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”. The unique architectural design of dendrimers, high degree of branching, multivalency, globular structure and well-defined molecular weight, clearly distinguishes these as unique and optimum nanocarriers in medical applications such as drug delivery, gene transfection, tumor therapy and diagnostics etc. An increasingly large number of drugs being developed today facing problems of poor solubility, bioavailability and permeability, dendrimers can work as a useful tool for optimizing drug delivery of such problematic drugs. Also the problem of biocompatibility and toxicity can be overcome by careful surface engineering. Recent successes in simplifying and optimizing the synthesis of dendrimers provide a large variety of structures with reduced cost of their production. Also as research progresses, newer applications of dendrimers will emerge and the future should witness an increasing numbers of commercialized dendrimer based drug delivery systems.
A dendrimer (from Greek dendra for tree) is a highly branched synthetic polymer and consists of a core where a monomer unit is attached, leading to a monodisperse, tree-like, star-shaped or generational structure with precise molecular weights and diameters in the 2 to 10 nm range size . Production of dendrimer requires a high level of synthetic control, which can be achieved via stepwise reactions, building the dendrimer up one monomer layer (or "generation") at a time.
The first monomer unit, in this example, has a functionality of three with one reactive site attached to the core or focal point and the other two making up a branching unit. This is considered the first generation or G1. The branching unit is then reacted with further monomer to produce G2 and a molecule with four end groups. [1-6]
Dendrimers are built from a starting atom, such as nitrogen, to which carbon and other elements are added by a repeating series of chemical reactions that produces a spherical branching structure. As the process repeats, successive layers are added, and the sphere can be expanded to the size required by the investigator. The result is a spherical macromolecular structure whose size is similar to albumin and hemoglobin, but smaller than such multimers as the gigantic IgM antibody complex.
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.
(iii) Exterior (terminal functionality) attached to the outermost interior generations.
Figure 1: The Dendrimer Structure
Components of dendrimer structure:
The number of focal points when going from the core towards the dendrimer surface is the generation number. That is, a dendrimer having five focal points when going from the centre to the periphery is denoted as the 5th generation dendrimer. Here, we abbreviate this term to simply a G5 dendrimer, e.g. a 5th generation polypropylene imine is abbreviated to a “G5-PPI-” dendrimer, The core part of the dendrimer is sometimes denoted as generation “zero”, or in the terminology presented here “G0”. The core structure thus presents no focal points, as hydrogen substituents are not considered focal points. Intermediates during the dendrimer synthesis are sometimes denoted half-generations; a well-known example is the carboxylic acid-terminated PAMAM dendrimers.
The dendrimer shell is the homo-structural spatial segment between the focal points, the “generation space”. The “outer shell” is the space between the last outer branching point and the surface. The “inner shells” are generally referred to as the dendrimer interior.
In dendrimers, the outer shell consists of a varying number of pincers created by the last focal point before reaching the dendrimer surface. In PPI and PAMAM dendrimers the number of pincers is half the number of surface groups (because in these dendrimers the chain divides into two chains in each focal point).
It is also generally referred to as the “terminal group” or the “surface group” of the dendrimer. Dendrimers having amine end-groups are termed “amino-terminated dendrimers”. [7,8]
Classification of Dendrimer
2.1 PAMAM Dendrimer
2.2 PAMAMOS Dendrimer
2.3 PPI Dendrimer
2.4 Tecto Dendrimer
2.5 Multilingual Dendrimer
2.6 Chiral Dendrimer
2.7 Hybrid Dendrimer Linear Polymer
2.8 Amphiphilic Dendrimer
2.9 Micellar Dendrimer
2.10 Multiple Antigen Peptide Dendrimer
2.11 Frechet Type Dendrimer
Methods of synthesis:
3.1 ‘Divergent’ Dendrimer Growth
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;
Figure 2: Divergent Dendrimer Growth
3.2 ‘Convergent’ Dendrimer Growth
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.
Figure 3: Convergent Dendrimer Growth
3.3 ‘Double Exponential’ and ‘Mixed’ 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. 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. [9-11]
A. Pharmaceutical Application:
1. Dendrimers Drug Delivery: Targeted and Controlled Release Drug Delivery
Ø Delivery of Anticancer Drugs by Dendrimers and Dendritic Polymers
Ø Noncovalent Encapsulation of Drugs / Host –Guest Relation
Ø Covalent Dendrimer–Drug Conjugates
2. Dendrimer as Solubility Enhancers
3. Cellular Delivery Using Dendrimer Carriers
4. Dendrimers as Nano-Drugs
5. Dendrimers in Photodynamic Therapy
6. Dendrimers in Gene Transfection
B. Non-Pharmaceutical Application:
2. Dendritic Catalysts / Enzymes
3. Industrial Processes
Delivery of Anticancer Drugs by Dendrimers and Dendritic Polymers:
The star polymer gave the most promising results regarding cytotoxicity and systemic circulatory half-life (72 h). In addition to improving drug properties such as solubility and plasma circulation time, polymeric carriers can also facilitate the passive targeting of drugs to solid tumors.
