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Dendrimers: A Review

Article January 2010

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 REVIEW ARTICLE

periphery of the molecule is activated for

Dendrimers: A Review reaction with more monomers. The two steps
Vineet Mathur*1, Yamini Satrawala2, Mithun Singh Rajput3 can be repeated. The divergent approach is
successful for the production of large
Abstract: Dendrimers are a new class of polymeric materials. They are highly branched, quantities of dendrimers since, in each
monodisperse macromolecules. Structural Advantages allow dendrimers to play an important generation-adding step, the molar mass of the
role in the fields of nanotechnology, pharmaceutical and medicinal chemistry. As a result of their dendrimer is doubled. The first synthesized
unique behaviour dendrimers are suitable for a wide range of biomedical and industrial dendrimers were polyamidoamines
applications. The bioactive agents can be easily encapsulated into the interior of the dendrimers (PAMAMs). They are also known as starbust
or chemically attached that is conjugated or physically adsorbed onto the dendrimer surface, dendrimers [7].
serving the desired properties of the carrier to the specific needs of the active material and its
therapeutic applications. The review aims to emphasize on construction, characterisation, drug
delivery and possible application of dendrimers in various areas of research, technology and
treatment.
Keywords: Dendrimer, drug delivery, polyamidoamine dendrimer (PAMAM).

INTRODUCTION an initiator core, interior layers (generations)

Dendrimers are repeatedly branched
molecules. The huge number of papers on
dendritic architectures such as dendrimers,
dendronized, hyperbranched and brush-
polymers has generated a vast variety of
inconsistent terms and definitions making a
clear and concise unfolding of this topic highly
difficult. A dendrimer is generally described as
a macromolecule, which is characterized by its
highly branched three diamentional structure
that provides a high degree of surface
functionality and versatility. Dendrimers have
often been referred to as the Polymers of the
21st century. Dendrimer chemistry was first
introduced in 1978 by Fritz Vogtle and co-
workers [1]. He synthesized the first cascade
molecules. In 1985, Donald A. Tomalia,
synthesized the first family of dendrimers [2].
The word dendrimer originated from two
words, the Greek word dendron, meaning tree,
and meros, meaning part. At the same time,
Newkome et al [3] independently reported
synthesis of similar macromolecules. They
called them arborols from the Latin word
arbor also meaning a tree. The term cascade
molecule is also used, but dendrimer is the
best established one. Due to their multivalent
and monodisperse character, dendrimers have
stimulated wide interest in the field of
chemistry and biology, especially in
applications like drug delivery, gene therapy
and chemotherapy. Dendrimers then
experienced an explosion of scientific interest
because of their unique molecular
architecture.
Dendrimers possess three distinguished
architectural components (Figure 1), namely
composed of repeating units, radically
attached to the interior core and exterior
(terminal functionality) attached to the
outermost interior generations [4, 5].
Figure 2. Divergent growth of dendrimer
Convergent dendrimer growth
The 'convergent' approach was developed as a
response to the weaknesses of divergent
syntheses. Convergent growth begins at what
will end up being the surface of the dendrimer,
and works inwards by gradually linking
surface units together with more. When the
Figure 1. Architecture of a dendrimer growing wedges are large enough, several are
attached to a suitable core to give a complete
Synthesis of dendrimers dendrimer (Figure 3). The advantages of
The synthesis used for dendrimer preparation convergent growth over divergent growth
permit almost entire control over the critical stem that only two simultaneous reactions are
molecular design parameters such as size, required for any generation-adding step [7].
shape, surface/interior chemistry, flexibility, The convergent methodology also suffers from
and topology. Many dendrimer syntheses rely low yields in the synthesis of large structures.
upon traditional reactions, such as the Michael
reaction or the Williamson ether synthesis
whilst others involve the use of modern
techniques and chemistry, such as solid-phase
synthesis, organo-transition-metal chemistry,
organo-silicon chemistry, organo-phosphorus
chemistry, or other contemporary organic
methodologies. The choice of the growth
reaction dictates the way in which the
Figure 3. Convergent growth of dendrimer
branching should be introduced into the
dendrimer. Branching may be present in the
building blocks as is more often the case or it
can be created as a function of the growth
reaction, as is the case with the
polyamidoamines and the
polypropyleneimines [6].

