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Dendrimers 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. Dendrimers have often been refered to as the “Polymers of the 21st century”. Dendrimer chemistry was first introduced in 1978 by Fritz Vogtle and coworkers. He synthesized the first “cascade molecules”. In 1985, Donald A. Tomalia, synthesized the first family of dendrimers. The word “dendrimer” originated from two words, the Greek word dendron, meaning tree, and meros, meaning part. At the same time, Newkome’s group independently reported synthesis of similar macromolecules. They called them arborols from the Latin word ‘arbor’ also meaning a tree. The term cascade molecule is also used, but ‘dendrimer’ is the best established one. 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. Crystal structure of a first-generation polyphenylene dendrimer reported by Müllen et al. 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. Types of Dendrimers 1. Pamam Dendrimer Poly (amidoamine) dendrimers (PAMAM) are synthesized by the divergent method starting from ammonia or ethylenediamine initiator core reagents. Products up to generation 10(7) (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). PAMAM dendrimers are commercially available, usually as methanol solutions. Starburst dendrimers is applied as a trademark name for a sub-class of PAMAM dendrimers based on a tris-aminoethylene-imine core. The name refers to the starlike pattern observed when looking at the structure of the high-generation dendrimers of this type in two-dimensions. 2. 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. 3. PPI Dendrimer PPI-dendrimers stand for “Poly (Propylene Imine)” describing the propylamine spacer moieties in the oldest known dendrimer type developed initially by Vögtle. These dendrimers are generally poly-alkyl amines having primary amines as end groups, the dendrimer interior consists of numerous of tertiary tris-propylene amines. PPI dendrimers are commercially available up to G5, and has found widespread applications in material science as well as in biology. As an alternative name to PPI, POPAM is sometimes used to describe this class of dendrimers. POPAM stands for Poly (Propylene Amine), which closely resembles the PPI abbreviation. In addition, these dendrimers are also sometimes denoted “DAB-dendrimers” where DAB refers to the core structure, which is usually based on Diamino butane. 4. 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. 5. Multilingual Dendrimers In these dendrimers, the surface contains multiple copies of a particular functional group. 6. Chiral Dendrimers The chirality in these dendrimers are based upon the construction of a constitutionally different but chemically similar branches to chiral core. 7. Hybrid Dendrimers Linear Polymers These are hybrids (block or graft polymers) of dendritic and linear polymers. 8. Amphiphilic Dendrimers They are built with two segregated sites of chain end, one half is electron donating and the other half is electron withdrawing. 9. Micellar Dendrimers These are unimolecular micelles of water soluble hyper branched polyphenylenes. 10. Multiple Antigen Peptide Dendrimers It is a dendron-like molecular construct based upon a polylysine skeleton. Lysine with its alkyl amino side-chain serves as a good monomer for the introduction of numerous of branching points. This type of dendrimer was introduced by J. P. Tam in 1988, has predominantly found its use in biological applications, e.g. vaccine and diagnostic research. Synthesis 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. 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, organo-transition-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. 1. ‘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. 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. 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. The first synthesized dendrimers were polyamidoamines (PAMAMs).They are also known as starbust dendrimers. Ammonia is used as the core molecule & In the presence of methanol, it reacts with methylacrylate and then ethylenediamine is added. NH3 + 3CH2CHCOOCH3 N(CH2 CH2COOCH3)3 3 NH2 CH2 CH2NH2 N(CH2 CH2CONHCH2 CH2NH2)3 + 3CH3OH At the end of each branch there is a free amino group that can react with 2 methyl acrylate monomers and 2 ethylenediamine molecules. Each complete reaction sequence results in a new dendrimer generation. The number of reactive surface sites is doubled with every generation since the mass increases more than twice. Divergent Dendrimer Growth 2. ‘Convergent’ Dendrimer Growth The 'convergent' approach was developed as a response to the weaknesses of divergent syntheses. 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 that only two simultaneous reactions are required for any generation-adding step. The convergent methodology also suffers from low yields in the synthesis of large structures. The convergent growth method has several advantages: 1. Relatively easy to purify the desired product and the occurrence of defects in the final structure is minimised. 2. Possible to introduce subtle engineering into the dendritic structure by precise placement of functional groups at the periphery of the macromolecules. 3. Approach does not allow the formation of high generation dendrimer because stearic problems occur in the reactions of the dendrons and the core molecule. Convergent Dendrimer Growth Two principle synthetic methods for constructing dendritic macromolecules (dendrons): (a) the divergent method, in which the synthesis begins from a polyfunctional core and continues radially outwards by successive stepwise activation and condensation, (b) the convergent method in which the synthesis begins at what will be the periphery of the final macromolecule and proceeds inwards. Synthesis of commercially available PAMAM dendrimer. 