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Dendrimers – fascinating nanoparticles

science • technique

in the application in medicine


Małgorzata 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 dendrimers The term “dendrimer” appeared for the first time in 1985 in the
The first information about the new class of branched molecules publication prepared by Donald Tomalia and co-workers. This name
appeared in 1974 [1] in a publication written by a team of German refers to their tree-like structure and is a combination of two Greek
chemist Fritz Vögtle, and because of their characteristic structure they words – “dendron” meaning tree and “meros” meaning part [3]. One
were called an “octopus molecules”. A few years later, in 1978, the year later the same team described the first of the two currently
same group described the synthesis of these compounds, this time known ways of synthesis of this compound – the divergent method,
giving them a name “cascade molecules”[2]. However, they were not based on the attachment of a new monomers to the multifunctional
a typical dendrimers (Fig.1). 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
Fig. 1. Octopus molecule obtained by Vögtle’s team to change their chemical and physical properties. There are two types
of dendrimer generation – a full generation with hydroxyl or amine
At that time, the aim of synthesis of these highly branched molecules surface group and a half generation with carboxyl surface group.
was obtaining particles, which would facilitate the dissolution of The last characteristic elements in the structure of dendrimers are
hydrophilic compounds in hydrophobic solvents. 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,
Fig. 2. The structure of dendrimer PAMAM G3 described polymers are characterized by unusually high reactivity.
These features enable the attachment of various particles to the
Corresponding author:
Małgorzata KUBIAK,, e-mail: malgosia.m.kubiak@gmail.com surface of dendrimers, e.g. drug substances, which are currently

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administered as a monomers. It was observed, that the compound It cannot be clearly determined which method is better,