1Niper,ITI Compound, Shri Bhawani Paper Mill Road,
Rae Bareli 229010, UP, India. E-mail:
vineet.mathur6@gmail.com
2Department of Pharmacy, Shri G S Institute of
Technology and Science 23 - Park Road, Indore -
452003, MP, India.
3Collegeof Pharmacy, IPS Academy, Rajendra Nagar,
A B Road, Indore- 452012, India.
Divergent dendrimer growth
The synthetic methodology employed in the
early dendrimer syntheses came to be known
as the 'divergent' approach (Figure 2). This
name comes from the way in which the
dendrimer grows outwards from the core,
diverging into space. Starting from a reactive
core, a generation is grown, and then the new
Figure 4. A schematic representation of
double exponential and mixed growth of
dendrimer
Double exponential and mixed growth
The most recent fundamental breakthrough in
the practice of dendrimer synthesis has come

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 REVIEW ARTICLE
with the concept and implications of 'double
exponential' growth (Figure 4). Double
exponential growth, similar to a rapid growth
technique for linear polymers, involves an AB2
monomer with orthogonal protecting groups
for the A and B functionalities. This approach
allows the preparation of monomers for both
convergent and divergent growth from a single
starting material [8].
Properties of dendrimers
Many of the properties of dendrimers include [9]:
1. Nanoscale sizes that have similar
dimensions to important bio-building blocks
for example, proteins, DNA.
2. Numbers of terminal surface groups (Z)
suitable for bio-conjugation of drugs,
signaling groups, targeting moieties or
biocompatibility groups.
3. Surfaces that may be designed with
functional groups to augment or resist trans-
cellular, epithelial or vascular bio-
permeability.
4. An interior void space may be used to
encapsulate small molecule drugs, metals, or
imaging moieties. Encapsulating in that void
space reduces the drug toxicity and
facilitates controlled release.
5. Positive biocompatibility patterns that are
associated with lower generation anionic or
neutral polar terminal surface groups as
compared to higher generation neutral
apolar and cationic surface groups.
6. Non- or low-immunogenicity associated with
most dendrimer surfaces modified with
small functional groups or polyethylene
glycol (PEG).
7. Surface groups that can be modified to
optimize bio-distribution; receptor mediated
targeting, therapy dosage or controlled
release of drug from the interior space.
Comparision of dendrimers with linear
polymers
Dendrimers are different with the linear
polymers in various properties, which are
listed in Table 1.
Applications of dendrimers
Oral drug delivery
Dendrimers with diameters in the range of 2.5
to 6 nm seemed to offer the ideal progression
to smaller and smaller systems. Problem of
flocculation and aggregation of the system in-
vivo, oral uptakes of dendrimers are not better
as accepted. Using polyoxyethylene glycol
chains or ionic groups can reduce this
problem, but oral uptake is then hindered by
the hydrophilic nature of the surface
dendrimers [10-13]. Dendrimer-drug size,
molecular weight, surface charge, incubation
time and concentration of active molecule
impart different characteristics for oral
delivery of dendrimers [14].
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Ocular drug delivery
Dendrimers provide unique solutions to
complex delivery problems for ocular drug
delivery. Recent research efforts for improving
residence time of pilocarpine in the eye was
increased by using PAMAM dendrimers with
carboxylic or hydroxyl surface groups. These
surface-modified dendrimers were predicted
to enhance pilocarpine bioavailability [15].
Topical application of active drugs to the eye is
the most prescribed route of administration
for the treatment of various ocular disorders.
It is generally agreed that the intraocular
bioavailability of topically applied drugs is
extremely poor. These results mainly due to
drainage of the excess fluid via nasolacrimal
duct and elimination of the solution by tear
turnover. Several research advances have been
made in ocular drug delivery systems by using
specialized delivery systems such as polymers,
liposomes, or dendrimers to overcome some of
these disadvantages. Ideal ocular drug-
delivery systems should be non-irritating,
sterile, isotonic, biocompatible, does not run
out from the eye and biodegradable [16].
Transdermal drug delivery
Dendrimers designed to be highly water-
soluble and biocompatible have been shown to
be able to improve drug properties such as
solubility and plasma circulation time via
transdermal formulations and to deliver drugs
efficiently [17]. The viscosity imparting
property of a dendrimer solution allows for
ease of handling of highly concentrated
dendrimer formulations for these applications.
