Synthesis, Physicochemical Characterization, and Self-Assembly of Linear, Dibranched, and Miktoarm Semifluorinated Triphilic Polymers

Article abstract of DOI:10.1002/pola.27394

Linear, dibranched, and miktoarm amphiphiles containing both hydrophobic and fluorophilic moieties were synthesized and characterized in an attempt to elucidate the relationship between semifluorinated amphiphile structure and aggregate behavior in aqueous solution. For the linear and dibranched amphiphiles, there was an exponential decrease in critical aggregation concentration (CMC) and a logarithmic increase in core microviscosity with increasing length of the fluorocarbon segments; while the miktoarm architecture produced no notable trend in microviscosity or CMC. Furthermore, the linear and dibranched surfactants showed enhanced kinetic stability, dissociating more slowly in the presence of human serum than did either the dibranched or miktoarm amphiphiles. Finally, encapsulation studies with the hydrophobic drug paclitaxel (PTX) showed that the ability to solubilize and retain PTX increased with the presence and with the increasing size of the fluorocarbon moiety for both the linear and dibranched amphiphiles, while no such trend was observed for the miktoarm amphiphiles. VC 2014 Wiley Periodicals, Inc.

Full text of DOI:10.1002/pola.27394

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Synthesis, Physicochemical Characterization, and Self-Assembly
of Linear, Dibranched, and Miktoarm Semifluorinated Triphilic Polymers
William B. Tucker,1 Aaron M. McCoy,1 Samantha M. Fix,1 Melissa F. Stagg,1 Matt M. Murphy,1
Sandro Mecozzi1,2
1Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706
2School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705
Correspondence to: S. Mecozzi (E-mail: sandro.mecozzi@wisc.edu)
Received 17 July 2014; accepted 30 August 2014; published online 24 September 2014
DOI: 10.1002/pola.27394
ABSTRACT: Linear, dibranched, and miktoarm amphiphiles con-
taining both hydrophobic and fluorophilic moieties were syn-
thesized and characterized in an attempt to elucidate the
relationship between semifluorinated amphiphile structure and
aggregate behavior in aqueous solution. For the linear and
dibranched amphiphiles, there was an exponential decrease in
stability, dissociating more slowly in the presence of human
serum than did either the dibranched or miktoarm amphi-
philes. Finally, encapsulation studies with the hydrophobic
drug paclitaxel (PTX) showed that the ability to solubilize and
retain PTX increased with the presence and with the increasing
size of the fluorocarbon moiety for both the linear and
critical aggregation concentration (CMC) and
a
logarithmic
dibranched amphiphiles, while no such trend was observed for
C
V
increase in core microviscosity with increasing length of the
fluorocarbon segments; while the miktoarm architecture pro-
duced no notable trend in microviscosity or CMC. Furthermore,
the linear and dibranched surfactants showed enhanced kinetic
the miktoarm amphiphiles.
2014 Wiley Periodicals, Inc. J.
Polym. Sci., Part A: Polym. Chem. 2014, 52, 3324–3336
KEYWORDS: fluorous; micelles; self-assembly; surfactants
Bates et al. have shown that multiblock amphiphiles can exhibit
a wide variety of structures and behaviors, with the potential to
offer unique materials for a wide variety of purposes.11 In the
past year, a number of studies have looked at the aggregation of
semifluorinated RAFT polymers in water.12–15 As it has been
noted, investigation into the relationship between structure and
aqueous self-assembly remains an important step in fully
exploring the behavior of triphilic species.16
INTRODUCTION Polymeric micelles have found applications
in fields ranging from catalysis,1,2 to antimicrobials3 to drug
delivery.4,5 Especially important is designing the amphiphile
structure such that specific characteristics appear in the
micellar aggregate, for example, particle size, critical micelle
concentration (CMC), microviscosity, and surface morphology.
In the field of drug delivery, Torchilin has demonstrated the
effectiveness of utilizing poly(ethylene glycol)ated (PEGy-
lated) phospholipids for use as micelle-based drug delivery
systems.6 These 1,2-distearoyl-sn-glycero-3-phosphoethanol-
amine-N-[methoxy(polyethylene glycol)] (mPEG–DSPE, Fig. 1)
polymeric micelles have been shown to not only efficiently
load poorly water-soluble drugs but also to be effective in
their delivery.7
This paper seeks to expand on our previous work with
mPEG–fluorocarbon–DSPE polymers by studying more
generally how the introduction of fluorocarbon moieties to
various amphiphilic architectures affects their physico-
chemical properties. Three polymeric architectures—linear,
dibranched, and miktoarm (Fig. 1)—along with various flu-
orinated moieties are presented. The physicochemical
properties of these amphiphiles are reported along with
data on kinetic stability and encapsulation ability for the
micelles prepared from these surfactants. This study dem-
onstrates that changes in amphiphile architecture and
block composition can be used to modulate the physico-
chemical properties of a micelle, including its stability in
physiological conditions and the ability to encapsulate
hydrophobic molecules.
Previous work in our lab has led to the development of
diblock, fluorinated surfactants for the solubilization8 and
emulsification9 of volatile, fluorous anaesthetics. Further
development of this synthetic methodology led to the prepa-
ration of semifluorinated mPEG–fluorocarbon–DSPE amphi-
philes, which showed enhanced kinetic and thermodynamic
stability with improved drug release profiles for amphoteri-
cin B compared to the commercially available, nonfluorinated
analogues.10
Additional Supporting Information may be found in the online version of this article.
C
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(St. Louis, MO) and were used as received, unless otherwise
specified. Chromatographic separations were performed
using Silicycle 60 Å SiO2. Surfactants were purified by auto-
R
mated flash chromatography using a CombiFlashV Rf 43 sys-
tem (Teledyne Isco, Lincoln, NE) equipped with ELSD for
compound visualization and a REDI-Sep Rf Gold C-18 silica
high-performance aqueous reverse phase cartridge. Products
were eluted with a 10–100% MeOH in water (0.1% formic
acid) gradient. 1H- and 19F-NMR spectra were obtained on
Varian Unity-Inova 400 and Unity-Inova 500 spectrometers
using deuterochloroform (CDCl3) as the solvent with TMS as
an internal reference.
Methods
mPEG Mesylate (Mx-OMs)
To a dry 100 mL roundbottom flask charged with argon
were added 50 mL DCM and 5 g monomethyl poly(ethylene
glycol) alcohol (4.9 mmol M1-OH/2.5 mmol M2OH/1.03
ꢀ
mmol M5OH). The mixture was cooled to 0 C before adding
TEA (2 mL, 14.7 mmol mPEG1000-OH/1.04 mL, 7.5 mmol
mPEG2000-OH/0.43 mL, 3.06 mmol mPEG5000-OH), which
was allowed to stir for 30 min before methanesulfonyl chlo-
ride was added (1 mL, 12.2 mmol mPEG1000-OH/0.48 mL,
6.25 mmol mPEG2000-OH/0.2 mL, 2.55 mmol mPEG5000-
OH). The reaction was allowed to stir overnight as it warmed
to room temperature. The reaction was then diluted with
100 mL DCM and washed with 3, 50 mL aliquots saturated
ammonium chloride solution, dried over magnesium sulphate
and then reduced to a minimum volume under reduced pres-
sure. The mPEG-OMs was then precipitated with cold ether,
vacuum filtered, and freeze dried from 50/50 DCM/benzene
to give a white, crystalline product in 67% (M1-OMs), 86%
(M2-OMs) and 93% (M5-OMs) yields. M1-OMs MALDI: Dis-
tribution centred on [M 1 Na1] 5 1063.4, PDI of starting
mPEG 1.27. NMR: 1H NMR (400 MHz, CDCl3): d 4.38 (m,
2H), 3.82 (m, 1H), 3.77 (m, 2H), 3.64 (m, 89H), 3.55 (m, 2H),
3.47 (m, 1H), 3.38 (s, 3H), 3.09 (s, 3H); M2-OMs MALDI:
Distribution centred on [M 1 Na1] 5 1938.4, PDI of starting
mPEG 1.10. NMR: 1H NMR (400 MHz, CDCl3): d 4.38 (m,
2H), 3.79 (m, 2H), 3.77 (m, 2H), 3.64 (m, 165H), 3.56 (m,
2H), 3.38 (s, 3H), 3.09 (s, 3H); M5-OMs MALDI: Distribution
centred on [M 1 Na1] 5 5161.5, PDI of starting mPEG 1.05.
NMR: 1H NMR (400 MHz, CDCl3): d 3.84–3.44 (m, 490H),
3.38 (s, 3 H), 3.08 (s, 3H).
FIGURE 1 Structures of amphiphiles presented with associated
nomenclature. Mx refers to mPEG hydrophilic block, x is the
average molecular weight in thousands; H# and F# refer to the
number of hydrogenated and fluorinated carbon atoms,
respectively. For nonlinear amphiphiles, di and l respectively
specify dibranched or miktoarm architecture. The presence of
an –O– indicated an ether linkage between blocks. PftB is the
fluorous perfluoro-tert-butoxy group.
