Mannose-Decorated Multicomponent Supramolecular Polymers Trigger Effective Uptake into Antigen-Presenting Cells

Article abstract of DOI:10.1002/cbic.201800114

A modular route to prepare functional self-assembling dendritic peptide amphiphiles decorated with mannosides, to effectively target antigen-presenting cells, such as macrophages, is reported. The monomeric building blocks were equipped with tetra(ethylen

Full text of DOI:10.1002/cbic.201800114

Accepted Article
Title: Mannose-Decorated Multicomponent Supramolecular Polymers
Trigger Effective Uptake into Antigen-Presenting Cells
Authors: David Straßburger, Natascha Stergiou, Moritz Urschbach,
Hajime Yurugi, Daniel Spitzer, Dieter Schollmeyer, Edgar
Schmitt, and Pol Besenius
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To be cited as: ChemBioChem 10.1002/cbic.201800114
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10.1002/cbic.201800114
ChemBioChem
COMMUNICATION
Mannose-Decorated Multicomponent Supramolecular Polymers
Trigger Effective Uptake into Antigen-Presenting Cells
D. Straßburger,[a] N. Stergiou,[b] M. Urschbach,[a] H. Yurugi,[c] D. Spitzer,[a] D. Schollmeyer,[a]
E. Schmitt,[b]* P. Besenius[a]*
Abstract: We describe a modular route to prepare functional self-
assembling dendritic peptide amphiphiles decorated with mannosides
(Man) to effectively target antigen-presenting cells such as
macrophages. The monomeric building blocks were equipped with
tetraethylene glycols (TEG) or labelled with a Cy3 fluorescent probe.
Experiments on the uptake of the multifunctional supramolecular
particles into murine macrophages (Mϕs) were monitored by confocal
microscopy and fluorescence-activated cell sorting (FACS).
Mannose-decorated supramolecular polymers trigger a significantly
higher cellular uptake and distribution, compared to TEG carrying
bare polymers. No cytotoxicity or negative impact on cytokine
production of the treated Mϕs was observed, emphasizing their
biocompatibility. The modular nature of the multicomponent
supramolecular polymer co-assembly protocol is a promising platform
to develop fully synthetic multifunctional vaccines, for example in
cancer immunotherapy.
case of supramolecular polymers, simple mixing of different well-
defined molecular building blocks guarantees full flexibility and
facile access to screen and optimize the composition of
multifunctional copolymers.[4] In contrast to conventional polymers,
where monomers are connected via irreversible covalent bonds,
supramolecular polymers are held together by a multitude of non-
covalent interactions.[4] E. W. Meijer and coworkers have shown
that benzene-tricarboxamides (BTA), bearing amino acid side
arms, self-assemble into multifunctional polymer arrays in water,
and were used to present RGDS and PHSRN integrin binding
peptides, as well as GdIII MRI labels at the periphery.[5]
Alternatively, large dodecyl chains in the arms also provide
sufficient hydrophobicity to protect the hydrogen bonding
supramolecular assemblies, for example bearing cationic side
chains which are used to condense siRNA and hydrophobic guest
molecules.[6] Brunsveld used bipyridine units connected to BTAs
in order to direct the self-assembly into columnar supramolecular
copolymers with a tunable surface density of mannose units for
the clustering and detection of E. coli bacteria or to assemble
wires of proteins via surface ligation.[7]
Vaccination and immunization against bacterial or viral
pathogens is one of biggest achievements in human healthcare.
Although an immune response can also be generated against
endogenous diseases like cancer[1] there is a need for more
elaborate and potent vaccine systems to activate specific immune
cell types. A modular chemical platform, which allows both
multivalent targeting of antigen-presenting cells (APCs such as
macrophages[2] and dendritic cells[3]) and presentation of multiple
immunogenic epitopes will facilitate the investigation of the
underlying mechanisms of the immune response. In view of the
synthetic accessibility of polyvalent and multifunctional epitopes,
classical iterative postfunctionalization or copolymerization
strategies in covalent polymer synthesis suffer from limitations
regarding the degree of functionalization. Therefore, total polymer
composition results in poor batch to batch reproducibility. In the
70
20
-30
-80
90 nm
-130
200
220
240
260
280
300
λ /nm
50 nm
[a]
D. Straßburger, M. Urschbach, D. Spitzer, Dr. D. Schollmeyer, Prof.
Dr. P. Besenius
Institute of Organic Chemistry
Figure 1. On the left: negative stained transmission electron microscopy image
obtained from a 25 µM aqueous solution of the self-assembled mannosylated
prototype monomer BM; on the right: circular dichroism spectra of the dentritic
peptide amphiphile BM in 60 µM aqueous buffered solution.