3. ‘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. 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. Double Exponential and Mixed Growth Applications Applications of dendrimers typically involves 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 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. Gene delivery The ability to deliver pieces of DNA 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. Based on this method, PAMAM dendrimer/DNA complexes were used to encapsulate functional biodegradable polymer films for substrate mediated 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 sensor technologies. Studied systems include proton or pH sensors using poly(propylene imine), cadmium-sulfide/polypropylenimine tetrahexacontaamine dendrimer composites to detect fluorescence signal quenching, and poly(propylenamine) first and second generation dendrimers for metal cation photodetection amongst others. Research in this field is vast and ongoing due to the potential for multiple detection and binding sites in dendritic structures. Dendrimer as Solubility Enhancers There are many substances, which have a strong therapeutic activity but due to their lack of solubility in pharmaceutically acceptable solvents have not been used for therapeutic purposes. Water soluble dendrimers are capable of binding and solubilizing small acidic hydrophobic molecules with antifungal or antibacterial properties. Dendrimers having a hydrophobic core and a hydrophilic surface layer, have been termed unimolecular micelles. Unlike traditional micelles, dendrimers do not have a critical micelle concentration. This characteristic offers the opportunity to soluble poorly soluble drugs by encapsulating them within the dendritic structure at all concentrations of dendrimer. A hydrophilic–hydrophobic core-shell dendrimer with PAMAM interior and long alkane chain exterior was shown to bind 5-flurouracil, a water-soluble antitumor drug. After phospholipid coating of the dendrimer–fatty- acid macromolecule, oral bioavailability in rats of 5-flurouracil was nearly twice the level of free 5-flurouracil. Dendrimerbased carriers could offer the opportunity to enhance the oral bioavailability of problematic drugs. Propranolol, conjugated to surface-modified G3 PAMAM dendrimer, the solubility of propranolol increased by over two orders of magnitude. Thus, dendrimer nanocarriers offer the potential to enhance the bioavailability of drugs that are poorly soluble and/or substrates for efflux transporters. Blood substitution Dendrimers are also being investigated for use as blood substitutes. Their steric bulk surrounding a heme-mimetic centre significantly slows degradation compared to free heme, and prevents the cytotoxicity exhibited by free heme. Nanoparticles Dendrimers also are used in the synthesis of monodisperse metallic nanoparticles. Poly(amidoamide), or PAMAM, dendrimers are utilized for their tertiary amine groups at the branching points within the dendrimer. Metal ions are introduced to an aqueous dendrimer solution and the metal ions form a complex with the lone pair of electrons present at the tertiary amines. After complexion, the ions are reduced to their zerovalent states to form a nanoparticle that is encapsulated within the dendrimer. These nanoparticles range in width from 1.5 to 10 nanometers and are aptly called Dendrimer-Encapsulated Nanoparticles. Dendritic Catalysts / Enzymes The combination of high surface area and high solubility makes dendrimers useful as nanoscale catalysts. Dendrimers have a multifunctional surface and all catalytic sites are always exposed towards the reaction mixture. They can be recovered from the reaction mixture by easy ultra filtration methods. Dendritic shells can be used to create a microenvironment favorable for catalysis or provide shielding for functional groups at the dendritic core. Because of their ‘pseudo’-spherical nature and their resultant conformations the metal sites in these well-defined polymeric catalysts should be easily accessible for substrate molecules and reagents, and therefore exhibit characteristics- fast kinetics, specificity and solubility. 1. Metallodendritic catalysts 2. Catalysis with phosphine-based dendrimers 3. Catalysis with (metallo)dendrimers containing chiral ligands 4. Non-metal containing dendrimers Industrial Processes Dendrimers can encapsulate insoluble materials, such as metals, and transport them into a solvent within their interior. Cooper and co-workers synthesized fluorinated dendrimers, which are soluble in supercritical CO2 and can be used to extract strongly hydrophilic compounds from water into liquid CO2. This may help develop Technologies in which hazardous organic solvents are replaced by liquid CO2. Nanocapsules and Dendrimers - Properties and Future Applications Nanocapsules A nanocapsule is any nanoparticle that consists of a shell and a space, in which desired substances may be placed. Technologies for microencapsulating materials have been around for several years, primarily for applications involving minimisation of hygroscopy and chemical interactions, elimination of oxidation, and controlled release of nutraceuticals. The Use of Man-Made Liposomes Man-made liposome’s have been used in cosmetics for some years to control the release of substances or protect them from the environment. Recently many other materials, such as polymers, have been used to make nanocapsules. The Properties of Polymeric Nanocapsules Polymeric nanocapsules can be made in specific sizes, shapes, and in reasonable quantities. Nanocapsules can be made to function in