DOI: 10.1002/chem.201302442
Zwitterionic Moieties from the Huisgen Reaction:
A Case Study with Amphiphilic Dendritic Assemblies
Rajasekhar R. Ramireddy, Ayyagari V. Subrahmanyam, and S. Thayumanavan*[a]
Abstract: Supramolecular nano-assem-
blies that reduce nonspecific interac-
tions with biological macromolecules,
such as proteins, are of great impor-
tance for various biological applica-
tions. Recently, zwitterionic materials
have been shown to reduce nonspecific
interactions with biomolecules, owing
both to their charge neutrality and
their ability to form a strong hydration
layer around zwitterions via electro-
static interactions. Here, new triazole-
based zwitterionic moieties are pre-
sented that are incorporated as the hy-
drophilic functionalities in facially am-
phiphilic dendrons. The amphiphilic
zwitterionic dendrons spontaneously
self-assemble in aqueous solutions
forming micelle-type aggregates, which
were confirmed by DLS, TEM, and
fluorescence techniques. The structural
and functional characteristics of the
zwitterionic dendrons are also com-
pared with the corresponding charge-
neutral PEG-based dendrons and
anionic carboxylate-based dendrons.
Surface-charge measurements, temper-
ature sensitivity and evaluation of in-
teractions of these assemblies with pro-
teins form the bases for these compari-
sons.
Keywords: dendrimers · micelles ·
protein–dendrimer interactions · tri-
azoles · zwitterions
Introduction
tions, which converts them into reactive aldehyde moiet-
ies.[26,27] These features have resulted in a search for alter-
nate functional groups that can reliably endow nonfouling
characteristics, and a significant part of that focus has been
on polyzwitterionics.
There has been significant emphasis on the development of
new antifouling materials, which reduce nonspecific interac-
tions with biological macromolecules.[1–4] These types of ma-
terials can impact a variety of applications ranging from an-
tifouling coatings in ships[5] to biomedical applications, as
well as applications such as drug delivery,[6–8] implants,[9] and
sensors.[10] Molecules that exhibit nonfouling features can be
generally divided into two major classes: polyhydrophilics
and polyzwitterionics. Popular polyhydrophilics include
polyethylene glycol (PEG),[11–14] polysaccharides,[15,16] and
polyhydroxy materials.[17–19] Besides being hydrophilic and
hence the requisite water solubility, the key functional
groups in these molecules are also charge neutral and pres-
ent hydrogen-bond donor/acceptor characteristics. PEG, the
most extensively studied among the polyhydrophilics, has
the advantage of being easily accessible and exhibits good
nonfouling characteristics. However, although the tempera-
ture sensitivity (often referred to as lower critical solution
temperature (LCST) behavior) of the PEG moieties has
been taken advantage of,[20–23] the phase and hydrophilicity
changes associated with this transition can be deleterious to
other applications.[24,25] Also, it has been shown that PEG is
susceptible to auto-oxidation at biologically relevant condi-
Zwitterionics, such as sulfobetaines,[28,29] carboxybe-
taines,[30,31] and phosphobetaines,[32,33] possess both positive
and negative charges on the same monomer unit. These pol-
ybetaines are gaining attention as potential alternatives to
PEG, due to their overall charge neutrality, high water solu-
bility, and their ability to bind water via electrostatic interac-
tions. These features have been shown to decrease the rate
of adsorption of proteins, cells, and bacteria to their surfa-
ces.[4,34,35] In general, the nonfouling nature of zwitterionics
are studied by coating them on various surfaces and then
measuring the extent of adsorption of proteins or cells upon
exposure to biological milieu.[36] Considering the versatility
of the 1,3-Huisgen cycloaddition reaction, the so-called click
chemistry, we were interested in developing zwitterionic
moieties that can be conveniently introduced with this reac-
tion. In addition, the versatility of this reaction allows for
high fidelity incorporation of the zwitterionic moieties on
multiple sites on a molecular surface. Moreover, due to the
continuing interest in amphiphilic supramolecular assem-
blies and their use in applications, such as delivery and sens-
ing, we were particularly interested in evaluating such a func-
tional group on surfaces of assemblies in solution rather
than on surfaces.
[a] R. R. Ramireddy,+ Dr. A. V. Subrahmanyam,+ Prof. S. Thayumanavan
Department of Chemistry, University of Massachusetts
Amherst, MA 01003 (USA)
[+] These authors contributed equally to this work.
Towards this goal, we envisaged the possibility of triazole-
based zwitterionic functionalities and introduced them as
hydrophilic groups on the surfaces of assemblies based on
facially amphiphilic dendrons (Figure 1). These dendrons
are known to form micelle-like assemblies in the aqueous
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16374
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Chem. Eur. J. 2013, 19, 16374 – 16381