery, gene therapy and chemotherapy.

Structure And Composition 4

A dendrimer is a synthetic, man-made, 3-dimensional macromolecule, which is prepared in a series of repetitive reactions from simple branched monomer units. Dendrimers consist of a series of chemical shells built on a small core molecule. For the first three generations, Dendrimers are very much like ordinary organic molecules but have certain distinct properties. Dendrimers are superior compared to linear polymers in various properties like structure, structural control, architecture, size, shape, hydrodynamic volume, crystallanity, aqueous solubility, apolar solubility, viscosity, compatibility, reactivity, compressibility, polydispersity, analogy, synthesis, architecture monomer units internal micro-environment ⁵ . They are small and floppy without much consistent or specific three-dimensional structure. By generation (G-4) they start assuming spherical shape and take on a preferred three-dimensional structure. By generation (G-5), they have a consistent and specific three- dimensional structure. They can be synthesized from almost any core molecules and the branches can be constructed from any bifunctional molecules (lysine or ornithine), while the terminal groups can be modified to achieve charged, hydrophilic or hydrophobic surface. Control of the chemical nature, control of molecular weight, control of surface, internal structure and character are vital for drug targeting. A dendritic structure is shown in Figure 1. Dendrimers possess three distinguished architectural components, namely (i) an initiator core, (ii) Interior layers (generations) composed of repeating units, radically attached to the interior core and (iii) Exterior (terminal functionality) attached to the outermost interior generations. The dendrimer microenvironment possesses interesting properties. In the interior of the molecule, cavities in the core structure and folding of the branches create cages and channels, which, depending upon how the dendrimer was constructed, may be either hydrophilic or hydrophobic in nature. Specific binding sites may also be incorporated. The initiator core multiplicity (N _C ) and branch juncture multiplicity (N _B ) directly affect the number of terminal groups (Z), the Number of Repeating Units (NRU) and Number of Branched Cells (NBC) and the Molar Mass (M) of Dendrimers as a function of generation number (G). These values can be predicated mathematically for an ideal system according to the following expressions:

No. of terminal groups: Z = N _C N _B G

No. of dendrimers Repeating Units: NRU = N _C [N _B G + (1 / N _B -1)]

No. of dendrimers branch cell: NBC = N _C [N _B G – (1 / N _B -1)]

Theoretical molar mass of dendrimers: M = M _C + N _C (MRU - NRU) + M _T (N _B G +1)

Where M _C is the initiator core molar mass, MRU is molar mass of repeating units and M _T is the molar mass of the terminal group.

Despite their characteristic nature, dendrimers are very likely to be confused with other linear or hyper branched polymers, proteins micelles, etc. Dendrimers, like liposomes, display the property of encapsulation or being able to sequester molecules within the cavity.

Figure 1: The Dendritic Structure

Synthesis ³

The synthesis used for dendrimer preparation permit almost entire control over the critical molecular design parameters such as size, shape, surface/interior chemistry, flexibility, and topology. Most syntheses of dendrimers involve the repetitious alternation of a growth reaction and an activation reaction. Often, these reactions have to be performed at many sites on the same molecule simultaneously. Clearly, the reactions must be very 'clean' and high yielding for the construction of large targets to be feasible. Many dendrimer syntheses rely upon traditional reactions, such as the Michael reaction or the Williamson ether synthesis whilst others involve the use of modern techniques and chemistry, such as solid-phase synthesis, organotransition-metal chemistry, organosilicon chemistry, organo-phosphorus chemistry, or other contemporary organic methodologies. The choice of the growth reaction dictates the way in which the branching should be introduced into the dendrimer. Branching may either be present in the building blocks as is more often the case or it can be created as a function of the growth reaction, as is the case with the poly (amidoamine)s and the poly (propylene imine)s.

'Divergent' Dendrimer Growth

The synthetic methodology employed in the early dendrimer syntheses came to be known as the 'divergent' approach. This name comes from the way in which the dendrimer grows outwards from the core, diverging into space. A schematic representation of divergent growth is shown in Figure 2. Starting from a reactive core, a generation is grown, and then the new periphery of the molecule is activated for reaction with more monomers. The two steps can be repeated. The divergent approach is successful for the production of large quantities of dendrimers since, in each generation-adding step, the molar mass of the dendrimer is doubled. Very large dendrimers have been prepared in this way, but incomplete growth steps and side reactions lead to the isolation and characterization of slightly imperfect samples. Divergently grown dendrimers are virtually impossible to isolate pure from their side products. The synthetic chemist must rely on extremely efficient reactions in order to ensure low polydispersities.  

