Communications
DOI: 10.1002/anie.201004253
Superamphiphiles
An Enzyme-Responsive Polymeric Superamphiphile**
Chao Wang, Qishui Chen, Zhiqiang Wang, and Xi Zhang*
[
7]
Stimuli-responsive polymers have developed greatly in recent
years as a result of their prospective uses in biotechnology and
beings, plays an important role in most biological activities.
In this work, this natural molecule was used as a highly
effective multinegatively charged and enzyme-responsive
building block for fabricating polymeric superamphiphiles
(Scheme 1). An important feature is that under physiological
[1]
drug-delivery systems.
Enzyme-responsive polymeric
assemblies are particularly attractive because of their good
[2]
biocompatibility and high degree of selectivity, since over-
expression of enzymes has frequently been implicated in the
diseased state of cells. For example, some liposomes can be
degraded by alkaline phosphatase, and a family of enzymes is
always found in elevated concentrations in various types of
tumor cells. Consequently, phosphatase-responsive systems
are especially interesting for drug delivery and cancer
[
3]
therapy. However, introducing enzyme-responsive sites
into polymers generally requires tedious covalent synthesis,
thus raising the cost of preparation. In addition, organic
solvents and toxic reagents used in chemical synthesis may be
incorporated into polymers and reduce their biocompatibility.
The new concept of “superamphiphile” has emerged as a
powerful method of fabricating stimuli-responsive self-assem-
blies. Superamphiphiles are amphiphiles that are synthesized
[
4]
by noncovalent interactions. Stimuli-responsive moieties
can be linked to the amphiphiles on the basis of noncovalent
interactions, greatly reducing the need for chemical syn-
[
5,6]
thesis. The objective of the present study was to develop an
inexpensive, highly efficient, and nontoxic procedure for
producing enzyme-responsive polymeric self-assemblies
based on the superamphiphile concept. An enzyme-respon-
sive polymeric superamphiphile was successfully prepared by
simply mixing a double-hydrophilic block polymer and a
natural multicharged enzyme-responsive molecule in water.
The superamphiphile self-assembles into spherical aggre-
gates, which disassemble in response to enzymatic stimulus
and subsequently release loaded molecules.
Scheme 1. Building blocks of the superamphiphile and the enzyme-
responsive property of the self-assembled aggregates. The super-
amphiphile self-assembles into spherical aggregates, which disassem-
ble upon addition of enzyme (calf intestinal alkaline phosphatase,
CIAP) as a result of the enzymatic hydrolysis of ATP.
Adenosine 5’-triphosphate (ATP), which is generally
acknowledged as an “energy currency” in most animate
conditions ATP contains a hydrophobic adenine group and
four negative charges. Another specific feature of ATP is that
its phosphoanhydride bonds are enzyme-reactive and can be
hydrolyzed by phosphatase, which results in a structural
change from a multinegatively charged molecule into neutral
[
*] C. Wang, Q. S. Chen, Prof. Z. Q. Wang, Prof. X. Zhang
Key Lab of Organic Optoelectronics & Molecular Engineering
Department of Chemistry, Tsinghua University
Beijing 100084 (P.R. China)
[8]
adenine. With these features in mind we chose the double-
hydrophilic block copolymer methoxy-poly(ethylene
glycol)114-block-poly(l-lysine hydrochloride)200 (PEG-b-
PLKC), in which the PLKC segment is positively charged,
for assembly with ATP. PEG-b-PLKC and ATP can form a
polymeric superamphiphile in aqueous solution as a result of
electrostatic interaction. ATP molecules noncovalently cross-
link the positively charged polylysine segments, thus intro-
ducing hydrophobic adenine groups and resulting in the
formation of self-assembled aggregates. Upon addition of
phosphatase, the multiply negatively charged ATP is hydro-
lyzed to single-charged phosphate and a neutral adenine
group. Hence, the PEG-b-PLKC–ATP complex dissociates,
accompanied by disassembly of the self-assembled aggre-
gates.
Fax: (86)10-62771149
E-mail: xi@mail.tsinghua.edu.cn
[
**] This work was financially supported by the National Basic Research
Program (2007CB808000), the NSFC (50973051, 20974059), an
NSFC–DFG joint grant (TRR 61), and the Tsinghua University
Initiative Scientific Research Program (2009THZ02230). The
authors acknowledge Prof. A. V. Kabanov at the University of
Nebraska Medical Center for providing the PEG-b-PLKC samples.
The authors acknowledge the help of Prof. Lidong Li and Fu Tang at
the University of Science & Technology Beijing with DLS experi-
ments. The authors also acknowledge the help of Prof. Fei Sun and
Dr. Gang Ji with cryo-TEM.
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 8612 –8615