Combined, these factors lead to the selective accumulation of macromolecules in tumor tissue – a phenomenon termed the ‘Enhanced Permeation and Retention’ (EPR) effect. Therefore, the anticancer drug doxorubicin was covalently bound to this carrier via an acid-labile hydrazone linkage. The cytotoxicity of doxorubicin was significantly reduced (80–98%), and the drug was successfully taken up by several cancer cell lines.The encapsulation behavior of these compounds for the anticancer drugs adriamycin and methotrexate was studied. The highest encapsulation efficiency, with on average 6.5, adriamycin molecules and 26 methotrexate molecules per dendrimer, was found for the G = 4 PAMAM terminated with PEG 2000 chains. The anticancer drug 5-fluorouracil encapsulated into G = 4 PAMAM dendrimers with carboxymethyl PEG5000 surface chains revealed reasonable drug loading, and reduced release rate and hemolytic toxicity compared to the non-PEGylated dendrimer .In contrast, up to 24 drug molecules were encapsulated into the hyper branched polyol. The drug was successfully transported into lung epithelial carcinoma cells by the dendrimers. Recent studies using Caco-2 cell lines have indicated that low generation PAMAM dendrimers cross cell membranes presumably through a combination of two processes, i.e., paracellular transport and adsorptive endocytosis, while cell efflux systems have a minor effect. 
Dendrimers in Gene Transfection:
Dendrimers can act as vectors, in gene therapy. PAMAM dendrimers have been tested as genetic material carriers. Numerous reports have been published describing the use of amino-terminated PAMAM or PPI dendrimers as non-viral gene transfer agents, enhancing the transfection of DNA by endocytosis and, ultimately, into the cell nucleus. A transfection reagent called SuperFectTM consisting of activated dendrimers is commercially available. Activated dendrimers can carry a larger amount of genetic material than viruses. SuperFect–DNA complexes are characterized by high stability and provide more efficient transport of DNA into the nucleus than liposomes. The high transfection efficiency of dendrimers may not only be due to their well-defined shape but may also be caused by the low pK of the amines (3.9 and 6.9). The low pK permit the dendrimer to buffer the pH change in the endosomal Compartment. PAMAM dendrimers functionalized with cyclodextrin showed luciferase gene expression about 100 times higher than for unfunctionalized PAMAM or for non-covalent mixtures of PAMAM and cyclodextrin. It should be noted that dendrimers of high structural flexibility and partially degraded high-generation dendrimers (i.e., hyper branched architectures) appear to be better suited for certain gene delivery operations than intact high-generation symmetrical Dendrimers.
Figure4: Dendrimer involved in gene transfection
Paramagnetic metal chelates such as Gd(III)- N,N’,N’’,N”’-tetracarboxymethyl-1,4,7,10-tetraazacy-clododecane (Gd(III)-DOTA), Gd(III)-diethylenetri- amine pentaacetic acid (Gd(III)-DTPA), and their derivatives used as contrast agents for magnetic resonance imaging (MRI). The (Gd(III)-DTPA) conjugate (MagnevistR) (Schering AG) and is a widely used MRI contrast agent. In another approach, the conjugation of (Gd(III)-DOTA) to poly(l-glutamic acid) (molecular weight 50 kDa) via the biodegradable disulfide spacer cystamine was studied to find a safe and effective macromolecular MRI contrast agent.
Consequently, dendrimer-based Gd(III) chelates consisting of generations 2 and 6 PAMAM dendrimers with 12 and 192 terminal surface amines conjugated to the chelating ligand
2-(4-isothiocyanatobenzyl)-6- ethyldiethylenetriamine- pentaacetic acid through a thiourea linkage were synthesized .These contrast agents exhibited excellent MRI images of blood vessels upon intravenous injection. These dendrimer polychelates were exploited for high-quality MR angiography (MRA) images up to 60 min post injection. DNA-dendrimers, which are constructed for routine use in high-throughput functional genomic analysis, and as biosensors for the rapid diagnosis have genetic, and pathogenesis diseases. Radiolabelled monoclonal antibodies with high specific activity have been Prepared by attachment of PAMAM dendrimers loaded with111In or153Gd complexes In vivo oxygen imaging is a strategy that offers the potential for diagnosing complications from diabetes and peripheral vascular diseases, as well as the detection of tumors and the design of their therapeutic treatment.
The dendrimers holds a promising future in various pharmaceutical applications and diagnostic field in the coming years as they possess unique properties, such as high degree of branching, multivalency, globular architecture and well-defined molecular weight, thereby offering new scaffolds for drug delivery. An increasingly large number of drugs being developed today facing problems of poor solubility, bioavailability and permeability. Dendrimers can work as a useful tool for optimizing drug delivery of such problematic drugs. Also the problem of biocompatibility and toxicity can be overcome by careful surface engineering. Recent successes in simplifying and optimizing the synthesis of dendrimers provide a large variety of structures with reduced cost of their production. Also as research progresses, newer applications of dendrimers will emerge and the future should witness an increasing numbers of commercialized dendrimer based drug delivery systems. The high level of control over the architecture of dendrimers, their size, shape, branching length and density, and their surface functionality, makes these compounds ideal carriers in biomedical applications such as drug delivery, gene transfection and imaging. The bioactive agents may either be encapsulated into the interior of the dendrimers or they may be chemically attached or physically adsorbed onto the dendrimer surface, with the option to tailor the properties of the carrier to the specific needs of the active material and its therapeutic applications.
Furthermore, the high density of surface groups allows attachment of targeting groups as well as groups that modify the solution behavior or toxicity of dendrimers. Surface modified dendrimers themselves may act as nano-drugs against tumors, bacteria, and viruses. Recent successes in simplifying the synthesis of dendrimers such as the degut and click approaches have provided a vastly expanded variety of dendritic compounds while at the same time reducing the cost of their production. The biomedical applications of dendrimers clearly illustrate the potential of this new fourth architectural class of polymers and substantiate the high optimism for the future of dendrimers in this important field.
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