Figure 2: Divergent Dendrimer Growth

'Convergent' Dendrimer Growth

The 'convergent' approach was developed as a response to the weaknesses of divergent syntheses. A schematic representation of convergent growth is shown in Figure 3. Convergent growth begins at what will end up being the surface of the dendrimer, and works inwards by gradually linking surface units together with more. When the growing wedges are large enough, several are attached to a suitable core to give a complete dendrimer. The advantages of convergent growth over divergent growth stem from the fact that only two simultaneous reactions are required for any generation-adding step. Most importantly, this protocol makes the purification of perfect dendrimers simple. There are also certain other advantages associated with convergent growth. The growth reactions do not have to be so stringently efficient, and it becomes possible to introduce subtle engineering into the dendritic structure. Convergent syntheses are not without their own shortcomings, however. The number of steps required to build up a large structure is not reduced compared with the divergent approach, yet a great deal more starting material is required. The convergent methodology also suffers from low yields in the synthesis of large structures. Dendritic wedges of higher generations encounter serious steric problems in the reactions of their 'focal points'. 

Figure 3: Convergent Dendrimer Growth

'Hypercores' and 'Branched Monomers'

These methods involve the pre-assembly of oligomeric species which can then be linked together to give dendrimers in fewer steps or higher yields. Hypercores and branched monomers allow the chemist to devise synthetic strategies that are more convergent in the classical synthetic sense of the word. An interesting comparison of convergent, divergent, and hypercore synthesis in the preparation of phenyl acetylene dendrimers was attempted by Moore , but solubility problems in the divergent steps made the convergent approach favorable. A schematic representation of hypercores and branched monomers is shown in Figure 4.

Figure 4: Hypercores and Branched Monomers

'Double Exponential' and 'Mixed' Growth

The most recent fundamental breakthrough in the practice of dendrimer synthesis has come with the concept and implications of 'double exponential' growth. A schematic representation of double exponential and mixed growth is shown in Figure 5. Double exponential growth, similar to a rapid growth technique for linear polymers, involves an AB2 monomer with orthogonal protecting groups for the A and B functionalities. This approach allows the preparation of monomers for both convergent and divergent growth from a single starting material. These two products are reacted together to give an orthogonally protected trimer, which may be used to repeat the growth process again. The strength of double exponential growth is more subtle than the ability to build large dendrimers in relatively few steps. In fact, double exponential growth is so fast that it can be repeated only two or perhaps three times before further growth becomes impossible. The double exponential methodology provides a means whereby a dendritic fragment can be extended in either the convergent or the divergent direction as required. In this way, the positive aspects of both approaches can be accessed without the necessity to bow to their shortcomings.

Figure 5: Double Exponential and Mixed Growth

Properties of Dendrimers ⁶

Polyvalency

The outer shell of a dendrimer admits functionalization fairly easily, allowing multiple functionalities to be added. Polyvalency is useful as it provides for versatile functionalization; it is also extremely important to produce multiple interactions with biological receptor sites, for example, in the design of antiviral therapeutic agents. Using dendrimers as a scaffold to present multiple copies of a surface group or groups, new biological activities are uncovered with unique pharmacokinetics. Different ligands can be coupled to dendrimers to use them as transfection reagent, e.g., ligands recognizing only the surface of a certain cell type combined with ligands that facilitate the escape from the endosome . Functionalization of the periphery can also result in copolymers with interesting properties, such as viscosity, stability, etc., and dendrimer fillers are already fairly widely used in composites and other materials to modify such properties. Dendrimer properties can be easily tuned by modifying the end groups (e.g. changing the end groups on a same skeleton induces solubility in organic solvents, in CFC or in water).

