Mimicking biological membranes with programmable glycan ligands self-assembled from amphiphilic Janus glycodendrimers

Article abstract of DOI:10.1002/anie.201403186

An accelerated modular synthesis produced 18 amphiphilic Janus glycodendrimers with three different topologies formed from either two or one carbohydrate head groups or a mixed constellation with a noncarbohydrate hydrophilic arm. By simple injection of their THF solutions into water or buffer, all of the Janus compounds self-assembled into uniform, stable, and soft unilamellar vesicles, denoted glycodendrimersomes. The mixed constellation topology glycodendrimersomes were demonstrated to be most efficient in binding plant, bacterial, and human lectins. This evidence with biomedically relevant receptors offers a promising perspective for the application of such glycodendrimersomes in targeted drug delivery, vaccines, and other areas of nanomedicine.

Full text of DOI:10.1002/anie.201403186

Angewandte
Chemie
DOI: 10.1002/anie.201403186
Dendrimers
Mimicking Biological Membranes with Programmable Glycan Ligands
Self-Assembled from Amphiphilic Janus Glycodendrimers**
Shaodong Zhang, Ralph-Olivier Moussodia, Hao-Jan Sun, Pawaret Leowanawat,
Adam Muncan, Christopher D. Nusbaum, Kathleen M. Chelling, Paul A. Heiney,
Michael L. Klein, Sabine Andrꢀ, Renꢀ Roy, Hans-J. Gabius, and Virgil Percec*
Abstract: An accelerated modular synthesis produced 18
amphiphilic Janus glycodendrimers with three different topol-
ogies formed from either two or one carbohydrate head groups
or a mixed constellation with a noncarbohydrate hydrophilic
arm. By simple injection of their THF solutions into water or
buffer, all of the Janus compounds self-assembled into uni-
form, stable, and soft unilamellar vesicles, denoted glycoden-
drimersomes. The mixed constellation topology glycodendri-
mersomes were demonstrated to be most efficient in binding
plant, bacterial, and human lectins. This evidence with
biomedically relevant receptors offers a promising perspective
for the application of such glycodendrimersomes in targeted
drug delivery, vaccines, and other areas of nanomedicine.
a primitive way. Vesicles, liposomes, and polymersomes are
endowed with an internal cavity,[3] thus making them candi-
dates for mimicking the supramolecular multivalency of
biological membranes.[4] A few examples of carbohydrate-
containing vesicles with a random distribution of glycan on
their surfaces were generated by complex and time-consum-
ing co-assembly.[4a,5] Recently, a simple method for the
assembly of amphiphilic Janus dendrimers to produce mono-
disperse, stable over time, and impermeable dendrimersomes
with predictable dimensions and properties was reported.[6]
Seven libraries, containing 51 amphiphilic Janus glycoden-
drimers (Figure 1a), were screened to discover ten that form
M
ultivalent displays of glycan ligands from the surface of
biological membranes are emulated by glycopolymers[1] and
glycodendrimers[2] with carbohydrates in each repeat unit or
at the chain ends. They are efficient for recognition of the
carbohydrate-binding proteins, lectins. Owing to their lack of
an encapsulating cavity and an imprecise spatial ligand
presentation, these multivalent glycoconjugates only mimic
the functionality of the surface of biological membranes in
[*] Dr. S. Zhang, Dr. R.-O. Moussodia, Dr. H.-J. Sun, Dr. P. Leowanawat,
A. Muncan, C. D. Nusbaum, K. M. Chelling, Prof. Dr. V. Percec
Roy & Diana Vagelos Laboratories, Department of Chemistry,
University of Pennsylvania, Philadelphia, PA 19104-6323 (USA)
E-mail: percec@sas.upenn.edu
Homepage: http://percec02.chem.upenn.edu/
Dr. H.-J. Sun, Prof. Dr. P. A. Heiney
Department of Physics and Astronomy, University of Pennsylvania
Philadelphia, PA 19104-6396 (USA)
Prof. Dr. M. L. Klein
Institute for Computational Molecular Science, Temple University
Philadelphia, PA 19122 (USA)
Priv.-Doz. Dr. S. Andrꢀ, Prof. Dr. H.-J. Gabius
Institute of Physiological Chemistry, Faculty of Veterinary Medicine
Ludwig-Maximilians-University, 80539 Munich (Germany)
Prof. Dr. R. Roy
Department of Chemistry, Universitꢀ du Quꢀbec ꢁ Montrꢀal
Montrꢀal, Quꢀbec, H3C 3P8 (Canada)
[**] Financial support by the National Science Foundation (grants DMR-
1066116 and DMR-1120901), the P. Roy Vagelos Chair at the
University of Pennsylvania (to V.P.), National Science Foundation
(grant DMR-1120901) (to M.L.K.), the EC (GLYCOPHARM, contract
no. 317297) (to H.J.G.) and an operating grant from the Natural
Sciences and Engineering Research Council of Canada (to R.R.) is
gratefully acknowledged.
