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Pocket Dendrimers
A Lost, Forgotten, or Overlooked Science?
Carissa Burton | Monday 15 June 2015 | ChEn 578: Polymer Science | Dr. Pitt

Introduction and Literature Review

What are dendrimers?
Dendrimers are a special kind of polymer with a well-defined structure made up of a
core, often formed around a metal, and dendrons (much like monomers) that build a
fractal-type lattice around the dendrimer core. [13] The dendrons can be added to the
core one generation at a time. Typically, the number of dendrons in a generation
increases exponentially, depending on the functionality of the dendrons. Two- and
three-generation dendrimers are commonly used, but four-generation dendrimers are
less common due to steric hindrances caused by the large number of dendrons added to
the fourth generation. [2, 4, 5]

Applications of dendrimers
There are many applications of dendrimers, such as for molecular recognition, catalysts,
and drug delivery. The rigid and patterned structures of dendrimers give them a high
specificity that is extremely useful in biological applications, since they share
similarities with enzymes and can be designed to be compatible with biological
particles. [2]

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Higher generation dendrimers tend to be more effective in catalytic and
biological-mimicking applications due to the higher number of functional groups that
can be designed to have very specific binding capabilities. For example, a thirdgeneration dendrimer designed to catalyze the reduction of carbon dioxide worked
more effectively than the corresponding second-generation dendrimer. However,
fourth-generation dendrimers frequently tend to be much less effective than would be
predicted when looking at the trend of effectiveness. This is often because the steric
hindrance of the dendrons prevents particles from accessing the core of the dendrimer,
which often plays a key role in the necessary reaction. [4]
One specific application of dendrimers is for very specialized drug delivery to
prevent the transmission of HIV. Misumi et. al. [6] performed a study to target M cells
on the mucosal site where HIV begins to infect the body. It was shown that by using a
dendrimer, the drug could be delivered orally and would only react at the mucosal site,
thereby preventing HIV from being able to attach to the mucosal site, which would then
prevent the subject from contracting HIVs.

Pocket dendrimers and other non-symmetrical dendrimers

Some polymer scientists found in their research during 20052007 that by modifying the
core to grow on only part of the normal sites, dendrimers with pockets could be
formed. [2, 4, 5] This means that instead of growing the dendrimer in all directions, one
side has a hole where no dendrons are added. This can be done using a core with fewer
functional groups to polymerize or by attaching a non-polymerizable group to one side
of the dendrimer core. Next the dendrons are attached to the rest of the core and

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functional groups. Creating a pocket like this reduces the steric hindrance around the
core, providing a parking spot for guest molecules to interact with the core.
A study by Imaoka, Tanaka, and Yamamoto [4] showed that a fourth-generation
pocket dendrimer had a similar molecular weight to its third-generation symmetrical
dendrimer counterpart. It also had a similar number of functional groups that aided in
the catalytic reduction of carbon dioxide. However, the accessibility to the core was
much greater, making the dendrimer more effective in its application.

Another study by Shinoda, Ohashi, and Tsukube [5] showed that attaching a
specific dendron that would not grow to one side of the core created two pockets with a
shape and functionality that could accommodate pyridine and thymine guests, with
very specific, if weak, interactions. This pocket dendrimer, with its weak bonding
interactions similar to those used in enzymes and other biological processes, was
particularly useful for drug delivery and enzyme-mimicking applications.

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Current developments with pocket dendrimers?

Despite the many benefits and applications of pocket dendrimers, [2, 4, 5] not
many studies on dendrimers between 2007 and 2015 have used pockets. Some
dendrimers are non-symmetrical, but almost none of them have left holes that can
accommodate guests or that give greater access to the cores of the dendrimers. The
potential of these pocket dendrimers appears to have been overlooked or forgotten,
somehow lost over time. In this paper, I will suggest potential applications where the
benefits of pocket dendrimers would prove useful, but have not been applied.