Johannes Gutenberg-University Mainz
Duesbergweg 10-14, 55128 Mainz
E-mail: besenius@uni-mainz.de
N. Stergiou, Prof. Dr. E. Schmitt
Institute of Immunology
University Medical Center Mainz
Langenbeckstrasse 1, Geb. 708, 55131 Mainz
E-mail: eschmitt@uni-mainz.de
Dr. H. Yurugi
Here, we report the use of BTA and triazine branched
[b]
[c]
nonaphenylalanines
that
direct
the
supramolecular
polymerization into anisotropic particles of up to 300 nm in length
(Figure 1). Given their resemblance to rod-like virus particles, we
were intrigued to prepare carbohydrate decorated supramolecular
polymers via the co-assembly of mannose functional monomers,
shielding dendritic TEG chains as protein repellent units and
fluorescent labels, in order to trigger the selective cellular uptake
into APCs, specifically murine Mϕs.
Molecular Signaling Unit-FZI
Research Center for Immune Therapy
University Medical Center Mainz
Langenbeckstrasse 1, Geb. 708, 55131 Mainz
Supporting information for this article is given via a link at the end of the
document.
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10.1002/cbic.201800114
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The first objective was the introduction of a targeting motif
into the monomeric self-assembling architecture. Carbohydrates
serve as water-solubilizing, as well as molecular recognition
in DMF. After removal of the Boc group with TFA followed by
consecutive lyophilization steps with aqueous HCl, the saccharide
functionalized arm 8 was isolated. After coupling of 8 to the
trimesic acid with PyBOP and DIPEA in DMF at room temperature,
and a final deprotection of the mannoside by treatment with
freshly prepared sodium methoxide in methanol, the amphiphilic
glycopeptide BM was obtained. In aqueous buffer, BM self-
assembles into supramolecular homopolymeric nanorods with a
length of up to 300 nm (Figure 1). Circular dichroism
spectroscopic analysis of these supramolecular homopolymers,
gives rise to a strong negative band at λ = 216 nm, indicative of
moieties.
Therefore,
the
extensively
used
tris
(hydroxymethyl)aminomethane (TRIS) based dendron was
equipped with mannose to obtain triple mannosylated TRIS-Man3,
which aims to introduce solubilizing properties as well as a similar
sterical demand compared to the dendritic TEG chains and thus
install colloidal stability of the supramolecular polymers.[8]
Mannose is known for its targeting properties to cells of the innate
immune system, inter alia, Mϕs and dendritic cells which expose
mannose recognizing receptors (MR) on their cell surface and
play a key role in host defense. Upon binding of mannosylated
compounds, these induce receptor-mediated endocytosis.[9] Note
that due to the importance of carbohydrate-protein interactions in
ß-sheet
directed
self-assembly
of
the
hydrophobic
oligophenylalanine core.[8a, 8b]
In order to provide access to a variety of structurally diverse
functional supramolecular monomers, including the possibility for
post-functionalization with imaging labels, an alternative synthetic
route for a C2-symmetric functional monomer (fM) was devised
using a dendritic core, extended with triphenylalanyl moieties
(Phe)3 and the Ahx spacer bearing a terminal alkyne group. The
latter allows to address one side-arm of the building blocks via
copper-mediated azide alkyne coupling (CuAAC),[13] as
functionalization site. Using cyanuric chloride as a branching point
thioglycolic acid and its methyl ester were sequentially attached
to create a C2-symmetric core. In a two-step procedure, the
orthogonally stably protected core CFM was synthesized, first by
double substitution using two equivalents of methyl-2-
thioglycolate and potassium carbonate. The third substitution on
the chlorotriazine 2 was carried out with thioglycolic acid and
DIPEA at elevated temperature (40 °C). Treatment of cyanuric
chloride with three equivalents of 2-thioglycolic acid at 60 °C in
acetonitrile and DIPEA gave the
biological processes, the polymer science[10] and supramolecular
11]
communities[7a,
has reported the synthesis of a variety of
covalent macromolecular architectures and scaffolds as artificial
glycoconjugates that mimic the multivalent display[12] of
carbohydrates. In a first attempt to prepare mannose-decorated
