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Figure 1: Dendrimer and dendron
Figure 2: Crystal structure of a first-generation polyphenylene dendrimer reported by Müllen et al.[1]


Dendrimers are repeatedly branched, roughly spherical large molecules. The name comes from the Greek word "δένδρον" (pronounced dendron), which translates to "tree". Synonymous terms for dendrimer include arborols and cascade molecules. However, dendrimer is currently the internationally accepted term. A dendrimer is typically symmetric around the core, and often adopts a spherical three-dimensional morphology. The word dendron is also encountered frequently. A dendron usually contains a single chemically addressable group called the focal point. The difference between dendrons and dendrimers is illustrated in figure one, but the terms are typically encountered interchangeably.[2]

The first dendrimers were made by divergent synthesis approaches by Vögtle in 1978[3], Denkewalter at Allied Corporation as in 1981 [4] [5], Donald Tomalia at Dow Chemical in 1983[6] and in 1985[7][8], and by Newkome in 1985[9]. In 1990 a convergent synthetic approach was introduced by Jean Fréchet[10]. Dendrimer popularity then greatly increased, resulting in more than 5,000 scientific papers and patents by the year 2005.

Properties and Types of Dendrimers

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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[11] [12] [13]. Dendritic encapsulation of functional molecules allows for the isolation of the active site, a structure that mimics that of active sites in biomaterials.[14][15] [16] 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.[2]

Figure 3: Synthesis to second generation arborol

Dendrimers are also classified by generation, which refers to the number of repeated branching cycles that are performed during its synthesis. For example if a dendrimer is made by convergent synthesis (see below), and the branching reactions are performed onto the core molecule three times, the resulting dendrimer is considered a third generation dendrimer. Each successive generation results in a dendrimer roughly twice the molecular weight of the previous generation. Higher generation dendrimers also have more exposed functional groups on the surface, which can later be used to customize the dendrimer for a given application.[17]

One of the very first dendrimers, the Newkome dendrimer, was synthesized in 1985. This macromolecule is also commonly known by the name arborol. Figure 3 outlines the mechanism of the first two generations of aborol through a divergent route (discussed below). Further repetition of the two steps leads to higher generations of arborol.[9]

Poly(amidoamine), or PAMAM, is perhaps the most well known dendrimer. The core of PAMAM is a diamine (commonly ethylenediamine), which is reacted with methyl acrylate, and then another ethylenediamine to make the generation-0 (G-0) PAMAM. Successive reactions create higher generations, which tend to have different properties. Lower generations can be thought of as flexible molecules with no appreciable inner regions, while medium sized (G-3 or G-4) do have interanal space that is essentially seperated from the outter shell of the dendrimer. Very large (G-7 and greater) dendrimers can be thought of more like solid particles with very dense surfaces due to the structure of their outter shell. The functional group on the surface of PAMAM dendrimers is ideal for click chemistry, which gives rise to many potential applications. [18]

Synthesis

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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[19] commercializes biocompatible bis-MPA dendrimers and Dendritech[20] is the only kilogram-scale producers of PAMAM dendrimers.


Divergent Methods

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Figure 4: Schematic of divergent synthesis of dendrimers

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 (some branches are shorter than the others). Such impurities can impact the functionality and symmetry of the dendrimer, but are extremely difficult to purify out because the relative size difference between perfect and imperfect dendrimers is very small.[17]

Convergent Methods

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Figure 5: Schematic of convergent synthesis of dendrimers

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.[17]

Applications

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Applications of dendrimers typically involve 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. This might allow researchers to attach both targeting molecules and drug molecules to the same dendrimer, which could reduce negative side affects of medications on healthy cells. [18]

Drug Delivery

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Figure 6: Schematic of a G-5 PAMAM dendrimer conjugated to both a dye molecule and a strand of DNA.

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 evaluation as drug delivery vehicles. There are three methods for using dendrimers in drug delivery: first, the drug is covalently attached to the periphery of the dendrimer to form dendrimer prodrugs, second the drug is coordinated to the outer functional groups via ionic interactions, or third the dendrimer acts as a unimolecular micelle by encapsulating a pharmaceutical through the formation of a dendrimer-drug supramolecular assembly.[21][22] The use of dendrimers as drug carriers by encapsulating hydrophobic drugs is a potential method for delivering highly active pharmaceutical compounds that may not be in clinical use due to their limited water solubility and resulting suboptimal pharmacokinetics. The dendrimer enhances both the uptake and retention of compounds within cancer cells, a finding that was not anticipated at the onset of studies. The encapsulation increases with dendrimer generation and this method may be useful to entrap drugs with a relatively high therapeutic dose. Studies based on this dendritic polymer also open up new avenues of research into the further development of drug-dendrimer complexes specific for a cancer and/or targeted organ system. These encouraging results provide further impetus to design, synthesize, and evaluate dendritic polymers for use in basic drug delivery studies and eventually in the clinic. [23] [21]