EXPERIMENTAL
Materials
All fluorinated compounds were obtained from SynQuest
Laboratories (Alachua, FL), except perfluoro-tert-butanol that
was obtained from Matrix Scientific (Columbia, SC). 1,2-dis-
tearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly-
ethylene glycol)-2000] (M2DSPE) and 1,2-distearoyl-sn-
glycero-3-phosphoethanolamine-N-[methoxy(polyethylene
glycol)-5000] (M5DSPE) were purchased from Avanti Polar
Lipids (Alabaster, AL). Paclitaxel was purchased from LC Lab-
oratories (Woburn, MA). 1,3-Bis-(1-pyrenyl)propane (P3P)
was purchased from Life Technologies (Carlsbad, CA). Pooled
normal human serum was purchased from Innovative
Research (Novi, MI). All solvents were of ACS grade or
higher and were purchased from Sigma-Aldrich (St. Louis,
MO). All other reagents were purchased from Sigma-Aldrich
Linear Alcohols
HO-H10F8: To a dry 10 mL roundbottom flask were added
1.02 mL (5.75 mmol) 9-decen-1-ol and 1.34 mL (5.0 mmol)
perfluorooctyl iodide. The mixture was degassed at room
temperature with argon for 45 min before 8.2 mg (0.05
mmol) AIBN were added and the mixture slowly heated to
80 ꢀC while being very rapidly stirred with a small stir bar.
This reaction was allowed to run overnight. The reaction
was then cooled to room temperature, diluted with 100 mL
DCM, washed 1, 50 mL aliquot each Na2S2O3 and brine.
The organic layers were dried over MgSO4 and condensed
under reduced pressure to give an off-white solid (1). This
was then dissolved in 10 mL acetic acid and stirred with
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0.98 g zinc powder for 24 h open to the air. The reaction
was then quenched with 200 mL saturated NaHCO3 solution
and extracted with 300 mL DCM. The organic layers were
then washed 1, 100 mL aliquot each saturated NaHCO3 solu-
tion and brine and then dried over MgSO4 and concentrated
under reduced pressures to give a white solid. The solid was
recrystallized twice from hot toluene to give pure HO-
H10F8 in 48% yield. NMR: 1H NMR (400 MHz, CDCl3): d
3.65 (t, J 5 6.9 Hz, 2H), 2.05 (ttt, J 5 18, 9.5, 2 Hz, 2H),
1.65–1.52 (m, 4H), 1.4–1.23 (m, 12H). 19F NMR (376 MHz,
To an oven-dried round-bottom flask was added BH3-THF
(1.0M, 16.5 mmol). The solution was diluted with 10 mL of
dry THF and then cooled to 0 C. The semifluorinated alkene
ꢀ
ether (10-(1H,1H-perfluorobutoxy)dec-1-ene (3.83 g, 11.2
mmol)/10-[1H,1H-perfluoroheptoxy)dec-1-ene (5.28 g, 10.8
mmol)] was added dropwise and the reaction was allowed
to stir at room temperature for 16 h. The reaction was
cooled to 10 ꢀC followed by addition of NaOH solution (3M,
20 mL). Hydrogen peroxide (30 wt % in water, 6 mL) was
added at 10 ꢀC. The reaction mixture was stirred at 50 ꢀC
for 2 h and then cooled to room temperature. Ether (20 mL)
was added and the organic phase was washed with water
(20 mL), brine (20 mL), and dried over MgSO4 and con-
densed under reduced pressure to give 3.9 g (98% yield
HO-H10-O-F3), 4.5 g (80% yield HO-H10-O-F6) of clear oil.
HO-H10-O-F3 NMR: 1H NMR (400 MHz, CDCl3): d 3.90 (tt,
J 5 14, 2 Hz, 2H), 3.64 (t, J 5 7 Hz, 2H), 3.58 (t, J 5 7 Hz,
2H), 1.60 (septet, J 5 7 Hz, 4H), 1.41–1.29 (m, 12H). 19F
NMR (376 MHz, CDCl3): d 281.51 (3F), 2121.08 (2F),
2128.28 (2F). HO-H10-O-F6 NMR: 1H NMR (400 MHz,
CDCl3): d 3.92 (tt, J 5 14, 2 Hz, 2H), 3.64 (t, J 5 7 Hz, 2H),
3.59 (t, J 5 7 Hz, 2H), 1.58 (septet, J 5 7 Hz, 4H), 1.36–1.29
(m, 12H). 19F NMR (376 MHz, CDCl3): d 281.29 (3F), -
120.07 (2F), 2122.71 (2F), 2123.32 (2F), -123.93 (2F), -
126.66 (2F).
CDCl3):
d 281.15 (3F), 2114.77 (2F), 2122.32 (6F),
2123.11 (2F), 2123.92 (2F), 2126.49 (2F).
HO-H10-O-F3 and HO-H10-O-F6: To a dry roundbottom, at
0
ꢀC argon, were added 25 mL dry DCM, 9-decen-1-ol (2.5
mL, 13 mmol) and TEA (4.3 mL, 31 mmol). This stirred for
30 min before methanesulfonyl chloride (1.3 mL, 16 mmol)
was added dropwise. After running overnight, the reaction
was diluted with 50 mL DCM and then washed with 3, 50
mL aliquots of saturated ammonium chloride solution. The
organic layers were dried over MgSO4 and condensed under
reduced pressure to give 3.21 g (quantitative yield) of yellow
oil. NMR: 1H NMR (400 MHz, CDCl3): d 5.81 (ddt, J 5 16.5,
10, 6.5 Hz, 1H), 4.99 (ddt, J 5 16.5, 2, 1 Hz, 1H), 4.93 (ddt,
J 5 10, 2, 1 Hz, 1H), 4.22 (t, J 5 7 Hz, 2H), 3.00 (s, 3H), 2.04
(qt, J 5 6.5, 1 Hz, 2H), 1.60 (q, J 5 7 Hz, 2H), 1.41–1.29
(m, 10H).
Dibranched Alcohols
HO-diH10, HO-diH10-O-F3, and HO-diH10-O-F6: To an
oven dried 25 mL round-bottom flask were added 22.7
mmol alcohol (3.59 g HO-H10, 8.1 g HO-H10-O-F3, 11.5 g
HO-H10-O-F6), and 0.51 g (9.08 mmol) of crushed KOH. This
was allowed to stir at room temperature until all of the KOH
dissolved. Epichlorohydrin (0.42 g, 4.54 mmol) was then
added and the reaction was head to 120 ꢀC and allowed to
react overnight, stirring vigorously. The reaction was then
allowed to cool and diluted with 100 mL brine and extracted
with 3, 100 mL aliquots DCM. The organic layers were then
dried over MgSO4 and concentrated under reduced pressure.
The resulting oil was then distilled under reduced pressure
To a 100 mL oven-dried roundbottom, under argon, were
added 35 mL of THF and 761 mg (31 mmol) of NaH. The
suspension was cooled to 0 ꢀC over the course of 10 min
before 28 mmol of semifluorinated alcohol were added [3.25
mL 1H,1H-perfluorobutan-1-ol (F3H1-OH)/5.8 mL (28
mmol) of 1H,1H-perfluoroheptan-1-ol (F6H1-OH)] was added
dropwise over the course of 1 h. Then 3.20 g (13 mmol) of
9-decen-1-yl methane sulfonate were added (as a solution in
10 mL of anhydrous THF). This was then warmed slowly to
reflux and allowed to react for 24 h. The reaction was then
allowed to cool and diluted with 100 mL of DCM. This was
washed with 3, 50 mL aliquots of saturated NH4Cl solution
and dried over MgSO4 and condensed under reduced pres-
sure to give an opaque, yellow liquid. The product was then
purified by column chromatography (4% ethyl acetate in
hexanes) to give 3.83 g (86% yield F3), and 5.28 g (83%
yield F6) of product as a clear liquid. 10-(1H,1H-perfluoro-
butoxy)dec-1-ene NMR: 1H NMR (400 MHz, CDCl3): d 5.81
(ddt, J 5 16.5, 10, 6.5 Hz, 1H), 4.99 (ddt, J 5 16.5, 2, 1 Hz,
1H), 4.93 (ddt, J 5 10, 2, 1 Hz, 1H), 3.90 (tt, J 5 14, 2 Hz,
2H), 3.58 (t, J 5 7 Hz, 2H), 2.04 (qt, J 5 6.5, 1 Hz, 2H), 1.60
(q, J 5 7 Hz, 2H), 1.41–1.29 (m, 10H). 19F NMR (376 MHz,
CDCl3): d 281.51 (3F), 2121.09 (2F), 2128.28 (2F). 10-
(1H,1H-perfluoroheptoxy)dec-1-ene NMR: 1H NMR (400
MHz, CDCl3): d 5.81 (ddt, J 5 16.5, 10, 6.5 Hz, 1H), 4.99
(ddt, J 5 16.5, 2, 1 Hz, 1H), 4.93 (ddt, J 5 10, 2, 1 Hz, 1H),
3.91 (tt, J 5 14, 2 Hz, 2H), 3.59 (t, J 5 7 Hz, 2H), 2.04 (qt,
J 5 6.5, 1 Hz, 2H), 1.59 (q, J 5 7 Hz, 2H), 1.39–1.29 (m, 10H).
19F NMR (376 MHz, CDCl3): d 281.26 (3F), 2120.03 (2F),
2122.69 (2F), 2123.29 (2F), 2123.91 (2F), 2126.59 (2F).
ꢀ
(20 mmHg at 200 C) to remove excess starting alcohol. The
remaining oil was then purified by flash chromatography
(twice, once with 17% EtOAc in hexanes and then again in
10% hexanes in DCM) to give semisolid product (2.7 g 32%
yield HO-diH10/0.550 g, 16% yield HO-diH10-O-F3/1.852 g,
43% yield HO-diH10-O-F6). HO-diH10 NMR: 1H NMR (400
MHz, CDCl3): d 3.94 (p, J 5 6.4 Hz, 1H), 3.47 (A of ABX, JAB
5
9.9 Hz, JAX 5 4.2 Hz, 2H), 3.45 (t, J 5 6.7 Hz, 4H), 3.45 (B of
ABX, JAB 5 9.9 Hz, JBX 5 6.4 Hz, 2H), 2.66 (broad s, 1H),
1.55–1.50 (m, 4H), 1.23 (broad s, 28H), 0.84 (t, J 5 7Hz, 6H).
