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Dendrimers – fascinating nanoparticles in the application in medicineMałgorzata KUBIAK* – Student Scientific Association FERMENT at Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Lodz, Poland

Please cite as: CHEMIK 2014, 68, 2, 141–150

A few words about the history of dendrimersThe first information about the new class of branched molecules

appeared in 1974 [1] in a publication written by a team of German chemist Fritz Vögtle, and because of their characteristic structure they were called an “octopus molecules”. A few years later, in 1978, the same group described the synthesis of these compounds, this time giving them a name “cascade molecules”[2]. However, they were not a typical dendrimers (Fig.1).

Fig. 1. Octopus molecule obtained by Vögtle’s team

At that time, the aim of synthesis of these highly branched molecules was obtaining particles, which would facilitate the dissolution of hydrophilic compounds in hydrophobic solvents.

Fig. 2. The structure of dendrimer PAMAM G3

The term “dendrimer” appeared for the first time in 1985 in the publication prepared by Donald Tomalia and co-workers. This name refers to their tree-like structure and is a combination of two Greek words – “dendron” meaning tree and “meros” meaning part [3]. One year later the same team described the first of the two currently known ways of synthesis of this compound – the divergent method, based on the attachment of a new monomers to the multifunctional core [4]. As a results of this research Tomalia obtained polyamidoamine (PAMAM) dendrimers, which are currently the best studied and, thanks to that, the best known molecules belonging to this group of compounds. At the same time, the group of Newkome synthesized the similar type of nanoparticles and called them “arborols” [5], but this name, which derives from Latin word “arbor” (also meaning tree), was not adopted.

At first, these fascinating branched molecules did not draw special attention of the scientific community, but the situation changed with the development of nanotechnology.

What are dendrimers?Dendrimers are highly branched, organic compounds with

well-defined, symmetrical structure. From chemical point of view they are three-dimensional polymers, characterized by a globular shape. As depicted in Figure 3, in the central part of molecule is located a multifunctional core, from which emanate radially perfectly branched monomers, called dendrons. At the end of the arms are terminals, functional groups, which can be easily modified in order to change their chemical and physical properties. There are two types of dendrimer generation – a full generation with hydroxyl or amine surface group and a half generation with carboxyl surface group. The last characteristic elements in the structure of dendrimers are internal cavities – the empty spaces, which can be used as a “pocket” for different kind of small particles.

Fig. 3. Schematic description of dendrimer structure

The structure of dendrimers has a significant impact on their chemical and physical properties and on their potential application. First of all, thanks to a large number of terminal functional groups, described polymers are characterized by unusually high reactivity. These features enable the attachment of various particles to the surface of dendrimers, e.g. drug substances, which are currently

Corresponding author: Małgorzata KUBIAK,, e-mail: malgosia.m.kubiak@gmail.com

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administered as a monomers. It was observed, that the compound itself exhibit a significantly weaker activity in comparisons with the equivalent amount of drug attached to dendrimer – it is referred to as “a dendrimeric effect” [6]. Moreover, due to the presence of empty spaces between branches, they can be used to encapsulate smaller molecules. An important feature of described polymers is the facility of changing the nature of these compounds only by modification of terminal functional groups. However, the high cytotoxicity of some types of dendrimers cannot be ignored, because this feature limits their use in medicine.

Synthesis of dendrimersDendrimers are produced in iterative sequence of several

reactions, each time leading to the creation of higher generation of polymer. Every new layer creates molecule with double number of active end groups and more than double molecular weight of the previous generation. One of the most appealing aspects of dendrimers is a possibility of precise control at every stage of synthesis, which allows to obtain a molecule with early designed, well-defined structure. Dendrimers can be made from any type of compounds, whose nature determines their solubility and biological activity. Most of the commonly encountered types in biological application are based on polyamidoamines, polyamines, polipeptydes, poliamides, polyesters, carbohydrates and nucleic acid.

As mentioned earlier, the first applied method of dendrimer synthesis was the divergent method proposed by the Tomalia group. In this process described polymers grow outward by successive attaching a new layer of the monomers to a multifunctional core (Fig.4). Each reaction step results in an increase of molecule diameter, and arms become more and more branched. The last phenomenon is the reason of one of the most important disadvantage of this method – congestion of the terminal functional groups with increased dendrimer generation, which results in loss of their reactivity. Furthermore, the post-reaction mixture consists a large number of molecules with various structural defects and with smaller than expected weight. To avoid these problems, a large excess of reagents (monomers) shall be used, however, this significantly increases the cost of synthesis and makes the purification of the final product more difficult.