Metal functionalization of the periphery has applications, for example, in catalysis. Other applications include sensing, nanoscale templates, ionic conductivity and photonic or electronic applications (e.g., enhancement of the electronic transfer: amplification effect, or, for optical applications, light funneling). Easy functionalization is also a key to enabling compatibility with other materials. The high number of reaction points can also allow dendrimers to concentrate materials. This has been used to concentrate nucleic acids to allow detection without use of amplification and also to combine in one structure multiple, closely held MRI (Magnetic Resonance Imaging) contrast agents.

Defined architecture, size and shape control

Dendrimers branch out in a highly predictable fashion to form amplified three-dimensional structures with highly ordered architectures. This property is relevant for applications such as protein modeling or catalysis. Size control is also important in therapeutic applications, as different molecular sizes exhibit different pharmacokinetics. Other dendritic polymers such as dendronised polymers or hybrid linear-dendritic structures can have more potential than pure dendrimers for certain medical applications, but a key requirement for biological applications will be the ability to deliver a pure product; hence hybrid dendritic structures for such applications will generally start with dendrimer construction followed by the hybridization phase. The shape persistence of dendrimers is very important, as it allows the defined placement of functions not only on the dendrimer surface but also inside the dendritic scaffold. This is of crucial importance for several applications, e.g. in sensing. Here, the shape persistent dendritic scaffold can prevent self-aggregation of peripherally attached chromophores , resulting in high fluorescence intensity of the particles. Furthermore, stiff dendritic architectures possess defined pores or voids. This is a prerequisite for defined interactions between the dendrimer and incorporated guest molecules. In the context of liquid crystal systems, this property allows the design of Liquid Quasi Crystals. Inorganic Quasi Crystals are interesting because of their particular (e.g. mechanical, optical) properties. According to some experts, dendrimers are the only organic material that has these properties. Furthermore, dendrimers have potential for the design of flexible displays. Soft self-assembly of dendrimers allows the tailoring of electronic properties in complex systems (multiple functionalities) with a precision approaching that of biological systems. According to the same source, the design of macromolecular devices (machines, motors, etc.) will be quite likely associated with dendrimers, which represent a significant step towards the creation of nanostructured complex systems.

Monodispersity

Step-wise synthetic processes enable the production of dendrimers with highly uniform sizes with defined surface functionality. Monodispersity offers researchers the possibility to work with a tool for well-defined scalable sizes. This property is useful for applications such as the synthesis of container molecules, use as templates or in electronic applications. Monodispersity is one of the most important differences between dendrimers and polymers. Well-defined structures are particularly important for biological and medical applications.

Loading capacity (molecular container property)

In addition to carrying materials on their surface, the internal cavities of dendritic structures can be used to carry and/or store a wide range of metals, organic, or inorganic molecules by encapsulation and absorption. The appropriate type (and degree) of functionalization will results in the desired loading capacity. This property makes dendrimers very suitable as drug delivery vehicles and also appropriate for obtaining electro-optic or magnetic devices. It also allows the use of dendrimers to store, for example, nanoparticles of metal and to prevent precipitation, allowing for the creation of dispersions of what some have called 'nanoreactors'. The possibility of loading dyes could lead to novel ways of labeling and has been used to color polymers with a dendrimer additive (dendrimers can mix and bond better than the raw dye filler). The possibility of transporting materials makes dendrimers an attractive potential carrier in biosubstrates or an additive for special materials.

Biocompatibility / low toxicity

Some dendrimer systems display very low toxicity levels – with dendrimers carrying anionic groups being less toxic than those carrying cationic groups. Dendrimers commonly show also negligible or very low immunogenic response when injected or used topically. These properties make them highly suitable for drug delivery and biolabeling. In this sense, high biocompatibility is crucial both for preventing toxic reaction and for seeking biodegradability options. Dendrimers can, of course, be made from biomaterials themselves, with DNA being a popular choice. Dendritic polymers have great potential in various kinds of therapies, especially given their ability to be designed for biological specificity, therefore their biocompatibility and lack of toxicity is important. However, not all dendrimers are biocompatible nor show low toxicities. Only some dendrimers have these properties. As said, dendrimers carrying cationic groups can have significant toxicities.

Transfection properties

The high diversity of chemical structures possible in dendritic architectures enables the design of selected macromolecules that are able to pass through membranes.

