Synthesis, characterization, and aqueous self-assembly of amphiphilic poly(ethylene oxide)-functionalized hyperbranched fluoropolymers

Article abstract of DOI:10.1002/pola.24149

Complex amphiphilic polymers were synthesized via core-first polymerization followed by alkylation-based grafting of poly(ethylene oxide) (PEO). Inimer 1-(4′-(bromomethyl)benzyloxy)-2,3,5,6-tetrafluoro-4-vinylbenzene was synthesized and subjected to atom

Full text of DOI:10.1002/pola.24149

Synthesis, Characterization, and Aqueous Self-Assembly of Amphiphilic
Poly(ethylene oxide)-Functionalized Hyperbranched Fluoropolymers
y
z
¨
WENJUN DU, YALI LI, ANDREAS M. NYSTROM,* CHONG CHENG, KAREN L. WOOLEY
Departments of Chemistry and Radiology, Washington University in Saint Louis, Saint Louis, Missouri 63130
Received 3 June 2009; accepted 22 May 2010
DOI: 10.1002/pola.24149
Published online in Wiley InterScience (www.interscience.wiley.com).
ABSTRACT: Complex amphiphilic polymers were synthesized
via core-first polymerization followed by alkylation-based graft-
ing of poly(ethylene oxide) (PEO). Inimer 1-(40-(bromomethyl)-
benzyloxy)-2,3,5,6-tetrafluoro-4-vinylbenzene was synthesized
and subjected to atom transfer radical self-condensing vinyl
polymerization to afford hyperbranched fluoropolymer (HBFP)
as the hydrophobic core component with a number-averaged
molecular weight of 29 kDa and polydispersity index of 2.1.
The alkyl halide chain ends on the HBFP were allowed to
undergo reaction with monomethoxy-terminated poly(ethylene
oxide) amine (PEOx-NH2) at different grafting numbers and
PEO chain lengths to afford PEO-functionalized HBFPs [(PEOx)y-
HBFPs], with x ¼ 15 while y ¼ 16, 22, or 29, x ¼ 44 while y ¼
16, and x ¼ 112 while y ¼ 16. The amphiphilic, grafted block
copolymers were found to aggregate in aqueous solution to
give micelles with number-averaged diameters (Dav) of 12–28
nm, as measured by transmission electron microscopy (TEM).
An increase of the PEO:HBFP ratio, by increase in either the
grafting densities (y values) or the chain lengths (x values), led
to decreased TEM-measured diameters. These complex,
amphiphilic (PEOx)y-HBFPs, with tunable sizes, might find
potential applications as nanoscopic biomedical devices, such
as drug delivery vehicles and 19F magnetic resonance imaging
C
V
agents.
2010 Wiley Periodicals, Inc. J Polym Sci Part A:
Polym Chem 48: 3487–3496, 2010
KEYWORDS: amphiphiles;
fluoropolymers;
hyperbranched;
micelles; self-assembly
INTRODUCTION The self-assembly of amphiphilic polymers
to construct various unique macromolecular morphologies
and to define three-dimensional complexities into nanostruc-
tured materials in the bulk or solution states has drawn
increasing attention because of their promise toward appli-
cations in the fields of advanced technologies, such as in the
electronics industry1–7 and biomedical research, including
gene therapy and drug delivery.8–14 Discrete nanoscale
objects result from assembly of amphiphilic block copoly-
mers of various architectures, in dilute solution, for which
many architectures have been observed, for example, tor-
oids,15 helices,16 rods,17 disks,18,19 and multicompartment
micelles (MCMs).20–26 Among them, MCMs are of special in-
terest because these materials have shown the potential to
uptake two or more compounds with different structures or
properties, such as genes, therapeutics, and imaging agents,
and to concurrently transport and deliver them to the target
in a prescribed manner, thus creating the promise of a novel
delivery approach called ‘‘double delivery’’ or ‘‘smart deliv-
ery.’’27–31 For example, Lodge et al. have demonstrated that
amphiphilic MCMs composed of poly(ethylene oxide) (PEO),
polyethylethylene (PEE), and poly(perfluoropropylene oxide)
(PFPO) were able to encapsulate two distinct and immiscible
dyes, pyrene and 1-naphthyl perfluoroheptanyl ketone simul-
taneously, without interfering with one another.27 This model
study for the ‘‘double delivery’’ approach could be useful,
especially with certain disease states, for which more than
one drug is administered in a controlled manner. The unique
uptake and release potential of MCMs may provide a practi-
cal device for such applications.
To produce MCMs, multiblock polymers or miktoarm block
polymers containing mutually immiscible block segments are
usually required because AB diblock polymers often give
core–shell micelles or vesicles. Upon self-assembly of unique
polymer structures, together also with the possibility for var-
iation in the solvent mixture and for the inclusion of addi-
tives,32,33 the multiple irreconcilable components rearrange,
whereby attraction of the like components and repulsion of
the dissimilar segments drive reorganization and regrouping,
which can afford several compartments or environments
within one single micelle.21,22,26,27
Hyperbranched polymers can be conveniently synthesized
from condensation of Ax þ By or ABx monomers,35 self-
34
*Present address: Department of Neuroscience and The Swedish Medical Nanoscience Center, Karolinska Institute, SE-17776 Stockholm, Sweden.
†Present address: Department of Chemical and Biological Engineering, the State University of New York at Buffalo, Buffalo, New York 14260.
‡Present address: Department of Chemistry, Texas A&M University, College Station, Texas 77842.
Correspondence to: K. L. Wooley (E-mail: wooley@chem.tamu.edu)
C
V
Journal of Polymer Science: Part A: Polymer Chemistry, Vol. 48, 3487–3496 (2010) 2010 Wiley Periodicals, Inc.
SELF-ASSEMBLY OF AMPHIPHILIC POLYMERS, DU ET AL.
3487

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
condensing vinyl polymerizations (SCVP),36–41 and from radi-
cal polymerization techniques such as nitroxide-mediated po-
lymerization42 using mixtures of monofunctional and difunc-
tional monomers. Upon further chemical modification or
polymerization, amphiphilic polymers can be produced,
which may exhibit unique self-assembly properties.43–52
Because of the hyperbranched architecture of the polymers,
complex micelles or MCMs are often produced.44,45,47 For
example, Mao et al. described the formation of MCMs from
self-assembly of hyperbranched star copolymers having a
poly(3-ethyl-3-hydroxymethyl)oxetane core, extended with
the growth of 2-(N,N-dimethyl amino)ethyl methacrylate
(DMAEMA) and 2,2,3,3,4,4,5,5-octafluoropentyl methacrylate
(OFPMA) block copolymer arms. The MCMs were produced
because of the hyperbranched architecture and the incom-
patibility of POFPMA with both the hyperbranched polyether
and hydrophilic PDMAEMA segments.44
chased from Interzyne (Tampa, FL) and used without further
purification.