Figure 1. Three different topologies of amphiphilic Janus glycoden-
drimers and the structure of the corresponding multivalent glycoden-
drimersomes: a) twin-twin carbohydrates, b) single-single carbohydrate
and c) twin-mixed TEG:carbohydrate. Color code: hydrophilic blue,
hydrophobic green, aromatic red.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403186.
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soft unilamellar multivalent glycodendrimersomes that are
stable in water and in buffers.[7] This enormous synthetic
effort prompted us to investigate the capability to predict the
assembly of soft unilamellar glycodendrimersomes from the
simplest primary structures of twin-twin carbohydrate,[7]
single-single carbohydrate, and twin-mixed TEG:carbohy-
drate amphiphilic Janus glycodendrimers (Figure 1). This
prediction was accessed by exploring a previously discovered
twin-twin carbohydrate frame[7] together with methodologies
employed for amphiphilic Janus dendrimers.[6a,c] Bioactivity
was tested by agglutination assays performed with a manno-
side-specific plant lectin (concanavalin A, ConA),[2d] a galac-
toside-specific bacterial lectin (PA-IL),[8] and the human
galectin-7 (hGal-7).[9]
Three libraries containing 18 Janus compounds with
different topologies were synthesized through an accelerated
modular strategy[7] (see the Supporting Information). These
libraries include ten twin-twin carbohydrate (Scheme 1),
seven single-single carbohydrate (Scheme 2), and three
twin-mixed TEG:carbohydrate (Scheme 3) amphiphilic
Janus glycodendrimers. In this study, we were concerned
with the simplest possible first generation dendrons, denoted
minidendrons,[10a] as models or maquettes for the discovery of
novel architectural motifs that may also be accessible from
higher generations during self-assembly in water. The role of
minidendrons[2g,10a,b] and Janus minidendrimers is analogous
to that of simple peptides used to understand the molecular
engineering involved in the assembly of more complex
proteins, or of maquettes used by sculptors and architects to
appreciate various aspects of full-size objects.[10a,c] The twin-
twin topology was inspired by a previous report.[7] The single-
single[6c] topology was generated by splitting the most
successful twin-twin structures into single-single carbohydrate
(Scheme 1 and 2). The twin-mixed TEG:carbohydrate were
designed by reassembling a single-single amphiphilic Janus
dendrimer discovered recently[6c] with a single-single carbo-
hydrate amphiphilic Janus glycodendrimer from Scheme 2.
Library 1 contains ten twin-twin carbohydrate Janus
glycodendrimers presenting three different carbohydrates;
d-mannose (Man), d-galactose (Gal), and d-lactose (Lac);
conjugated to the hydrophobic parts of minidendrons
(Scheme 1). Regardless of the type of carbohydrate and the
pattern of the alkyl groups from the hydrophobic part, all of
the Janus molecules self-assembled into monodisperse[4f] and
Scheme 1. Modular synthesis of library 1, which consists of ten constitutional isomeric twin-twin carbohydrate compounds with d-Man, d-Gal,
and d-Lac as headgroups. Reagents and conditions: CuSO4·5H2O, sodium ascorbate, THF/water, 238C. The diameter (in nm) and polydispersity
(PDI) of the glycodendrimersomes were measured by DLS in water and in HEPES and PBS (0.5 mgmLÀ1). THF=tetrahydrofuran, HEPES=2-[4-
(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid, PBS=phosphate buffered saline.
