SpringerOpen Newsletter

Receive periodic news and updates relating to SpringerOpen.

Open Access Nano Review

Dendrimers: synthesis, applications, and properties

Elham Abbasi1, Sedigheh Fekri Aval12, Abolfazl Akbarzadeh1*, Morteza Milani13, Hamid Tayefi Nasrabadi1*, Sang Woo Joo4*, Younes Hanifehpour4*, Kazem Nejati-Koshki12 and Roghiyeh Pashaei-Asl1

Author Affiliations

1 Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 5154853431, Iran

2 Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 5154853431, Iran

3 Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 5154853431, Iran

4 School of Mechanical Engineering, Yeungnam University, Gyeongsan 712-749, South Korea

For all author emails, please log on.

Nanoscale Research Letters 2014, 9:247  doi:10.1186/1556-276X-9-247


The electronic version of this article is the complete one and can be found online at: http://www.nanoscalereslett.com/content/9/1/247


Received:3 March 2014
Accepted:3 May 2014
Published:21 May 2014

© 2014 Abbasi et al.; licensee Springer.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

Abstract

Dendrimers are nano-sized, radially symmetric molecules with well-defined, homogeneous, and monodisperse structure that has a typically symmetric core, an inner shell, and an outer shell. Their three traditional macromolecular architectural classes are broadly recognized to generate rather polydisperse products of different molecular weights. A variety of dendrimers exist, and each has biological properties such as polyvalency, self-assembling, electrostatic interactions, chemical stability, low cytotoxicity, and solubility. These varied characteristics make dendrimers a good choice in the medical field, and this review covers their diverse applications.

Keywords:
Dendrimer; Pseudorotaxane; Nanoscale; PAMAM

Review

Introduction

Dendrimers are nano-sized, radially symmetric molecules with well-defined, homogeneous, and monodisperse structure consisting of tree-like arms or branches [1]. These hyperbranched molecules were first discovered by Fritz Vogtle in 1978, by Donald Tomalia and co-workers in the early 1980s, and at the same time, but independently by George R. Newkome. The second group called synthesized macromolecules ‘arborols’ means, in Latin, ‘trees’. Dendrimers might also be called ‘cascade molecules’ , but this term is not as much established as ‘dendrimers’ [2-4]. Dendrimers are nearly monodisperse macromolecules that contain symmetric branching units built around a small molecule or a linear polymer core [5-7]. ‘Dendrimer’ is only an architectural motif and not a compound. Polyionic dendrimers do not have a persistent shape and may undergo changes in size, shape, and flexibility as a function of increasing generations [8-10]. Dendrimers are hyperbranched macromolecules with a carefully tailored architecture, the end-groups (i.e., the groups reaching the outer periphery), which can be functionalized, thus modifying their physicochemical or biological properties [11-16]. Dendrimers have gained a broad range of applications in supramolecular chemistry, particularly in host-guest reactions and self-assembly processes. Dendrimers are characterized by special features that make them promising candidates for a lot of applications. Dendrimers are highly defined artificial macromolecules, which are characterized by a combination of a high number of functional groups and a compact molecular structure [17]. The emerging role of dendritic macromolecules for anticancer therapies and diagnostic imaging is remarkable. The advantages of these well-defined materials make them the newest class of macromolecular nano-scale delivery devices [18]. Dendritic macromolecules tend to linearly increase in diameter and adopt a more globular shape with increasing dendrimer generation. Therefore, dendrimers have become an ideal delivery vehicle candidate for explicit study of the effects of polymer size, charge, and composition on biologically relevant properties such as lipid bilayer interactions, cytotoxicity, internalization, blood plasma retention time, biodistribution, and filtration [19] (Figure 1).

thumbnailFigure 1. Schematic representation of a generation G4 dendrimer with 64 amino groups at the periphery. This dendrimer starts from an ethylene diamine core; the branches or arms were attached by exhaustive Michael addition to methyl acrylate followed by exhaustive aminolysis of the resulting methyl ester using ethylene diamine [20].

Structure and chemistry

The structure of dendrimer molecules begins with a central atom or group of atoms labeled as the core. From this central structure, the branches of other atoms called ‘dendrons’ grow through a variety of chemical reactions. There continues to be a debate about the exact structure of dendrimers, in particular whether they are fully extended with maximum density at the surface or whether the end-groups fold back into a densely packed interior [21,22]. Dendrimers can be prepared with a level of control not attainable with most linear polymers, leading to nearly monodisperse, globular macromolecules with a large number of peripheral groups as seen in Figure 2, the structure of some dendrimer repeat units, for example, the 1,3-diphenylacetylene unit developed by Moore [23].

thumbnailFigure 2. Types of dendrimers. (A) More type dendrimers consisting of phenyl acetylene subunits at the third-generation different arms may dwell in the same space, and the fourth-generation layer potential overlaps with the second-generation layer. (B) Parquette-type dendrons are chiral, non-racemic, and with intramolecular folding driven by hydrogen bonding [24].