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Discussion and Analysis

To symmetry, or not to symmetry?
It seems that dendrimers are symmetrical by default. There is a preconception that
dendrimers must be symmetrical, which likely stems from the definition of dendrimers,
the science behind creating them, and the fact that symmetrical dendrimers are more
common. Some studies use dendrimers with different dendrons attached, but
frequently they are still attached in a symmetrical pattern with all sides of the
dendrimer grown to the same length, never creating a pocket in the dendrimer.
However, even these dendrimers with different functional groups show higher
selectivity and effectiveness over uniform dendrimers for certain applications.
Non-symmetrical dendrimers tend to have more customizability, making them
more selective and effective in applications such as drug-delivery to particular sites.

Effectiveness increase from pocket vs. higher generation

Many studies explore different dendrimers for a certain application, comparing
dendrimers with different functional groups and of different generations. Some of these
studies seemed to me like they did not do as much research as they could have, and
found very similar results to just about every other dendrimer study, where they find
that the higher-generation dendrimers get more effective until they reach the point of
steric hindrance (typically at the fourth generation), when the rate of increase of
effectiveness suddenly drops dramatically. Most studies conclude that the thirdgeneration dendrimers work best. But rarely do they try pocket dendrimers, which

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make it possible to continue using higher-generation dendrimers with reduced steric
hindrance. Using a pocket in a third-generation dendrimer is approximately 40% more
effective than the symmetrical dendrimer counterpart (see Appendix).

5 th generation pocket dendrimers?

Using pocket dendrimers has proven more effective for drug-delivery by providing
specific binding sites and as catalysts by reducing the steric hindrances to the cores of
the dendrimers. But is there more we can do to utilize these pockets? Might it be
possible to use these pockets to grow even higher-generation dendrimers? Can pockets
be added to second-generation sites instead of the core?
With the lower steric hindrance provided by introducing pockets to dendrimer, I
propose that it may be possible to build a fifth-generation dendrimer with pockets. The
resulting pocket dendrimer would then have a very high molecular weight and an
increased number of functional groups to provide binding sites for guest molecules.
This would make the dendrimer more customizable. The dendrimer could be designed
to accommodate very specific molecules, and could potentially hold two or three
different molecules, selectively collecting and releasing these molecules. The potential
drug-delivery applications are astounding. These dendrimers could be designed to
carry specific drugs to specific sites in the body, possibly being able to deliver drugs
selectively to cancer cells, particular bacteria, membranes where certain viruses attack,
or specific parts of the body.

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Pocket dendrimers have been proven to be more effective in catalytic, enzymatic, and
drug-delivering applications, yet there seem to have been few cases where pockets have
been put to use between 2007 and 2015. Many dendrimers have been designed for
particular purposes, and have proven useful, but have been stunted in their
effectiveness due to the steric hindrances of high-generation dendrimers. By adding
pockets to some of these dendrimers, it should be possible to make certain dendrimers
more selective and increase the effectiveness of various dendrimers. It may even be
possible to make a fifth-generation dendrimer with pockets, allowing for even more
guest accommodation sites, giving the possibility of more customizable and selective
applications and higher-molecular-weight dendrimers with more functional groups
capable of binding to guest molecules.

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[1] Reymond, J., Bergmann, M., and Darbre, T. (2013), Glycopeptide dendrimers as
Pseudomonas aeruginosa biofilm inhibitors. Chem. Soc. Rev., 42: 481422.
[2] Shinoda, S. (2007), Nanoscale substrate recognition by porphyrin dendrimers with
patched structures. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 59: 19.
[3] He, X., et. al. (2015), RGD peptide-modified multifunctional dendrimer platform for
drug encapsulation and targeted inhibition of cancer cells. Colloids and Surfaces B:
Biointerfaces, 125: 8289.
[4] Imaoka, T., Tanaka, R., and Yamamoto, K. (2006), Synergetic Activation of Carbon
Dioxide Molecule Using Phenylazomethine Dendrimers as a Catalyst. Journal of
Polymer Science, 44: 522936.
[5] Shinoda, S., Ohashi, M. and Tsukube, H. (2007), Pocket Dendrimers as Nanoscale
Receptors for Bimolecular Guest Accommodation. Chem. Eur. J., 13: 8189.
[6] Misumi, S., et. al. (2009), Targeted Delivery of Immunogen to Primate M Cells with
Tetragalloyl Lysine Dendrimer. The Journal of Immunology, 182: 606170.