Fig. 4. Divergent method of dendrimer synthesis

As a response to the weaknesses of the divergent method, in 1990 Hawker and Fréchet proposed a different way of dendrimer synthesis – convergent method [7]. In this approach the first step is obtaining highly branched dendrons, which can be then connected to multifunctional core (Fig.5). The great advantage in this case is easier and more precise control of synthesis, and thanks to that, it is possible to obtain highly pure molecules, which are free from any defects. What is more, this method enables to design dendrimers, in which every dendrons are different. However, this is not an ideal way for producing describing polymers, because – due to the steric effect – it allows only for the synthesis of small molecule.

Fig. 5. Convergent method of dendrimer synthesis

It cannot be clearly determined which method is better, therefore, before the selection of one of them, many different factors should be taken into consideration (e.g. type of monomer or structure of dendrimer).

Biomedical application of dendrimersDendrimers, thanks to their unique feature, may in the future

be applied in many various fields of science and industry. Currently, a fundamental limitation is the high cost of production of these compounds. A lot of attention is paid to the research on the use of these polymers in medicine, chemistry, genetic engineering and environmental protection. The first of these trends arouses the greatest interest due to the permanent demand for a new, better and more effective forms of therapy, especially, in the case of diseases, for which no cure has not yet been found.

Studies on the dendrimer application in medicine can be divided into two major categories – described molecules can be used as carrier for other substances or as therapeutic agent themselves. One of the first in vitro studies in this field was associated with the production of magnetic resonance imaging (MRI) contrast agent using dendrimers. Mostly used contrast agents are based on the complex of gadolinium ion (Gd3+) and chelating ligand such as DOTA (1,4,7,10-tetraazacyclododecane tetraacetic acid) or DTPA (diethylenetriaminepentaacetic acid) [8, 9]. Chelators are required due to the high toxicity of free gadolinium ions – it accumulates in human body including the liver, brain or bones [10, 11]. Described contrast agents are characterized by low molecular weight and therefore, they are removed too quickly from the body. The solution to this problem could be to conjugate gadolinium complexes with natural or synthetic polymers such as polysaccharides, proteins, polylysine [12]. These conjugates showed a better efficiency in imaging of tissues, however, this time they reminded in the body for too long, which might results in undesirable accumulation of gadolinium compound. In 1994 Wiener group proposed for the first time the use of PAMAM dendrimer as a carrier for the gadolinium complexes [13]. The results of these studies were so promising, that it drew the attention one of the pharmaceutical companies, Schering AG, whose product – Gadomer 17 – is currently in phase II clinical trials. Another extremely popular research direction arose from two unique structural features of dendrimers – a large number of terminal groups and empty cavities between the arms. Thanks to these properties, described polymers may be used as drug carriers both on the surface of molecule and in its interior. Amidst numerous advantages of this application it should be mentioned the increase of effectiveness and elimination of side effects of cancer therapy, the possibility of controlled drug release, the solubility enhancement of hydrophobic compounds (as a carrier – dendrimer with hydrophobic interior and hydrophilic surface) and in the distant future – the opportunity to design the targeted therapy [14]. The exceptional ability of dendrimers to penetrate the cell membrane was the reason for starting the research on the use of them as a non-viral transfecting agent. Dendrimers with positively charged terminal groups (e.g. PAMAM) can easily bind to the negatively charged phosphate residues of nucleic acids. These complexes exhibit an increase stability and high transfection efficiency. The use of viral vectors carries some risk for the researcher, which can be avoided by applying dendrimer transection agents [15]. Another application of these nanoparticles is connected with their multivalency – described feature may be used to create a new generation of vaccines. Presence of numerous functional groups on the surface of particles enables the attachment of multiple copies of both the identical and the different antigens, and therefore enhance the immunogenicity of the vaccines [6].

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Table 1Summary of the most important application of dendrimers in medicine

Biomedical application of dendrimers The advantages of using dendrimers Selected examples

Dendrimers + active substances

Magnetic resonance imaging (MRI) contrast agent

1) Optimal circulation time within the body 2) Reduced risk of accumulations of gadolinium compounds 3) Good quality of imaging

Gadomer 17 – contrast agent containing gadolinium chelates based on polylysine dendrimers

Drug carrier:

- particles encapsulated inside dendrimers

- particles attached to the surface groups

1) Increase the solubility of hydrophobic drugs in aqueous environment of body fluids [25]