Dendrimers are a new class of polymeric belongings. Their chemistry is one of the most attractive and hastily growing areas of new chemistry [25-27]. Dendrimer chemistry, as other specialized research fields, has its own terms and abbreviations. Furthermore, a more brief structural nomenclature is applied to describe the different chemical events taking place at the dendrimer surface. Dendrigrafts are a class of dendritic polymers like dendrimers that can be constructed with a well-defined molecular structure, i.e., being monodisperse [28]. The unique structure of dendrimers provides special opportunities for host-guest chemistry (Figure 3) and is especially well equipped to engage in multivalent interactions. At the same time, one of the first proposed applications of dendrimers was as container compounds, wherein small substrates are bound within the internal voids of the dendrimer [29]. Experimental evidence for unimolecular micelle properties was established many years ago both in hyperbranched polymers [30] and dendrimers [31].

thumbnailFigure 3. Three main parts of a dendrimer: the core, end-groups, and subunits linking the two molecules.

Synthesis

Dendrimers are just in between molecular chemistry and polymer chemistry. They relate to the molecular chemistry world by virtue of their step-by-step controlled synthesis, and they relate to the polymer world because of their repetitive structure made of monomers [32-35]. The three traditional macromolecular architectural classes (i.e., linear, cross-linked, and branched) are broadly recognized to generate rather polydisperse products of different molecular weights. In contrast, the synthesis of dendrimers offers the chance to generate monodisperse, structure-controlled macromolecular architectures similar to those observed in biological systems [36,37]. Dendrimers are generally prepared using either a divergent method or a convergent one [38]. In the different methods, dendrimer grows outward from a multifunctional core molecule. The core molecule reacts with monomer molecules containing one reactive and two dormant groups, giving the first-generation dendrimer. Then, the new periphery of the molecule is activated for reactions with more monomers.

Cascade reactions are the foundation of dendrimer synthesis

The basic cascade or iterative methods that are currently employed for synthesis were known to chemists much earlier. For example, similar schemes form the basis of solid-phase peptide synthesis. In turn, biology has long exploited similar iterative strategies in biochemical synthetic pathways; one example is provided by fatty acid biosynthesis [39] (Figure 4).

thumbnailFigure 4. Cascade reaction sequences developed for the synthesis of ‘non-skid-chain like’ polyazamacrocyclic compounds [40].

The synthesis of dendrimers follows either a divergent or convergent approach

Dendrimers can be synthesized by two major approaches. In the divergent approach, used in early periods, the synthesis starts from the core of the dendrimer to which the arms are attached by adding building blocks in an exhaustive and step-wise manner. In the convergent approach, synthesis starts from the exterior, beginning with the molecular structure that ultimately becomes the outermost arm of the final dendrimer. In this strategy, the final generation number is pre-determined, necessitating the synthesis of branches of a variety of requisite sizes beforehand for each generation [41] (Figure 5).

thumbnailFigure 5. Approaches for the synthesis if dendrimers. (A) Divergent approach: synthesis of radially symmetric polyamidoamine (PAMAM)dendrimers using ammonia as the trivalent core; the generations are added at each synthetic cycle (two steps), leading to an exponential increase in the number of surface functional groups [37]. (B) Convergent approach: synthesis of dendrons or wedges or branches that will become the periphery of the dendrimer when coupled to a multivalent core in the last step of the synthesis [13].

Properties of dendrimers

When comparing dendrimers with other nanoscale synthetic structures (e.g., traditional polymers, buck balls, or carbon nanotubes), these are either highly non-defined or have limited structural diversity.

Pharmacokinetic properties

Pharmacokinetic properties are one of the most significant aspects that need to be considered for the successful biomedical application of dendrimers, for instance, drug delivery, imaging, photodynamic therapy, and neutron capture therapy. The diversity of potential applications of dendrimers in medicine results in increasing interest in this area. For example, there are several modifications of dendrimers' peripheral groups which enable to obtain antibody-dendrimer, peptide-dendrimer conjugates or dendritic boxes that encapsulate guest molecules [42].

Covalent conjugation strategies

The strategy of coupling small molecules to polymeric scaffolds by covalent linkages to improve their pharmacological properties has been under experimental test for over three decades [43-46]. In most cases, however, the conjugated dendritic assembly functions as ‘pro-drug’ where, upon internalization into the target cell, the conjugate must be liberated to activate the drug (Figure 6).

thumbnailFigure 6. Requirements for dendrimer-based, cancer-targeted drug delivery. (A) Dendrimers with multiple surface functional groups can be directed to cancer cells by tumor-targeting entities that include folate or antibodies specific for tumor-associated antigens (TAAs). (B) The next step is ingestion into the cell which, in the case of folate targeting, occurs by membrane receptor-mediated endocytosis. (C) Once inside the cell, the drug generally must be released from the dendrimer, which, for the self-immolative method, results in the simultaneous disintegration of the dendritic scaffold (D).

Polyvalency

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.

Self-assembling dendrimers

Another fascinating and rapidly developing area of chemistry is that of self-assembly. Self-assembly is the spontaneous, precise association of chemical species by specific, complementary intermolecular forces. Recently, the self-assembly of dendritic structures has been of increasing interest [47]. Because dendrimers contain three distinct structural parts (the core, end-groups, and branched units connecting the core and periphery), there are three strategies for self-assembling dendrimers. The first is to create dendrons with a core unit that is capable of recognizing itself or a ditopic or polytopic core structure, therefore leading to spontaneous formation of a dendrimer [48-51]. A self-assembling dendrimer using pseudorotaxane formation as the organizing force was reported by Gibson and coworkers (Figure 7) [52].

thumbnailFigure 7. Gibson's self-assembling dendrimers using pseudorotaxane formation. (A) Crown ethers with dendritic substituents. (B) Triammonium ion core. (C) Schematic of tridendron formed by triple pseudorotaxane self-assembly.