Dendrimers have been shown to be useful as
transdermal drug delivery systems for
nonsteroidal anti-inflammatory drugs
(NSAIDs), antiviral, antimicrobial, anticancer,
or antihypertensive drugs [18]. PAMAM
dendrimers have been studied as carrier
transdermal systems for the model NSAIDs:
ketoprofen and diflunisal [19]. It is well known
that the molecular transport through intact
skin is related to the molecular weight of the
Table 1. Comparison of various properties of dendrimers with linear polymer
Property Dendrimer
Structure Compact, Globular
Careful & stepwise growth
Synthesis
amorphous
Structural control Very high
Architecture Regular
Shape Spherical
Non-crystalline, amorphous
Crystallinity
materials -lower glass temperature materials -high glass temperature
Aqueous solubility High
Nonpolar solubility High
Non linear relationship with
Viscosity
molecular weight
Reactivity High
Compressibility Low
Dispersity Monodisperse
drug-carrier molecule. Dendrimers failed to
show enhancement in drug transport through
intact skin, because of its high molecular
weights. More research efforts are required in
this area to understand the relationship of
dendrimers to skin transport mechanism.
Targeted gene delivery
Dendrimers can act as carriers, called vectors,
in gene therapy. Vectors transfer genes
through the cell membrane into the nucleus.
Currently liposomes and genetically
engineered viruses have been mainly used for
this. PAMAM dendrimers have also been tested
as genetic material carriers. Cationic
dendrimers (Polypropylenimine (PPI)
dendrimer) deliver genetic materials into cells
by forming complexes with negatively charged
genetic materials through electrostatic
interaction. Cationic dendrimers lend
themselves as non-viral vectors for gene
delivery because of their ability to form
compact complexes with DNA. Another
potential application could be the use of
dendrimers coated with sialic acid for the
influenza virus to attach to the cell surface. In
addition, dendrimers are non-immunogenic
and are thus uniquely suited as carrier
structures for drugs or bioactive molecules
without degradation in immune system [20].
CNS delivery
Dendrimers, are regularly branched polymer
molecules with branches growing from one or
several centers. They can be formulated non-
covalently with biological agents, such as DNA
or conjugated with pro-drug or imaging agents
and thus can be used as delivery vehicles for
drug therapy or molecular imaging [21-26]. To
the best of our knowledge dendrimers have
not been evaluated so far for CNS delivery
except for few studies on intratumoral
delivery of dendrimer conjugates with anti-
cancer agents to treat glioma [27, 28]. Notably,
the generation and surface properties of
dendrimers were found to be very important.
Linear polymer
Not compact
Single step polycondensation
Low
Irregular
Random coil
Semi-crystalline/crystalline
Low
Low
Linear relationship with
molecular weight
Low
High
Polydisperse
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 REVIEW ARTICLE
Cationic dendrimers were generally more
toxic and disrupted the tight junctions. These
effects increased as dendrimer generation and,
consequently, net surface area increased.
Surface modification of dendrimers with
carboxylic groups greatly decreased the
toxicity, although the modified dendrimers
still opened tight junctions. In our opinion, it is
a matter of time before various dendrimers
are applied for CNS delivery of diagnostic and
therapeutic agents.
Anticancer drug delivery
One of the major applications of dendrimers is
as a delivery vehicle for various anticancer
drugs. The structure and tunable surface
functionality of dendrimers allows for the
encapsulation/conjugation of multiple entities,
either in the core or on the surface, rendering
them ideal carriers for various anticancer
drugs. There are numerous examples of
dendrimer mediated targeted drug delivery. In
2002, Jesus et al [29] had explored the
possibility of a 2, 2-bis (hydroxymethyl)
propanoic acid based dendritic scaffold as a
delivery carrier for doxorubicin in-vitro and
in-vivo. This dendritic nano-formulation,
which contains doxorubicin covalently bound
through a hydrazone linkage to a high
molecular weight three-arm polyethylene
oxide; exhibits reduced cytotoxicity in-vitro. In
an attempt to improve the efficacy of
doxorubicin, Lai et al [30] utilize photochemical
internalization (PCI) technology for site-
specific delivery of membrane impermeable
macromolecules from endocytic vesicles into
the cytosol.