2) Increased cell membrane permeability for drugs 3) The protection of unstable drugs during the transport within

the body4) Controlled and prolonged release of drugs, and thereby

reducing their toxicity 5) The possibility of lower dosage of the drugs6) Minimizing the negative side effects of medicines [14]7) The possibility of attachment of various active substances to

one molecule of dendrimer [28]8) The possibility of targeting the drug to certain tissues

- targeted therapy [25]

Niclosamide – antiparasitic drug, almost insoluble in water – after encapsulation in PAMAM drendrimers increased solubility This also enabled the controlled drug released [26]

Cisplatin – popular anticancer drug – thanks to the combination with PAMAM dendrimer it was possible to achieve slower release, lower toxicity, and also increased accumulation in tumor cells [27]

Ketoprofen – nonsteroidal anti-inflammatory drug – the medicine was bound to the PAMAM dendrimer – thereby obtained enhanced solubility in aqueous solution, an increase in its concentration in the blood, and prolonged effect of this drug [29]

Gene therapy (non-viral transfection agents)

1) High efficiency of nucleic acids transport

2) Protection from degradation

3) High stability under the wide range of pH

4) Easy transfer of genes through the cell wall

5) Gene expression in vitro in various mammalian cell lines and in vivo in various animal tissues [30, 31, 32, 33]

Dendrimer-oligonucleotide-plasmid complex – tumor growth inhibitory factor. Plasmid contains a gene encoding tissue inhibitor of metalloproteinase or angiostatin (endogenous angiogenesis inhibitor) [34]

SuperFect® (Qiagen) – commercially available transfection agent, based on PAMAM dendrimers [35, 36]

Dendrimer-based vaccines 1) The ability to bind multiple copies of an antigen - increased immunogenicity of the vaccine

2) The possibility to omit protein carriers, which could be a potential sensitiser.

Vaccine against malaria – based on multiple antigenic peptide (MAP) dendrimers, currently in phase I clinical trials [6]

Vaccines against HIV – created using various kinds of dendrimers [37]

Dendrimers per se

Antiviral and antibacterial agents 1) The ability to block receptors on the surface of the virus

2) Prevention of the attachment of pathogens to mammalian cells either by strong adhesion to the bacterial cell wall and surface of the virus or by coating the potentially attacked cells.

3) The ability to destroy the negatively charged bacterial membrane, which results in the lysis of the cell [38, 29]

Sialodendrimers – inhibitors of hemagglutination process of human erythrocytes induced by influenza virus [17]

VivaGel® (Starpharma Ltd.) – drug for women based on polylysine dendrimers (G4), protects against HIV infection. It works by blocking the receptors on the surface of the virus. Currently in phase III clinical trials [40]

Treatment of neurodegenerative diseases (Alzheimer’s, Parkinson’s, prion)

1) Prevention of the formation of harmful amyloid deposits

2) The ability to destroy existing fibrillar protein aggregates

PAMAM Denrimers G3, G4, G5 – inhibitors of formation of amyloid plaques. They are also characterized by the ability to degrade the existing deposites [41]

Anti-inflammatory agents 1) The ability to inhibit the synthesis of protein secreted during the induction of inflammatory response of the body

2) The ability to reduce existing inflammatory response

3) High solubility in water (compared with non-steroidal anti-inflammatory drugs)

Half-generation PAMAM dendrimers (G4.5) with functional groups conjugated with glucosamine – the presence of these nanoparticles inhibits the secretion of proinflammatory chemokines and cytokines by LPS

Phosphorus dendrimers covered with bisphosphonate (ABP) groups – as above, additionally enhance the NK cell proliferation

PAMAM dendrimers - exhibit anti-inflammatory activity in vivo in studies using models representing the two types of inflammation - acute and chronic

Besides the use of dendrimers as a complex with other molecules, it is possible to apply them as an independent active substance. First of all, these nanoparticles show strong antibacterial and antiviral properties. Dendrimers may act in two ways: either by coating viruses and bacterial cells or by covering potentially attacked mammalian cells, thereby protecting from the infection [16]. One of the first studies in this area concerned the use of

described nanoparticles against the influenza virus. For this purpose they applied sialic acid-conjugated dendrimers [17]. Described nanopolymers bind to the haemagglutinin present on the surface of the virus and thus prevent the adhesion of the pathogen to the cell. Another direction of research on the application of dendrimers per se is associated with attempts to use them in the treatment of neurodegenerative diseases such as Parkinson’s