supramolecular polymers, BTA-dendritic nonaphenylalanine
scaffolds were equipped with TRIS-Man3. To this end, the
glycosyl donor 3 was prepared from D-mannose by acetylation in
pyridine/acetic anhydride. Acceptor 4 was obtained by amidation
of TRIS with Cbz-protected aminohexanoic acid (Ahx) using
EEDQ as coupling reagent. The glycosylation was catalyzed at
0 °C in DCM with BF3 etherate and gave moderate yields with high
stereoselectivity. The optimized conditions for the removal of the
Cbz group were a solvent mixture of dioxane/TFA and Pd/C
(10 wt%) as hydrogenation catalyst. The obtained TRIS-Man3 6
was coupled to Boc-Phe3-OH 1a with PyBOP, HOAt and DIPEA
trisubstituted core CSM. Coupling of the
alkyne terminated triphenylalanine 16
on one arm of CFM, followed by methyl
ester hydrolysis using 0.1 M LiOH in
THF, double amidation with TRIS-
Man3 decorated triphenylalanine 8 and
subsequent deprotection with NaOMe,
turned out to be a straightforward
strategy to afford the alkyne-functional
mannosylated monomer fM+. Using the
TRIS-(TEG)3 carrying triphenylalanine
12,
the
alkyne-functionalized
TEGylated monomer fM- was obtained,
that lacks targeting motifs. In a final
step, both monomers fM+ and fM- were
conjugated
fluorescent azide dye via CuAAC in
degassed DMSO, aqueous
with
a
Sulfo-Cy3
CuSO4 × 5H2O, sodium ascorbate and
tris(benzyltriazolylmethyl)amine
(TBTA) as chelating agent to stabilize
the Cu(I) species generated in situ.
Scheme 1. Scheme for the synthesis of selected triazine based structural and functional monomers (i). HSAcOH, DIPEA, MeCN, 60%, (ii). HSAcOMe, K2CO3,
THF, 58% (iii). HSAcOH, DIPEA, MeCN, 56%. (iv). pyridine, Ac2O, DMAP, quant. (v). TRIS, EEDQ, EtOH, 60% (vi). BF3×Et2O, DCM, 40% (vii). dioxane, TFA,
Pd/C, H2, 79% (viii). Boc-Phe3-OH 1a, PyBOP, HOAt, DIPEA, 66% (iix). TFA/DCM, TIS, quant. (ix). CSM, PyBOP, DIPEA, DMF, 88% (x). NaOMe, MeOH, quant.
(xi). HATU, HOAt, DMF, 56% (xii).DCM/TFA, 97% (xiii). 1a, PyBOP, HOAt, NMM, DMF, 95% (xiv). DCM/TFA, TIS, 96% (xv). CFM, HATU, HOAt, DIPEA, DMF,
quant. (xvi). LiOH 0.1 M, THF 72% (xvii). Dnd-Ahx-Phe3-NH2 12, PyBOP, HOBt, DIPEA, DMF, 79%.
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10.1002/cbic.201800114
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The reaction took place at 40 °C (80 °C) within 2 days. Excessive
copper was removed by passing the reaction mixture through a
short bed of IRC-148 resin and subsequent size exclusion
chromatography on Sephadex LH-20 in DMF. Structural C3-
symmetric monomers that lack the alkyne moiety and carry either
three TRIS-(TEG)3 dendrons as solubilizing chains at the
periphery (sM-), or three dendritic TRIS-Man3 units (sM+) were
obtained via amidation of the trisubstituted core CSM using the
same conditions as described above for the C2-symmetric
building blocks.
The supramolecular polymers were characterized in aqueous
solution with CD spectroscopy (Figures S2) and TEM (Figures S3),
which both confirmed the self-assembly into nanorod-like b-
ordered materials, irrespective of the functional group density in
the periphery. These results confirm the high robustness and
fidelity of the dendritic nonaphenylalanine-driven architectures, as
already indicated for the simpler building block BM. Encouraged
by these results the cellular uptake behavior of self-assembled
mannosylated supramolecular polymers by murine Mϕs in vitro
was tested. The self-assembled Cy3-labeled building blocks with
(FM+) and without TRISMan3 units (FM-), were added as 25 µM
monomer solutions to cultured bone marrow-derived Mϕs
differentiated in M-CSF-conditioned medium at a concentration of
25 µM and incubated at 4 °C for 2 h to reduce unspecific binding.
Subsequently, Mϕs were co-stained with a fluorophore-labelled
mannose receptor (MR, CD206) antibody to determine the extent
of MR expression. Binding of the polymeric FM- and FM+ was
determined by FACS analysis (for details see SI) which revealed
a marginal unspecific absorption of FM- (1%) while 46% of Mϕs
stained positive after incubation with mannose-decorated FM+
(Figure S4A). The high selectivity was corroborated by plotting the
mean fluorescence intensity, which was more than an order of
magnitude higher after treatment with mannosylated FM+,
compared to Mϕs that were incubated with TEGylated FM- (Figure
S4B).