Electrostatic interactions

Molecular recognition events at dendrimer surfaces are distinguished by the large number of often identical end-groups presented by the dendritic host. When these groups are charged, the surface may have as a polyelectrolyte and is likely to electrostatically attract oppositely charged molecules [53]. One example of electrostatic interactions between polyelectrolyte dendrimers and charged species include the aggregation of methylene blue on the dendrimer surface and the binding of EPR probes such as copper complexes and nitroxide cation radicals [54,55].

Applications

Today, dendrimers have several medicinal and practical applications.

Dendrimers in biomedical field

Dendritic polymers have advantage in biomedical applications. These dendritic polymers are analogous to protein, enzymes, and viruses, and are easily functionalized. Dendrimers and other molecules can either be attached to the periphery or can be encapsulated in their interior voids [56]. Modern medicine uses a variety of this material as potential blood substitutes, e.g., polyamidoamine dendrimers [57].

Anticancer drugs

Perhaps the most promising potential of dendrimers is in their possibility to perform controlled and specified drug delivery, which regards the topic of nanomedicine. One of the most fundamental problems that are set toward modern medicine is to improve pharmacokinetic properties of drugs for cancer [58]. Drugs conjugated with polymers are characterized by lengthened half-life, higher stability, water solubility, decreased immunogenicity, and antigenicity [59]. Unique pathophysiological traits of tumors such as extensive angiogenesis resulting in hypervascularization, the increased permeability of tumor vasculature, and limited lymphatic drainage enable passive targeting, and as a result, selective accumulation of macromolecules in tumor tissue. This phenomenon is known as ‘enhanced permeation and retention’ (EPR) [58,60]. The drug-dendrimer conjugates show high solubility, reduced systemic toxicity, and selective accumulation in solid tumors. Different strategies have been proposed to enclose within the dendrimer structure drug molecules, genetic materials, targeting agents, and dyes either by encapsulation, complexation, or conjugation.

Dendrimers in drug delivery

In 1982, Maciejewski proposed, for the first time, the utilization of these highly branched molecules as molecular containers [61]. Host-guest properties of dendritic polymers are currently under scientific investigation and have gained crucial position in the field of supramolecular chemistry. Host-guest chemistry is based on the reaction of binding of a substrate molecule (guest) to a receptor molecule (host) [62].

Transdermal drug delivery

Clinical use of NSAIDs is limited due to adverse reactions such as GI side effects and renal side effects when given orally. Transdermal drug delivery overcomes these bad effects and also maintains therapeutic blood level for longer period of time. Transdermal delivery suffers poor rates of transcutaneous delivery due to barrier function of the skin. Dendrimers have found applications in transdermal drug delivery systems. Generally, in bioactive drugs having hydrophobic moieties in their structure and low water solubility, dendrimers are a good choice in the field of efficient delivery system [63].

Gene delivery

The primary promise that the combination of understanding molecular pathways of disease and the complete human genome sequence would yield safer and more efficient medicines and revolutionize the way we treat patients has not been fulfilled to date. However, there is little doubt that genetic therapies will make a significant contribution to our therapeutic armamentarium once some of the key challenges, such as specific and efficient delivery, have been solved [64]. 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 [65-67].

Dendrimers as magnetic resonance imaging contrast agents

Dendrimer-based metal chelates act as magnetic resonance imaging contrast agents. Dendrimers are extremely appropriate and used as image contrast media because of their properties [56].

Dendritic sensors

Dendrimers, although are single molecules, can contain high numbers of functional groups on their surfaces. This makes them striking for applications where the covalent connection or close proximity of a high number of species is important. Balzani and coworkers investigated the fluorescence of a fourth-generation poly (propylene amine) dendrimer decorated with 32 dansyl units at the periphery (Figure 8) [68]. Since the dendrimer contains 30 aliphatic amine units in the interior, suitable metal ions are able to coordinate. It was observed that when a Co2+ ion is incorporated into the dendrimer, the strong fluorescence of all the dansyl units is quenched. Low concentrations of Co2+ ions (4.6 × 10-7 M) can be detected using a dendrimer concentration of 4.6 × 10-6 M. The many fluorescent groups on the surface serve to amplify the sensitivity of the dendrimer as a sensor [69].

thumbnailFigure 8. Poly (propylene amine) dendrimer, containing 32 dansyl units at its periphery.

Dendrimers used for enhancing solubility

PAMAM dendrimers are expected to have potential applications in enhancing solubility for drug delivery systems. Dendrimers have hydrophilic exteriors and interiors, which are responsible for its unimolecular micelle nature. Dendrimer-based carriers offer the opportunity to enhance the oral bioavailability of problematic drugs. Thus, dendrimer nano carriers offer the potential to enhance the bioavailability of drugs that are poorly soluble and/or substrates for efflux transporters [70,71].

Photodynamic therapy

Photodynamic therapy (PDT) relies on the activation of a photosensitizing agent with visible or near-infrared (NIR) light. Upon excitation, a highly energetic state is formed which, upon reaction with oxygen, affords a highly reactive singlet oxygen capable of inducing necrosis and apoptosis in tumor cells. Dendritic delivery of PDT agents has been investigated within the last few years in order to improve upon tumor selectivity, retention, and pharmacokinetics [72-75].