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binding. Two approaches were elaborated to
answer this question. The first involved
seven single-single carbohydrate from
Library 2 with a single hydrophobic dendron
and a single carbohydrate headgroup, which
reduce their mass by half compared to their
twin-twin analogues (Figure 1b and
Scheme 2). The second involved three com-
pounds from Library 3 with two identical
hydrophobic dendrons, one carbohydrate
headgroup, and one hydrophilic dendron
containing three triethylene glycol (TEG)
monomethyl ether groups, denoted twin-
mixed TEG:carbohydrate. In order to
reduce the steric hindrance of binding to
the target,[4d] the carbohydrates were
appended to the distal end of a long stretch-
ing chain so that the targeting ligands are
extended beyond the vesicle surface (Fig-
ure 1c and Scheme 3). All of the single-
single carbohydrate and twin-mixed TEG:
carbohydrate self-assembled into uniform
vesicles with submicron size in water, PBS,
and HEPES (Figure 2 and Figure SF2,3).
These glycodendrimersomes were used to
test bioactivity.
To do so, the known capacity of di- and
tetrameric lectins to form bridges between
cells (agglutination) was exploited and three
types of lectins were selected based on
1) their different sugar specificities and
involvement of Ca2+, and 2) their biofunc-
tionality, deliberately including a virulence
factor and a potent endogenous (human)
Scheme 2. Modular synthesis of library 2, which consists of seven constitutional single-
single carbohydrate compounds with d-Man, d-Gal, and d-Lac as headgroups. Reagents
and conditions: CuSO4·5H2O, sodium ascorbate, THF/water, 238C. The diameter (in nm)
and polydispersity (PDI) of the glycodendrimersomes were measured by DLS in water and
in HEPES and PBS (0.5 mgmLÀ1).
soft unilamellar glycodendrimersomes (Scheme 1
and Figure SF1 in the Supporting Information).
This demonstrates the predictability of the pri-
mary structures and their assembly in water by
small variations of a previously discovered chem-
ical frame.[7] Glycodendrimers 47b–d, which have
more than nine carbon atoms in linear alkyl
chains, and compounds 42 and 43, which have
branched hexyl groups, self-assembled into stable
vesicles in HEPES and PBS (Scheme 1). Vesicles
formed by 47a, which contains only nine carbon
atoms in the alkyl chains (highlighted in blue in
Scheme 1), showed bimodal size distribution in
PBS and precipitated from HEPES.
A key feature of bioregulation on a cell
surface is the modulation of ligand presentation
to make it relevant for cell adhesion and signal-
ing.[11] Even though the glycan ligands of glyco-
dendrimersomes formed with twin-twin carbohy-
Scheme 3. Modular synthesis of library 3, which consists of three twin-mixed TEG:car-
bohydrate compounds with d-Man, d-Gal, and d-Lac as headgroups. Reagents and
conditions: CuSO4·5H2O, sodium ascorbate, THF/water, 238C. The diameter (in nm)
and polydispersity (PDI) of the glycodendrimersomes were measured by DLS in water
drates were demonstrated to be multivalent,[7] it
is fundamental to understand whether the exces-
sively high number of carbohydrates from the
hydrophilic part of these vesicles is required for and in HEPES and PBS (0.5 mgmLÀ1).
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vesicles co-assembled from glycolipids and phospholipids,[5d]
carbohydrate ligands are likely randomly distributed on the
surface of vesicles formed from the physical mixture of 51
(0.4 mmolmLÀ1)
and
(3,5)12G1-I-PhE-(3,4,5)-3EO-G1-
(OCH3)3,[6c] while the ligand distribution can be chemically
controlled by twin-mixed 55. The advantage of this type of
chemical control of ligand distribution becomes evident when
considering the highest bioactivity exhibited by the vesicles
derived from twin-mixed topology (Figure 1c) in binding
plant (Figure SF5), bacterial (Figure SF6), and human (Fig-
ure 2c) lectins.