Different Types Of Dendrimers ^{2, 4, 7, 8}

PAMAM Dendrimer

Poly (amidoamine) dendrimers (PAMAM) are synthesized by the divergent method starting from ammonia or ethylenediamine initiator core reagents. They are constructed using a reiterative sequence consisting of (a) a double Michael addition of methyl acrylate to a primary amino group followed by (b) amidation of the resulting carbomethoxy intermediate with a large excess of ethylenediamine. Products up to generation 10 (a molecular weight of over 9,30,000 g/mol) have been obtained (by comparison, the molecular weight of human hemoglobin is approximately 65,000 g/mol).

PAMAMOS Dendrimer

Radially layered poly (amidoamine-organosilicon) dendrimers (PAMAMOS) are inverted unimolecular micelles that consist of hydrophilic, nucleophilic polyamidoamine (PAMAM) interiors and hydrophobic organosilicon (OS) exteriors. These dendrimers are exceptionally useful precursors for the preparation of honeycomb-like networks with nanoscopic PAMAM and OS domains.

PPI Dendrimer

Poly (propylene imine) dendrimers (PPI) are synthesized by the divergent method starting from 1, 4-diaminobutane. They are grown by a reiterative sequence consisting of (a) a double Michael addition of acrylonitrile to the primary amino groups followed by (b) hydrogenation under pressure in the presence of Raney cobalt. Products are made up to generation 5.

Tecto Dendrimer:

These are composed of a core dendrimer, surrounded by dendrimers of several steps (each type design) to perform a function necessary for a smart therapeutic nanodevice. Different compounds perform varied functions ranging from diseased cell recognition, diagnosis of disease state drug delivery, reporting location to reporting outcomes of therapy.

Multilingual Dendrimers:

In these dendrimers, the surface contains multiple copies of a particular functional group.

Chiral Dendrimers:

The chirality in these dendrimers are based upon the construction of a constitutionally different but chemically similar branches to chiral core.

Hybrid Dendrimers linear polymers:

These are hybrids (block or graft polymers) of dendritic and linear polymers.

Amphiphilic Dendrimers:

They are built with two segregated sites of chain end, one half is electron donating and the other half is electron withdrawing

Micellar Dendrimers:

These are unimolecular micelles of water soluble hyper branched polyphenylenes.

Applications Of Dendrimers

The dendrimers have wide range of applications not only to the pharmaceutical field but also to the other fields. Various applications of dendrimers are shown in figure 6.

Figure 6: Applications of Dendrimers

Pharmaceutical and Biomedical applications ⁹

The formation of particulate systems with well-defined sizes and shapes is of eminent interest in certain medical applications such as drug delivery, gene transfection, and imaging. The high level of control possible over the architectural design of dendrimers; their size, shape, branching length/density, and their surface functionality, clearly distinguishes these structures as unique and optimum carriers in those applications. The bioactive agents may be encapsulated into the interior of the dendrimers or chemically attached/physically adsorbed onto the dendrimer surface, with the option of tailoring the carrier to the specific needs of the active material and its therapeutic applications. In this regard, the high density of exo-presented surface groups allows attachment of targeting groups or functionality that may modify the solution behavior or toxicity of dendrimers. Quite remarkably, modified dendrimers have been shown to act as nano-drugs against tumors, bacteria, and viruses. Recent successes in simplifying and optimizing the synthesis of dendrimers such as the ' lego ' and ' click ' approaches, provide a large variety of structures while at the same time reducing the cost of their production.

Drug Delivery: As a Drug ¹⁰

Dendrimers, a new class of candidate topical microbicides with activity against herpes simplex virus (HSV) infection was investigated. Dendrimers can have in vitro activity against HSV-1 and HSV-2. This activity generally required that the compound be present at or before the time that cells were exposed to virus. This suggested that the compounds might have utility as topical microbicides. This was evaluated in a mouse model of genital HSV-2 infection and represents the first demonstration that dendrimers are effective in an in vivo setting. The studies were conducted with solutions of the dendrimers, and thus it is probable that with an appropriate formulation designed for vaginal delivery, efficacy could be improved. The prophylactic efficacy suggested that the dendrimers might have potential as topical microbicides; products intended to be applied to the vaginal or rectal mucosa to protect against sexually transmitted infections.