various ways. They can be produced as monodisperse particles with exactly defined biochemical, electrical, optical, and magnetic properties. They can be tailored to suit the complexity of whatever application they are intended for, such causing the release of the contents in response to a particular bimolecular triggering mechanism in targeted drug-delivery systems. The Use of Nanocapsules as Smart Drugs Nanocapsules can be used as smart drugs that have specific chemical receptors and only bind to specific cells. It is this receptor that makes the drug ‘smart,’ allowing it to target cancer or disease. The advantages of nano-encapsulation technologies for pharmaceutical applications include: • Higher dose loading with smaller dose volumes • Longer site-specific dose retention • More rapid absorption of active drug substances • Increased bioavailability of the drug • Higher safety and efficacy • Improved patient compliance The Future Benefits of Nanocapsules in Drugs Beyond the ability to deliver existing drugs to their target, nanocapsules would allow for as much as a 10,000-fold decrease in drug dosages, reducing the harmful side effects of drugs used in chemotherapy. Quite often, drugs don’t make it to market is because they have too many unwanted side effects. However, placing the same drug inside a nanocapsule and delivering it directly to its intended target in a reduced dosage, eliminates some of those side effects, or at least reduces them to an acceptable level. Further Applications of Nanocapsules Nanocapsules also have potential applications in agrochemicals, cosmetics, genetic engineering, wastewater treatments, cleaning products, and adhesive component applications. They can be used to encapsulate enzymes, catalysts, oils, adhesives, polymers, inorganic micro- and nanoparticles, latex particles, or even biological cells. Dendrimers as nanocapsules A dendrimer is an artificially manufactured or synthesized large molecule comprised of many smaller ones linked together - built up from branched units called monomers. Technically, dendrimers are a unique class of a polymer, about the size of an average protein, with a compact, tree-like molecular structure, which provides a high degree of surface functionality and versatility. Their shape gives them vast amounts of surface area, making them useful building blocks and carrier molecules at the nanoscale and they come in a variety of forms, with different physical (including optical, electrical and chemical) properties. Dendrimer as a Biologically Active Carrier Dendrimers can act as biologically active carrier molecules in drug delivery to which can be attached therapeutic agents and as scavengers of metal ions, offering the potential for environmental clean-up operations because their size allows them to be filtered out with ultrafiltration techniques. HYPERBRANCHED POLYMERS Hyperbranched polymers are imperfect architectural relatives of dendrimers which have pronounced similarities but also differences compared to the latter. For example, similar to dendrimers, hyperbranched polymers have highly branched molecular architecture and a multitude of reactive or non-reactive end-groups, but in contrst to dendrimers they do not contain molecular core, have less defined intramolecular cargo space and often quite broad distribution of molecular shapes and sizes. Hyperbranched polymers are highly branched macromolecules with three-dimensional dentritic architecture. Due to their unique physical and chemical properties and potential applications in various fields from drug-delivery to coatings, interest in hyperbranched polymers is growing rapidly. Because of their architectural similarities, hyperbranched polymers have attracted considerable research attention as possible cheaper alternatives to the more precise dendrimers. This expectation was primarily based on the fact that in contrast to long multi-step reiterative syntheses that both divergent and convergent approaches require for higher generation dendrimers, resulting in high costs of labor and energy associated with repeated reaction and separation procedures, hyperbranched polymers can be prepared by relatively simple, onepot-one-shot, relatively rapid polymerization reactions. This technology uses “branched” monomers of the general type ABx where A and B represent functional groups that can react with each other (i.e., A + B → -A-B-) but not with themselves (i.e., A + A → no reaction and B + B → no reaction), while x is an integer equal or larger than 2. For the simplest case of AB2 monomers, this polymerization can be represented as shown in the following scheme: Hyperbranched polymers have a very large number of branches. They can be prepared in several ways, but most commonly from AB2 monomers or from combining A2 and B3 monomers. When prepared from AB2 monomers, gelation does not occur. The polymer molecules have a single A terminus (the focus) and many B termini (the chain ends). Individual monomers can react at 1, 2, or 3 sites. Monomers that react at only 1 site (the A site) have two free B sites and are considered terminal (T). Monomers that react at 2 sites (the A site and 1 B site) have one free B site and are considered linear (L). Monomers that have reacted at 3 sites (the A site and both B sites) are considered dendritic (D). Hyperbranched polymers are characterized by a degree of branching (DB) which represents the percentage of dendritic and terminal monomers among the total monomers in the polymer: DB = D + T/ (D + T + L) Statistical treatments show that batch polymerization of AB2 monomers gives a DB of ~0.5. Higher degrees of branching can be obtained using special reaction conditions (slow addition of monomer, addition of a core). Perfect