science • technique
itself exhibit a significantly weaker activity in comparisons with the therefore, before the selection of one of them, many different
equivalent amount of drug attached to dendrimer – it is referred to as factors should be taken into consideration (e.g. type of monomer
“a dendrimeric effect” [6]. Moreover, due to the presence of empty or structure of dendrimer).
spaces between branches, they can be used to encapsulate smaller
molecules. An important feature of described polymers is the facility Biomedical application of dendrimers
of changing the nature of these compounds only by modification of Dendrimers, thanks to their unique feature, may in the future
terminal functional groups. However, the high cytotoxicity of some be applied in many various fields of science and industry. Currently,
types of dendrimers cannot be ignored, because this feature limits a fundamental limitation is the high cost of production of these
their use in medicine. compounds. A lot of attention is paid to the research on the use
of these polymers in medicine, chemistry, genetic engineering and
Synthesis of dendrimers environmental protection. The first of these trends arouses the
Dendrimers are produced in iterative sequence of several greatest interest due to the permanent demand for a new, better
reactions, each time leading to the creation of higher generation of and more effective forms of therapy, especially, in the case of
polymer. Every new layer creates molecule with double number of diseases, for which no cure has not yet been found.
active end groups and more than double molecular weight of the Studies on the dendrimer application in medicine can be divided
previous generation. One of the most appealing aspects of dendrimers into two major categories – described molecules can be used as
is a possibility of precise control at every stage of synthesis, which carrier for other substances or as therapeutic agent themselves.
allows to obtain a molecule with early designed, well-defined One of the first in vitro studies in this field was associated with the
structure. Dendrimers can be made from any type of compounds, production of magnetic resonance imaging (MRI) contrast agent
whose nature determines their solubility and biological activity. Most using dendrimers. Mostly used contrast agents are based on the
of the commonly encountered types in biological application are complex of gadolinium ion (Gd3+) and chelating ligand such as
based on polyamidoamines, polyamines, polipeptydes, poliamides, DOTA (1,4,7,10-tetraazacyclododecane tetraacetic acid) or DTPA
polyesters, carbohydrates and nucleic acid. (diethylenetriaminepentaacetic acid) [8, 9]. Chelators are required
As mentioned earlier, the first applied method of dendrimer due to the high toxicity of free gadolinium ions – it accumulates in
synthesis was the divergent method proposed by the Tomalia group. human body including the liver, brain or bones [10, 11]. Described
In this process described polymers grow outward by successive contrast agents are characterized by low molecular weight and
attaching a new layer of the monomers to a multifunctional core therefore, they are removed too quickly from the body. The solution
(Fig.4). Each reaction step results in an increase of molecule diameter, to this problem could be to conjugate gadolinium complexes with
and arms become more and more branched. The last phenomenon is natural or synthetic polymers such as polysaccharides, proteins,
the reason of one of the most important disadvantage of this method polylysine [12]. These conjugates showed a better efficiency in
– congestion of the terminal functional groups with increased dendrimer imaging of tissues, however, this time they reminded in the body
generation, which results in loss of their reactivity. Furthermore, the for too long, which might results in undesirable accumulation of
post-reaction mixture consists a large number of molecules with gadolinium compound. In 1994 Wiener group proposed for the first
various structural defects and with smaller than expected weight. time the use of PAMAM dendrimer as a carrier for the gadolinium
To avoid these problems, a large excess of reagents (monomers) shall complexes [13]. The results of these studies were so promising,
be used, however, this significantly increases the cost of synthesis and that it drew the attention one of the pharmaceutical companies,
makes the purification of the final product more difficult. 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
Fig. 4. Divergent method of dendrimer synthesis 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
As a response to the weaknesses of the divergent method, in
enhancement of hydrophobic compounds (as a carrier – dendrimer
1990 Hawker and Fréchet proposed a different way of dendrimer
with hydrophobic interior and hydrophilic surface) and in the distant
synthesis – convergent method [7]. In this approach the first step is
future – the opportunity to design the targeted therapy [14]. The
obtaining highly branched dendrons, which can be then connected
exceptional ability of dendrimers to penetrate the cell membrane
to multifunctional core (Fig.5). The great advantage in this case is
was the reason for starting the research on the use of them as
easier and more precise control of synthesis, and thanks to that, it
a non-viral transfecting agent. Dendrimers with positively charged
is possible to obtain highly pure molecules, which are free from any
terminal groups (e.g. PAMAM) can easily bind to the negatively
defects. What is more, this method enables to design dendrimers,
charged phosphate residues of nucleic acids. These complexes
in which every dendrons are different. However, this is not an ideal
exhibit an increase stability and high transfection efficiency. The
way for producing describing polymers, because – due to the steric
use of viral vectors carries some risk for the researcher, which
effect – it allows only for the synthesis of small molecule.
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
Fig. 5. Convergent method of dendrimer synthesis the immunogenicity of the vaccines [6].

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Table 1
science • technique
Summary 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) 1) Optimal circulation time within the body Gadomer 17 – contrast agent containing gadolinium chelates
contrast agent 2) Reduced risk of accumulations of gadolinium compounds based on polylysine dendrimers
3) Good quality of imaging

Drug carrier: 1) Increase the solubility of hydrophobic drugs in aqueous Niclosamide – antiparasitic drug, almost insoluble in water –
environment of body fluids [25] after encapsulation in PAMAM drendrimers increased solubility
- particles encapsulated inside dendrimers
2) Increased cell membrane permeability for drugs This also enabled the controlled drug released [26]
3) The protection of unstable drugs during the transport within
the body Cisplatin – popular anticancer drug – thanks to the combination
- particles attached to the surface groups
4) Controlled and prolonged release of drugs, and thereby with PAMAM dendrimer it was possible to achieve slower
reducing their toxicity release, lower toxicity, and also increased accumulation in tumor
5) The possibility of lower dosage of the drugs cells [27]
6) Minimizing the negative side effects of medicines [14]
Ketoprofen – nonsteroidal anti-inflammatory drug – the
7) The possibility of attachment of various active substances to
medicine was bound to the PAMAM dendrimer – thereby
one molecule of dendrimer [28]
8) The possibility of targeting the drug to certain tissues obtained enhanced solubility in aqueous solution, an increase in its
- targeted therapy [25] concentration in the blood, and prolonged effect of this drug [29]