Many investigators have also explored the
feasibility of cisplatin incorporation in
dendrimers. One of the early examples is
PAMAM dendrimer generation 3.5 conjugated
to cisplatin through the sodium carboxylate
surface giving a dendrimerplatinate
(dendrimerPt; 2025 wt% platinum), which
resulted in a fairly water soluble nano-
formulation with the ability to release cisplatin
slowly in-vitro [31]. Zhou et al [32] synthesized
poly (amide-amine) based dendrimers with a
cyclic core and four direction branches using
the method referred to as time-sequenced
propagation technique. Using this technique,
they successfully synthesized dendrimers from
generation 0.5 to generation 5.5. Further,
dendrimers were then reacted with 1-
bromoacetyl-5-fluorouracil to form
dendrimer5FU conjugates. PEGylated
dendrimers are one of the sub-classes of
dendrimers that attract numerous scientists
due to its prolonged blood circulation time,
lower level of toxicity and relatively lower
accumulation in different organs. Also, in-vivo
experiments show a significantly higher
accumulation in the tumor tissues due to the
enhanced permeability and retention (EPR)
effect [33]. PEG-dendrimers are generally
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synthesized by the conjugation of PEG or
polyethylene oxide (PEO) chains to a
multifunctional dendritic chain. A study by Lee
and colleagues [34] showed the feasibility of
polyester-based dendrimerPEOdoxorubicin
conjugate to substantially inhibit the
progression of DOX-insensitive C-26 tumor
subcutaneously implanted in BALB/c mice.
Additionally, Bhadra et al used PEGylated
PAMAM dendrimers for the incorporation of
5FU [35]. Thus, as anticipated, it was observed
that this is formulation is suitable for
prolonged delivery of anticancer drugs by in-
vitro and blood-level studies in albino rats,
without producing any significant
hematological disturbances. PEGylation
contributed an additional advantage to the
dendrimer formulation by reducing drug
leakage and hemolytic toxicity. This, in turn,
could improve drug-loading capacity and
stabilize such systems in the body.
Dendrimer and carbon nanotube
The utilization of dendrimers as
nanotemplates for carbon nanotube
formation in a controlled manner has been a
growing area of research interest since Choi
and his group introduced the idea of utilizing
PAMAM dendrimers for the synthesis of
catalytic nanoparticles for single-walled
carbon nanotube (SWNT). Thus, using this
dendritic platform, chemical vapor deposition
(CVD) nanotubes with a narrow diameter
distribution between 1 and 2 nm were
obtained [36]. Later, in another study by
Amama et al, the use of fourth-generation
PAMAM dendrimers as a platform for
synthesizing multi-walled carbon nanotubes
(MWCNTs) with systematically varied
diameter distributions and defect densities by
microwave plasma-enhanced chemical vapor
deposition was demonstrated [37].
Dendritic micelles
Dendrimers, the highly branched
monodisperse macromolecules, have a large
number of tunable surface groups and an
interior that provides space as well as
microenvironment suitable for host-guest
chemistry. [38, 39] Dendritic micelles are
generally unimolecular and do not suffer from
even the low CMC that the linear polymer
based micelles have. Also, these have been
shown to be rapidly internalized into cells
through endocytosis due to their nanometer-
scale dimensions. By virtue of these unique
features, dendrimers are being recently
studied for applications in gene therapy and as
drug carriers and as contrast agents in imaging
[40, 41]. It is evident from the above discussion
that dendritic micelles with anionic or PEG
groups on the periphery are promising
carriers for drug delivery. Further,
functionalized biocompatible dendrimers will
be attractive for multiple dendrimer-drug
conjugates. It will be interesting not only to
have highly functionalized dendrimers but also
to direct the functionalities towards the
concave interior of the dendrimer for better
encapsulation of the drug.
Dendrimer-based nanoparticles for lung
delivery
Kukowska-Latallo et al investigated the ability
of PAMAM dendrimers to augment plasmid
DNA gene transfer in-vivo and evaluates the
targeting of the lung by alternative routes of
administration [42]. They suggested that
vascular administration seemed to achieve
expression in the lung parenchyma, mainly
within the alveoli, while endobronchial
administration primarily targeted bronchial
epithelium, indicating that each delivery route
requires different vectors to achieve optimal
trans-gene expression that each approach
appears to target different cells within the
lung.