In conclusion, three libraries containing 18 amphiphilic
Janus glycodendrimers with d-mannose, d-galactose, and d-
lactose in the hydrophilic part have been synthesized through
an accelerated modular strategy. These compounds exhibit
three different topologies (Figure 1): ten are twin-twin
carbohydrate amphiphilic Janus glycodendrimers constructed
with two identical hydrophobic dendrons and two identical
carbohydrate headgroups (Library 1), seven are single-single
carbohydrate glycodendrimers built with one hydrophobic
dendron and one carbohydrate (Library 2), and three are
twin-mixed TEG:carbohydrate glycodendrimers endowed
with two identical hydrophobic dendrons, one TEG mono-
methyl ether containing hydrophilic dendron, and one
carbohydrate (Library 3). Monodisperse and stable soft
unilamellar vesicles, denoted glycodendrimersomes, were
prepared by simple injection of THF solutions of the
glycodendrimers into water or buffer. Notably, all 18 of the
Janus compounds self-assemble into soft unilamellar multi-
valent glycodendrimersomes, a result that highlights the
extremely high reliability of the prediction strategy based
on the primary structure of the Janus glycodendrimers.[7] By
performing agglutination assays with the biomedically rele-
vant plant lectin ConA, bacterial lectin PA-IL, and human
galectin-7, specific and potent bioactivity for the glycoden-
drimersomes was demonstrated, which proves the spatial
arrangement of multivalent glycan display of glycodendri-
mersomes. With the multivalent glycan ligands extending out
of the vesicle surface, the glycodendrimersomes formed by
twin-mixed amphiphilic Janus glycodendrimers (Figure 1c)
showed the highest binding affinity for lectins and proved to
have the optimal glycan ligand display. We demonstrated that
the most efficient supramolecular glycan multivalency is
determined by a combination of numbers and topology rather
than only numbers. This novel biological membrane mimic is
expected to be of interest for targeted drug delivery,
vaccines,[11c] and various fundamental and technological
areas of nanomedicine.[13]
Figure 2. Representative cryo-TEM images of glycodendrimersomes
self-assembled by injection of THF solutions of a) 45 (0.5 mgmLÀ1) in
PBS or b) 50a (0.5 mgmLÀ1) in HEPES. c) Agglutination assay with
Lac-containing glycodendrimersomes (in mmolmLÀ1) with different
topologies in the presence of hGal-7 (0.5 mgmLÀ1) in PBS buffer.
effector.[2d,8,12] The absorbance profiles of agglutination assays
with ConA (Figure SF4,5), PA-IL (Figure SF6), and hGal-7
(Figure 2) in HEPES or PBS were recorded by UV/Vis
spectroscopy. The availability of glycodendrimersomes with
different sugar headgroups afforded rigorous specificity
controls, as illustrated by the lack of reactivity of hGal-7
with Man-presenting glycodendrimersome 53 (Figure 2c).
After adding hGal-7 to the solution of Lac-presenting
vesicles, the absorbance increased steadily until a plateau
was reached (Figure 2c). Similar results were obtained from
assays of ConA with vesicles self-assembled by d-Man-
containing dendrimers (Figure SF5) and PA-IL with vesicles
derived from d-Gal-containing dendrimers (Figure SF6).
These results support the hypothesis of maintained selectivity
and bioactivity.
In order to study the effect of the topology of these
glycodendrimers on the bioactivity of the corresponding
glycodendrimersomes, it is reasonable to keep the molar
concentration of the ligand identical in each solution. The
final concentration of twin-mixed molecule 55 and single-
single 51 was adjusted to 0.4 mmolmLÀ1 to give 0.4 mmolmLÀ1
of d-lactose. The concentration of twin-twin 45 had to be set
to 0.2 mmolmLÀ1. Interestingly, the agglutination curve of 51
at 0.4 mmolmLÀ1 overlapped with that of 45 at 0.2 mmolmLÀ1,
which may indicate that the hydrodynamic volume of single-
single glycodendrimers on the vesicle surface is half that of
their twin-twin counterparts. On the other hand, twin-mixed
55 at 0.4 mmolmLÀ1 showed the highest absorbance in the
series, which indicates that a diluted density of glycan ligand
favors the contact between the carbohydrate and protein
because it leads to reduced steric hindrance.[4d] The steric
hindrance can also be reduced in the vesicles co-assembled
with 51 (0.4 mmolmLÀ1) and the nonsugar dendrimer
(3,5)12G1-I-PhE-(3,4,5)-3EO-G1-(OCH3)3,[6c] for which the
density of sugar on the vesicle surface was diluted, thus
leading to higher binding efficiency than with self-assembly
by 51 (0.4 mmolmLÀ1). Similar to carbohydrate-containing
Received: March 10, 2014
Revised: May 2, 2014
Published online: June 12, 2014
Keywords: agglutinins · biomembrane glycans · dendrimers ·
.
lectins · vesicles
[1] a) Y. Ruff, J.-M. Lehn, Angew. Chem. Int. Ed. 2008, 47, 3556 –
3559; Angew. Chem. 2008, 120, 3612 – 3615; b) K. Godula, D.