Gene Delivery

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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 substratemediated gene delivery. Research has shown that the fast degrading functional polymer has great potential for localized transfection.[24] [25]

Sensors

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Scientists have also studied dendrimers for use in sensor technologies. Studied systems include proton or pH sensors using poly(propylene imine) [26], cadmium-sulfide/polypropylenimine tetrahexacontaamine dendrimer composites to detect fluorescence signal quenching[27], and poly(propylenamine) first and second generation dendrimers for metal cation photodetection[28] amongst others. Research in this field is vast and ongoing due to the potential for multiple detection and binding sites in dendritic structures.

See Also

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References

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  1. ^ Roland E. Bauer, Volker Enkelmann, Uwe M. Wiesler, Alexander J. Berresheim, Klaus Müllen (2002). "Single-Crystal Structures of Polyphenylene Dendrimers". Chemistry: A European Journal. 8 (17): 3858–3864. doi:10.1002/1521-3765(20020902)8:17<3858::AID-CHEM3858>3.0.CO;2-5.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ a b Nanjwade, Basavaraj K.; Bechra, Hiren M.; Derkar, Ganesh K.; Manvi, F.V.; Nanjwade, Veerendra K. (2009). "Dendrimers: Emerging polymers for drug-delivery systems". European Journal of Pharmaceutical Sciences. 38 (3). Elsevier: 185–196. doi:10.1016/j.ejps.2009.07.008. PMID 19646528.
  3. ^ Egon Buhleier, Winfried Wehner, Fritz Vögtle (1978). ""Cascade"- and "Nonskid-Chain-like" Syntheses of Molecular Cavity Topologies". Synthesis. 1978 (2): 155–158. doi:10.1055/s-1978-24702.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ U.S. patent 4,289,872 Denkewalter, Robert G., Kolc, Jaroslav, Lukasavage, William J.
  5. ^ U.S. patent 4,410,688
  6. ^ U.S. patent 4,507,466
  7. ^ D. A. Tomalia, H. Baker, J. Dewald, M. Hall, G. Kallos, S. Martin, J. Roeck, J. Ryder and P. Smith (1985). "A New Class of Polymers: Starburst-Dendritic Macromolecules". Polymer Journal. 17: 117–132. doi:10.1295/polymj.17.117. S2CID 95287356.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ http://findarticles.com/p/articles/mi_m1200/is_n2_v149/ai_17817461/
  9. ^ a b George R. Newkome, Zhongqi Yao, Gregory R. Baker, Vinod K. Gupta (1985). "Micelles. Part 1. Cascade molecules: a new approach to micelles. A [27]-arborol". J. Org. Chem. 50 (11): 2003–2004. doi:10.1021/jo00211a052.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Hawker, C. J.; Fréchet, J. M. J. (1990). "Preparation of polymers with controlled molecular architecture. A new convergent approach to dendritic macromolecules". J. Am. Chem. Soc. 112 (21): 7638–7647. doi:10.1021/ja00177a027.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Bifunctional Dendrimers: From Robust Synthesis and Accelerated One-Pot Postfunctionalization Strategy to Potential Applications P. Antoni, Y. Hed, A. Nordberg, D. Nyström, H. von Holst, A. Hult and M. Malkoch Angew. Int. Ed., 2009, 48 (12), pp 2126-2130 doi:10.1002/anie.200804987
  12. ^ J. R. McElhanon and D. V. McGrath JOC, 2000, 65 (11), pp 3525-3529 doi:10.1021/jo000207a
  13. ^ C. O. Liang and J. M. J. Fréchet Macromolecules, 2005, 38 (15), pp 6276-6284 doi:10.1021/ma050818a
  14. ^ S. Hecht, J. M. J. Fréchet (2001). "Dendritic Encapsulation of Function: Applying Nature's Site Isolation Principle from Biomimetics to Materials Science". Angew. Chem. Int. Ed. 40: 74–91. doi:10.1002/1521-3773(20010105)40:1<74::AID-ANIE74>3.0.CO;2-C.
  15. ^ Frechet, Jean M. (March 2002). Dendrimers and Other Dendritic Polymers. New York, NY: John Wiley & Sons. ISBN 978-0-471-63850-6. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  16. ^ M. Fischer, F. Vogtle (1999). "Dendrimers: From Design to Application—A Progress Report". Angew. Chem. Int. Ed. 38 (7): 884–905. doi:10.1002/(SICI)1521-3773(19990401)38:7<884::AID-ANIE884>3.0.CO;2-K. PMID 29711851.