 Further studies with these compounds appear warranted.

Drug Delivery: Targeted and controlled release drug delivery ¹¹

An ideal drug delivery system possesses two elements: the ability to target and controlled release. Targeting will ensure a high efficiency of the drug and possibly reduces side effects of the drug. Dendrimers have unique characteristics including monodispersity and modifiable surface functionality, along with highly defined size and structure. This makes these polymers attractive candidates as carriers in drug delivery applications. Drug delivery can be achieved by coupling a drug to polymer through one of two approaches. Hydrophobic drugs can be complexed within the hydrophobic dendrimer interior to make them water-soluble or drugs can be covalently coupled onto the surface of the dendrimer. The reduction or even prevention of side effects can also be achieved by controlled release. Modified dendrimers can be used to carry drug molecules to a specific location and release them in a controlled way. Methods to achieve controlled release include chemical or enzymatic reaction, diffusion through a matrix, or solvent activation. Currently the two common drug delivery systems are liposomes and polymeric systems. These both have limited applications, as liposome-based systems have poor stability and difficulty in targeting specific tissues, and linear polymers are polydisperse. Dendrimers offer advantages including a lower polydispersity index, multiple sites of attachment, and a controllable, well-defined size and structure that can be easily modified to change the chemical properties of the system. In addition, macromolecules such as dendrimers have an enhanced permeability and retention effect that allows them to target tumor cells more effectively than small molecules. Two methods of dendrimer drug delivery are encapsulation of drugs and dendrimer-drug conjugates. Encapsulation of drugs uses the steric bulk of the exterior of the dendrimer or interactions between the dendrimer and the drug to trap the drug inside the dendrimer. Dendrimer-drug conjugates have the drug attached to the exterior of the dendrimer. Most of these conjugates are prodrugs and are inactive or have decreased activity relative to the free drug. Dendrimers are also used in transdermal delivery ¹² and colonic delivery ¹³ of some drugs.

Drug Delivery: Solubility Enhancement ¹⁴

Poor solubility and hydrophobicity of drugs/bioactives limit their possible applications in drug delivery and formulation development. Apart from conventional methods of solubility enhancement, there are some novel methods which can be used in solubilization. Dendrimers represent a novel type of polymeric material that has generated much interest in solubility enhancement due to their unique structure and properties. Dendrimer-mediated solubility enhancement mainly depends on factors such as generation size, dendrimer concentration, pH, core, temperature, and terminal functionality. Added advantage in solubilization can be achieved considering these factors.

Gene Delivery ¹⁵

Dendrimers have unique molecular architectures and properties that make them attractive materials for the development of nanomedicines. Key properties such as defined architecture and a high ratio of multivalent surface moieties to molecular volume also make these nanoscaled materials highly interesting for the development of synthetic (non-viral) vectors for therapeutic nucleic acids. Rational development of such vectors requires the link to be made between dendrimer structure and the morphology and physicochemistry of the respective nucleic acid complexes and, furthermore, to the biological performance of these systems at the cellular and systemic level. Dendrimer-based transfection agents have become routine tools for many molecular and cell biologists but therapeutic delivery of nucleic acids remains a challenge. Perhaps the family of dendrimers most investigated for drug delivery is the polyamidoamine (PAMAM) dendrimer. PAMAM dendrimers are biocompatible, nonimmunogenic, water-soluble and possess terminal-modifiable amine functional groups for binding various targeting or guest molecules. The internal cavities of PAMAM dendrimers can host metals or guest molecules because of the unique functional architecture, which contains tertiary amines and amide linkages.