Characterization Methods
IR spectra were obtained on a Perkin-Elmer Spectrum BX
Fourier-transform infrared (FTIR) spectrometer using NaCl
plates, with the sample being deposited from CH2Cl2 and
allowing for evaporation of the solvent.
1H NMR spectra were recorded at 300 or 500 MHz on a Var-
ian Unity-plus 300 or Varian Inova 500 spectrometer, respec-
tively, with the solvent proton signal as standard. 13C NMR
spectra were recorded at 125 MHz on a Varian Inova 500
spectrometer, with the solvent carbon signal as standard. 19F
NMR spectra were recorded at 470 MHz on a Varian Inova
500 spectrometer with CF3COOH as an external standard.
Gel permeation chromatography (GPC) was conducted on a
Waters 1515 HPLC (Waters Chromatography) equipped with
a Waters 2414 differential refractometer and a three-column
series PL gel 5 lm Mixed C, 500 Å, and 104 Å, 300 mm ꢀ
7.5 mm columns (Polymer Laboratories). The system was
equilibrated at 35 ꢁC in stabilized THF, which served as the
polymer solvent and eluent with a flow rate of 1.0 mL
minꢂ1. Polymer solutions were prepared at a known concen-
tration (ca. 3 mg mLꢂ1), and an injection volume of 200 lL
was used. Data collection and analyses were performed with
Precision Acquire software and Discovery 32 software,
respectively (Precision Detectors).
We are especially interested in the construction of MCMs
from amphiphilic hyperbranched fluoropolymers (HBFPs) to
serve as 19F imaging and delivery agents.14 Previously, it has
been demonstrated that upon PEGylation of HBFPs, either to
create amphiphilic macromolecules43 or nanoscopically
resolved crosslinked networks,53–56 MCM-type nanostruc-
tures were produced, which exhibited unique properties
such as promoted release of small guest molecules54 and un-
usual mechanical properties.55 Recently, we reported the
syntheses of complex amphiphilic HBFPs via atom transfer
radical self-condensing vinyl polymerization (ATR-SCVP) of a
tri(ethylene glycol) (TEG)-functionalized tetrafluorostyrene
inimer.43 We have investigated the self-assemblies of these
HBFPs in water and observed micellar structures having
number-average hydrodynamic diameters (Dh)n of 170–190
nm.43 The construction of micelles from such amphiphilic
HBFPs prompted further exploration of the self-assembly
behaviors of PEO-functionalized HBFPs to refine the sizes
and architectures of the macromolecules and their micelles,
and to investigate the possibility of creating MCMs with 20–
30 nm sizes for in vivo imaging and delivery applications.
Such MCMs were designed to package hydrophobic thera-
peutic agents and serve as 19F-based MR imaging agents, as
well. We hypothesized that if sufficient ethylene oxide (EO)
units were anchored within the HBFP core, creating strong
PEO shielding and allowing the EO units to extend into the
aqueous environment to produce a pseudo-core–shell mor-
phology, a decrease of the core–core association between the
HBFPs would be observed, resulting in MCMs of small sizes.
In this study, we designed and synthesized a series of hyper-
branched polymers having the same hydrophobic HBFP core
and different lengths and numbers of PEO arms. The self-as-
sembly and formation of MCMs from these PEO-functional-
ized HBFPs were then investigated.
Thermogravimetric analysis (TGA) was performed on a TGA/
SDTA851 instrument (Mettler-Toledo) measuring the total
mass loss on about 5 mg samples from 25 to 550 ꢁC at a
heating rate of 10 ꢁC minꢂ1 in a nitrogen flow of 50 mL
minꢂ1. Glass transition temperature (Tg) determinations
were measured by differential scanning calorimetry (DSC) on
a DSC822 instrument (Mettler-Toledo) in a temperatuꢂre1
range of ꢂ75 to 150 ꢁC with a heating rate of 10 ꢁC min
under nitrogen. For both TGA and DSC, data were acquired
and analyzed with STARe software (Mettler-Toledo). The Tg
values were taken at the midpoint of the inflection tangent,
and Tm values were taken as the onset, upon the third heat-
ing scans.
Dynamic light scattering (DLS) measurements were acquired
using a Brookhaven Instruments (Worcestershire, UK) sys-
tem, including a model BI-200SM goniometer, a model BI-
9000AT digital correlator, a model EMI-9865 photomultiplier,
and a model 95-2 Ar ion laser (Lexel Corp., Farmindale, NY)
operated at 514.5 nm. Measurements were made at 25 6 1
ꢁC. Before analysis, solutions were filtered through a 0.45-
R
lm Gelman Nylon AcrodiscV 13 membrane filter to remove
dust particles. Scattered light was collected at a fixed angle
of 90ꢁ. The digital correlator was operated with 522 ratio
spaced channels, and initial delay of 5 ls, a final delay of
100 ms, and a duration of 10 min. A photomultiplier aper-
ture of 400 lm was used, and the incident laser intensity
was adjusted to obtain a photon counting of between 200
and 300 kcps. The calculations of the particle size distribu-
tions and distribution averages were performed with the
EXPERIMENTAL
Materials
All chemicals were purchased from Sigma-Aldrich, unless
otherwise noted. Poly(ethylene oxide) amine (PEOx-NH2, x ¼
15, 44, and 112 for Mn ¼ 750, 2000, and 5000 Da) was pur-
3488
INTERSCIENCE.WILEY.COM/JOURNAL/JPOLA

ARTICLE
ISDA software package (Brookhaven Instruments), which
used CONTIN particle size distribution analysis. The data are
presented as the average values from four measurements.
FTIR (NaCl): 2916, 1629, 1486, 1438, 1404, 974, 958 cmꢂ1
.
1H NMR (300 MHz, CDCl3) d: 4.51 (s, 2H, ArCH2Br), 5.26 (s,
2H, ArCH2O-ArF4), 5.65 (d, J ¼ 12.0 Hz, 1H, cis CH¼¼CH2),
6.05 (d, J ¼ 18.0 Hz, 1H, trans CH¼¼CH2), 6.59 (dd, J ¼ 18.0,
12.0 Hz, 1H, CH¼¼CH2), 7.44 (m, 4H, ArH) ppm. 13C NMR (75
MHz, CDCl3) d 32.81, 75.8, 111.1, 122.0, 122.3, 122.4, 128.5,
128.8, 128.9, 135.9, 138.4, 141.2 (d, J ¼ 250 Hz), 145.0 (d, J
¼ 250 Hz) ppm. 19F NMR (282 MHz, CDCl3): d 46.55 (s, 2F),
57.21 (s, 2F) ppm. ELEM. ANAL. Calcd. for C16H11BrF4O: C,
51.22%; H, 2.96%; Br, 21.30%; F, 20.26%; found: C, 51.46%;
H, 2.93%; Br, 20.97%; F, 21.04%.
