Journal of the American Chemical Society
ARTICLE
solution. The LCST behaviors were examined at these different
pH values (Figure 4). Deprotonation of the carboxylic acid at
basic pH increases the hydrophilicity due to an increase in the
number of negatively charged carboxylate anions. Similarly,
protonation of the carboxylates at lower pH should decrease
the hydrophilicity. Indeed, at pH 5.0 and 6.5, we found that Tt
decreases to 39.9 and 44.4 and the FWHM decreases to 7.0 and
5.3, respectively, compared to a Tt of 47.3 and FWHM of 8.9
at neutral pH, 7.2. Similarly, at pH 8.5 and 10.8, Tt increased
compared to that at neutral pH, while the FWHM did not signifi-
cantly change at pH 8.5 (in fact, it decreased slightly) and increased
greatly at pH 10.8. These observations are indeed consistent with
our hypothesis.
’ AUTHOR INFORMATION
Corresponding Author
’ ACKNOWLEDGMENT
We thank the NIGMS of the NIH (GM 065255) and the U.S.
Army Research Office (57858-CH) for partial support of this
work. We also thank the Materials Research Science and
Engineering Center at UMass for infrastructural support.
Although consistent, there is a possibility that the esters might
also be hydrolyzed at different pH's, and this could cause further
changes in the HLB. We were concerned about this, especially
because of the rather significant change noted at pH 10.8. Acc-
ordingly, we incubated the pentamer 5 at different pH's (Figure5).
When analyzed from pH 5 to 8.5, the free pentamer 5 did not
exhibit any difference. However, at pH 10.8, the pentamer 5 did
exhibit a significant change that indicates hydrolysis of the ester.
To further test this, we analyzed the pentamer 5 solution at
different time intervals, and indeed the LCST systematically
evolved with time, further supporting the observation that
hydrolysis of the ester over time affects the observed LCST
behavior (Figure 5). Under these conditions at lower pH, how-
ever, there is no observable hydrolysis of the ester. Therefore, it is
clear that there is indeed a pH-dependent temperature sensitivity
of the enzymatic product. However, these observations are not
reliable at high pH (>8.5), where an independent base-catalyzed
hydrolysis of the ester occurs.
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’ SUMMARY
We have designed, synthesized, and characterized a series of
amphiphilic oligomers containing penta(ethylene glycol) func-
tionalities as the hydrophilic segment and esters as the hydro-
phobic moiety. By systematically comparing the oligomers, we
note that (i) non-covalent organization of the OEG units through
aggregation causes a significant increase in temperature sensitivity;
(ii) cooperativity is further enhanced when these OEG units are
covalently tethered in the oligomers, as evidenced by the increase
in transition kinetics with increasing oligomerization; (iii) when an
enzyme-sensitive functionality is incorporated onto the lipophilic
segment of the amphiphile, these molecules can be rendered
sensitive to both enzyme and temperature; and (iv) since the
product of the enzymatic reaction provides a pH-sensitive func-
tionality, the amphiphilic assembly is rendered responsive to three
different stimuli. Overall, our studies here provide insights into the
need for multimeric presentation of oligoethylene glycol units
based on either non-covalent assemblies and/or covalent tether-
ing. Our report also outlines a strategy to design a molecule that
can be sequentially sensitive to three different stimuli. We believe
that this work will have implications in designing molecular
scaffolds for applications such as drug delivery and tissue engineer-
ing, where stimuli-sensitive materials are used.
’ ASSOCIATED CONTENT
S
Supporting Information. Synthesis and other experi-
b
mental details. This material is available free of charge via the
13502
dx.doi.org/10.1021/ja204121a |J. Am. Chem. Soc. 2011, 133, 13496–13503