Multivalent Diagnostics for MRI ¹⁶

The applications of gadolinium chelating poly (propylene imine) dendrimers for Magnetic Resonance Imaging (MRI) are possible. Gadolinium-based MRI contrast agents can be effective at a approximately 100-fold lower concentration of Gadolinium ions in comparison to the concentration of Iodine atoms required for CT imaging. Therefore, a number of dendrimer based macromolecular MRI contrast agents of various sizes and properties prepared employing relatively simple chemistry are readily available that can provide sufficient contrast enhancement for various applications. Molecules up to 20 nm in diameter behave differently in the body depending on their size. Even if these molecules possess similar chemical properties, small changes in size can greatly impact their pharmacokinetics. Changes in molecular size up to 15 nm in diameter altered permeability across the vascular wall, excretion route, and recognition by the reticuloendothelial system. Smaller sized polyamidoamine (PAMAM) dendrimer-based contrast agents, i.e., less than 3 nm in diameter, easily “leak” across the vascular wall resulting in rapid perfusion throughout the body. Contrast agents of 3-6 nm in diameter were quickly excreted through the kidney indicating these agents to be potentially suitable as functional renal contrast agents. Contrast agents 7-12 nm in diameter were retained in circulation and were better suited for use as blood pool contrast agents. Hydrophobic variants of contrast agents formed with polypropylenimine diaminobutane dendrimer cores quickly accumulated in the liver and potentially have use as liver contrast agents. Larger hydrophilic agents have suitable characteristics for lymphatic imaging. Finally, contrast agents conjugated with either monoclonal antibodies or with avidin are able to function as tumor-specific contrast agents and might also be employed as either gadolinium neutron capture therapy or in conjunction with radioimmunotherapy.

Sensors ^{6, 17, 18}

Due to their organized structure ease of modification, and strong adsorption behavior to a variety of substrates, PAMAM dendrimers can be used to produce monolayers or stacked film layers, which can be used as sensors to detect hazardous chemical vapors. A hydrogen peroxide biosensor based on nano-Au/PAMAM dendrimer is also reported.

Molecular Weight and Size Standards ^{6, 17, 19}

The exceptionally uniform molecular size of the various generations of PAMAM dendrimers makes them excellent size standards for calibration of analytical instruments.

Extraction and Phase Transfer Catalysis in Supercriticical Carbon Dioxide ²⁰

The liquid-like densities and gas-like diffusivities and viscosities of supercritical fluids make them especially attractive for phase transfer catalysis and extraction. Especially CO ₂ is interesting because it has a relatively low critical temperature and pressure (31.1 °C and 73.8 bar). Poly (propylene imine) dendrimers, modified with apolar end groups, have been tested for their use as reactive extractant and phase transfer catalyst. In fact a dendritic reactive extractant and phase transfer catalyst can be seen as a unimolecular (polymerized) version of the traditional low molecular weight surfactant or a multi-site version of a traditional tertiary amine phase transfer catalyst

The dye methyl orange has been extracted using a 5 ^th generation dendrimer (Gf5) into a CO ₂ phase and using Gp5 into a tetrachlorocarbon phase. There is almost no solvent effect for the extraction of methyl orange into the core of both Gf5 and Gp5.

The following Sn-2 reversible reaction was performed in supercritical CO ₂ . A large excess of KBr was present.

                        C ₆ H ₅ -CH ₂ -Cl + KBr        ------►      C ₆ H ₅ -CH ₂ -Br + KCl 

Depending on the generation of the dendrimer, the perfluorooctanyl functionalized dendrimers can catalyze this reaction quite well. The higher the generation, the more the interior of the dendrimer (where the substrate Br- is located) is shielded from the bulk CO ₂ phase (where the substrate benzyl chloride is located). This leads to a lower efficiency for the 4 ^th generation dendrimer, as compared to the 2 ^nd and 3 ^rd generation.

Multivalent Bioconjugates ²¹

The presence of multiple biologically active molecules on a dendritic scaffold may lead to enhanced effects. These complexes are made by non covalent fictionalization of dendrimer periphery ²² .

Light Harvesting ^{6, 23, 24}

Light harvesting is the trapping of energy via peripheral chromophores and funneling to a central point where it is converted back into visible light. The dendrimer possesses the properties that facilitate such a conversion. These properties include its tree-like structure that acts as an energy gradient for the funneling of energy. The large amount of absorbing units on the periphery, gives the high probability of capture of light. The relatively short distance from the periphery to the core allows for high efficiency energy transfer. The mechanism begins with the periphery chromophore molecules capturing the energy of photons from light. These photons excite the electrons in the molecules and raise them from their ground state to their excited state. Interchromophore energy transfer then occurs in one of two ways, Dexter excitation transfer, or Forster excitation transfer. In Dexter excitation transfer the energy is transferred through-bond electron exchange. This electron exchange requires a strong donor to acceptor orbital overlap and is therefore a short-range interaction (<10 Å). In Forster excitation transfer the energy is transferred through-space dipole-dipole interaction. In this case, the donor to acceptor orbital overlap is not necessary, allowing the chromophores to be separated by larger distances (10-100 Å). Depending on the monomers used to synthesize the dendrimer that will affect the energy transfer mechanism utilized. Using any of the above energy transfer mechanisms, the energy is channeled to the core where it is converted into visible light.