Transmission electron microscopy (TEM) measurements
were conducted on a Hitachi H600 microscope. Micrographs
were collected at 100,000ꢀ magnification and calibrated
using a 41-nm polyacrylamide bead from NIST. Carbon-
coated copper grids were treated with oxygen plasma before
deposition of the micellar samples. The samples were depos-
ited on the carbon grids for 1 min, and excess samples were
wicked away. The samples were stained with 1% phospho-
tungstic acid for 1 min; excess stain solution was wicked
away, and the samples were allowed to dry under ambient
conditions. The number-average particle diameters (Dav) and
standard deviations were generated from the analysis of a
minimum of 100 particles from at least three different
micrographs.
Synthesis of HBFP (4)
To a solution of 3 (3.0 g, 8 mmol) in PhF (15 mL) in a
Schlenk flask was added bipyridine (1.8 g, 0.22 mmol). After
one cycle of freeze-pump-thaw, CuCl (79 mg, 0.80 mmol)
and CuCl2 (11 mg, 0.08 mmol) were added. The reaction
mixture was subjected to three additional freeze-pump-thaw
cycles and placed in an oil bath set at 65 ꢁC. After 8 h, the
reaction was quenched by immersion of the reaction flask
into a liquid N2 bath. The copper catalysts were removed by
filtration of the reaction mixture through a short plug of ba-
sic alumina. The solvent was removed under reduced pres-
sure, and the polymer was purified by precipitation into
hexanes (3 ꢀ 1000 mL). The polymer was collected by cen-
trifugation (3000 rpm ꢀ 5 min) to give HBFP 4 as an off-
white powder (1.6 g, 53% based on mass). MGnPC ¼ 28 kDa,
Mw/MGnPC ¼ 2.1.
Elemental analyses were conducted by Galbraith Laborato-
ries (Knoxville, TN).
Synthesis of 1-(40-(Hydroxymethyl)benzyloxy)-2,3,5,6-
tetrafluoro-4-vinylbenzene (2)
To a solution of 1,4-benzenedimethanol (1, 9.4 g, 68 mmol)
in THF (200 mL) was added NaH (1.6 g, 68 mmol) at 0 ꢁC.
2,3,4,5,6-Pentafluorostyrene (PFS, 12 g, 62 mmol, in 100 mL
THF) was added dropwise through an addition funnel over a
period of 12 h. The reaction was stirred under argon at
room temperature overnight. H2O (100 mL) and EtOAc (100
mL) were added, and the aqueous solution was extracted
with EtOAc (3 ꢀ 100 mL). The organic solutions were com-
bined and dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure, and the residues
were purified by silica gel column chromatography (hex-
anes/EtOAc ¼ 7/3 v/v) to give 2 as a white powder (12.6 g,
65%).
FTIR (NaCl): 2945, 1648, 1458, 1420, 1376, 1225, 1140,
1086, 960 cmꢂ1 1H NMR (500 MHz, CDCl3) d: 0.8–3.1 (br,
.
m, CH2 and CH of backbone), 4.4–4.6 (m, ArCH2Br), 4.9–5.4
(m, br, ArCH2O-ArF4), 6.9–7.4 (m, br, ArH) ppm. 13C NMR
(125.7 MHz, CDCl3) d: 31.5–40.5, 75.9, 116.4–118.6, 128.4–
129.3, 135.7–146.3 ppm. 19F NMR (282 Hz, CDCl3) d: 46.8
(m, br), 57.3 (m, br) ppm. ELEM. ANAL. Calcd. for
(C16H11BrF4O)75: C, 51.22%; H, 2.96%; Br, 21.30%; F,
20.26%; found: C, 51.07%; H, 2.89%; Br, 17.01%; Cl, 1.29%;
F, 20.24%. DSC: Tg ¼ 56 ꢁC; TGA: 25–220 ꢁC, ꢃ0% mass
loss; 220–280 ꢁC, 22% mass loss; and 280–450 ꢁC, 47%
mass loss.
FTIR (NaCl): 3246, 2918, 1647, 1489, 1382, 1149, 964
cmꢂ1 1H NMR (500 MHz, CDCl3) d: 4.58 (s, 2H, ArCH2OH,),
.
5.23 (s, 2H, ArCH2O-ArF4), 5.61 (d, J ¼ 12.0 Hz, 1H, cis
CH¼¼CH2), 6.00 (d, J ¼ 18.0 Hz, 1H, trans CH¼¼CH2), 6.59
(dd, J ¼ 18.0, 12.0 Hz, 1H, CH¼¼CH2), 7.30 (1/2 ABq, J ¼ 8.0
Hz, 2H, ArH), 7.40 (1/2 ABq, J ¼ 8.0 Hz, 2H ArH) ppm. 13C
NMR (125.7 MHz, CDCl3) d: 64.7, 76.2, 111.1, 121.9, 122.3,
122.4, 127.0, 128.6, 134.9, 141.4 (d, J ¼ 250 Hz), 145.1 (d, J
¼ 250 Hz) ppm. 19F NMR (282 MHz, CDCl3 with CF3COOH
as an external reference) d: 46.48 (s, 2F), 57.10 (s, 2F) ppm.
ELEM. ANAL. Calcd. for C16H12F4O2: C, 61.54%; H, 3.87%; F,
24.34%; found: C, 61.41%; H, 3.82%; F, 24.90%.
Synthesis of (PEOx)y-HBFPs (5a–5e)
To five separate solutions of 4 (100 mg, 0.26 mmol Br) in
CH2Cl2 (30 mL) was added PEO15-NH2 (0.10, 0.08, and 0.06
mmol, 75, 60, and 45 mg each for 5a, 5b, and 5c, respec-
tively), PEO43-NH2 (0.06 mmol, 120 mg for 5d), and PEO112
-
NH2 (0.06 mmol, 300 mg for 5e). Diisopropylethyl amine
(DIPEA, 100 mg, 0.78 mmol) was added to each reaction,
and the reaction mixtures were allowed to stir under argon
at room temperature for 72 h. The solvent was removed
under reduced pressure, and the residues were precipitated
into hexanes/ethyl acetate (8/2, v/v) to give 5a–5e as off-
white powders.