Miscellaneous dendrimer applications

Clearly, there are many other areas of biological chemistry where application of dendrimer systems may be helpful. Cellular delivery using carrier dendritic polymers is used in the purification of water dendrimer-based product in cosmetics contaminated by toxic metal ion and inorganic solute, and dendrimer-based commercial products organic solutes [76]. Furthermore, highly sensitive analytical devices [77,78], MRI contrast agents [79], prion research [80], burn treatment [81], and EPR imaging with spin-labeled dendrimers [82-106] are some of the diverse areas of fascinating ongoing dendrimer research that are beyond the scope of this article.

Conclusion

Dendrimers are characterized by individual features that make them hopeful candidates for a lot of applications. Dendrimers are highly defined artificial macromolecules, which are characterized by a combination of a high number of functional groups and a compact molecular structure. A rapid increase of importance in the chemistry of dendrimers has been observed since the first dendrimers were prepared. Work was established to determine the methods of preparing and investigating the properties of the novel class of macro and micromolecules. In spite of the two decades since the finding of dendrimers, the multi-step synthesis still requires great effort.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

SWJ conceived the study and participated in its design and coordination. EA participated in the sequence alignment and drafted the manuscript. AA, RPA, SFA, HTN, YH, KNK, and MM helped in drafting the manuscript. All authors read and approved the final manuscript.

Acknowledgements

The authors thank the Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences of Tabriz University of Medical Sciences for all the support provided. This work is funded by Grant 2011-0014246 of the National Research Foundation of Korea.

References

  1. Srinivasa-Gopalan S, Yarema KJ: Nanotechnologies for the Life Sciences: Dendrimers in Cancer Treatment and Diagnosis, Volume 7. New York: Wiley; 2007. OpenURL

  2. Klajnert B, Bryszewska M: Dendrimers: properties and applications.

    Acta Biochim Pol 2001, 48:199-208. OpenURL

  3. Tomalia DA, Frechet JMJ: Discovery of dendrimers and dendritic polymers: a brief historical perspective.

    J Polym Sci A Polym Chem 2002, 40:2719-2728. OpenURL

  4. Tomalia DA: The dendritic state.

    Mater Today 2005, 8:34-36. OpenURL

  5. Tomalia DA, Baker H, Dewald J, Hall M, Kallos M, Martin S, Roeck J, Ryder J, Smith P: A new class of polymers: starburst-dendritic macromolecules.

    Polym J (Tokyo) 1985, 17:117. OpenURL

  6. Newkome GR, Yao Z-Q, Baker GR, Gupta VK: Cascade molecules: a new approach to micelles.

    J Org Chem 1985, 50:2003. OpenURL

  7. Hawker CJ, Frechet JMJ: Preparation of polymers with controlled molecular architecture: a new convergent approach to dendritic macromolecules.

    J Am Chem Soc 1990, 112:7638-7647. OpenURL

  8. De Gennes PG, Hervet H: Statistics of starburst polymers.

    J de Physique Lett (Paris) 1983, 44:9-351. OpenURL

  9. Mansfield ML, Klushin LI: Monte Carlo studies of dendrimer macromolecules.

    Macromolecules 1993, 26:4262. OpenURL

  10. Bhalgat MK, Roberts JC: Molecular modeling of polyamidoamine (PAMAM) Starburst™ dendrimers.

    Eur Polym J 2000, 36:647-651. OpenURL

  11. Bosman AW, Meijer EW: About dendrimers: structure, physical properties, and applications.

    Chem Rev 1999, 99:1665-1688. OpenURL

  12. Gilles ER, Frechet JMJ: Dendrimers and dendritic polymers in drug delivery.

    Drug Discov Today 2005, 10:35-43. OpenURL

  13. Tomalia DA, Baker H, Dewald JR, Hall M, Kallos G, Martin S, Roeck J, Ryder J, Smith P: Dendrimers II: architecture, nanostructure and supramolecular chemistry.

    Macromolecules 1986, 19:2466. OpenURL

  14. Kim Y, Zimmerman SC: Applications of dendrimers in bio-organic chemistry.

    Curr Opin Chem Biol 1998, 2:733-742. OpenURL

  15. Smith DK, Diederich F: Functional dendrimers: unique biological mimics.

    Chem Eur J 1998, 4:1353-1361. OpenURL

  16. Stiriba S-E, Frey H, Haag R: Dendritic polymers in biomedical applications: from potential to clinical use in diagnostics and therapy.

    Angew Chem Int Ed 2002, 41:1329-1334. OpenURL

  17. Tomalia DA, Frechet JMJ: Discovery of dendrimers and dendritic polymers: a brief historical perspective.

    J Polym Sci Part A 2002, 40:2719. OpenURL

  18. Wolinsky JB, Grinstaff MW: Therapeutic and diagnostic applications of dendrimers for cancer treatment.

    Adv Drug Deliv Rev 2008, 60:1037-1055. OpenURL

  19. Svenson S, Tomalia DA: Dendrimers in biomedical applications—reflections on the field.

    Adv Drug Deliv Rev 2005, 57:2106-2129. OpenURL

  20. Tomalia DA, Baker H, Dewald J, Hall M, Kallos G, Martin S, Roeck J, Ryder J, Smith P: Dendritic macromolecules: synthesis of starburst dendrimers.