Catalysis ^{6, 25}

The dendritic molecule has emerged as an attractive material in the field of catalysis and various dendrimer catalysts have been applied not only to catalytic reactions but also to non-catalytic ones such as nanoscale reactor systems. In the field of catalysis, the hope is that dendrimer catalysts will retain the benefits of homogeneous catalysts (high activity, high selectivity, good reproducibility, accessibility of the metal site and so on), and unlike most other polymeric species they will be readily recoverable after reaction. In principle, dendrimer is one of the most promising candidates which can meet the needs for an ideal catalyst: persistent and controllable nanoscale dimensions, chemically reactive surface, favorable configurations in which all the active sites would always be exposed towards the reaction mixture so that they are easily accessible to migrating reactants, and soluble but can be easily recovered by filtration. These properties, or some combination of them, are what makes dendrimers so useful not only in catalytic applications but also in non-catalytic ones such as nanoscale reactor systems. In particular, chiral dendrimers have drawn much attention because the highly ordered structures of dendrimers are considered to be suitable for realizing approximately the same chiral environments. Dendrimers make themselves attractive in the design of asymmetric catalysts by combining chirality or asymmetry with their highly symmetrical nature. There are three types of chiral dendrimers according to chiral active sites: 1. Focal point-functionalized chiral dendrimers; 2. Periphery-functionalized chiral dendrimers; and 3. Core-functionalized chiral dendrimers.

Artificial Enzymes ²⁶

Dendrimers are regular tree-like macromolecules accessible by chemical synthesis from a variety of building blocks. Their topology enforces a globular shape that offers a unique opportunity to design artificial enzymes. Catalytic groups such as metal complexes and cofactors can be placed at the dendrimer core to exploit microenvironment and selectivity effects of the dendritic shell.

Nanocomposites ²⁷

According to the general concept of reactive encapsulation, dendrimer nanocomposites are made by preorganizing small precursors by an appropriately selected dendrimer. This pre-organization is followed by in-situ chemical reaction(s) or physical treatment (irradiation, etc.,) that generates reaction products immobilized in a polymeric network. This procedure yields dispersed small domains of guest molecules that are integrated with the dendrimer molecule(s) without creating covalent bonds between the dendrimer and the topologically entrapped matter. It was only recently discovered that PAMAM dendrimers form stable interior molecular nanocomposites with metal cations, zero-valent metals, other electrophilic ligands, and semiconductor particles. These materials are actively being investigated in electronics, optoelectronics and catalysis.

Organosilane Coatings ^{17, 28, 29}

PAMAM dendrimers are the basis of poly (amidoamine) - organosilane (PAMAMOS) coating technology. PAMAMOS coatings are tough, transparent, flexible coatings, which have many of the same attributes of PAMAM dendrimers in coating form. They are being investigated for applications in microelectronics.

Inkjet Inks and Toners ^{6, 17, 30, 31, 32}

PAMAM dendrimers, at low additive levels, dramatically improve water resistance and adhesion of inks to a variety of porous or nonporous substrates such as paper, glass, plastic, or metal. Their water and alcohol solubility permit formulation of low viscous inks. These polymers exhibit Newtonian flow behavior for shear stability in these formulations. In toners, they impart good admix and flow characteristics, stable properties, and high image quality.