10902 www.angewandte.org
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Chemie
Rabuka, K. T. Nam, C. R. Bertozzi, Angew. Chem. Int. Ed. 2009,
48, 4973 – 4976; Angew. Chem. 2009, 121, 5073 – 5076; c) G.
Coullerez, P. H. Seeberger, M. Textor, Macromol. Biosci. 2006, 6,
634 – 647; d) Q. Zhang, D. M. Haddleton, Adv. Polym. Sci. 2013,
262, 39 – 60; e) L. L. Kiessling, J. C. Grim, Chem. Soc. Rev. 2013,
42, 4476 – 4491.
Ravoo, Chem. Eur. J. 2010, 16, 2790 – 2796; c) J. R. Kramer,
A. R. Rodriguez, U.-J. Choe, D. T. Kamei, T. J. Deming, Soft
Matter 2013, 9, 3389 – 3395; d) N. Jayaraman, K. Maiti, K.
Naresh, Chem. Soc. Rev. 2013, 42, 4640 – 4656.
[6] a) V. Percec, D. A. Wilson, P. Leowanawat, C. J. Wilson, A. D.
Hughes, M. S. Kaucher, D. A. Hammer, D. H. Levine, A. J. Kim,
F. S. Bates, K. P. Davis, T. P. Lodge, M. L. Klein, R. H. DeVane,
E. Aqad, B. M. Rosen, A. O. Argintaru, M. J. Sienkowska, K.
Rissanen, S. Nummelin, J. Ropponen, Science 2010, 328, 1009 –
1014; b) M. Peterca, V. Percec, P. Leowanawat, A. Bertin, J. Am.
Chem. Soc. 2011, 133, 20507 – 20520; c) S. Zhang, H.-J. Sun,
A. D. Hughes, B. Draghici, J. Lejnieks, P. Leowanawat, A.
Bertin, L. O. D. Leon, O. V. Kulikov, Y. Chen, D. J. Pochan, P. A.
Heiney, V. Percec, ACS Nano 2014, 8, 1554 – 1565.
[7] V. Percec, P. Leowanawat, H.-J. Sun, O. Kulikov, C. D. Nusbaum,
T. M. Tran, A. Bertin, D. A. Wilson, M. Peterca, S. Zhang, N. P.
Kamat, K. Vargo, D. Moock, E. D. Johnston, D. A. Hammer,
D. J. Pochan, Y. Chen, Y. M. Chabre, T. C. Shiao, M. Bergeron-
Brlek, S. Andre, R. Roy, H.-J. Gabius, P. A. Heiney, J. Am.
Chem. Soc. 2013, 135, 9055 – 9077.
[2] a) H. W. I. Peerlings, S. A. Nepogodiev, J. F. Stoddart, E. W.
Meijer, Eur. J. Org. Chem. 1998, 1879 – 1886; b) S.-K. Wang, P.-
H. Liang, R. D. Astronomo, T.-L. Hsu, S.-L. Hsieh, D. R. Burton,
C.-H. Wong, Proc. Natl. Acad. Sci. USA 2008, 105, 3690 – 3695;
c) B. Lepenies, J. Yin, P. H. Seeberger, Curr. Opin. Chem. Biol.
2010, 14, 404 – 411; d) E. M. Munoz, J. Correa, R. Riguera, E.
Fernandez-Megia, J. Am. Chem. Soc. 2013, 135, 5966 – 5969; e) S.
Svenson, D. A. Tomalia, Adv. Drug Delivery Rev. 2005, 57,
2106 – 2129; f) C. C. Lee, J. A. MacKay, J. M. J. Frꢀchet, F. C.