HO-diH10-O-F3 NMR: 1H NMR (400 MHz, CDCl3): d 3.93
(pentet, J 5 5 Hz, 1H), 3.90 (tt, J 5 14, 2 Hz, 5H), 3.58 (t, J 5
7 Hz, 4H), 3.47 (t, J 5 7 Hz, 4H), AB of an ABX with signals
at 3.45 and 3.47 (JAB 5 10 Hz, JAX 5 JBX 5 5 Hz, 4H),
2.49 (broad singlet, 1H), 1.58 (sextet, J 5 7 Hz, 8H), 1.41–
1.29 (m, 24H). 19F NMR (376 MHz, CDCl3): d 281.51 (3F),
1
2121.08 (2F), 2128.28 (2F). HO-diH10-O-F6 NMR: H NMR
(400 MHz, CDCl3): 3.91 (2 signals, 1 the obscured 3 of an
ABX and 1 tt, J 5 14, 2 Hz, 5H), 3.59 (t, J 5 6.6 Hz, 4H),
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3.46 (t, J 5 6.7 Hz, 4H), AB of an ABX with signals at 3.48
and 3.43 (JAB 5 10 Hz, JAX 5 11 Hz, JBX 5 9 Hz, 4H), 1.58
(sextet, J 5 7 Hz, 8H), 1.39–1.24 (m, 24H). 19F NMR (376
MHz, CDCl3): d 281.37 (6F), 2120.11 (4F), 2122.76 (4F),
2123.36 (4F), 2123.37 (4F), 2126.69 (4F).
5-(decyloxy)-2-phenyl-1,3-dioxane (10.33 mmol, 51%) (3a),
8.060 g 5-(octadecyloxy)-2-phenyl-1,3-dioxane (3b) (18.63
mmol, 70%). 3a: H NMR (400 MHz, CDCl3): d 7.50 (m, 2H),
1
7.33 (m, 3H), 5.54 (s, 1H), 4.31 (dd, J 5 12.4, 1.2 Hz, 2H),
4.02 (dd, J 5 12.4, 1.6 Hz, 2H), 3.53 (t, J 5 6.8 Hz, 2H), 3.24
(t, J 5 2.0 Hz, 1H), 1.65 (p, J 5 6.8 Hz, 2H), 1.28 (m, 14H),
0.88 (t, J 5 6.8 Hz, 3H). 3b: 1H NMR (400 MHz, CDCl3): d
7.51 (m, 2H), 7.33 (m, 3H), 5.54 (s, 1H), 4.32 (dd, J 5 12.5,
1.4 Hz, 2H), 4.03 (dd, J 5 12.5, 1.8 Hz, 2H), 3.54 (t, J 5 6.7
Hz, 2H), 3.25 (p, J 5 1.8 Hz, 1H), 1.65 (p, J 5 7.6 Hz, 2H),
1.25 (m, 30H), 0.88 (t, J 5 6.9 Hz, 3H).
Miktoarm Alcohols
HO-lF8H10, HO-lF8H18, HO-lPftBH18: Alcohol (decanol
5.012 g, 31.66 mmol/octadecanol 1.609 g, 5.95 mmol) was
dissolved in anhydrous DCM (50.0 mL) and flask flushed
with Ar. TEA [decanol (8.80 mL, 63.1 mmol)/octadecanol
(1.3 mL, 9.33 mmol)] was added to solution and flask cooled
in ice bath. MsCl [decanol (3.70 mL, 47.6 mmol)/octadecanol
(0.6 mL, 7.72 mmol)] was then added via syringe, dropwise,
and reaction stirred under Ar overnight, allowing the ice
bath to warm to room temperature. Reaction was then
stopped and washed with 4, 100 mL aliquots of aqueous
NH4Cl, dried over MgSO4 and condensed under reduced
pressure. Yield: 7.413 g decyl methane sulfonate (99%),
1.973 g octadecyl methane sulfonate (95%). Decyl methane
sulfonate: 1H NMR (400 MHz, CDCl3): d 4.22 (t, J 5 6.6 Hz,
2H), 3.00 (s, 3H), 1.75 (p, J 5 6.7 Hz, 2H), 1.42 (t, J 5 7.5
Hz, 2H), 1.26 (m, 12H), 0.88 (t, J 5 6.8 Hz, 3H). Octadecyl
3-(benzyloxy)-2-(decyloxy)propan-1-ol (4a) and 3-(ben-
zyloxy)-2-(octadecyloxy)propan-1-ol (4b): 3a (7.745 g,
24.17 mmol) 3b (903.1 mg, 2.087 mmol) was dissolved in
anhydrous DCM to achieve 400 mmol L21 concentration and
the flask flushed with argon. Reaction cooled in ice bath, and
1M DIBAL (4a 48.3 mL/4b 4.2 mL) was added dropwise
over 20 min and reaction stirred overnight, allowing reaction
to warm to room temperature. Reaction was quenched drop-
wise with 0.5M NaOH (4a 30 mL/4b 3 mL), then diluted
with 0.5M NaOH (10 mL) and extracted with 2, 50 mL ali-
quots DCM. Combined organics were washed with 2, 100 mL
aliquots Rochelle’s salt, 100 mL brine, dried over MgSO4 and
condensed under reduced pressure. The crude oil was puri-
fied by column chromatography (0–5% methanol in DCM) to
1
methane sulfonate: H NMR (400 MHz, CDCl3): d 4.16 (t, J 5
6.4 Hz, 2H), 2.95 (s, 3H), 1.69 (p, J 5 6.8 Hz, 2H), 1.37–1.12
(m, 30H), 0.83 (t, J 5 6.8 Hz, 3H).
yield 6.01
g 3-(benzyloxy)-2-(decyloxy)propan-1-ol (4a)
(18.6 mmol, 77%), 650 mg 3-(benzyloxy)-2-(octadecyloxy)-
propan-1-ol (4b) (1.50 mmol, 72%). 4a 1H NMR (400 MHz,
CDCl3): d 7.36–7.26 (m, 5H), 4.54 (AB quartet, 2H), 3.74 (m,
1H), 3.66–3.48 (m, 6H), 2.10 (dd, J 5 5.7, 6.9 Hz, 1H), 1.57
(p, J 5 7.0 Hz, 2H), 1.26 (m, 14H), 0.88 (t, J 5 6.8 Hz, 3H).
4b 1H NMR (400 MHz, CDCl3): d 7.35–7.24 (m, 5H), 4.53
(AB quartet, 2H), 3.72 (m, 1H), 3.64–3.48 (m, 6H), 2.27 (t,
J 5 5.0 Hz, 1H), 1.57 (p, J 5 7.0 Hz, 2H), 1.26 (m, 32H), 0.88
(t, J 5 6.8 Hz, 3H).
2-phenyl-1,3-dioxan-5-ol (2): glycerol (24.31 g, 264.0
mmol) and benzaldehyde (28.03 g, 264.1 mmol) were dis-
solved in anhydrous toluene (70 mL) and flask flushed with
argon. Para-toluenesulfonic acid monohydrate (115.1 mg,
0.61 mmol) was added and flask fitted with Dean–Stark trap
and heated to reflux. After 72 h, reaction was cooled to
room temperature and washed with sodium bicarbonate
(100 mL), brine (100 mL), dried over MgSO4, and remaining
toluene was placed in freezer overnight to crystallize out
product. White crystals were then collected by filtration and
dried under vacuum to yield 4.487 g (24.90 mmol, 9%
3-(benzyloxy)-2-(decyloxy)propyl methanesulfonate (5a)
and 3-(benzyloxy)-2-(octadecyloxy)propyl methanesulfo-
nate (5b): 4 (4a 6.01 g, 18.6 mmol/4b 215.4 mg, 0.495
mmol) was dissolved in anhydrous DCM to achieve a 50
mmol L21 concentration and the flask was flushed with Ar.
TEA (5a 5.20 mL/5b 0.14 mL) was added and reaction
cooled in ice bath. MsCl (5a 2.20 mL/5b 0.06 mL) was
added dropwise and reaction was stirred under Ar overnight,
allowing ice bath to warm to room temperature. Reaction
was then diluted with DCM (50 mL) and washed with three
aliquots saturated NH4Cl solution, dried over MgSO4 and
condensed under reduced pressure to give pale yellow oil
(5a 7.102 g, 95% yield/5b 0.253 g, quantitative yield). 5a
1H NMR (400 MHz, CDCl3): d 7.33 (m, 5H), 4.54 (dd, J 5
12.1, 2.3 Hz, 2H), 4.39 (dd, J 5 10.9, 3.8 Hz, 1H), 4.27 (dd, J
5 10.8, 5.7 Hz, 1H), 3.70 (p, J 5 4.7 Hz, 1H), 3.55 (m, 4H),
3.00 (s, 3H), 1.56 (p, J 5 6.8 Hz, 2H), 1.28 (m, 14H), 0.88 (t,
J 5 6.8 Hz, 3H). 5b 1H NMR (500 MHz, CDCl3): d 7.41–7.33
(m, 5H), 4.60 (dd, J 5 14.8, 12.1 Hz, 2H), 4.44 (dd, J 5 10.9,
3.8 Hz, 1H), 4.33 (dd, J 5 10.9, 5.6 Hz, 1H), 3.76 (m, 1H),
3.62 (m, 4H), 3.04 (s, 3H), 1.62 (p, J 5 6.8 Hz, 2H), 1.32 (m,
32H), 0.95 (t, J 5 7.0 Hz, 3H).