branching (DB = 1) can be found in the dendritic polymers (see below). Dendrimers are a subset of hyperbranched polymers in that they have no imperfections: they branch at each monomer unit (DB = 1). Dendrimers also differ in method of preparation. They are usually prepared by an iterative synthesis, with purification of intermediate stages or "generations". This requires much effort, but allows for perfect branching. Hyperbranched polymers are prepared in "one-pot" methods that result in imperfect branching. Synthesis methodology The synthetic techniques used to prepare hyperbranched polymers could be divided into two major categories. The first category contains techniques of the single-monomer methodology (SMM), in which hyperbranched macromolecules are synthesized by polymerization of an ABn or a latent ABn monomer. According to the reaction mechanism, the SMM category includes at least four specific approaches: (1) polycondensation of ABn monomers; (2) self-condensing vinyl polymerization (SCVP); (3) self-condensing ring-opening polymerization (SCROP); (4) proton-transfer polymerization (PTP). The other category contains methods of the double monomer methodology (DMM) in which direct polymerization of two types of monomers or a monomer pair generates hyperbranched polymers. 1. SMM - polycondensation of ABn monomers A broad range of hyperbranched polymers, including hyperbranched polyphenylenes, polyethers, polyesters, polyamides, polycarbonates, and poly(ether ketone)s, are prepared via one-step polycondensation of ABn type monomers. If one group of ABn monomers contains double or triple bonds, small molecules may not be formed in the polymerization. Through polyaddition of the ABn monomers, hyperbranched polyurethanes, polycarbosilanes, polyamides, and poly(acetophenone)s have been successfully obtained. AB3, AB4, AB5, and even AB6 monomers are also used to synthesize hyperbranched polymers while controlling the branching pattern. 2. SMM—self-condensing vinyl polymerization SCVP was invented by Fre´chet and coworkers in 1995. This polymerization method is quite versatile, as hyperbranched polymers can be approached via polymerization of AB vinyl monomers. In the reaction, the B groups of the AB monomers are activated to generate the initiating Bp sites. Bp initiates the propagation of the vinyl group A in the monomer, forming a dimer with a vinyl group, a growth site, and an initiating site. The dimer can function as an AB2 monomer, and undergo further polymerization to yield the hyperbranched polymer. In SCVP, the activities of chain propagation of the growth sites and the initiating sites differ, resulting in a lower DB when compared to the DB of the hyperbranched polymer prepared via polycondensation of AB2 monomers. The theoretical maximum DB of SCVP is 46.5%. On the other hand, SCVP does exhibit some disadvantages. For example, side reactions may lead to gelation, the molecular weight distribution is usually very broad, and it is difficult to determine DB directly via an NMR analysis. 3. SMM—self-condensing ring-opening and proton-transfer polymerizations Hyperbranched polyamines, polyethers and polyesters have been prepared through SCROP. 4. SMM-PTP (proton-transfer polymerization)- Hyperbranched polyesters with epoxy or hydroxyl end groups and hyperbranched polysiloxanes were synthesized through PTP (proton-transfer polymerization). Scientists have developed an impressive alternative technology for the preparation of hyperbranched polymers by the bimolecular non-linear polymerization, BMNLP. Just like the traditional monomolecular polymerizations of ABX monomers, BMNLP also utilizes a stepgrowth reaction mechanism, but in contrast to the former, it involves, two reactive monomers AX and BY, where A and B also denote two types of mutually reactive functional groups, while x and y are integers which must both be equal to or larger than 2, while one of them (either x or y) must be equal to or larger than 3. Thus, the most common BMNLP systems include A2 + B3, A2 + B4, and A3 + B4 monomer combinations. In general, the simplest of these, the A2 + B3 system, in which the minor component has completely reacted, can be represented as shown in the following scheme: The essential and common feature of all BMNLP systems is the need for careful control of the polymerization process, by appropriate selection of the relative concentrations of the reacting A and B groups and the extent of the reaction, in order to prevent their natural tendency to crosslink to a gel. BMNLP reactions offer some important advantages over traditional ABX polymerization systems. (i) (ii) (iii) the extreme versatility of the process to yield a practically unlimited variety of polymer compositions from a vast number of commercially available monomers, the unique ability to produce compositionally identical polymers, -[AB]n<, with different (A or B) end-groups, and the complete elimination of the monomer shelf-life problems that are often encountered with many ABX compounds which can polymerize either without the need for reaction catalyst or under less stringent storage conditions. Utilizing the BMNLP approach, we have developed and patented a wide variety of different hyperbranched polymers, including polyamides, polyamidoamines, polyureas, polyurethanes, polyesters, polycarbosilanes, polycarbosiloxanes, polycarbosilazanes, perfluorinated derivatives of many of the preceding polymers, etc. They are ideally suited for a variety of specialty coating applications including antimicrobial, antifouling and decontamination coatings, superhydrophobic and superhydrophilic coatings, chemical and biological sensors, semipermeable membranes, electronic and photonic parts and materials, etc.