    Macromolecules 1986, 19:2466-2468. OpenURL

  21. Zimmerman SC: Dendrimers in molecular recognition and self-assembly.

    Curr Opin Colloid Interfac Sci 1997, 2:89. OpenURL

  22. Zeng FW, Zimmerman SC: Dendrimers in supramolecular chemistry: from molecular recognition to self-assembly.

    Chem Rev 1997, 97:1681. OpenURL

  23. Moore JS: Shape-persistent molecular architectures of nanoscale dimension.

    Acc Chem Res 1997, 30:402. OpenURL

  24. Zimmerman SC, Lawless LJ: Topics in Current Chemistry: Supramolecular Chemistry of Dendrimers, Volume 217. New York: Springer; 2001. OpenURL

  25. Boris D, Rubinstein M: A self-consistent mean field model of a starburst dendrimers: dense core vs. dense shells.

    Macromolecules 1996, 29:7251-7260. OpenURL

  26. Tomalia DA, Baker H, Dewald JR, Hall M, Kallos G, Martin S: A new class of polymers: starburst-dendritic macromolecules.

    Polym J 1985, 17(1):117-132. OpenURL

  27. Spataro G, Malecaze F, Turrin CO, Soler V, Duhayon C, Elena PP: Designing dendrimers for ocular drug delivery.

    Eur J Med Chem 2010, 45(1):326-334. OpenURL

  28. Tomalia DA, Hedstrand DM, Ferritto MS: Comb-burst dendrimer topology: new macromolecular architecture derived from dendritic grafting.

    Macromolecules 1991, 24:1435. OpenURL

  29. Maciejewski M: Concepts of trapping topologically by shell molecules.

    J Macromol Sci Chem 1982, A17:689. OpenURL

  30. Kim YH, Webster OW: Water soluble hyperbranched polyphenylene: “a unimolecular micelle?”.

    J Am Chem Soc 1990, 112:4592. OpenURL

  31. Newkome GRM, Baker GR, Saunders MJ, Grossman SH: Uni-molecular micelles.

    Angew Chem Int Ed Engl 1991, 30:1178. OpenURL

  32. Frechet JMJ, Tomalia DA: Dendrimers and Other Dendritic Polymers. Chichester: Wiley; 2001. OpenURL

  33. Newkome GR, Moorefield CN, Vögtle F: Dendrimers and Dendrons: Concepts, Syntheses, Applications. Wiley: Weinheim; 2001. OpenURL

  34. Majoral JP, Caminade AM: Dendrimers containing heteroatoms (Si, P, B, Ge, or Bi).

    Chem Rev 1999, 99:845-880. OpenURL

  35. Bosman AW, Janssen HM, Meijer EW: About dendrimers: structure, physical properties, and applications.

    Chem Rev 1999, 99:1665-1688. OpenURL

  36. Tomalia DA: Birth of a new macromolecular architecture: dendrimers as quantized building blocks for nanoscale synthetic organic chemistry.

    Aldrichimica Acta 2004, 37:39-57. OpenURL

  37. Tomalia DA: Dendrimer molecules.

    Sci Am 1995, 272:62-66. OpenURL

  38. Hodge P: Polymer science branches out.

    Nature 1993, 362:18-19. OpenURL

  39. Gitsov I, Lin C: Dendrimers – nanoparticles with precisely engineered surfaces.

    Curr Org Chem 2005, 9:1025-1051. OpenURL

  40. Buhleier E, Wehner W, Vögtle F: “Cascade”- and “nonskid-chain-like” synthesis of molecular cavity topologies.

    Synthesis 1978, 1978(2):155-158. OpenURL

  41. Grayson SM, Frechet JMJ: Convergent dendrons and dendrimers: from synthesis to applications.

    Chem Rev 2001, 101:3819-3868. OpenURL

  42. Szymanski P, Markowicz M, Mikiciuk-Olasik E: Nanotechnology in pharmaceutical and biomedical applications: Dendrimers.

    Nano Brief Rep Rev 2011, 6:509-539. OpenURL

  43. Ringsdorf H: Structure and properties of pharmacologically active polymers.

    J Polym Sci Polym Symp 1975, 51:135-153. OpenURL

  44. Bader H, Ringsdorf H, Schmidt B: Water-soluble polymers in medicine.

    Angew Makromol Chem 1984, 123/124:457-485. OpenURL

  45. Gillies ER, Dy E, Frechet JMJ, Szoka FC: Biological evaluation of polyester dendrimer: poly (ethylene oxide) “bow-tie” hybrids with tunable molecular weight and architecture.

    Mol Pharm 2005, 2:129-138. OpenURL

  46. Kolhe P, Khandare J, Pillai O, Kannan S, Lieh-Lai M, Kannan RM: Preparation, cellular transport, and activity of polyamidoamine-based dendritic nanodevices with a high drug payload.

    Biomaterials 2006, 27:660-669. OpenURL

  47. Emrick T, Fréchet JMJ: Self-assembly of dendritic structures.

    Curr Opin Coll Interface Sci 1999, 4:15-23.