1
yield). NMR: H NMR (400 MHz, CDCl3): d 7.48 (m, 2H), 7.36
(m, 3H), 5.50 (s, 1H), 4.12 (dd, J 5 12.0, 1.4 Hz, 2H), 4.02
(dd, J 5 12.0, 1.3 Hz, 2H), 3.54 (dt, J 5 10.6, 1.5 Hz, 1H),
3.36 (d, J 5 10.5 Hz, 1H).
5-(decyloxy)-2-phenyl-1,3-dioxane (3a) and 5-(octadecy-
loxy)-2-phenyl-1,3-dioxane (3b): 2-phenyl-1,3-dioxan-5-ol
(2) (3a 3.686 g, 20.46 mmol/3b 4.860 g, 26.97 mmol) was
dissolved in anhydrous toluene (3a 80 ml/3b 130 mL) and
crushed KOH (5a 2.30 g, 41.0 mmol/5b 3.08 g, 54.9 mmol)
added. Reaction fitted with Dean–Stark trap and heated to
reflux for 6 h. Reaction then cooled, and alkyl methane sulfo-
nate (decyl methane sulfonate 7.413 g, 31.36 mmol/octa-
decyl methane sulfonate 5.218 g, 14.97 mmol) added as
solution in toluene (20 mL). Reaction fitted with condenser
and heated to reflux for 5 days. Reaction was then cooled to
room temperature, diluted with 100 mL water, extracted
with 3, 100 mL aliquots of ether, dried over MgSO4 and con-
densed under reduced pressure. Crude oil purified by flash
column (5% ethyl acetate in hexanes) to obtain 3.309 g
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((2-(decyloxy)-3-(1H,1H-perfluorononyloxy)propoxy) meth-
yl)benzene (6a) and ((2-(octadecyloxy)-3-(1H,1H-per-
pure product (HO-lH10F8 2.875 g, 89% yield/HO-lH18F8
1.400 g, 69% yield/HO-lH18PftB 0.091 g, 98% yield). HO-
lH10F8 1H NMR (400 MHz, CDCl3): d 4.00 (t, J 5 13.7 Hz,
2H), 3.73 (m, 3H), 3.57 (m, 4H), 2.00 (t, J 5 6.1 Hz, 1H),
1.57 (p, J 5 7.1 Hz, 2H), 1.26 (m, 14H), 0.88 (t, J 5 6.8 Hz,
3H). 19F NMR (376 MHz, CDCl3): d 281.25 (3F), 2120.16
(2F), 2122.42 (6F), 2123.16 (2F), 2123.82 (2F), 2126.57
(2F). HO-lH18F8 1H NMR (400 MHz, CDCl3): d 3.99 (t, J 5
13.8 Hz, 2H), 3.73 (m, 3H), 3.52 (m, 4H), 2.11 (t, J 5 5.9 Hz,
1H), 1.57 (p, J 5 7.2 Hz, 2H), 1.26 (m, 32H), 0.88 (t, J 5 6.8
Hz, 3H). 19F NMR (376 MHz, CDCl3): d 281.18 (3F),
2120.12 (2F), 222.39 (6F), 2123.13 (2F), 2123.79 (2F),
2126.53 (2F). HO-lH18PftB 1H NMR (400 MHz, CDCl3): d
4.05 (d, J 5 4.0 Hz, 2H), 3.71 (q, J 5 6.0 Hz, 1H), 3.57 (m,
4H), 2.32 (t, J 5 5.6 Hz, 1H), 1.56 (p, J 5 7.2 Hz, 2H), 1.25
(m, 30H), 0.87 (t, J 5 6.8 Hz, 3H). 19F NMR (376 MHz,
CDCl3): d 270.80.
fluorononyloxy)propoxy)methyl)benzene (6b):
5
(5a
3.160 g, 7.9 mmol/5b 1.79 g, 3.49 mmol) was dissolved in
anhydrous benzotrifluoride, F8H1-OH (6a 5.21 g, 11.57
mmol/6b 3.14 g, 6.98 mmol) added, and flask flushed with
Ar. NaH slowly added (6a 667 mg, 28 mmol/6b 335 mg, 14
mmol), and reaction heated to reflux for 3 days. Reaction
was quenched dropwise with H2O and further diluted with
water and DCM and layers separated. Organics dried over
MgSO4 and condensed under vacuum. Purified by column
chromatography (5% ethyl acetate in hexanes) to obtain
pure product (6a 3.985 g, 67% yield/6b 2.29 g, 76% yield).
6a 1H NMR (400 MHz, CDCl3): d 7.33 (m, 5H), 4.54 (s, 2H),
4.00 (t, J 5 13.9 Hz, 2H), 3.76 (dd, J 5 10.4, 4.0 Hz, 1H),
3.68 (dd, J 5 10.4, 5.6 Hz, 1H), 3.61 (p, J 5 4.7 Hz, 1H), 3.54
(m, 4H), 1.56 (p, J 5 6.8 Hz, 2H), 1.28 (m, 14H), 0.88 (t, J 5
6.8 Hz, 3H). 19F NMR (376 MHz, CDCl3): d 281.19 (3F),
2120.22 (2F), 2122.38 (6F), 2123.12 (2F), 2123.80 (m,
Linear and Dibranched Amphiphiles
1
2F), 2126.52 (2F). 6b H NMR (400 MHz, CDCl3): d 7.33 (m,
General procedure: To a dry 100 mL flask charged with
argon were added 50 mL benzotrifluoride (BTF) and 4.0
mmol alcohol. The mixture was cooled on ice and 5.0 mmol
NaH were added. This was allowed to stir for 30 min before
adding 2.0 mmol mPEG-OMs. The reaction was then heated
to reflux and allowed to react for 7 days. The reaction was
cooled, diluted with 100 mL DCM and washed with 150 mL
NH4Cl solution, 50 mL brine, and dried over MgSO4. The
organics were then concentrated to a minimum volume
under reduced pressure and the surfactants precipitated
upon addition of 500 mL cold ether. The solid was collected
by vacuum filtration and then purified by reverse-phase
chromatography. The product was then freeze dried from
50/50 DCM/Benzene to give a powdery solid.
5H), 4.54 (s, 2H), 3.99 (t, J 5 14.4 Hz, 2H), 3.77 (dd, J 5
10.4, 4.2 Hz, 1H), 3.69 (dd, J 5 10.4, 5.5 Hz, 1H), 3.61 (p, J
5 4.9 Hz, 1H), 3.54 (m, 4H), 1.55 (p, J 5 7.0 Hz, 2H), 1.28
(m, 32H), 0.88 (t, J 5 6.8 Hz, 3H). 19F NMR (376 MHz,
CDCl3):
d 281.31 (3F), 2120.28 (2F), 2122.44 (6F),
2123.19 (2F), 2123.85 (2F), 2126.60 (2F).
((3-(perfluoro-tert-butyloxy)-2-(octadecyloxy)propoxy)
methyl)benzene (6c): 5.604 g (10.93 mmol) 5b was dis-
solved in 50 mL anhydrous DMF. 3.64 g (13.28 mmol) potas-
sium perfluoro-tert-butoxide was added, and reaction heated
to 120 ꢀC. After 24 h reaction was stopped, cooled to room
temperature, diluted with H2O, and extracted with ether. The
ethereal layer was dried over MgSO4 and condensed under
vacuum. Crude oil purified by column chromatography
M1H10: 60% Yield, MALDI: Distribution centred on [M 1
Na1] 5 1255.2, 1H NMR (400 MHz, CDCl3): d 3.85–3.81 (m,
1H), 3.68–3.61 (m, 91H), 3.58–3.54 (m, 5H), 3.44 (t, J 5 7
Hz, 2H), 3.38 (s, 3H), 1.57 (pentet, J 5 7.3 Hz, 2H), 1.33–
1.16 (m, 14H), 0.878 (t, J 5 6.9 Hz, 3H).
1
(DCM) to yield 6.48 g (91% yield) white solid. H NMR (400
MHz, CDCl3): d 7.41–7.33 (m, 5H), 4.60 (dd, J 5 14.8, 12.1
Hz, 2H), 4.44 (dd, J 5 10.9, 3.8 Hz, 1H), 4.33 (dd, J 5 10.9,
5.6 Hz, 1H), 3.76 (m, 1H), 3.62 (m, 4H), 3.04 (s, 3H), 1.62 (p,
J 5 6.8 Hz, 2H), 1.32 (m, 32H), 0.95 (t, J 5 7.0 Hz, 3H). 19F
NMR (376 MHz, CDCl3): d 270.7.
M1F13: 58% Yield, MALDI: Distribution centred on [M 1
1
Na1] 5 1749.5, H NMR (400 MHz, CDCl3): d 4.04 (t, J 5 14
Hz, 2H), 3.46–3.46 (m, 106H), 3.38 (s, 3H). 19F NMR (376
MHz, CDCl3): d 281.10 (3F), 2120.13 (2F), 2122.01 (16F),
2123.01 (2F), 2123.79 (2F), 2126.45 (2F).
