Transition Metal-Catalyzed One-Pot Synthesis of Water-Soluble Dendritic Molecular Nanocarriers

Article abstract of DOI:10.1021/ja039829e

Here, we report the first example of transition metal-catalyzed one-pot synthesis of water-soluble dendritic molecular nanocarriers behaving like unimolecular micelles. Using the palladium-α-diimine chain walking catalyst, copolymerization of ethylene and comonomer 3 afforded, in one step, amphiphilic copolymer 1 having a hydrophobic core and a hydrophilic shell. A much larger amphiphilic core?shell copolymer 2 was synthesized by a two-step approach: a copolymer having many free hydroxyl groups was first prepared, which was subsequently coupled to poly(ethylene glycol) (PEG) to afford the copolymer 2. Light-scattering, fluorescence, and UV/vis spectroscopic studies with Nile Red in aqueous solution showed unimolecular micellar properties for both copolymers 1 and 2. The dye encapsulation capacity for the core?shell copolymers is nearly proportional to the molecular weight of the hydrophobic core. The unimolecular micellar properties coupled with the good water solubility and biocompatibility of the PEG moieties make these molecular nanocarriers promising candidates for many applications including drug delivery and controlled drug release. Copyright

Full text of DOI:10.1021/ja039829e

Published on Web 02/14/2004
Transition Metal-Catalyzed One-Pot Synthesis of Water-Soluble Dendritic
Molecular Nanocarriers
Guanghui Chen and Zhibin Guan*
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine, California 92697-2025
Received November 26, 2003; E-mail: zguan@uci.edu
Scheme 1
Amphiphilic core-shell structured nanocarriers have attracted
much attention recently because of their many potential applications
including controlled drug delivery and release,1 phase transfer,2
preparation of nanomaterials,3,4 and catalysis.5,6 As one example,
dendrimers having amphiphilic core-shell structures were shown
to have interesting unimolecular micelle properties.7-9 Because of
the unique dendritic architecture and the covalent linkage between
the hydrophobic and hydrophilic segments, these unimolecular
Scheme 2
micelles are much more stable than conventional micelles formed
from small molecule amphiphiles, making them attractive candidates
as molecular nanocarriers for the above-mentioned applications.
Whereas perfect dendrimers offer precise structural control and
uniformity, the multistep synthesis involved in their preparations
limits their general applicability. It is desirable to develop more
efficient syntheses to access dendritic molecular nanocarriers. In
addition, most of the reported dendritic unimolecular micelles are
reverse micelles soluble only in organic solvents. The general
approach for their preparation was hydrophobization of hydrophilic
dendrimer cores, such as alkylation of polyamidoamine (PAM-
AM),10 poly(propylene imines) (PPI),11 and hyperbranched poly-
glycerols.12,13 Water-soluble unimolecular micelles having hydro-
philic shells and hydrophobic cores, although more relevant to
biological applications, are less explored due to synthetic diffi-
culties.1,14-16 Here, we report the first transition metal-catalyzed
one-pot synthesis of water-soluble dendritic molecular nanocarriers
having a hydrophobic core and a hydrophilic shell (Scheme 1).
By copolymerizing ethylene with a comonomer having a poly-
(ethyleneglycol) (PEG) tail using the Brookhart palladium-R-
diimine chain walking catalyst,17,18 a core-shell dendritic polymer
with a hydrophobic polyethylene (PE) core and a hydrophilic PEG
shell was obtained in one step (Scheme 1). We have shown
previously that the branching topology of ethylene homo- and
copolymers can be systematically tuned in a single synthetic
operation by using the chain walking catalyst.19-22 Linear, hyper-
branched, and dendritic copolymers containing a range of func-
tionalities were obtained by changing ethylene pressures for
copolymerizations.22 Because dendritic topology is obtained at low
ethylene pressure and the insertion of substituted olefins occurs
only when Pd walks to a primary carbon, that is, a chain end,23
copolymerization of ethylene and an PEG containing olefin at low
ethylene pressure will produce a dendritic copolymer with a
hydrophobic PE core and a hydrophilic PEG shell (Scheme 1).
The synthesis of the water-soluble core-shell copolymers is
shown in Scheme 2. Comonomer 3 with a hexa(ethyleneglycol)
tail was prepared by coupling a tert-butyldiphenylsilyl (TBDPS)
protected mono-alcohol with 2,2-dimethylpent-4-enyl chlorofor-
mate. Copolymerization of ethylene and 3 at 0.1 atm ethylene
pressure followed by deprotection of TBDPS afforded copolymer
1 in one step. The number-averaged molecular weight (Mn) for
copolymer 1 is 9800 g/mol as measured by size exclusion
chromatography (SEC) coupled with a multiangle light-scattering
(MALS) detector. The comonomer incorporation ratio (r) was
determined to be 24 mol % by H NMR. A much larger core-
1
shell copolymer 2 was synthesized by a two-step approach (Scheme
2). An ethylene copolymer 6 having many hydroxyl groups was
first prepared and subsequently coupled to PEG to afford the
copolymer 2. Copolymer 2 has a much higher molecular weight
(Mn ) 463 000 g/mol, radius of gyration Rg ) 20.8 nm in THF)
but a similar comonomer incorporation ratio (r ) 26 mol %). Both
copolymers 1 and 2 are soluble in water with solubility up to 10
g/L. They form a stable molecular solution in water as evidenced
by light-scattering (LS) studies. The hydrodynamic radius (Rh) and
Rg for the copolymer 2 in water were measured to be 26.0 and
17.7 nm, respectively. The slight decrease of Rg in water versus in
THF was presumably due to contraction of the hydrophobic PE
core in water. The ratio of Rh/Rg is around 1.4, which is close to
the theoretical value of a filled sphere, 1.3.24 These data support
that the copolymers exist as unimolecular nanospheres in water (see
Supporting Information for detailed LS characterizations).