    CrossRef, Web of Science® Times Cited: 80

    OpenURL

  48. Christine D, Ijeoma FU, Andreas GS: Dendrimers in gene delivery.

    Adv Drug Deliv Rev 2005, 57:2177-2202. OpenURL

  49. Wang Y, Zeng FW, Zimmerman SC: Dendrimers with anthyridine-based hydrogen-bonding units at their cores - synthesis, complexation and self-assembly studies.

    Tetrahedron Lett 1997, 38:5459. OpenURL

  50. Kolotuchin SV, Zimmerman SC: Self-assembly mediated by the donor-donor-acceptor, acceptor-acceptor-donor (DDA, AAD) hydrogen-bonding motif: formation of a robust hexameric aggregate.

    J Am Chem Soc 1998, 120:9092. OpenURL

  51. Issberner J, Vogtle F, Decola L, Balzani V: Dendritic bipyridine ligands and their tris(bipyridine)ruthenium(II) chelates—syntheses, absorption spectra, and photophysical properties.

    Chem Eur J 1997, 3:706. OpenURL

  52. Gibson HW, Hamilton L, Yamaguchi N: Molecular self-assembly of dendrimers, non-covalent polymers and polypseudorotaxanes.

    Polym Adv Technol 2000, 11:791. OpenURL

  53. Zeng F, Zimmerman SC: Dendrimers in supramolecular chemistry: from molecular recognition to self-assembly.

    Chem Rev 1997, 97:1681-1712. OpenURL

  54. Ottaviani MF, Bossmann S, Turro NJ, Tomalia DA: Characterization of starburst dendrimers by the EPR technique. 1. Copper complexes in water solution.

    J Am Chem Soc 1994, 116:661-671. OpenURL

  55. Ottaviani MF, Cossu E, Turro NJ, Tomalia DA: Characterization of starburst dendrimers by electron paramagnetic resonance. 2. Positively charged nitroxide radicals of variable chain length used as spin probes.

    J Am Chem Soc 1995, 117:4387-4398. OpenURL

  56. Patel HN, Patel DRPM: Dendrimer applications – a review.

    Int J Pharm Bio Sci 2013, 4(2):454-463. OpenURL

  57. Ruth D, Lorella I: Dendrimer biocompatibility and toxicity.

    Ad Drug Deliv Rev 2005, 57:2215-2237. OpenURL

  58. Sampathkumar SG, Yarema KJ: Chapter 1: dendrimers in cancer treatment and diagnosis. In Nanotechnologies for the Life Sciences. Volume 6: Nanomaterials for Cancer Diagnosis and Therapy. Edited by Kumar CSSR. Hoboken: Wiley; 2007:1-47. OpenURL

  59. Pasut G, Veronese FM: Polymer - drug conjugation, recent achievements and general strategies.

    Prog Polym Sci 2007, 32:933. OpenURL

  60. Gillies ER, Frechet JMJ: Dendrimers and dendritic polymers in drug delivery.

    DDT 2005, 10(1):35-43. OpenURL

  61. Maciejewski M: Concepts of trapping topologically by shell molecules.

    J Macromol Sci Chem A 1982, 17:689. OpenURL

  62. Herrmann A, Mihov G, Vandermeulen GWM, Klok H-A, Mullen K: Peptide-functionalized polyphenylene dendrimers.

    Tetrahedron 2003, 59:3925. OpenURL

  63. Cheng Y, Man N, Xu T, Fu R, Wang X, Wang X, Wen L: Transdermal delivery of nonsteroidal anti-inflammatory drugs mediated by polyamidoamine (PAMAM) dendrimers.

    J Pharm Sci 2007, 96:595-602. OpenURL

  64. Pearson S, Jia H, Kandachi K: China approves first gene therapy.

    Nat Biotechnol 2004, 22:3-4. OpenURL

  65. Fu H-L, Cheng S-X, Zhang X-Z, Zhuo R-X: Dendrimer/DNA complexes encapsulated functional biodegradable polymer for substrate-mediated gene delivery.

    J Gene Med 2008, 10(12):1334-1342. OpenURL

  66. Fu HL, Cheng SX, Zhang XZ: Dendrimer/DNA complexes encapsulated in a water soluble polymer and supported on fast degrading star poly (DL-lactide) for localized gene delivery.

    J Gene Med 2007, 124(3):181-188. OpenURL

  67. Tathagata D, Minakshi G, Jain NK: Poly (propyleneimine) dendrimer and dendrosome based genetic immunization against hepatitis B.

    Vaccine 2008, 26(27–28):3389-3394. OpenURL

  68. Balzani V, Ceroni P, Gestermann S, Kauffmann C, Gorka M, Vögtle F: Dendrimers as fluorescent sensors with signal amplification.

    Chem Commun 2000, 2000:853-854. OpenURL

  69. Beer PD, Gale PA, Smith DK: Supramolecular Chemistry. Oxford: Oxford University Press; 1999. OpenURL

  70. Tomalia DA, Baker H, Dewald JR, Hall M, Kallos G, Martin S, Roeck J, Ryder J, Smith P: Dendrimers II: architecture, nanostructure and supramolecular chemistry.