Other applications ⁶

There are also some others applications like: for cellular transport, as artificial cells, for diagnostics and analysis, as protein / enzyme mimics or modeling, for manufacture of artificial bones, for development of topical microbicide creams; antimicrobial, antiviral (e.g. for use against HIV) and antiparasitic agents, for biomedical coatings (e.g. for artificial joints), as artificial antibodies and biomolecular binding agents, for carbon fibre coatings and ultra thin films, as polymer and plastics additives (e.g. for lowering viscosity, increasing stiffness, incorporating dyes, compatibilisers, etc.) for creation of foams (i.e. synthetic zeolites or insulating material), as building blocks for nanostructured materials, as dyes and paints, as industrial adhesives, for manufacture of nanoscale batteries and lubricants, as decontamination agents (trapping metal ions), for ultrafiltration, molecular electronics for data storage, 3D optical materials, for light-harvesting systems, quantum dots, liquid crystals, printed wire boards, etc.

Dendrimer Disassembly ³³

Dendrimer disassembly is entirely a new concept in nanotechnology. Dendrimer disassembly is a process that relies on a single triggering event to initiate multiple cleavages throughout a dendritic structure that result in release of individual dendrimer subunits or larger dendrimer fragments. The potential of this process lies in the nature of dendrimers as covalent assemblages of active species, and using the chemistry of disassembly to release these species into a system; and the role of dendritic components of a system in influencing solubility, energy harvesting, or insulating capabilities, and using the chemistry of disassembly to reverse those contributions to a system. This is a powerful construct, in that dendrimers and dendritic structures can be made up of a wide variety of subunits, compatibilized with many different environments, and incorporated into countless systems. Dendritic materials with disassembly capabilities will be useful for traditional polymer degradation technologies and have potential applications in nanotechnology, biomedicine, and sensors.

Biodegradable Dendrimers ^{34, 35}

The chemical and physical properties of a dendrimer can be optimized by systematically changing the monomer(s). By optimizing the monomer(s), dendrimers can be made to degrade into biodendrimers, which degrade to biocompatible building blocks in vivo . Suitable monomers for biodendrimers include α-hydroxy acids, sugars, amino acids, fatty acids, polyethylene glycol, poly caproic acid, and poly (trimethylene carbonate). Factors affecting the degradation rate include: the strength of the chemical bond between the monomers, the hydrophobicity of the dendrimer, the generation and molecular weight of the dendrimer, and the chemical reactivity of the macromolecule. By combining the ideas of drug carriers and degradability, research has recently focused on controlled degradation of dendrimers and release of compounds. Some of the methods to initiate the release include light, removal of protecting groups, and antibodies.

Dendrimer Biocompatibility And Toxicity ³⁶

The field of biomedical dendrimers is still in its infancy, but the explosion of interest in dendrimers and deodorized polymers as inherently active therapeutic agents, as vectors for targeted delivery of drugs, peptides and oligonucleotides, and as permeability enhancers able to promote oral and transdermal drug delivery makes it timely to review current knowledge regarding the toxicology of these dendrimer chemistries (currently under development for biomedical applications). Clinical experience with polymeric excipients, plasma expanders, and most recently the development of more ‘classical polymer’-derived therapeutics can be used to guide development of “safe” dendritic polymers. Moreover, in future it will only ever be possible to designate a dendrimer as “safe” when related to a specific application. The so far limited clinical experience using dendrimers make it impossible to designate any particular chemistry intrinsically “safe” or “toxic”. Although there is widespread concern as to the safety of nano-sized particles, preclinical and clinical experience gained during the development of polymeric excipients, biomedical polymers and polymer therapeutics shows that judicious development of dendrimer chemistry for each specific application will ensure development of safe and important materials for biomedical and pharmaceutical use.

Summary

The flexibility of dendrimers is that they can be designed and synthesized for specific applications, as truly functional excipients. The most commonly studied system has been the family of PAMAM dendrimers, but the variety of constructs of dendrimers and their building blocks of partial dendrimers grows rapidly. The interest in these dendrimers have grown mainly due the fact that these mono-disperse polymers offer the control that modern drug delivery and targeting demands. As the drug industry strives to meet the increasingly difficult task of producing new drugs and especially new blockbuster drugs, it is seeking new drug discovery technologies that can improve R & D success rate and time to market. Dendrimers are the future of the polymer world as they can themselves be the building blocks of novel supra-molecular constructs which can be interesting carriers for drugs and genes.

Acknowledgment

The author gratefully acknowledges the support of Tim Harper (Cientifica), A. N. Shipway and Willems and van den Wildenberg (NanoRoadMap Project).

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