Nile Red, a common hydrophobic dye and an excellent UV/vis
and fluorescence probe,16 was chosen for investigating the uni-
molecular micellar properties of copolymers 1 and 2 in water. Nile
Red is insoluble and does not fluoresce in water, but once it is
encapsulated inside micelles, its aqueous solution starts to fluoresce.
We monitored the fluorescence intensity as we added different
amounts of copolymer 1 or 2 into an aqueous dispersion of Nile
Red (16 mg/L). For comparison, a classical small molecule
surfactant, sodium dodecyl sulfate (SDS), was also used to
encapsulate the dye in water.
Figure 1a shows that the fluorescence intensity of Nile Red
increases gradually with the increase of copolymer 1 concentration,
indicating copolymer 1 is effective in encapsulating Nile Red. The
fluorescence intensities at λmax of excitation spectra for Nile Red
were plotted against the concentration of copolymer 1, copolymer
2, and SDS, respectively (Figure 1b). For SDS, a typical S-shaped
curve was obtained with the deflection point at its critical micelle
concentration (CMC ) 2.3 mg/mL or 8 mM).16 At concentrations
9
2662
J. AM. CHEM. SOC. 2004, 126, 2662-2663
10.1021/ja039829e CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
between the number-of-dye per polymer molecule and the molecular
structure of the copolymers indicates that the dye encapsulation
capacity for our copolymer is mainly determined by the size of the
hydrophobic core.
In summary, we have shown the first example of transition metal-
catalyzed one-pot synthesis of water-soluble amphiphilic molecular
nanocarriers behaving like unimolecular micelles. Using the chain
walking catalyst, copolymerization of ethylene and comonomer 3
afforded, in one step, amphiphilic copolymer 1 having a hydro-
phobic core and a hydrophilic shell. The light-scattering, fluores-
cence, and UV/vis studies of Nile Red in aqueous solution showed
unimolecular micellar properties for the copolymers. Quantitative
data indicated that the dye encapsulation capacity is nearly
proportional to the Mn of the hydrophobic core. The unimolecular
micellar properties coupled with the good water solubility and
biocompatibility of PEG make these molecular nanocarriers promis-
ing candidates for many applications including drug delivery and
controlled drug release.
Figure 1. (a) Excitation spectra (λem ) 650 nm) for Nile Red in water at
different concentrations of copolymer 1. (b) Fluorescence intensity at λmax
for excitation spectra of Nile Red as a function of concentration of
copolymer 1 (blue 9), copolymer 2 (red 2), and SDS (purple b),
respectively.
Acknowledgment. We thank the National Science Foundation
(DMR-0135233), the Army Research Office (42395-CH-H), and
the University of California at Irvine for partial financial support,
and Dr. Michelle Chen at the Wyatt Technology Corp. for help
with the light-scattering measurements.
Supporting Information Available: Experimental details for the
synthesis, light-scattering, and spectroscopic studies (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
Figure 2. Concentration of encapsulated Nile Red as a function of the
concentration of copolymer 1 (blue 9) and copolymer 2 (red 2),
respectively.
References
(1) Liu, M. J.; Kono, K.; Frechet, J. M. J. J. Controlled Release 2000, 65,
121-131.
(2) Cooper, A. I.; Londono, J. D.; Wignall, G.; McClain, J. B.; Samulski, E.
T.; Lin, J. S.; Dobrynin, A.; Rubinstein, M.; Burke, A. L. C.; Frechet, J.
M. J.; DeSimone, J. M. Nature 1997, 389, 368-371.
(3) Huang, H.; Remsen, E. E.; Kowalewski, T.; Wooley, K. L. J. Am. Chem.
Soc. 1999, 121, 3805-3806.
below its CMC, there is no micelle formation, and SDS is unable
to encapsulate Nile Red. There is a rapid increase in the number
of SDS micelles above CMC, causing a sharp increase of
encapsulated Nile Red. For the copolymers 1 and 2, on the contrary,
the fluorescence intensity at λmax for Nile Red increases gradually
with the concentration of copolymers. No sharp transition was
observed because there is no CMC for the covalently linked
unimolecular nanocarriers.
(4) Connor, E. F.; Sundberg, L. K.; Kim, H.-C.; Cornelissen, J. J.; Magbitang,
T.; Rice, P. M.; Lee, V. Y.; Hawker, C. J.; Volksen, W.; Hedrick, J. L.;
Miller, R. D. Angew. Chem., Int. Ed. 2003, 42, 3785-3788.