Synthesis of 1-(40-(Bromomethyl)benzyloxy)-2,3,5,6-
tetrafluoro-4-vinylbenzene (3)
To a solution of 2 (6.6 g, 21 mmol) in CH2Cl2 (100 mL) was
added Ph3P (11.0 g, 42 mmol) and CBr4 (20.8 g, 63 mmol).
The reaction was allowed to stir at room temperature for 4
h. The solvent was removed under reduced pressure, and
the residue was purified by silica gel column chromatogra-
phy (hexanes/EtOAc ¼ 8/2, v/v) to give 3 as a white pow-
der (5.5 g, 70%).
5a: 99 mg (56%). MNnMR ¼ 48 kDa. FTIR (NaCl): 2918, 2849,
2362, 1647, 1492, 1459, 1348, 1259, 1100 cmꢂ1 1H NMR
.
(500 MHz, CDCl3) d: 0.8–3.1 (br, m, CH2 and CH of back-
bone), 3.2–3.3 (s, br, PEO-OCH3), 3.5–3.8 (m, br, PEO-H), 4.5–
4.6 (s, br, ArCH2Br), 4.9–5.4 (m, ArCH2O-ArF4), 6.9–8.1 (m,
SELF-ASSEMBLY OF AMPHIPHILIC POLYMERS, DU ET AL.
3489

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
br, ArH) ppm. 19F NMR (282 Hz, CDCl3) d: 46.9 (m, br), 57.5
(m, br) ppm. ELEM. ANAL. Calcd. for C2157H2797Br46F300N29O539
(47 kDa): C, 55.78%; H, 6.01%; F, 12.21%; found: C, 55.95%;
H, 6.04%; F, 12.09%. DSC: Tm ¼ 50 ꢁC; TGA: 25–230 ꢁC,
ꢃ0% mass loss; 230–380 ꢁC, 22% mass loss; and 380–460
ꢁC, 62% mass loss.
room temperature for 2 h. Nanopure water (25 mL) was
added dropwise to each solution over a period of 3 h. The
solutions were stirred for another 4 h and then dialyzed
against nanopure water for 72 h to afford the micelle
solutions.
5a micelles: 0.30 mg mLꢂ1. TEM: Dav: 13 6 4 nm, DLS:
5b: 106 mg (66%). MNnMR ¼ 44 kDa. FTIR (NaCl): 2917,
D
h(n): 20 6 5 nm; Dh(v): 29 6 4 nm; Dh(i): 150 6 30 nm.
2849, 1648, 1492, 1459, 1348, 1260, 1101 cmꢂ1 1H NMR
.
5b micelles: 0.32 mg mLꢂ1. TEM: Dav: 19 6 6 nm; DLS:
(500 MHz, CDCl3) d: 0.9–3.1 (br, m, CH2 and CH of back-
bone), 3.2–3.3 (s, br, PEO-OCH3), 3.5–3.9 (m, br, PEO-H), 4.4–
4.7 (s, br, ArCH2Br), 4.9–5.4 (m, ArCH2O-ArF4), 6.9–8.0 (m,
br, ArH) ppm. 19F NMR (282 Hz, CDCl3) d: 46.8 (m, br), 57.4
(m, br) ppm. ELEM. ANAL. Calcd. for C1926H2321Br53F300N22O427
(43 kDa): C, 54.37%; H, 5.50%; F, 13.40%; found: C, 54.84%;
H, 5.70%; F, 12.56%. DSC: Tm ¼ 45 ꢁC; TGA: 25–230 ꢁC,
ꢃ0% mass loss; 230–330 ꢁC, 10% mass loss; and 330–420
ꢁC, 68% mass loss.
D
h(n): 22 6 5 nm, Dh(v): 29 6 5 nm, and Dh(i): 230 6 40 nm.
5c micelles: 0.30 mg mLꢂ1. TEM: Dav: 28 6 5 nm; DLS:
D
h(n): 32 6 5 nm, Dh(v): 35 6 6 nm, and Dh(i): 350 6 60 nm.
5d micelles: 0.31 mg mLꢂ1. TEM: Dav: 16 6 3 nm; DLS:
D
h(n): 24 6 3 nm, Dh(v): 28 6 3 nm, and Dh(i): 210 6 30 nm.
5e micelles: 0.29 mg mLꢂ1. TEM: Dav: 12 6 2 nm; DLS:
D
h(n): 19 6 5 nm, Dh(v): 27 6 5 nm, and Dh(i): 150 6 40 nm.
5c: 101 mg (69%). MNnMR ¼ 40 kDa. FTIR (NaCl): 2920,
2940, 1649, 1492, 1458, 1348, 1259, 1100, 1060 cmꢂ1 1H
.
RESULTS AND DISCUSSION
NMR (500 MHz, CDCl3) d: 0.8–3.1 (br, m, CH2 and CH of
backbone), 3.2–3.4 (s, br, PEO-OCH3), 3.5–3.8 (m, br, PEO-H),
4.4–4.6 (s, br, ArCH2Br), 4.9–5.4 (m, ArCH2OArF), 6.9–8.0 (m,
br, ArH) ppm. 19F NMR (282 Hz, CDCl3) d: 46.8 (m, br), 57.5
(m, br) ppm. ELEM. ANAL. Calcd. for C1728H1913Br59F300N16O331
(39 kDa): C, 53.75%; H, 4.99%; F, 14.76%; found: C, 54.04%;
H, 5.20%; F, 13.96%. DSC: Tm ¼ 39 ꢁC; TGA: 25–110 ꢁC,
ꢃ0% mass loss; 110–240 ꢁC,ꢁ 17% mass loss; 240–380 ꢁC,
26% mass loss; and 380–420 C, 65% mass loss.
The synthetic strategy for the preparation of amphiphilic
(PEOx)y-HBFPs involved the construction of HBFP as a core
unit by ATR-SCVP, followed by covalent attachment of PEO
chains via nucleophilic substitution of benzylic halide func-
tionalities on HBFP with amine-functionalized PEO. The
aggregation behaviors of the resulting (PEOx)y-HBFPs upon
transitioning from organic solvent to water were then inves-
tigated as a function of chain length and grafting number of
the PEO arms.
5d: 116 mg (53%). MNnMR ¼ 59 kDa. FTIR (NaCl): 3503,
Synthesis of HBFP 4
2917, 2849, 1648, 1492, 1459, 1348, 1260, 1101 cmꢂ1 1H
.