HO-lH10F8, HO-lH18F8 and HO-lH18PftB: 6 (6a 3.679 g,
4.8 mmol/6b 2.265 g, 2.6 mmol/6c 0.108 g, 0.2 mmol) was
dissolved in anhydrous DCM to achieve 20 mmol/L concen-
tration and anisole (HO-lH10F8 2.10 mL, 19.8 mmol/HO-
lH18F8 1.14 mL, 10.45 mmol/HO-lH18PftB 0.08 mL, 0.74
mmol) was added. Flask was flushed with Ar and cooled in
ice bath. AlCl3 (HO-lH10F8 1.951 g, 14.63 mmol/HO-
lH18F8 1.045 g, 7.84 mmol/HO-lH18PftB 0.076 g, 0.57
mmol) was added and reaction was stirred under Ar. After
(HO-lH10F8 18 h/HO-lH18F8 1.5 h/HO-lH18PftB 1 h)
reaction was quenched dropwise with 0.5M HCl, and further
diluted with 0.5M HCl and layers separated. Organic layer
was washed with H2O, brine, dried over MgSO4, and con-
densed under reduced pressure. Crude oil was purified by
column chromatography, [(HO-lH10F8 10–40%/HO-lH18F8
10%/HO-lH18PftB 0–5%) ethyl acetate in hexanes] to give
M1H10-O-F3: 52% Yield, MALDI: Distribution centred on [M
1
1 Na1] 5 1581.6, H NMR (400 MHz, CDCl3): d 3.90 (tt, J 5
13.7, 1.7 Hz, 2H), 3.84–3.81 (m, 1H), 3.75–3.71 (m, 1H),
3.68–3.61 (m, 95H), 3.60–3.54 (m, 6H), 3.44 (t, J 5 6.9 Hz,
2H), 3.38 (s, 3H), 1.58 (sextet, J 5 7.1 Hz, 4H), 1.35–1.22 (m
12H). 19F NMR (376 MHz, CDCl3): d 281.39 (3F), 2121.12
(2F), 2128.20 (2F).
M1H10-O-F6: 42% Yield, MALDI: Distribution centred on [M
1 Na1] 5 1600.2, 1H NMR (400 MHz, CDCl3): d 3.92 (tt, J
5 13.3, 2.2 Hz, 2H), 3.70–3.62 (m, 95H), 3.61–3.54 (m, 9H),
3.44 (t, J 5 6.6 Hz, 2H), 3.38 (s, 3H), 1.63–1.52 (m, 4H),
1.33–1.23 (m, 12H). 19F NMR (376 MHz, CDCl3): d 281.28
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(3F), 2120.07 (2F), 2122.73 (2F), 2123.34 (2F), 2123.95
(2F), 2126.64 (2F).
13.9 Hz, 2H), 3.82 (m, 2H), 2.76 (dd, J 5 10.5, 3.6 Hz, 1H),
3.60–3.50 (m, 144H), 3.55 (m, 6H), 3.47 (m, 2H), 3.38 (s,
3H), 1.55 (p, J 5 6.8 Hz, 2H), 1.26 (m, 26H), 0.88 (t, J 5 7.0
Hz, 3H). 19F NMR (400 MHz, CDCl3): d 281.27 (3F),
2120.28 (2F), 2122.49 (6F), 2123.22 (2F), 2123.89 (2F),
2126.65 (2F).
M1H10F8: 79% Yield, MALDI: Distribution centred on [M 1
Na1] 5 1670.8, 1H NMR (400 MHz, CDCl3): d 3.86–3.80 (m,
1H), 3.76–3.54 (m, 98H), 3.45 (t, J 5 6.7 Hz, 2H), 3.38 (s,
3H), 2.05 (ttt, J 5 19, 8.2, 2 Hz, 2H), 1.57 (septet, J 5 6.7
Hz, 2H), 1.42–1.20 (m, 10H). 19F NMR (376 MHz, CDCl3): d
281.19 (3F), 2114.74 (2F), 2122.36 (6F), 2123.16 (2F),
2123.96 (2F), 2126.57 (2F).
M2lH18PftB: 42% Yield, MALDI: Distribution centred on [M
1 Na1] 5 2184.7, 1H NMR (400 MHz, CDCl3): d 4.14 (m,
1H), 4.04 (m, 1H), 3.79 (m, 1H), 3.69–3.59 (m, 144H), 3.55
(m, 4H), 3.50 (m,1H), 3.38 (s, 3H), 1.54 (p, J 5 7.2 Hz, 2H),
1.27 (m, 32H), 0.88 (t, J 5 6.8 Hz, 3H). 19F NMR (400 MHz,
CDCl3): d 270.66.
M5diH10: 70% Yield, MALDI: Distribution centred on [M 1
Na1] 5 5120.8, 1H NMR (400 MHz, CDCl3): d 3.82 (dd, J 5
6.4, 4.6 Hz, 2H), 3.76 (dd, J 5 6.5, 4.7 Hz, 2H), 3.70–3.59 (m,
530H), 3.56–3.53 (m, 3H), 3.50–3.45 (m, 6H), 3.42 (t, J 5 6.8
Hz, 4H), 3.38 (s, 3H), 1.55 (pentet, J 5 7.8 Hz, 4H), 1.34–
1.21 (m, 28H), 0.88 (t, J 5 6.3 Hz, 6H).
M5lH18PftB: 50% Yield, MALDI: Distribution centred on [M
1 Na1] 5 5503.8, 1H NMR (400 MHz, CDCl3): d 4.13 (m,
1H), 4.03 (m, 1H), 3.82 (m, 2H), 3.70–3.60 (m, 386H), 3.55
(m, 5H), 3.47 (m, 2H), 3.38 (s, 3H), 1.54 (p, J 5 7.1 Hz, 2H),
1.28 (m, 32H), 0.88 (t, J 5 6.8 Hz, 3H). 19F NMR (400 MHz,
CDCl3): d 271.15.
M5diH10-O-F3: 87% Yield, MALDI: Distribution centred on
1
[M 1 Na1] 5 5695.7, H NMR (400 MHz, CDCl3): d 3.90 (tt,
J 5 13.8, 1.7 Hz, 4H), 3.82 (dd, J 5 5.8, 4.6 Hz, 2H), 3.71
(dd, J 5 6.3, 4.9 Hz, 2H), 3.71–3.53 (m, 453H), 3.50–3.41 (m,
12H), 3.38 (s, 3H), 1.63–1.51 (m, 8H), 1.39–1.23 (m 28H).
19F NMR (376 MHz, CDCl3): d 281.39 (6F), 2121.096 (4F),
2128.200 (4F).
All amphiphiles are at most as polydisperse as the mPEG-OH
from which they are synthesized. MALDI spectra for starting
mPEG-OMs and synthesized polymers can be found in the
Supporting Information.
M5diH10-O-F6: 45% Yield, MALDI: Distribution centred on [M
Physicochemical Characterization
1
1 Na1] 5 6173.0, H NMR (400 MHz, CDCl3): d 3.917 (tt, J 5
Micelle Preparation—Solvent Evaporation Method (SEM)
Polymer is dissolved in MeOH or ACN to a desired concen-
tration. 1 mL of polymer solution and additive (e.g., PTX in
ACN) are added to a 25 mL roundbottom flask and rotated
for 5 min at 60 ꢀC on a rotary evaporator, no vacuum, and
then the solvent was removed in vacuo with rotation for 15
min. The film was then dispersed with Millipore water
13.2, 2.8 Hz, 4H), 3.75–3.79 (m, 6H), 3.68–3.45 (m, 480H), 3.42
(t, J 5 7 Hz, 4H), 3.38 (s, 3H), 1.61–1.53 (m, 8H), 1.33–1.27 (m,
26H); 19F NMR (376 MHz, CDCl3): d 281.13 (6F), 2119.94 (4F),
2122.66 (4F), 2123.21 (4F), 2123.82 (4F), 2126.50 (4F).
All amphiphiles are at most as polydisperse as the mPEG-OH
from which they are synthesized. MALDI spectra for starting
mPEG-OMs and synthesized polymers can be found in the
Supporting Information.
ꢀ
heated to 60 C and filtered with a 0.45-lm nylon filter.
Particle Size Determination by Dynamic Light Scattering
(DLS)
Miktoarm Amphiphiles
Micelles were prepared by solvent evaporation, polymer
solution concentration 1 mg mL21 in MeOH. Particle sizes of
polymeric aggregates were analysed by dynamic light scat-
tering (NICOMP 380ZLS, Particle Sizing Systems, Santa Bar-
bara, CA). The surfactant solution was measured directly
without dilution and analysed. Each particle size analysis
was run at room temperature and repeated in triplicate with
the number of scans of each run determined automatically
by the instrument according to the concentration of the solu-
tion. The data were analyzed using NICOMP analysis and
reported as volume weighted average diameters.
Typical Procedure: Alcohol and mPEG-OMs were dissolved
in 20–75 mL BTF to achieve 20 mM concentrations. Flask
flushed with Ar, NaH added (to achieve 40 mM concentra-
tion), and flask heated to reflux. After 5 days reaction was
cooled to room temperature and quenched dropwise with
H2O. The organics were dried over MgSO4. Solvents evapo-
rated under reduced pressure, and crude polymer purified
by reverse-phase chromatography. Solid was lyophilized to
give white, fluffy product.
M1lH10F8: 89% Yield, MALDI: Distribution centred on [M
1
1 Na1] 5 1715.0, H NMR (400 MHz, CDCl3): d 4.02 (t, J 5
Critical Aggregation Concentration (CMC)
Determination—Surface Tensiometry
14 Hz, 2H), 3.81 (m, 1H), 3.75 (dd, J 5 10.4, 3.6 Hz, 2H),
3.67–3.62 (m, 80H), 3.59–3.51 (m, 7H), 3.46 (m, 1H), 3.38
(s, 3H), 1.57 (p, J 5 7.2 Hz, 2H), 1.26 (m, 16H), 0.88 (t, J 5
6.8 Hz, 3H). 19F NMR (400 MHz, CDCl3): d 281.14 (3F),
2120.18 (2F), 2122.36 (6F), 2123.09 (2F), 2123.77 (2F),
2126.48 (2F).