    Macromolecules 1986, 19:2466. OpenURL

  71. Froehling PE: Dendrimers and dyes – a review.

    Dyes Pigments 2001, 48:187-195. OpenURL

  72. Triesscheijn M, Baas P, Schellens JH, Stewart FA: Photodynamic therapy in oncology.

    Oncologist 2006, 11:1034-1044. OpenURL

  73. Nishiyama N, Stapert HR, Zhang GD, Takasu D, Jiang DL, Nagano T, Aida T, Kataoka K: Light-harvesting ionic dendrimer porphyrins as new photosensitizers for photodynamic therapy.

    Bioconjug Chem 2003, 14:58-66. OpenURL

  74. Zhang GD, Harada A, Nishiyama N, Jiang DL, Koyama H, Aida T, Kataoka K: Polyion complex micelles entrapping cationic dendrimer porphyrin: effective photosensitizer for photodynamic therapy of cancer.

    J Control Release 2003, 93:141-150. OpenURL

  75. Battah SH, Chee CE, Nakanishi H, Gerscher S, MacRobert AJ, Edwards C: Synthesis and biological studies of 5-aminolevulinic acid containing dendrimers for photodynamic therapy.

    Bioconjug Chem 2001, 12:980-988. OpenURL

  76. Tiwari DK, Behari J, Sen P: Application of nanoparticles in waste water treatment.

    World Appl Sci J 2008, 3:417-433. OpenURL

  77. Yoon HC, Lee D, Kim H-S: Reversible affinity interactions of antibody molecules at functionalized dendrimer monolayer: affinity-sensing surface with reusability.

    Anal Chim Acta 2002, 456:209-218. OpenURL

  78. Benters R, Niemeyer CM, Drutschmann D, Blohm D, Wohrle D: DNA microarrays with PAMAM dendritic linker systems.

    Nucleic Acid Res 2002, 30:1-11. OpenURL

  79. Konda SD, Wang S, Brechbiel M, Wiener EC: Biodistribution of a 153Gd-folate dendrimer, generation = 4, in mice with folate-receptor positive and negative ovarian tumor xenografts.

    Invest Radiol 2002, 37:199-204. OpenURL

  80. Supattapone S, Nishina K, Rees JR: Pharmacological approaches to prion research.

    Biochem Pharmacol 2002, 63:1383-1388. OpenURL

  81. Halkes SBA, Vrasidas I, Rooijer GR, van den Berg AJJ, Liskamp RMJ, Pieters RJ: Synthesis and biological activity of polygalloyl-dendrimers as stable tannic acid mimics.

    Bioorg Med Chem Lett 2002, 12:1567-1570. OpenURL

  82. Yordanov AT, Yamada K-I, Krishna MC, Mitchell JB, Woller E, Cloninger M, Brechbiel MW: Spin-labeled dendrimers in EPR imaging with low molecular weight nitroxides.

    Angew Chem Int Ed Engl 2001, 40:2690-2692. OpenURL

  83. Akbarzadeh A, Mikaeili H, Asgari D, Zarghami N, Mohammad R, Davaran S: Preparation and in-vitro evaluation of doxorubicin-loaded Fe3O4 magnetic nanoparticles modified with biocompatible copolymers.

    Int J Nanomed 2012, 7:511-526. OpenURL

  84. Abolfazl A, Nosratollah Z, Haleh M, Davoud A, Amir Mohammad G, Khaksar Khiabani H, Soodabeh D: Synthesis, characterization and in vitro evaluation of novel polymer-coated magnetic nanoparticles for controlled delivery of doxorubicin.

    Inter J Nanotechnol Sci Environ 2012, 5:13-25. OpenURL

  85. Akbarzadeh A, Samiei M, Joo SW, Anzaby M, Hanifehpour Y, Nasrabadi HT, Davaran : Synthesis, characterization and in vitro studies of doxorubicin-loaded magnetic nanoparticles grafted to smart copolymers on A549 lung cancer cell line.

    J Nanobiotechnol 2012, 10:46-58. OpenURL

  86. Zohreh E, Nosratollah Z, Manoutchehr K, Soumaye A, Abolfazl A, Mohammad R, Zohreh Mohammad T, Kazem N-K: Inhibition of hTERT gene expression by silibinin-loaded PLGA-PEG-Fe3O4 in T47D breast cancer cell line.

    Bio Impacts 2013, 3(2):67-74. OpenURL

  87. Soodabeh D, Samira A, Kazem N-K, Hamid Tayefi N, Abolfazl A, Amir Ahmad K, Mojtaba A, Somayeh A: Synthesis and study of physicochemical characteristics of Fe3O4 magnetic nanocomposites based on poly(nisopropylacrylamide) for anti-cancer drugs delivery.

    Asian Pac J Cancer Prev 2014, 15(1):049-054. OpenURL

  88. Rogaie R-S, Nosratollah Z, Abolfazl B, Akram E, Abolfazl A, Mustafa R-T: Studies of the relationship between structure and antioxidant activity in interesting systems, including tyrosol, hydroxytyrosol derivatives indicated by quantum chemical calculations.

    Soft 2013, 2:13-18. OpenURL

  89. Kazem N-K, Abolfazl A, Mohammad P-M, San Woo J: Inhibition of leptin and leptin receptor gene expression by silibinin-curcumin combination.

    Asian Pac J Cancer Prev 2013, 14(11):6595-6599. OpenURL

  90. Ghasemali S, Nejati-Koshki K, Akbarzadeh A, Tafsiri E, Zarghami N, Rahmati-Yamchi M, Alizadeh E, Barkhordari A, Tozihi M, Kordi S: Study of inhibitory effect of β-cyclodextrin-helenalin complex on HTERT gene expression in T47D breast cancer cell line by real time quantitative PCR (q-PCR).