Rudolph et al compared the properties of
branched polyethylenimine (PEI) 25 kDa and
fractured PAMAM dendrimers for topical gene
transfer to the airways in-vivo [43]. Bai et al
produced low molecular weight heparin
(LMWH)dendrimer complex through
electrostatic interactions using various
PAMAM dendrimers then evaluated both the
safety and the efficacy of the drugdendrimer
formulations in preventing deep vein
thrombosis in-vivo and in-situ [44]. They
concluded that cationic dendrimers can be
used as pulmonary delivery carriers for a
relatively large molecular weight anionic drug.
These carriers bind anionic drug molecules
most likely via electrostatic interactions and
increase drug absorption through charge
neutralization.
Dendritic catalysts / enzymes
The combination of high surface area and high
solubility makes dendrimers useful as
nanoscale catalysts. Dendrimers have a
multifunctional surface and all catalytic sites
are always exposed towards the reaction
mixture. They can be recovered from the
reaction mixture by easy ultra filtration
methods [45]. Dendritic shells can be used to
create a microenvironment favorable for
catalysis or provide shielding for functional
groups at the dendritic core. Because of their
pseudo-spherical nature and their resultant
conformations the metal sites in these well-
dened polymeric catalysts should be easily
accessible for substrate molecules and
reagents, and therefore exhibit characteristics-
fast kinetics, specicity and solubility [46].
Metallodendritic catalysts, catalysis with
phosphine-based dendrimers, catalysis with
(metallo) dendrimers containing chiral
ligands, non-metal containing dendrimers are
some of the examples of dendritic catalysts
and enzymes.
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 REVIEW ARTICLE
Dendrimer as solubility enhancers
There are many substances, which have a
strong therapeutic activity but due to their
lack of solubility in pharmaceutically
acceptable solvents have not been used for
therapeutic purposes. Water soluble
dendrimers are capable of binding and
solubilizing small acidic hydrophobic
molecules with antifungal or antibacterial
properties. Dendrimers having a hydrophobic
core and a hydrophilic surface have been
termed unimolecular micelles. Unlike
traditional micelles, dendrimers do not have a
critical micelle concentration. This
characteristic offers the opportunity to soluble
poorly soluble drugs by encapsulating them
within the dendritic structure at all
concentrations of dendrimer. A hydrophilic
hydrophobic core-shell dendrimer with
PAMAM interior and long alkane chain
exterior was shown to bind 5-flurouracil, a
water-soluble anti-tumor drug [47]. After
phospholipid coating of the dendrimerfatty-
acid macromolecule, oral bioavailability in rats
of 5-flurouracil was nearly twice the level of
free 5-flurouracil. Dendrimer-based carriers
could offer the opportunity to enhance the oral
bioavailability of problematic drugs.
Propranolol, conjugated to surface-modied
G3 PAMAM dendrimer, the solubility of
propranolol increased by over two orders of
magnitude. Thus, dendrimer nanocarriers
offer the potential to enhance the
bioavailability of drugs that are poorly soluble
and/or substrates for efux transporters [48].
Dendrimers as imaging agents
Macromolecular contrast agents have become
very important tools of modern diagnostic
medicine. An early application of dendrimer to
imaging technology was disclosed in the US
patent [49]. The patent discloses the new stable
complexing agent for radionucleotide-
derivatized phosphonate dendrimers imaging
the skeletal system in mammals. Dendrimers
provide multiple binding sites on the
periphery, allowing many magnetic resonance
imaging (MRI) contrasting agent complexes to
attach to them. One dendrimer molecule can
host up to 24 contrasting agent complexes
(depending on generation), thereby attaining a
higher signal to noise ratio [50].
FUTURE PROSPECT
Dendrimer drug delivery systems are
increasingly viewed as an advantageous
solution for bioactive like drugs and gene.
They provide a platform for the attachment of
drugs or genes and their release through
several mechanisms. Scientists have explored
the use of dendrimers for various applications
in oral, transdermal, ophthalmic, and gene
delivery. Although dendrimer drug delivery
requires attention to certain manufacturing
and biological considerations to be successful.
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Boosting of commercial applications of
dendrimer technology will provide strength
for its usefulness in coming years.
CONCLUSION
The high level of control over the architecture
of dendrimers, their size, shape, branching
length and density, and their surface
functionality, makes these compounds ideal
carriers in biomedical application such as drug
delivery, gene transfection and imaging.
Despite two decades since the discovery of
dendrimers the multi-step synthesis still
requires great effort. Unless there is a
significant breakthrough in this field, only few
applications for which the unique dendrimer
structure is crucial will pass the cost-benefit
test.
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