The synthesis of HBFP involved the preparation and poly-
merization of inimer 3 (Scheme 1). Nucleophilic substitution
of PFS with an excess of 1,4-benzenedimethanol (1) was con-
ducted in the presence of NaH in THF to give mono-substi-
tuted 2 as the major product. The hydroxyl group present in
2 was subsequently converted to a bromide functionality
using Ph3P/CBr4 to afford 3 in 70% yield. ATR-SCVP of
inimer 3 was performed according to the protocol reported
previously.57 The polymerization was monitored by GPC and
1H NMR analysis. As expected, the GPC traces (Fig. 1) illus-
trated an increase in molecular weight along the reaction
time. The kinetic data showed a steady increase of molecular
weight upon reaction time (Fig. 2), with a parallel increase
in the PDI values of the resulting polymers. As a typical
behavior for ATR-SCVP, along with the increase of inimer
conversion, the average molecular weight increases sharply
because of the combined addition- and step-growth polymer-
ization processes, which in turn implies the formation of a
hyperbranched structure.58
NMR (500 MHz, CDCl3) d: 0.9–3.1 (br, m, CH2 and CH of
backbone), 3.2–3.3 (s, br, PEO-OCH3), 3.5–3.9 (m, br, PEO-H),
4.4–4.7 (s, br, ArCH2Br), 4.9–5.4 (m, ArCH2O-ArF4), 6.9–8.1
(m, br, ArH) ppm. 19F NMR (282 Hz, CDCl3) d: 46.7 (m, br),
57.3
(m,
br)
ppm.
ELEM.
ANAL.
Calcd.
for
C2656H3769Br59F300N16O795 (59 kDa): C, 54.02%; H, 6.43%; F,
9.65%; found: C, 54.88%; H, 6.61%; F, 9.07%; DSC: Tm ¼ 52
ꢁ
ꢁ
ꢁC; TGA: 25–230 C, ꢃ0% mass loss; 230–330 C, 10% mass
ꢁ
loss; and 330–420 C, 68% mass loss.
5e: 148 mg (37%). MNnMR ¼ 108 kDa. FTIR (NaCl): 2920,
2940, 1649, 1492, 1458, 1348, 1259, 1100, 1060 cmꢂ1 1H
.
NMR (500 MHz, CDCl3) d: 0.8–3.1 (br, m, CH2 and CH of
backbone), 3.2–3.4 (s, br, PEO-OCH3), 3.5–3.9 (m, br, PEO-H),
4.4–4.6 (s, br, ArCH2Br), 4.9–5.4 (m, ArCH2OArF), 6.9–8.1 (m,
br, ArH) ppm. 19F NMR (282 Hz, CDCl3) d: 46.8 (m, br), 57.5
(m, br) ppm. ELEM. ANAL. Calcd. for C4832H8121Br59
F300N16O1883 (103 kDa): C, 54.25%; H, 7.65%; F, 5.33%;
found: C, 54.84%; H, 7.70%; F, 4.66%; DSC: Tm ¼ 56 ꢁC;
TGA: 25–110 ꢁC, ꢃ0% mass loss; 110–240 ꢁC, 17% mass
loss; 240–380 ꢁC, 26% mass loss; and 380–420 ꢁC, 65%
mass loss.
Syntheses of (PEOx)y-HBFPs (5a–5e)
PEO chains in different lengths and numbers were conju-
gated onto 4 by taking advantage of the large number of
benzylic halide groups (ca. 75 Br/Cl readily available on
each HBFP, based on 1H NMR spectroscopy and elemental
analysis). The alkylation reactions were first conducted using
equal molar equivalents of the benzyl halide moiety and
PEOx-NH2 in the presence of DIPEA in CH2Cl2 to test the
Formation of Micelles of 5a–5e
(PEOx)y-HBFPs (5a–5e, 25 mg each) were dissolved in N,N-
dimethyl formamide (DMF, 25 mL) to make solutions with
concentration of 1 mg mLꢂ1. The solutions were stirred at
3490
INTERSCIENCE.WILEY.COM/JOURNAL/JPOLA

ARTICLE
SCHEME 1 Synthetic route for the preparation of (PEOx)y-HBFPs 5a–5e with illustrations that show the pictorial representation of
HBFP 4, and the (PEOx)y-grafted polymers 5a–5e. The green, branched structure depicts a single molecule of the HBFP precursor 4,
whereas the blue, wavy lines illustrate the functionalization of 4 with various lengths and amounts of PEO to produce 5a–5e.
reaction efficiency. Only a portion of PEOx-NH2 was able to
attach to the HBFP core, and the reaction efficiency
decreased as the length of the PEOx-NH2 increased (39, 29,
and 22% for PEO15-NH2, PEO44-NH2, and PEO112-NH2,
respectively), presumably because of steric hindrance. Efforts
to increase the extent of alkylation, by either an increase in
PEOx-NH2 feed or an increase in reaction time, did not signif-
icantly improve the degree of substitution, suggesting that
the reaction may be limited to only the surface available
alkyl halides. It was found that an average of 29 short PEO15
could be coupled onto 4, whereas only about 16 PEO112
chains could be grafted onto 4. Therefore, the breadth in the
chain numbers and chain lengths provided for a systematic
investigation of the effects of each of the supramolecular as-
sembly of these amphiphilic hybrid branched-star polymers
in water. Comparisons were made between 5a, 5b, and 5c,
having 29, 22, and 16 PEO arms, respectively, to determine
the effects of the PEO grafting density, and between 5c, 5d,
and 5e, having 16 arms of PEO15, PEO44, and PEO112, respec-
tively, to evaluate the effects of the PEO length (Scheme 1).
The synthesized (PEOx)y-HBFPs (5a–5e) were characterized
by 1H NMR and 19F NMR spectroscopy, IR, elemental analy-
sis, and GPC analysis. Attempts to characterize the synthe-
sized (PEOx)y-HBFPs by GPC were not successful, except for
the polymer having the lowest grafting density of the short-
est PEO chains, 5c, because of the low solubility of (PEOx)y-
HBFPs in THF (less than 1 mg mLꢂ1). Even in other organic
solvents (such as CH2Cl2), these (PEOx)y-HBFPs self-
assembled to form gel-like materials, as also observed by
SELF-ASSEMBLY OF AMPHIPHILIC POLYMERS, DU ET AL.
3491

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
FIGURE 1 GPC traces of ATR-SCVP of monomer 3 to yield
HBFP 4, ([3]0/[CuCl]0/[CuCl2]0/[bipy]0 ¼ 1.0/0.1/0.01/0.22, PhF,
65 ꢁC).