    Asian Pac J Cancer Prev 2013, 14(11):6949-6953. OpenURL

  91. Mollazade M, Nejati-Koshki K, Abolfazl A, Younes H, Zarghami N, Sang Woo J: PAMAM dendrimers augment inhibitory effects of curcumin on cancer cell proliferation: possible inhibition of telomerase.

    Asian Pac J Cancer Prev 2013, 14(11):6925-6928. OpenURL

  92. Soodabeh D, Akbar R, Somayeh A, Amir Ahmad K, Kazem N-K, Hamid Tayefi N, Abolfazl A: Synthesis and physicochemical characterization of biodegradable star-shaped poly lactide-co-glycolide–β-cyclodextrin copolymer nanoparticles containing albumin.

    Adv Nanoparticles 2014, 3:14-22. OpenURL

  93. Soodabeh D, Abolfazl A, Kazem N-K, Somayeh A, Mahmoud Farajpour G, Mahsa Mahmoudi S, Akbar R, Amir Ahmad K: In vitro studies of NIPAAM-MAA-VP copolymer-coated magnetic nanoparticles for controlled anticancer drug release.

    J Encapsul Adsorption Sci 2013, 3:108-115. OpenURL

  94. Ahmadi A, Shirazi H, Pourbagher N, Akbarzadeh A, Omidfar K: An electrochemical immunosensor for digoxin using core-shell gold coated magnetic nanoparticles as labels.

    Mol Biol Rep 2014, 41(3):1659-1668. OpenURL

  95. Abolfazl A, Samiei M, Soodabeh D: Magnetic nanoparticles: preparation, physical properties and applications in biomedicine.

    Nanoscale Res Lett 2012, 7:144-157. OpenURL

  96. Alireza V, Haleh M, Mohammad S, Samad Mussa F, Nosratollah Z, Mohammad K, Abolfazl A, Soodabeh D: Quantum dots: synthesis, bioapplications, and toxicity.

    Nanoscale Res Lett 2012, 7:276. OpenURL

  97. Abolfazl A, Rogaie R-S, Soodabeh D, Sang Woo J, Nosratollah Z, Younes H, Mohammad S, Mohammad K, Kazem N-K: Liposome: classification, preparation, and applications.

    Nanoscale Res Lett 2013, 8:102. OpenURL

  98. Mohammad P-M, Mohammad R-Y, Abolfazl A, Hadis D, Kazem N-K, Younes H, Sang Woo J: Protein detection through different platforms of immuno-loop-mediated isothermal amplification.

    Nanoscale Res Lett 2013, 8:485. OpenURL

  99. Mohammad K, Ali V, Abolfazl A, Younes H, Sang Woo J: Investigation of quadratic electro-optic effects and electro absorption process in GaN/AlGaN spherical quantum dot.

    Nanoscale Res Lett 2014.

    in press

    OpenURL

  100. Fariba B, Alireza V, Kazem B, Samane M, Samad Mussa F, Nasrin S, Najme Malekzadeh G, Abolfazl A, Younes H, Sang Woo J, Mohammad R-Y: Nanodetection and nanodrug delivery in lung cancer.

    Nano Rev 2014.

    in press

    OpenURL

  101. Sohrabi N, Sohrabi Z, Valizadeh A, Mohammadi S, Mussa Farkhani S, Malekzadeh Gonabadi N, Mohammadi M, Badrzade F, Akbarzadeh A, Woo Joo S, Hanifehpour Y: Basic of DNA biosensors and cancer diagnosis.

    Nano Rev 2014.

    in press

    OpenURL

  102. Tabatabaei Mirakabad FS, Akbarzadeh A, Zarghami N, Zeighamian V, Rahimzadeh A, Alimohammadi S: PLGA-cased nanoparticles as cancer drug delivery systems.

    APJCP 2014, 15(1):517-535. OpenURL

  103. Valizadeh H, Mohammadi G, Ehyaei R, Milani M, Azhdarzadeh M, Zakeri-Milani P, Lotfipour F: Antibacterial activity of clarithromycin loaded PLGA nanoparticles.

    Pharmazie Int J Pharm Sci 2012, 67(1):63-68. OpenURL

  104. Hasani A, Sharifi Y, Ghotaslou R, Naghili B, Aghazadeh M, Milani M: Molecular screening of virulence genes in high-level gentamicin-resistant Enterococcus faecalis and Enterococcus faecium isolated from clinical specimens in Northwest Iran.

    Indian J Med Microbiol 2012, 30:2. OpenURL

  105. Sharifi Y, Hasani A, Ghotaslou R, Varshochi M, Hasani A, Soroush MH, Aghazadeh M, Milani M: Vancomycin-resistant Enterococci among clinical isolates from north-west Iran: identification of therapeutic surrogates.

    J Med Microbiol 2012, 61(4):600-602. OpenURL

  106. Farajnia S, Hassan M, HallajNezhadi S, Mohammadnejad L, Milani M, Lotfipour F: Determination of indicator bacteria in pharmaceutical samples by multiplex PCR.

    J Rapid Meth Aut Mic 2009, 17(3):328-338. OpenURL