(5) Newkome, G. R.; Moorefield, C. N.; Keith, J. M.; Baker, G. R.; Escamilla,
G. H. Angew. Chem., Int. Ed. Engl. 1994, 33, 666-668.
(6) Hecht, S.; Frechet, J. M. J. J. Am. Chem. Soc. 2001, 123, 6959-6960.
(7) Newkome, G. R.; Moorefield, C. N.; Baker, G. R.; Saunders, M. J.;
Grossman, S. H. Angew. Chem., Int. Ed. Engl. 1991, 30, 1178-1180.
(8) Hawker, C. J.; Wooley, K. L.; Frechet, J. M. J. J. Chem. Soc., Perkin
Trans. 1: Org. Bio-Org. Chem. 1993, 1287-1297.
To further gain quantitative information of dye encapsulation,
UV/vis absorption experiments were conducted. The λmax values
for the UV/vis spectra of Nile Red are 554, 551, and 578 nm after
addition of the copolymer 1, 2, and SDS, respectively. The blue
shift in λmax indicates the cores of our copolymers are more
hydrophobic than that of the SDS micelle. The concentration of
encapsulated Nile Red was obtained from its absorbance at λmax
using Beer’s Law, which was plotted against the concentration of
copolymer 1 or 2 (Figure 2). The nearly linear increase of
encapsulated dye with increasing concentration of copolymers
indicates the copolymers behave as unimolecular micelles in water.15
The dye encapsulation capacities for copolymers 1 and 2 were
quantified on the basis of the UV/vis data. The amounts of Nile
Red being encapsulated by unit amounts of copolymer 1 or 2 are
nearly the same, that is, 16 µmol of Nile Red per gram of copolymer
or 0.46 wt %. This value is about twice as much as for SDS micelle
(0.21 wt % at 4 mg/mL of SDS). Copolymer 1 has a number-of-
dye per polymer molecule of 0.15, while copolymer 2 shows a 50-
fold increase to 7.6. These values are constant at different copolymer
concentrations ranging from 0.2 to 2 mg/mL for both copolymers
(Supporting Information Figure S7), indicating that they reflect the
inherent property of the copolymers. On the basis of the molecular
weights and chemical compositions, it is estimated that the Mn of
the hydrophobic core of copolymer 2 (∼116 000 g/mol) is about
40 times that of copolymer 1 (∼3000 g/mol). The correlation
(9) Tomalia, D. A.; Berry, V.; Hall, M.; Hedstrand, D. M. Macromolecules
1987, 20, 1164-1167.
(10) Kojima, C.; Haba, Y.; Fukui, T.; Kono, K.; Takagishi, T. Macromolecules
2003, 36, 2183-2186.
(11) Stevelmans, S.; vanHest, J. C. M.; Jansen, J. F. G. A.; vanBoxtel, D. A.
F. J.; vandenBerg, E. M. M. D.; Meijer, E. W. J. Am. Chem. Soc. 1996,
118, 7398-7399.
(12) Sunder, A.; Kramer, M.; Hanselmann, R.; Mulhaupt, R.; Frey, H. Angew.
Chem., Int. Ed. 1999, 38, 3552-3555.
(13) Kramer, M.; Stumbe, J.-F.; Turk, H.; Krause, S.; Komp, A.; Delineau,
L.; Prokhorova, S.; Kautz, H.; Haag, R. Angew. Chem., Int. Ed. 2002, 41,
4252-4256.
(14) Kim, Y. H.; Webster, O. W. J. Am. Chem. Soc. 1990, 112, 4592-4593.
(15) Liu, H.; Jiang, A.; Guo, J.; Uhrich, K. E. J. Polym. Sci., Part A: Polym.
Chem. 1999, 37, 703-711.
(16) Watkins, D. M.; Sayed-Sweet, Y.; Klimash, J. W.; Turro, N. J.; Tomalia,
D. A. Langmuir 1997, 13, 3136-3141.
(17) Johnson, L. K.; Killian, C. M.; Brookhart, M. J. Am. Chem. Soc. 1995,
117, 6414-6415.
(18) Johnson, L. K.; Mecking, S.; Brookhart, M. J. Am. Chem. Soc. 1996,
118, 267-268.
(19) Guan, Z.; Cotts, P. M.; McCord, E. F.; McLain, S. J. Science 1999, 283,
2059-2062.
(20) Guan, Z. Chem.-Eur. J. 2002, 8, 3086-3092.
(21) Guan, Z. J. Polym. Sci., Part A: Polym. Chem. 2003, 41, 3680-3692.
(22) Chen, G.; Ma, X. S.; Guan, Z. J. Am. Chem. Soc. 2003, 125, 6697-
6704.
(23) Gottfried, A. C.; Brookhart, M. Macromolecules 2003, 36, 3085-3100.
(24) Burchard, W. AdV. Polym. Sci. 1983, 48, 1-124.
JA039829E
9
J. AM. CHEM. SOC. VOL. 126, NO. 9, 2004 2663