FIGURE 3 GPC traces (THF, 1.0 mL minꢂ1) for PEO15-NH2 (Mn
¼
750 Da), HBFP 4, and (PEO15)16-HBFP 5c.
other groups.59 Even for 5c, the molecular weight when
1
A representative H NMR spectrum of 5c is shown in Figure
4. The appearance of a resonance at 3.2–3.8 ppm and the
reduction in the benzylic halide protons of the grafted
amphiphilic structures, in comparison to those of 4, indi-
cated the conjugation of PEO units to the HBFP 4. Based on
the (PEOx)y-HBFP structures analyzed by 1H NMR spectros-
copy, it was calculated that the Mn values were 48, 44, 40,
60, and 108 kDa for polymers 5a–5e, respectively, starting
from a Mn value of 29 kDa for HBFP 4. The experimental
elemental analysis data were in good agreement with the
calculated values for these structures.
determined by GPC was found to be lower than the data
obtained by H NMR spectroscopy, because of the poor solu-
bility in THF, resulting in a collapse of the polymers and
smaller apparent molecular weights than expected. In fact,
the retention time for (PEO15)16-HBFP (5c) was longer than
that of the starting core material 4 (Fig. 3). No free PEO
chains were observed for GPC curve of 5c, indicating that
the purification by precipitation into hexanes/ethyl acetate
removed nonconjugated PEO chains. Therefore, 1H NMR, 19F
NMR, and elemental analysis could be used to determine the
average numbers of PEO arms grafted onto each HBFP core,
relying on the GPC-derived molecular weight of 4.
1
The 19F NMR spectra of 3, 4, and representative 5c are
shown in Figure 5. There were two broad peaks observed at
46 and 57 ppm, representing the meta-(Fa) and ortho-(Fb)
fluorine atoms, respectively. PEO attachment, as expected,
did not have any impact in the chemical shifts of the fluorine
nuclei. The integration values for these two peaks were
maintained at a ratio of 1:1. Both NMR and elemental analy-
sis suggest that there was no fluorine loss in the PEGylation
reaction. The peak widths were about 800 Hz, significantly
narrower than that of TEG-functionalized HBFPs previously
reported (ca. 2000 Hz).43 The narrow 19F resonance may
allow these (PEOx)y-HBFPs to serve as 19F imaging agents.
Micelle Formation
The amphiphilic (PEOx)y-functionalized HBFPs, containing a
hydrophobic core and a hydrophilic PEO shell, were found to
readily form micelles in water. The resulting micelles were
characterized by TEM and DLS. The uniform, circular two-
dimensional objects having average diameters of 13 6 4, 19
6 6, 28 6 6, 16 6 3, and 12 6 2 nm for micelles derived
from 5a–5e, respectively, observed by TEM (Fig. 6) suggest
that the micelles were uniform, globular assemblies. The
number-averaged hydrodynamic diameter values ((Dh)n), 20
6 5, 22 6 5, 32 6 5, 24 6 3, and 19 6 5 nm for micelles
FIGURE 2 Plots of molecular weight versus conversion (l) and
PDI versus conversion (~), indicating the sharp increase of Mn
after about 50% conversion, and progressively increasing PDI
values.
3492
INTERSCIENCE.WILEY.COM/JOURNAL/JPOLA

ARTICLE
FIGURE
CDCl3) spectra of inimer 3, HBFP
4, and (PEO15 16-HBFP 5c.
4
1H NMR (300 MHz,
)
FIGURE 5 19F NMR spectra of 3, 4, and 5c (282 MHz, CDCl3 with CF3COOH as an external reference).
SELF-ASSEMBLY OF AMPHIPHILIC POLYMERS, DU ET AL.
3493

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
FIGURE 6 TEM images of micelles 5a–5e (1% phosphotungstic acid negative stain).
CONCLUSIONS
derived from 5a–5e, respectively, measured by DLS (Fig. 7),
were in good agreement with the dry-state TEM diameters,
taking into consideration swelling by water. However, the in-
tensity-averaged hydrodynamic diameter values ((Dh)i), 150
6 30, 230 6 40, 350 6 60, 210 6 30, and 150 6 40 nm for
micelles derived from 5a–5e, respectively, were unexpectedly
large, suggesting there were large micelles formed. Because
((Dh)i) values are very sensitive to large-size particles, a
small amount of large particles can lead to a large increase
in ((Dh)i) values. Although we did not observe large micelles
in the TEM studies, DLS data indicated that they did exist,
possibly because of multiple micelle–micelle aggregation, as
observed by Mao et al.44
In summary, a series of (PEOx)y-HBFPs, which share the
same HBFP core but differ in the grafting numbers and chain
lengths of PEO arms, have been designed and synthesized.
These amphiphilic macromolecules were found to readily
form micelles upon transitioning from organic solvent to
water. The particle sizes, determined by TEM and DLS,
decreased as the grafting numbers or the chain lengths of
PEOx increased, suggesting an increase in the PEO shielding
effect and a reduction in the HBFP core–core interactions.
Based upon comparisons to seminal studies from which this
work is derived, the effect of PEO shielding is greater when
the PEO arms are grafted onto the HBFP core through
attachment of one PEO end, rather than being integrated as
short segments locked within the HBFP matrix by coupling
of both ends of short oligomers. These (PEOx)y-HBFPs could
be potentially useful in biomedical applications as 19F mag-
netic resonance imaging agents and therapeutic delivery
vehicles. The high grafting densities of PEO chains may allow
the application of these nanostructures in biomedical
research to resist nonspecific protein adsorption and to limit
opsonization and clearance by the mononuclear phagocytic
system.61 Such studies and potential applications are cur-
rently being explored.
The micellar assemblies were believed to be the result of
multimolecular aggregation of (PEOx)y-HBFPs. The aggrega-
tion numbers (Table 1) can be calculated to be 16, 54, 190,
24, and 6 for 5a–5e, respectively, according to the published
method.60 Because of the strong hydrophobic interactions
between the fluoropolymer components, high aggregation
numbers were obtained when the numbers of PEO units
were low, as illustrated by the trend in size observed from
5a–5c, whereby each polymer has the same PEO chain
length but decreasing grafted PEO densities. Similarly,
increased PEO chain lengths led to decreased aggregation
numbers and smaller supramolecular assemblies, 5c versus
5d versus 5e.
Supramolecular attractions of the HBFP cores, based upon
hydrophobic effects and p–p stacking interactions, are
expected to be the dominant factor to drive the aggregation
of (PEOx)y-HBFPs. However, as these results suggested, the
surface PEO units can serve as a shielding layer to diminish
the HBFP core–core attractions. In our initial investigation of
preparation and micelle formation, amphiphilic HBFPs were
synthesized via ATR-SCVP of a PEO-functionalized inimer
with an integrated tri(ethylene oxide) unit. The micelles
derived from such HBFPs gave (Dh)n of 170–190 nm.43 Even
though the PEO wt % was 32%, comparable to that of 5b
(wt % ¼ 33%, Table 1), the size of the micelles in the parent
study was significantly larger than that derived from 5b
((Dh)n ¼ 22 nm, Table 1), indicating that the PEO shielding
effect is more pronounced when the PEOs are attached as
mono-attached grafts onto the HBFP framework, to give a
star-like structure, rather than incorporated as many short
units within the HBFP matrix.