Szoka, Nat. Biotechnol. 2005, 23, 1517 – 1526; g) B. M. Rosen,
C. J. Wilson, D. A. Wilson, M. Peterca, M. R. Imam, V. Percec,
Chem. Rev. 2009, 109, 6275 – 6540; h) Y. M. Chabre, R. Roy,
Chem. Soc. Rev. 2013, 42, 4657 – 4708.
[3] a) A. D. Bangham, M. M. Standish, J. C. Watkins, J. Mol. Biol.
1965, 13, 238 – 252; b) B. M. Discher, Y.-Y. Won, D. S. Ege, J. C.-
M. Lee, F. S. Bates, D. E. Discher, D. A. Hammer, Science 1999,
284, 1143 – 1146.
[8] A. Imberty, E. P. Mitchell, M. Wimmerova, Curr. Opin. Struct.
Biol. 2005, 15, 525 – 534.
[9] D. D. Leonidas, E. H. Vatzaki, H. Vorum, J. E. Celis, P. Madsen,
K. R. Acharya, Biochemistry 1998, 37, 13930 – 13940.
[4] a) H. Ringsdorf, B. Schlarb, J. Venzmer, Angew. Chem. Int. Ed.
Engl. 1988, 27, 113 – 158; Angew. Chem. 1988, 100, 117 – 162;
b) J. L. Thomas, D. A. Tirrell, Acc. Chem. Res. 1992, 25, 336 –
342; c) X. Guo, F. C. Szoka, Jr., Acc. Chem. Res. 2003, 36, 335 –
341; d) V. P. Torchilin, Nat. Rev. Drug Discovery 2005, 4, 145 –
160; e) T. M. Allen, P. R. Cullis, Adv. Drug Delivery Rev. 2013,
65, 36 – 48; f) T. F. Zhu, J. W. Szostak, PLoS ONE 2009, 4,
e5009 – e5009; g) E. P. Holowka, V. Z. Sun, D. T. Kamei, T. J.
Deming, Nat. Mater. 2007, 6, 52 – 57; h) P. Tanner, P. Baumann,
R. Enea, O. Onaca, C. Palivan, W. Meier, Acc. Chem. Res. 2011,
44, 1039 – 1049; i) M. Marguet, L. Edembe, S. Lecommandoux,
Angew. Chem. Int. Ed. 2012, 51, 1173 – 1176; Angew. Chem.
2012, 124, 1199 – 1202; j) J. Gaitzsch, D. Appelhans, L. Wang, G.
Battaglia, B. Voit, Angew. Chem. Int. Ed. 2012, 51, 4448 – 4451;
Angew. Chem. 2012, 124, 4524 – 4527.
[10] a) V. Percec, C.-H. Ahn, T. K. Bera, G. Ungar, D. J. P. Yeardley,
Chem. Eur. J. 1999, 5, 1070 – 1083; b) C. Roche, H.-J. Sun, M. E.
Prendergast, P. Leowanawat, B. E. Partridge, P. A. Heiney, F.
Araoka, R. Graf, H. W. Spiess, X. Zeng, G. Ungar, V. Percec, J.
Am. Chem. Soc. 2014, 136, 7169 – 7185 ; c) D. E. Robertson, R. S.
Farid, C. C. Moser, J. L. Urbauer, S. E. Mulholland, R. Pidikiti,
J. D. Lear, A. J. Wand, W. F. DeGrado, P. L. Dutton, Nature
1994, 368, 425 – 432.
[11] a) A. Varki, Glycobiology 1993, 3, 97 – 130; b) Y. C. Lee, R. T.
Lee, Acc. Chem. Res. 1995, 28, 321 – 327; c) C. Anish, B.
Schumann, C. L. Pereira, P. H. Seeberger, Chem. Biol. 2014,
21, 38 – 50.
[12] a) F.-T. Liu, G. A. Rabinovich, Nat. Rev. Cancer 2005, 5, 29 – 41;
b) K. Drickamer, Nat. Struct. Biol. 1995, 2, 437 – 439.
[5] a) S. A. DeFrees, L. Phillips, L. Guo, S. Zalipsky, J. Am. Chem.
Soc. 1996, 118, 6101 – 6104; b) J. Voskuhl, M. C. A. Stuart, B. J.
[13] O. C. Farokhzad, R. Langer, ACS Nano 2009, 3, 16 – 20.
Angew. Chem. Int. Ed. 2014, 53, 10899 –10903
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