Surfactant was dissolved in Millipore water to a concentra-
tion of 1 mM and concentrations down to 1 nM were pre-
pared by serial dilution and transferred to 20 mL disposable
scintillation vials. After solutions were made, the samples
ꢀ
were heated in a water bath at 40 C with sonication for 2–3
M2lH18F8: 58% Yield, MALDI: Distribution centred on [M
h and allowed to equilibrate for 24 h. Surface tensions were
1
1 Na1] 5 2586.5, H NMR (400 MHz, CDCl3): d 4.03 (t, J 5
measured on
a
KSV sigma 701 tensiometer (KSV
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Instruments, Helsinki, Finland) equipped with a Julabo F12-
MC circulator for constant temperature control. Custom
round rod made of platinum with a diameter of 1.034 nm
with wetted length of 3.248 mm was used. The rod was sub-
merged in absolute alcohol and flame dried with a Bunsen
burner for 4 s. This was repeated after 4 min. The rod was
then hung on the instrument and allowed to cool to room
temperature without touching any surface. Before running
the experimental samples, the surface tension of millipore
water was measured as a control to confirm the rod was
fully cleaned and surface tension was within 1 of 78.2 mN/
m. The surface tension measurements began with the least
concentrated solution and proceeded to successively more
concentrated solutions. The surface tension at each concen-
tration was measured in quadruplet and average recorded.
The critical micelle concentration value was determined
from the crossover point of two lines: the baseline of mini-
mal surface tension and the slope where surface tension
showed linear decline; error determined by weighted least
squares analysis.
correct for baseline), 150 lL FRET dye loaded micelles and
2.85 mL human serum (mixed gently before first measure-
ment and vigorously before each measurement, every 15 min,
thereafter. The fluorescence analysis was carried out on an
AMINCO-Bowman Series 2 spectrometer with excitation at.
The FRET ratio calculated was the ratio of I565/(I501 1 I565).
Paclitaxel (PTX) Encapsulation Measurements
Micelles solutions were prepared in triplicate using the sol-
vent evaporation method. PTX stock solution was generated
by dissolving PTX in ACN, aided by sonication, at a concen-
tration of 1 mg/mL. Surfactant was dissolved in ACN to give
a final concentration of 2.4 3 1023 mol/L. 1 mL of surfac-
tant solution was then mixed with 230 lL PTX solution. The
sample was then centrifuged at 12,000 rpm for 5 min and
filtered through 0.45-lm nylon syringe filter to remove any
insoluble precipitate. A 100-lL aliquot of micelle solution
was mixed with 900 lL of ACN and the remaining micelle
solution was allowed to sit for 24 h. The sample was then
re-centrifuged at 12,000 rpm for 5 min and filtered through
0.45-lm nylon syringe filter to remove any insoluble precipi-
tate. A 100-lL aliquot of micelle solution was mixed with
900 lL of ACN. The paclitaxel loaded in the micelle was
quantified by reverse phase HPLC. The HPLC system used
Critical Aggregation Concentration (CMC)
Determination—Pyrene Fluorescence
Based on the methodology developed by Torchilin et al.17
Micelles were prepared by the solvent evaporation method.
200 lL micelle solutions in MeOH ranging in concentration
from 1024.5 to 1028 M were delivered to 25 mL roundbot-
tom flasks with 100 lL 10 mg/mL pyrene solution. The thin
was
a Shimadzu prominence HPLC system (Shimadzu,
Japan), consisting of a LC-20AT pump, SIL-20 AC HT auto-
sampler, CTO-20 AC column oven and an SPD-M20A diode
array detector. 20 lL of the mixture was injected into a C18
column (Agilent XDB-C8, 4.6 Å 3 150 mm), eluting with an
isocratic mixture of 25% water in acetonitrile. The run time
was 7 min, the flow rate was 1.0 mL/min and the detection
was set at 227 nm.
ꢀ
films were dispersed with 2 mL 60 C PBS and filtered with
a 0.45-lm nylon filter. The fluorescence analysis was carried
out on an AMINCO-Bowman Series 2 spectrometer with exci-
tation at 339 nm, emission at 390 nm, and a spectral win-
dow of 370–400 nm. The analysis was carried out in
triplicate and the average CMC and standard deviation are
reported.
RESULTS AND DISCUSSION
The synthesis of both linear and dibranched alcohols starts
with 9-decen-1-ol. Two methodologies were developed: radi-
cal and anionic syntheses (Scheme 1). The radical synthesis
utilizes methodology developed by Brace.18 In an atom trans-
fer radical addition, perfluorooctyl iodide is added to 9-
decen-1-ol with AIBN as a radical initiator. Subsequent
reduction by zinc in acetic acid then removes the iodide
(Scheme 1).
Microviscosity Measurement
Surfactant solutions of 0.2 mmol/L in MeOH and a 2.7 ng/mL
1,3-bis-(1-pyrenyl)propane (P3P) in chloroform were pre-
pared. Micelle solutions were then prepared via the solvent
evaporation method with 67 lL of the P3P solution added
and solutions stored in amber vials. The fluorescence analysis
was carried out on an AMINCO-Bowman Series 2 spectrome-
ter with excitation at 333 nm, emission at 378 nm and a spec-
tral window of 350–500 nm.
This methodology worked in moderate to good yields for
producing F8H10-OH and F6H10-OH, not shown. F8H10-OH
worked well in subsequent Williamson ether syntheses, but
the smaller F6H10-OH decomposed under the basic reaction
conditions. F6H10-OH suffered from HF elimination across
the CF2–CH2, a potential pitfall when using semifluorinated
molecules under basic conditions.19
€
Foster Resonance Energy Transfer (FRET) Stability
Surfactant solutions of 1 mg/mL in methanol and 0.1 mg/mL
of 1,10-dioctadecyl-3,3,30,30-tetramethylindocarbocyanine per-
chlorate (DiI) and 3,30-dioctadecyloxacarbocyanine perchlorate
(DiO) in methanol were prepared. Micellar solutions were
then prepared by the solvent evaporation method. For blank
micelles only polymer solution is used; for FRET loaded
micelles, 46 lL DiI and 44 lL of DiI are added.
To circumvent the basic instability of the radical-synthesis
products, an anionic synthesis was developed that produced
more stable alcohols for further reactions (Scheme 1). A semi-
fluorinated alkene ether is prepared by Williamson ether
synthesis using 9-decen-1-yl methane sulfonate and 1H,1H-
perfluorobutan-1-ol (F3-O-H10-OH) or 1H,1H-perfluoro-
heptan-1-ol (F6-O-H10-OH). Only 1H,1H-perfluoro-alcohols
Three analytic samples were then prepared (the two compo-
nents were mixed just before analysis: 50 lL of FRET dye
loaded micelles and 950 lL PBS (used to set sensitivity),
50 lL empty micelles and 950 lL human serum (used to
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For the hydrophilic head group, the size of the mPEG was
selected so as to favor micelle formation. In our lab we have
seen that diblock amphiphiles with mPEG1000 form micellar
aggregates thus mPEG1000 was selected as a hydrophilic
group for the linear amphiphiles. Similarly, it was found that
mPEG1000 with dibranched hydrophobic tails yielded random
aggregates,9 as such mPEG2000 and mPEG5000 were selected
for coupling to the miktoarm and dibranched alcohols,
respectively, to ensure micelle formation.
Each amphiphile was analysed by MALDI mass spectrometry
to determine average molecular weight (Tables 1 and 2). To
determine the critical micelle concentration (CMC), the con-
centration above which aggregates begin to form, surface
tension analysis was used. Surfactant solutions were pre-
pared in deionized water at concentrations from 1 mM to 1
nM. The CMC was then determined as the cross over of two
lines and the error was determined by weighted, least-
squares analysis (Tables 1 and 2). M5diH10-O-F6 produced
inconclusive results by surface tension measurements and
was thus analysed by pyrene encapsulation fluorescence.17
The inconclusive surface tension measurements are possibly
due to slow kinetics in the equilibration of polymer chains.
Solutions above the CMC were analysed by dynamic light
scattering (DLS) (Tables 1 and 2). Most of the surfactants
showed small (<20 nm), narrow size-distributions consistent
with spherical micelles. Note that cryogenic transmission
electron microscopy (cryo-TEM) is typically used to verify
the morphology of the aggregates formed. For the amphi-
philes presented here, cryo-TEM failed due to the highly sol-
vated nature of the PEG (rendering it indistinguishable from
SCHEME 1 Synthesis of linear and dibranched alcohols.
were found to proceed in high yields, as 1H,1H,2H,2H-per-
fluoroalcohols suffered from complete HF elimination in
lieu of any SN2 reaction.20 Hydroboration oxidation of the
semifluorinated alkene yields the linear semifluorinated
alcohols in good overall yield. The linear alcohols can then
be used to form dibranched alcohols by a concomitant SN2
reaction and ring opening of epichlorohydrin (Scheme 1).
This represents a more robust methodology for the synthe-
sis of linear (and subsequently dibranched) alcohols than
the radical mechanism because these alcohols did not suffer
from base-induced decomposition.