FIGURE 7 Number-averaged hydrodynamic diameter (Dh)n size
distributions of the micelles as determined by DLS.
3494
INTERSCIENCE.WILEY.COM/JOURNAL/JPOLA

ARTICLE
TABLE 1 (PEOx)y-HBFPs 5a–5e and Their Characterization Data
5a
5b
5c
5d
5e
Mn of HBFP core (kDa)a
x value
29
29
29
29
29
15
15
15
44
112
y value
29
22
16
16
16
PEO units/HBFPb
435
330
240
704
1792
79
Mn of total PEO units (kDa)a
Mn of (PEOx)y-HBFP (kDa)
Wt % of PEO
19
15
11
31
48
44
40
60
108
40%
13 6 4
20 6 5
29 6 4
150 6 30
1150
80
33%
19 6 6
22 6 5
29 6 5
230 6 40
3589
72
27%
28 6 5
32 6 5
35 6 6
350 6 60
11,488
66
52%
16 6 3
24 6 3
28 6 3
210 6 30
2143
100
73%
12 6 2
19 6 5
27 6 5
150 6 40
904
Dav (TEM, nm)
(Dh)n (DLS, nm)
(Dh)v (DLS, nm)
(Dh)i (DLS, nm)
Volume per aggregate (nm3)c
Volume per (PEOx)y-HBFP (nm3)d
Aggregation numbere
179
16
54
190
24
6
a
e
Based on 1H NMR data.
Aggregation number
¼
(volume per aggregate)/(volume per PEOx-
b
PEO units/HBFP ¼ x ꢀ y.
HBFP).
c
Based on TEM diameters and V ¼ 4/3(pr3).
d
Volume per (PEOx)y-HBFP ¼ (Mn/Avogadro’s number)/density of PEO
(1.1 g mLꢂ1).
The authors thank G. Michael Veith (Washington University
Electron Microscopy Laboratory) for assistance with TEM.
Postdoctoral and assistant professor fellowships provided by
the Knut and Alice Wallenberg Foundation (A. M. Nystro¨m) and
Niko Foundation (W. Du) are gratefully acknowledged. This ma-
terial is based upon work supported by the National Heart
Lung and Blood Institute of the National Institutes of Health as
a Program of Excellence in Nanotechnology (HL080729), the
Children’s Discovery Institute of Washington University in Saint
Louis, and the Office of Naval Research (N00014-08-1-0398).
10 Torchilin, V. P. Pharm Res 2007, 24, 1–16.
11 Bae, Y.; Nishiyama, N.; Fukushima, S.; Koyama, H.; Yasuhiro,
M.; Kataoka, K. Bioconjugate Chem 2005, 16, 122–130.
12 Cabral, H.; Nishiyama, N.; Kataoka, K. J Control Release
2007, 121, 146–155.
13 Du, W.; Nystrom, A. M.; Zhang, L.; Powell, K. T.; Li, Y.;
¨
Cheng, C.; Wickline, S. A.; Wooley, K. L. Biomacromolecules
2008, 9, 2826–2833.
14 Du, W.; Xu, Z.; Nystrom, A. M.; Zhang, K.; Leonard, J. R.;
¨
Wooley, K. L. Biomacromolecules 2008, 19, 2492–2498.
15 Chen, Z.; Cui, H.; Hales, K.; Li, Z.; Qi, K.; Pochan, D. J.; Woo-
REFERENCES AND NOTES
ley, K. L. J Am Chem Soc 2005, 127, 8592–8593.
1 Husemann, M.; Mecerreyes, D.; Hawker, C. J.; Hedrick, J. L.;
16 Hamley, I. W.; Ansari, I. A.; Castelletto, V.; Nuhn, H.; Rosler,
Shah, R.; Abbott, N. L. Angew Chem Int Ed 1999, 38, 647–649.
A.; Klok, H. A. Biomacromolecules 2005, 6, 1310–1315.
2 Thurn-Albrecht, T.; Steiner, R.; DeRouchey, J.; Stafford, C.
M.; Huang, E.; Bal, M.; Tuominen, M.; Hawker, C. J.; Russell, T.
P. Adv Mater 2000, 12, 787–791.
17 Hanley, K. J.; Lodge, T. P.; Huang, C. I. Macromolecules
2000, 33, 5918–5931.
18 Hou, S.; Man, K. Y. K.; Chan, W. K. Langmuir 2003, 19,
3 Black, C. T. ACS Nano 2007, 1, 147–150.
2485–2490.
4 Cheng, J. Y.; Ross, C. A.; Smith, H. I.; Thomas, E. L. Adv
19 Li, Z.; Chen, Z.; Cui, H.; Hales, K.; Qi, K.; Wooley, K. L.;
Mater 2006, 18, 2505–2521.
Pochan, D. J. Langmuir 2005, 21, 7533–7539.
5 Hawker, C. J.; Russell, T. P. MRS Bull 2005, 30, 952–966.
6 Li, M.; Ober, C. K. Mater Today 2006, 9, 30–39.
20 Zheng, R.; Liu, G.; Yan, X. J Am Chem Soc 2005, 127,
15358–15359.
21 Kubowicz, S.; Baussard, J.-F.; Lutz, J.-F.; Thunemann, A. F.;
¨
7 Stoykovich, M. P.; Kang, H.; Daoulas, K. C.; Liu, G.; Liu, C.-C.;
Berlepsch, H. V.; Laschewsky, A. Angew Chem Int Ed 2005, 44,
5262–5265.
de Pablo, J. J.; Muller, M.; Nealy, P. F. ACS Nano 2007, 1,
¨
168–175.
22 Li, Z.; Hillmyer, M. A.; Lodge, T. P. Langmuir 2006, 22,
8 Torchilin, V. P. Cell Mol Life Sci 2004, 56, 2549–2559.
9409–9417.
9 Ahmed, F.; Pakunlu, R. I.; Srinivas, G.; Brannan, A.; Bates, F.;
Klein, M. L.; Minko, T.; Discher, D. E. Mol Pharm 2006, 3,
340–350.
23 Lodge, T. P.; Hillmyer, M. A.; Zhou, Z.; Talmon, Y. Macro-
molecules 2004, 37, 6680–6682.