Gene therapy (non-viral transfection 1) High efficiency of nucleic acids transport Dendrimer-oligonucleotide-plasmid complex – tumor
agents) growth inhibitory factor. Plasmid contains a gene encoding
2) Protection from degradation
tissue inhibitor of metalloproteinase or angiostatin (endogenous
3) High stability under the wide range of pH angiogenesis inhibitor) [34]
4) Easy transfer of genes through the cell wall SuperFect® (Qiagen) – commercially available transfection
5) Gene expression in vitro in various mammalian cell lines and in agent, based on PAMAM dendrimers [35, 36]
vivo in various animal tissues [30, 31, 32, 33]

Dendrimer-based vaccines 1) The ability to bind multiple copies of an antigen - increased Vaccine against malaria – based on multiple antigenic peptide
immunogenicity of the vaccine (MAP) dendrimers, currently in phase I clinical trials [6]
2) The possibility to omit protein carriers, which could be Vaccines against HIV – created using various kinds of
a potential sensitiser. dendrimers [37]

Dendrimers per se

Antiviral and antibacterial agents 1) The ability to block receptors on the surface of the virus Sialodendrimers – inhibitors of hemagglutination process of
2) Prevention of the attachment of pathogens to mammalian human erythrocytes induced by influenza virus [17]
cells either by strong adhesion to the bacterial cell wall and
surface of the virus or by coating the potentially attacked
cells. VivaGel® (Starpharma Ltd.) – drug for women based on
polylysine dendrimers (G4), protects against HIV infection. It
3) The ability to destroy the negatively charged bacterial
works by blocking the receptors on the surface of the virus.
membrane, which results in the lysis of the cell [38, 29]
Currently in phase III clinical trials [40]

Treatment of neurodegenerative diseases 1) Prevention of the formation of harmful amyloid deposits PAMAM Denrimers G3, G4, G5 – inhibitors of formation of
(Alzheimer’s, Parkinson’s, prion) 2) The ability to destroy existing fibrillar protein aggregates 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 Half-generation PAMAM dendrimers (G4.5) with
the induction of inflammatory response of the body functional groups conjugated with glucosamine – the
2) The ability to reduce existing inflammatory response presence of these nanoparticles inhibits the secretion of
proinflammatory chemokines and cytokines by LPS
3) High solubility in water (compared with non-steroidal anti-
inflammatory drugs) 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 described nanoparticles against the influenza virus. For this purpose
molecules, it is possible to apply them as an independent active they applied sialic acid-conjugated dendrimers [17]. Described
substance. First of all, these nanoparticles show strong antibacterial nanopolymers bind to the haemagglutinin present on the surface
and antiviral properties. Dendrimers may act in two ways: either of the virus and thus prevent the adhesion of the pathogen
by coating viruses and bacterial cells or by covering potentially to the cell. Another direction of research on the application of
attacked mammalian cells, thereby protecting from the infection dendrimers per se is associated with attempts to use them in
[16]. One of the first studies in this area concerned the use of 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 4. Tomalia D.A., Baker H., Dewald J., Hall M., Kallos G., Martin S., Roeck

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and Food Sciences at Lodz University of Technology in November
33. Qin L., Pahud D.R., Ding Y., Bielinska A.U., Kukowska-Latallo J.F., Baker J.R.Jr.,
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in mice. Clin. Cancer Res. 2001, 7, 11, 3606–3612

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się: 27 marca 2014 r. o godzinie 16:00.   nie fotoniki, w obszarze: Optoelectronic components and systems for
Ogłoszone w ramach I Konkursu tematy zawierają się w trzech ob- smart production,communication and medicine.
szarach tematycznych wskazanych w Założeniach Wspólnego Przed- NCBR przeznacza kwotę 1 500 000 EUR na dofinansowanie pro-
sięwzięcia CuBR. jektów polskich podmiotów, które zostaną zaakceptowane do finanso-
• Obszar I Górnictwo i geologia wania w procedurze konkursowej. Termin składania wniosków upływa
Temat zagadnienia: Opracowanie innowacyjnej technologii udostęp- 31 marca 2014 r. (em)
niania złoża głębokiego (http://www.ncbir.pl/ 16 luty 2014 r.)
dokończenie na stronie 160

150 • nr 2/2014 • tom 68

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