The miktoarm alcohols were prepared starting from glycerol
(Scheme 1). Acetal protection of the two primary alcohols
proceeds in low yield due to the mixture of 1,2- and 1,3-pro-
tection products.21 Subsequent alkylation of the secondary
alcohol was then found to proceed best using alkyl methane
sulfonates in a mixture of KOH and toluene at reflux. Reduc-
tive ring opening with DIBALH affords 3-benzyloxy-2-alkoxy-
1-propanols. Mesylation and Williamson ether synthesis with
semifluorinated alcohols 1H,1H-perfluorononan-1-ol (F8H1-
OH) or perfluoro-tert-butanol (PftB-OH) followed by depro-
tection gave the miktoarm alcohols (Scheme 2).
The linear, dibranched, and miktoarm alcohols were
coupled to mono-methoxy capped poly(ethylene glycol)
methane sulfonate (Scheme 3). The reactions were found to
proceed best in benzotrifluoride (BTF) rather than THF, as
higher temperatures could be achieved for reflux. Purifica-
tion of the produced amphiphiles was achieved by reverse-
phase chromatography.
SCHEME 2 Synthesis of miktoarm alcohols.
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for micelle formation, with M1H10 showing the formation of
random aggregates by DLS and M1H10-O-F3 showing a DLS
consistent with small, spherical micelles. Further changes in
the length of the fluorocarbon block do not show significant
changes in average particle size going from M1H10-O-F3 to
M1H10F8. The dibranched amphiphiles show a very similar
trend (Table 1). While there is a noticeable change between
M5diH10 and M5diH10-O-F3, M5diH10-O-F3 and M5diH10-
O-F6 show similar particle sizes. It can be seen that in a lin-
ear arrangement of moieties, the introduction of a fluorocar-
bon segment has an effect on particle size, but changes of
the fluorocarbon block size have little to no effect among
these triphilic amphiphiles.
Upon analysis of Table 1 trends between CMC and the number
of fluorocarbons can be observed. As shown in Fig. 2, there is a
linear relationship between pCMC (2log(M)) and the number
of fluorinated carbon atoms. Linear relationships between CMC
(log(M)) and the number of –CH2–24 or –CF2–25 has been
reported previously. Here, the interesting result is the differ-
ence in slope between the linear and dibranched surfactants
(Fig. 2). There are two differences between the two classes of
amphiphiles that could account for this. The first is the differ-
ence in PEG block size (M1 compared to M5). To evaluate the
effect of PEG size, the pCMC of the linear M1H10F8 (5.85) was
compared to that of the linear M5H10F8 (5.60). There is a dif-
ference in CMC; however, the linear fit for the dibranched
amphiphiles predicts a pCMC of 4.67, almost a full order of
magnitude different. As such, it seems that the difference in
PEG size is not the determining factor. The second difference is
that of hydrophobic architecture itself. The difference between
the linear and dibranched series can be explained by the differ-
ences in hydrophobic architecture. The linear polymers have a
much smaller base hydrophobic block (H10) than the
dibranched polymers (diH10). Thus the addition of each fluoro-
carbon to the linear architecture has a larger effect, whereas
the addition of fluorocarbons to the larger dibranched hydro-
phobic block has a diminished effect. This difference in the
effectiveness of each fluorocarbon on the CMC thus explains
the difference in slope for Figure 2, a result of the size of the
hydrocarbon block size relative to the fluorocarbon block size.
SCHEME 3 PEGylation of semifluorinated alcohols.
the surrounding vitrified water),22 and the relatively small
size of the hydrophobic blocks. Core microviscosity for each
amphiphile was determined by encapsulation and fluores-
cence analysis of 1,3-bis-(1-pyreneyl)propane. The microvis-
cosity is presented as the ratio of the monomer fluorescence
(Im) over the eximer fluorescence (Ie), with higher Im/Ie ratios
corresponding to greater microviscosities (Tables 1 and 2).23
The first trend to notice is the effect of the fluorinated moi-
eties on the average particle size (Table 1). For these linear
amphiphiles, the addition of the fluorous block was essential
TABLE 1 Physicochemical Data of Linear and Dibranched Amphiphiles
Amphiphile
Mol. Wt. (g/mol)
pCMC (2log(M) 6 SD)
Ave Size (nm)
Microviscosisty (Im/Ie)
M5diH10
5,097.8
5,672.7
6,150.0
1,232.2
1,558.6
1,577.2
1,647.8
1,726.5
3.92 6 0.14
4.44 6 0.18
5.05 6 0.03
3.01 6 0.25a
3.82 6 0.08
4.53 6 0.12
5.85 6 0.06
6.08 6 0.13
16.1 6 1.6
21.6 6 5.9
20.3 6 6.5
149.7 6 36.0
9.5 6 1.3
3.64 6 0.23
6.76 6 0.13
6.83 6 0.17
2.75 6 0.11
5.99 6 0.32
6.26 6 0.19
6.81 6 0.11
3.40 6 0.18
M5diH10-O-F3
M5diH10-O-F6
M1H10
M1H10-O-F3
M1H10-O-F6
M1H10F8
10.6 6 1.0
10.7 6 1.2
11.9 6 1.3
M1F13
a
pCAC, -log(critical aggregation concentration), reported. M1H10 does not form spherical micelles, but rather it randomly aggregates to yield a vari-
ety of assemblies of various sizes.
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TABLE 2 Physicochemical Data of Miktoarm Amphiphiles
Amphiphile
Mol. Wt. (g/mol)
pCMC (2log(M) 6 SD)
Ave Size (nm)
Microviscosity (Im/Ie)
M1lH10F8
M2lH18F8
M2lH18PftB
M2DSPE
1,692.0
2,563.5
2,161.7
2,805.5
5,480.4
5,801.1
5.51 6 0.05
4.61 6 0.07
4.62 6 0.42
4.90 6 0.17
5.22 6 0.22
5.38 6 0.10
10.8 6 1.0
11.5 6 1.5
12.5 6 1.5
13.9 6 1.6
19.6 6 2.7
18.6 6 2.8
5.08 6 0.06
5.38 6 0.08
4.43 6 0.08
5.60 6 0.22
4.25 6 0.07
5.23 6 0.03
M5lH18PftB
M5DSPE
Microviscosity measurements of the triblock surfactants
show dramatically different behavior than either the hydro-
carbon M1H10/M5diH10 or fluorocarbon M1F13 diblock
amphiphiles (Table 1). The diblock surfactants show similar
Im/Ie ratios, while the smallest triblock amphiphiles–M1H10-
O-F3 and M5diH10-O-F3—show a sharp increase in micro-
viscosity. Typically, increases in microviscosity are associated
with more crystalline micelles resulting from either chain
entanglement or tighter packing of unimers.4 The triblock
amphiphiles are believed to show higher microviscosities,
compared to the diblock surfactants, due to hydrophobic
phase segregation of the hydrocarbon and fluorocarbon
blocks, which results in tighter unimer packing within the
micelles.
sequent fluorocarbon, however, does not lead to further
phase-segregation but merely diminishes unimer dynamics.
A third general surfactant design (Scheme 2) in which a pure
hydrocarbon is used as one branch and a pure fluorocarbon is
used as the second branch (miktoarm surfactants) was seen as
an alternative that would allow for a wider variety of surfac-
tant design. Furthermore, the miktoarm architecture offered a
distinctly different design, which in reference to the linear and
dibranched amphiphiles already presented offers an interesting
comparison. The miktoarm semifluorinated surfactants’ physi-
cochemical data are summarized in Table 2.
One of the most immediate trends to notice is the relatively
small change that is observed in the CMC among nonfluori-
nated polymeric amphiphiles (M2DSPE and M5DSPE) and
fluorinated miktoarm analogues (M2lH10F8, M2lH18PftB,
M5lH18PftB). The parallel arrangement of fluorocarbon and
hydrocarbon chains does not lead to the decrease in CMC
that was observed for linear and dibranched amphiphiles.
This could be due to the compartmental segregation of fluo-
rocarbon and hydrocarbon blocks, which increases unfavora-
ble hydrocarbon–fluorocarbon interfacial interactions.26
The higher rigidity of the triblock polymeric micelles has
important implications in terms of kinetic stability and
encapsulation. In Figure 3, the microviscosities for all
hydrocarbon-diblock and triblock amphiphiles are plotted
against the number of fluorocarbons in each amphiphile.
This plot shows a logarithmic increase in microviscosity with
the number of fluorocarbons. Hence the initial addition of a
small number of fluorocarbons causes the most dramatic
increase in microviscosity (Fig. 3) compared to the diblock
analogues. This is the result of phase segregation. Each sub-
For the miktoarm amphiphiles there is no consistent trend in
average particle size associated with the changes in
FIGURE 3 Relationship between microviscosity (Im/Ie ratio 6
SD, n 5 3) and the number of fluorocarbons for linear and
dibranched amphiphiles.
FIGURE 2 Relationship between linear and dibranched amphiphile
number of fluorocarbons and pCMC (2log(M) 6 SD, n 5 4).
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the linear amphiphiles. The less efficient packing contributed
to a smaller effect of each fluorocarbon, in the dibranched
amphiphiles, on the kinetic stability.
The relationship between microviscosity and kinetic stability
is further underlined by the results of the miktoarm surfac-
tants, which did not show such dramatic improvements in
stability when comparing M2lH18PftB versus M2lH18F8.
The less viscous M2lH18PftB micelle demonstrates much
more rapid dissociation, mirroring the trend in microviscos-
ity and supporting the idea that the M2lH18PftB micelles
pack less efficiently due to the spherical nature of the fluo-
rous moiety. Measurement of M1lH10F8 particle stability
was especially difficult and was not shown. This polymer
failed to encapsulate the FRET dyes. As such, after numerous
trials, only one run showed any initial FRET ratio above the
0.400 minimum, which, however, decreased very quickly.