SELF-ASSEMBLY OF AMPHIPHILIC POLYMERS, DU ET AL.
3495

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
24 Cui, H.; Chen, Z.; Zhong, S.; Wooley, K. L.; Pochan, D. J. Sci-
43 Powell, K. T.; Cheng, C.; Wooley, K. L. Macromolecules
ence 2007, 317, 647–650.
2007, 40, 4509–4515.
25 Liu, C.; Hillmyer, M. A.; Lodge, T. P. Langmuir 2009, 25,
44 Mao, J.; Ni, P.; Mai, Y.; Yan, D. Langmuir 2007, 23,
13718–13725.
5127–5134.
26 Saito, N.; Liu, C.; Lodge, T. P.; Hillmyer, M. A. Macromole-
45 Mai, Y.; Zhou, Y.; Yan, D. Macromolecules 2005, 38,
cules 2008, 41, 8815–8822.
8679–8686.
27 Lodge, T. P.; Rasdal, A.; Li, Z.; Hillmyer, M. A. J Am Chem
46 Jia, Z.; Zhou, Y.; Yan, D. J Polym Sci Part A: Polym Chem
Soc 2005, 127, 17608–17609.
2005, 43, 6534–6544.
28 Kotzev, A.; Laschewsky, A.; Adriaensens, P.; Gelan, J. Mac-
47 Hong, H.; Mai, Y.; Zhou, Y.; Yan, D.; Cui, J. Macromol Rapid
romolecules 2002, 35, 1091–1101.
Commun 2007, 28, 591–596.
29 Stahler, K.; Selb, J.; Candau, F. Langmuir 1999, 15,
48 Zhou, Y.; Yan, D. Angew Chem Int Ed 2004, 43, 4896–4899.
7565–7576.
49 Tian, H.; Chen, X.; Lin, H.; Deng, C.; Zhang, P.; Wei, Y.; Jing,
30 Nasongkla, N.; Bey, E.; Ren, J.; Ai, H.; Khemtong, C.; Guthi,
J. S.; Chin, S. F.; Sherry, A. D.; Boothman, D. A.; Gao, J. Nano
Lett 2006, 6, 2427–2430.
X. Chem Eur J 2006, 12, 4305–4312.
50 Hong, H.; Mai, Y.; Zhou, Y.; Yan, D.; Chen, Y. J Polym Sci
Part A: Polym Chem 2008, 46, 668–681.
31 Sawant, R. M.; Hurley, J. P.; Salmaso, S.; Kale, A.; Tolcheva,
E.; Levchenko, T. S.; Torchilin, V. P. Bioconjugate Chem 2006,
17, 943–949.
51 Urbani, C. N.; Lonsdale, D. E.; Bell, C. A.; Whittaker, M. R.;
Monteiro, M. J. J Polym Sci Part A: Polym Chem 2008, 46,
1533–1547.
32 Solomatin, S. V.; Bronich, T. K.; Eisenberg, A.; Kabanov, V.
52 Wang, H.-B.; Chen, X.-S.; Pan, C.-Y. J Polym Sci Part A:
Z.; Kabanov, A. V. Langmuir 2007, 23, 2838–2842.
Polym Chem 2008, 46, 1388–1401.
33 Cui, H.; Chen, Z.; Wooley, K. L.; Pochan, D. J. Macromole-
53 Gudipati, C. S.; Greenlief, C. M.; Johnson, J. A.; Prayong-
pan, P.; Wooley, K. L. J Polym Sci Part A: Polym Chem 2004,
42, 6193–6208.
cules 2006, 39, 6599–6607.
34 Kricheldorf, H. R. J Polym Sci Part A: Polym Chem 2009, 47,
1971–1987.
54 Brown, G. O.; Bergquist, C.; Ferm, P.; Wooley, K. L. J Am
35 Hawker, C. J.; Lee, R.; Fre´chet, J. M. J. J Am Chem Soc
Chem Soc 2005, 127, 11238–11239.
2002, 113, 4583–4588.
55 Xu, J.; Bohnsack, D. A.; Mackay, M. E.; Wooley, K. L. J Am
36 Hawker, C. J.; Fre´chet, J. M. J.; Grubbs, R. B.; Dao, J. J Am
Chem Soc 2007, 129, 506–507.
Chem Soc 1995, 117, 10763–10764.
56 Powell, K. T.; Cheng, C.; Wooley, K. L.; Singh, A.; Urban, M.
37 Fre´chet, J. M. J.; Henmi, M.; Gitsov, I.; Aoshima, S.; Leduc,
W. J Polym Sci Part A: Polym Chem 2006, 44, 4782–4794.
M. R.; Grubbs, R. B. Science 1995, 269, 1080–1083.
57 Cheng, C.; Wooley, K. L.; Khoshdel, E. J Polym Sci Part A:
38 Matyjaszewski, K.; Gaynor, S. G.; Muller, A. H. E. Macromo-
Polym Chem 2005, 43, 4754–4770.
¨
lecules 1997, 30, 7034–7041.
58 Gaynor, S. G.; Edelman, S.; Matyjaszewski, K. Macromole-
39 Matyjaszewski, K.; Pyun, J.; Gaynor, S. G. Macromol Rapid
cules 1996, 29, 1079–1081.
Commun 1998, 19, 665–670.
59 Yan, D.; Zhou, Y.; Hou, J. Science 2004, 303, 65–67.
40 Georgi, U.; Erber, M.; Stadermann, J.; Abulikemu, M.; Kom-
ber, H.; Lederer, A.; Voit, B. J Polym Sci Part A: Polym Chem
2010, 48, 2224–2235.
60 Sun, G.; Hagooly, A.; Xu, J.; Nystrom, A. M.; Li, Z.; Rossin,
¨
R.; Moore, D. A.; Wooley, K. L.; Welch, M. J. Biomacromole-
cules 2008, 9, 1997–2006.
41 Tsarevsky, N. V.; Huang, J.; Matyjaszewski, K. J Polym Sci
61 Pressly, E. D.; Rossin, R.; Hagooly, A.; Fukukawa, K.; Mess-
more, B. W.; Welch, M. J.; Wooley, K. L.; Lamm, M. S.; Hule, R.
A.; Pochan, D. J.; Hawker, C. J. Biomacromolecules 2007, 8,
3126–3134.
Part A: Polym Chem 2009, 47, 6839–6851.
42 Khan, A.; Malkoch, M.; Montague, M. F.; Hawker, C. J.
J Polym Sci Part A: Polym Chem 2008, 46, 6238–6254.
3496
INTERSCIENCE.WILEY.COM/JOURNAL/JPOLA