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disease, Alzheimer’s disease or prion diseases. In all of cases the characteristic feature is the formation, and then the accumulation of amyloid deposits – fibrillar aggregates built from proteins, which are normally dissolved. It turned out that dendrimers not only inhibit the formation of amyloid plaques, but also destroy the already existing [18, 19]. This direction seems to be particularly important, due to the fact that there are still no effective treatment methods for these diseases. Among the numerous studies on the properties of dendrimers in relation to their potential use in medicine, anti-inflammatory activity of these compounds is one of the most recent and promising discoveries in this field, therefor in this paper more attention was paid to this. Great interest in this subject is enhanced by an urgent need for a new, effective ways of treatment of autoimmune diseases such as rheumatoid arthritis, celiac disease, lupus or psoriasis. The first report mentioning the anti-inflammatory effects of dendrimers appeared in 2004, and its main topic was the prevention of scar tissue formation [20]. The research has been conducted using the half-generation PAMAM dendrimers (G4.5), in which a few of terminal carboxyl groups were conjugated with glucosamine. It turned out that despite the lipopolysaccharide (LPS, from Salmonella minnesota) stimulation, in the presence of these nanoparticles the immune cells did not produced neither proinflammatory chemokines nor cytokines – proteins secreted during the induction of inflammatory response of the body. Another study, this time with the use of phosphorus dendrimers covered with bisphosphonate (ABP) groups, has led to the discovery of strong immunomodulatory and anti-inflammatory properties of these molecules [21, 22]. As in the previous example, they inhibited the release of pro-inflammatory proteins.

It is worth mentioning, that the described dendrimers enhance the proliferation of natural killer (NK) cells [23], which are cytotoxic effectors against bacteria-, virus- or parasite-infected cells, and also against tumor cells – what gives a chance to use them in cancer therapy. In 2009 the Tomalia group conducted in vivo studies on the use of PAMAM dendrimers as a potential carrier for indomethacin – compound belongs to the group of non-steroidal anti-inflammatory drugs. Rats with induced inflammation were divided into three groups – the first was treated with indomethacin alone, the second with complex of dendrimer and indomethacin and the third with dendrimer alone (it was intended to be a negative control). Unexpectedly, it turned out that the free PAMAM dendrimer showed anti-inflammatory activity, and what is even more interesting – it was comparable to the effect induced by the complex of nanopolymer and indomethacin [24].

The most important biomedical applications, their advantages and selected examples are summarised in Table 1.

SummaryDendrimers are polymers characterized by a unique structure

from which derive their unique properties. In this study attention was drawn to the potential use of these compounds in medicine, however, it should be noted that all these examples are still in the phase of intensive research. Nevertheless, dendrimers give hope to create new methods for the treatment of diseases for which it have not yet be found a cure, such as neurodegenerative diseases or autoimmune diseases.

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* Małgorzata KUBIAK – she graduated from the Faculty of Biotechnology

and Food Sciences at Lodz University of Technology in November

2013 with an excellent result with Master’s Degree in Biotechnology

(specialization: Molecular Biotechnology and Technical Biochemistry). She

is the author of 5 posters (2 at the international conferences and 3 at the

national conferences). She has been a member of Scientific Association of

Biotechnology Students FERMENT since October 2010.

Uchida E., Mizuguchi H., Ishii-Watabe A., Hayakawa T.: 35. Comparison of the efficiency and safety of non-viral vector-mediated gene transfer into a wide range of human cells. Biol. Pharm. Bull.2002, 25, 7, 891–897Leng Q., Mixson A.J.: 36. Modified branched peptides with a histidine-rich tail enhance in vitro gene transfection. Nucleic Acids Res. 2005, 33, 4, e40Dzmitruk V., Shcharbin D., Pedziwiatr E., Bryszewska M.: 37. Dendrimers in Anti-HIV Therapy. Advances in Nanocomposite Technology 2011Boas U., Heegaard P.M.: 38. Dendrimers in drug research. Chem. Soc. Rev. 2004, 33,1, 43–63Chen C.Z., Cooper S.L.: 39. Interactions between dendrimer biocides and bacterial membranes. Biomaterials 2002, 23, 16, 3359–3368Price C.F,, Tyssen D., Sonza S., Davie A., Evans S., Lewis G.R., Xia 40. S., Spelman T., Hodsman P., Moench T.R., Humberstone A., Paull J.R., Tachedjian G.: SPL7013 Gel (VivaGel®) retains potent HIV-1 and HSV-2 inhibitory activity following vaginal administration in humans. PLOS One 2011, 6, 9, e24095Klajnert B., Cortijo-Arellano M., Cladera J., Bryszewska M.: 41. Influence of dendrimer’s structure on its activity against amyloid fibril formation. Biochem. Biophys. Res. Commun. 2006, 345, 1, 21–28

Translation into English by the Author

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