Given the poor encapsulation ability no comparison could be
made, using this methodology, between the linear M1H10F8
and the miktoarm M1lH10F8.
FIGURE 4 FRET stability of representative amphiphiles.
hydrocarbon or fluorocarbon moieties. There are noticeable
differences in particle size, which can be attributed solely to
the changes in the size of the mPEG block. This follows logi-
cally as the change in the size of the hydrophilic block is the
greatest change occurring among the various miktoarm
surfactants.
Given the possible structure of the linear/dibranched (fluo-
rocarbon core-hydrophobic intermediate shell-hydrophilic
corona)16,30 and miktoarm (compartmental structure)
amphiphiles,26 encapsulation of paclitaxel (PTX), a model
hydrophobic species, was investigated. It is known that
hydrophobic molecules can be encapsulated in classical
hydrocarbon-based micelles by sequestration within the
hydrophobic core.31 Here PTX encapsulation was investi-
gated to probe the effect of a fluorous core (linear/
dibranched amphiphiles) or a mixed hydrocarbon/fluorocar-
bon core (miktoarm amphiphiles) on the solubilization of
hydrophobic species.
The microviscosity among the various miktoarm amphiphiles
differs little. The exceptions to this trend are the M2lH18PftB
and M5lH18PftB surfactants. Here spherical perfluoro-tert-
butanoxy is used, which interferes with chain packing and
lowers the microviscosity compared to F8H1-OH.
The use of fluorocarbon segments was investigated not only
for their potential effects on thermodynamic stability, CMC,
micelle formation, or microviscosity of aggregates, but also
for their potential to improve kinetic stability in vivo.
Micelles have found widespread use in the development of
drug delivery and of central importance is the lifetime of
micelles in vivo.27 For this application, better results have
been observed with long circulating particles.28
Paclitaxel was chosen as the model hydrophobic drug
because it is not solubilized to any extent in a purely fluoro-
philic micelle (Fig. 5). This allows for the direct interrogation
of how PTX is encapsulated into a hydrophobic shell, in the
case of the linear and dibranched amphiphiles, or a mixed
core, in the case of the miktoarm amphiphiles. PTX loaded
micelles were prepared by the solvent evaporation method
Using methodology developed by Chen et al. the dissociation
€
of micelles in human serum was monitored through Forster
Resonance Energy Transfer (FRET)29 (Fig. 4), FRET data for
all polymers can be found in the Supporting Information. It
was found that nonfluorinated micelles (M5diH10 and
M5DSPE) rapidly dissociated in vitro when exposed to
human serum (observed by a decrease in FRET ratio). For
fluorinated micelles, both the architecture and block compo-
sition are important. The linear surfactants showed a dra-
matic increase in stability with only the addition of an F3
block and even greater stability with an F8 (an F6 block fell
in between F3 and F8). This trend follows the microviscosity
trend observed (Table 1) and suggests that the more crystal-
line (more viscous) micelles are more resistant to dissocia-
tion. For dibranched, triphilic amphiphiles, only M5diH10-O-
F6 shows any increase in stability (Fig. 4), while M5diH10-
O-F3 (not shown) does not show any increase in stability
over M5diH10. This is likely due to the less efficient packing
of the dibranched hydrophobic amphiphiles—compared to
FIGURE 5 Percent weight encapsulation (mean 6 SD, n 5 3)
by linear and dibranched amphiphiles.
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mercially available M2DSPE and M5DSPE. Perhaps
unsurprisingly, this suggests that one of the key parameters
in encapsulation and retention of hydrophobic species is the
hydrophobic carrying capacity—which is analogous to the
number of hydrocarbons in the aggregate. For example,
M2lH18F8 has half the number of hydrocarbons in the core
compared to M2DSPE and the percent weight encapsulation
of PTX after 24 h for M2lH18F8 (1.89 wt %) is slightly
more than half of that for M2DSPE (3.21 wt %). Interest-
ingly, it seems that sufficiently high microviscosity can com-
pensate for a reduction in hydrophobic carrying capacity as
seen in comparing M1H10F8 (2.00 wt % PTX encapsulated
after 24 h) and M2lH18F8. M1H10F8 performs better than
M2lH18F8 despite having 55% of the number of methylene
groups of M2lH18F8.
FIGURE 6 Percent weight encapsulation (mean 6 SD, n 5 3) of
PTX by miktoarm and DSPE amphiphiles.
It should be noted that compared to the mPEG-DSPE poly-
meric surfactants, all triphilic amphiphiles presented here
retain significantly less PTX than they initially encapsulate.
The loss of PTX over time is associated with two factors.
First, hydrophobic molecules that are poorly encapsulated—
in the mPEG corona rather than in the hydrophobic core—
are lost rapidly.33,34 Second, overall stability of the micellar
aggregate is critical, with more stable, less dynamic micelles
showing greater overall retention of encapsulated species.35
For the polymers presented here, all possess much smaller
(SEM), which we found to give more reproducible results
than other methods and to give higher drug loading.32 All
encapsulation data are presented as the average percent
weight of the encapsulated PTX in linear and dibranched
amphiphiles (Fig. 5) and miktoarm amphiphiles (Fig. 6).
Equimolar amounts of surfactants were used in all encapsu-
lation studies to allow for direct comparisons.
Each of the linear amphiphiles is able to initially encapsulate
the same amount of PTX on a percent weight basis (Fig. 5),
despite varying the fluorocarbon length. However, after 24 h
—when poorly encapsulated PTX is lost33,34—an increase in
the PTX remaining encapsulated in the micelles can be seen
with increasing size of the fluorocarbon moiety. The increase
in PTX remaining encapsulated after 24 h trends with the
increase in microviscosity. This suggests that more PTX is
retained for a longer period of time in M1H10F8 due to its
less dynamic, higher microviscosity aggregates. A similar
inclination is also seen in the dibranched amphiphiles. Here,
the higher microviscosity of M5diH10-O-F3 and M5diH10-O-
F6 is directly related to the higher encapsulation of and
retention of PTX after 24 h (Fig. 5) compared to M5diH10.
Note that M1H10 was not studied for its encapsulation abil-
ity because it forms random aggregates.
hydrophobic
blocks
than
mPEG-DSPE—the
largest
M2lH18F8 has 50% of the hydrophobic groups in mPEG-
DSPE. As such, there is less space to encapsulate PTX. How-
ever, despite the overall smaller hydrophobic carry capacity,
the linear and dibranched triblock polymers show high
microviscosities, which correlate well with the size of the flu-
orocarbon block. As the microviscosity, and therefore the
aggregate stability, increases so does the overall retention
of PTX.
Ultimately, when one directly compares the linear
(M1H10F8) and miktoarm (M1lH10F8) architectures several
points stand out. Both M1H10F8 and M1lH10F8 have very
similar CMCs and particle sizes. Their point of divergence is
microviscosity. M1H10F8 has a microviscosity (6.81, Table 1)
36% greater than that of M1lH10F8 (5.01, Table 2). This
results in a higher net retention of PTX by M1H10F8 than
M1lH10F8. Given the poor encapsulation of the FRET dyes
by M1lH10F8, no direct comparison can be made on archi-
tecture stability differences, but one can infer from the per-
formance of M2lH18F8 (which has a higher microviscosity)
that M1lH10F8 would dissociate far more rapidly than
M1H10F8.
The linear and dibranched amphiphile encapsulation data
show that an inner hydrophobic core is not necessary for
stable encapsulation of hydrophobic species such as PTX.
Moreover, as the fluorous innercore increases in size, the
micelles show enhanced retention ability as a result of the
ꢀ
more tightly packed micellar structure, vis-a-vis microviscos-
ity. The linear arrangement of hydrocarbon and fluorocarbon
segments shows both enhanced kinetic stability and
enhanced ability to retain hydrophobic species over time. In
the case of the miktoarm amphiphiles (Fig. 6), trends that
relate the amount of PTX encapsulated to the microviscosity
can be observed. The less viscous micelle (M2lH18PftB)
retains less PTX than the more viscous (M2lH18F8). The
more noticeable trend, however, is the overall reduction in
both initial and retained PTX encapsulated when the semi-
fluorinated miktoarm amphiphiles are compared to the com-
CONCLUSIONS
The peculiar properties of fluorocarbons offer a means of
not only improving micellar kinetic and thermodynamic sta-
bility, but also a way of improving and probing encapsulation
behavior. Herein the syntheses for the preparation of linear,
dibranched, and miktoarm semifluorinated amphiphiles have
been presented. Each class of polymer was studied in an
attempt to elucidate relationships between the ternary
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7 V. Weissig, K. R. Whiteman, V. P. Torchilin, Pharm. Res.
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behavior of the aggregates. For linear and dibranched amphi-
philes, the introduction of fluorocarbon moieties significantly
increases their thermodynamic stability and microviscosity;
while for miktoarm amphiphiles, the more important factors
are the shape of the fluorocarbon block and the size of the
hydrophobic and hydrophilic segments. For the linear surfac-
tants alone, the introduction of fluorocarbon blocks leads to
significantly greater kinetic stability, which was correlated
with higher microviscosity. All triblock amphiphiles that
formed small, narrow size distributions in water that were
consistent with micelles, were studied for their ability to
encapsulate PTX. Overall, the semifluorinated surfactants
retained less of the PTX initially encapsulated as compared to
the phospholipid-based mPEG2000DSPE and mPEG5000DSPE
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compared to that present in mPEG-DSPE. Taken together, the
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philes blocks can be rationally used to modulate the physico-
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#
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