  17. ^ a b c Holister, Paul (October 2003). "Dendrimers: Technology White Papers" (PDF). Cientifica. Retrieved 17 March 2010. {{cite web}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  18. ^ a b Hermanson, Greg T. (2008). "7". Bioconjugate Techniques (2nd ed.). London: Academic Press of Elsevier. ISBN 978-0-12-370501-3.
  19. ^ Polymer Factory AB, Stockholm, Sweden.Polymer Factory
  20. ^ Dendritech Inc., from Midland, Michigan, USA.Dendritech.
  21. ^ a b Morgan, Meredith T. (2006Meredith T. Morgan1). "Dendrimer-Encapsulated Camptothecins". American Association for Cancer Research. 66 (24). 1 Department of Chemistry, Duke University, 2 Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina; 3 Natural Products Laboratory, Research Triangle Institute, Research Triangle Park, North Carolina; and 4 Departments of Biomedical Engineering and Chemistry, Metcalf Center for Science and Engineering, Boston University, Boston, Massachusetts: 11913–21. doi:10.1158/0008-5472.CAN-06-2066. PMID 17178889. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  22. ^ Tekade, Rakesh Kumar (2009). "Exploring dendrimer towards dual drug delivery". Journal of Microencapsulation. 26 (4). Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences, Dr Hari Singh Gour University: 287–296. doi:10.1080/02652040802312572. PMID 18791906. S2CID 44523215. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  23. ^ Cheng, Yiyun; Wu, Qinglin; Li, Yiwen; Xu, Tongwen (2008). "External Electrostatic Interaction versus Internal Encapsulation between Cationic Dendrimers and Negatively Charged Drugs: Which Contributes More to Solubility Enhancement of the Drugs?". Journal of Physical Chemistry B. 112 (30). Laboratory of Functional Membranes, Department of Chemistry, University of Science and Technology of China: 8884–8890. doi:10.1021/jp801742t. PMID 18605754.
  24. ^ Fu, Hui-Li; Cheng, Si-Xue; Zhang, Xian-Zheng; Zhuo, Ren-Xi (2008). "Dendrimer/DNA complexes encapsulated functional biodegradable polymer for substrate-mediated gene delivery". The Journal of Gene Medicine. 10 (12). Key Laboratory of Biomedical Polymers of Ministry of Education,Department of Chemistry, Wuhan University, Wuhan, People’s Republic of China: 1334–1342. doi:10.1002/jgm.1258. S2CID 46011138.
  25. ^ Fu, Hui-Li; Cheng, Si-Xue; Zhang, Xian-Zheng; Zhuo, Ren-Xi (2007). "Dendrimer/DNA complexes encapsulated in a water soluble polymer and supported on fast degrading star poly(DL-lactide) for localized gene delivery". Journal of Control Release. 124 (3). Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University: 181–188. doi:10.1016/j.jconrel.2007.08.031. PMID 17900738.
  26. ^ Fernandes, Edson G. R.; Vieira, Nirton C. S.; De Queiroz, Alvaro A. A.; Guimarães, Francisco E. G.; Zucolotto, Valtencir (2010). "Immobilization of Poly(propylene imine) Dendrimer/Nickel Phtalocyanine as Nanostructured Multilayer Films To Be Used as Gate Membranes for SEGFET pH Sensors". Journal of Physical Chemistry C. 114 (14). American Chemical Society: 6478–6483. doi:10.1021/jp9106052.
  27. ^ Campos, Bruno B.; Algarra, Manuel; Esteves Da Silva, Joaquim C. G. (2010). "Fluorescent Properties of a Hybrid Cadmium Sulfide-Dendrimer Nanocomposite and its Quenching with Nitromethane". Journal of Fluorescence. 20 (1). Springer: 143–151. doi:10.1007/s10895-009-0532-5. PMID 19728051. S2CID 10846628.
  28. ^ Grabchev, Ivo; Staneva, Desislava; Chovelon, Jean-Marc (2010). "Photophysical investigations on the sensor potential of novel, poly(propylenamine) dendrimers modified with 1,8-naphthalimide units". Dyes and Pigments. 85 (3). Elsevier Ltd.: 189–193. doi:10.1016/j.dyepig.2009.10.023.
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