Figure 2. Confocal microscopy images of murine Mϕs incubated with self-
assembled monomers (all added at building block concentrations of 25 µM) in
growth media at 4 °C, A: Cy3 labelled mannosylated polymer (fM+); B: Cy3
labelled polymer without mannose (fM-), C: co-assembled 1:1 mixture of non-
fluorescent mannosylated sM+ and Cy3 labelled TEGylated fM- containing no
mannose.
assembly with mannosylated SM+ (Figure 2C) indicating that
these two components form stable supramolecular polymers
under physiological conditions. Control experiments using
homopolymeric SM+ and SM- were performed to exclude
unspecific interactions between the Cy3 dye and the hydrophobic
core of the peptide supramolecular polymers. Both components
were mixed with free Cy3 dye and incubated with Mϕs. Close
inspection of the LSCM images did not reveal any Cy3-related
fluorescence (Figures S5 A-C). Using LSCM we further confirmed
that the cellular uptake in macrophages triggered by mannose
presentation on supramolecular homo- and copolymers at 37 °C
is undistinguishable from the uptake at 4 °C (Figures S5 D-F). In
conclusion, LSCM and FACS analyses provide strong evidence
that the copolymers are stable and that the incorporation of
mannosylated monomers induces the internalization into Mϕs via
a mannose receptor-mediated pathway.
In order to confirm the FACS data, we performed laser
scanning confocal microscopy (LSCM) and further examined the
receptor-mediated uptake of the FM+ particles after binding to the
MR. Mϕs were prepared as described above for FACS analyses.
In addition, the cell nuclei were stained with DAPI as blue
fluorescent dye (for details see SI). The LSCM images clearly
show that the mannosylated and Cy3 labelled building block FM+
is internalized into the Mϕs (Figure 2A). In contrast, no uptake was
observed for the TEG-bearing and Cy3 labelled building block FM-
(Figure 2B), confirming the MR-mediated endocytosis.
Encouraged by these findings, mixing experiments of monomers
into multicomponent copolymers were performed, in order to
evaluate the potential of these rod-like particles as modular
platform in the development of multifunctional targeted synthetic
vaccines. A 1:1 mixture of the fluorescence (Cy3) labelled TEG-
bearing fM- was used, in combination with the mannosylated, but
non-labelled monomer sM+. LSCM images showed that
TEGylated Cy3-labelled self- assembled polymeric FM- were
taken up by Mϕs after co-
For biomedical applications of nanomaterials, cytotoxicity is a
crucial factor that limits the applicability of new drugs and their
carriers. Therefore, Mϕs were stimulated with lipopolysaccharide
(LPS, 100 ng mL-1) in the absence and presence of FM-, FM+ and
FM-/SM+ for 24 h at 37 °C. Subsequently, FACS analyses in
combination with a fixable viability dye revealed that these
functional supramolecular polymers exhibited no cytotoxicity
against Mϕs (Figure S6). In order to further exclude negative
effects on the bioactivity of Mϕs, the resulting supernatants were
tested for the production of inflammatory cytokines interleukin-6
(IL-6)[14] and tumor necrosis factor alpha (TNF-a)[15], known to be
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10.1002/cbic.201800114
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(Figure S7). These findings are promising for the development of
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vaccines.
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Nanorod-like supramolecular polymers bearing a high-density
shell of mannosides or ethylene glycol moieties at their surface
were prepared via the self-assembly of functional comonomers,
which were further labelled with a fluorescent probe using copper-
mediated azide alkyne coupling. The resulting labelled polymers
were used to monitor cellular uptake into bone marrow-derived
murine Mϕs. A dendritic tetraethylene glycol and fluorescence
labeled homopolymeric FM- did not show measurable
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assembly of a fluorescent TEGylated monomer fM- with a non-
fluorescent mannosylated sM+ into supramolecular FM-/SM+
copolymers triggered cellular uptake. Surface mannose units thus
facilitate efficient cellular uptake via a mannose receptor-
mediated pathway, as confirmed by FACS analyses. Furthermore,
the incubation of the multifunctional supramolecular copolymers
with Mϕs did not negatively affect the cell viability or production of
proinflammatory cytokines. The copolymerization properties will
allow cross-presentation of various antigens, saccharides and
immunostimulants which are necessary to develop potent
multifunctional anti-tumor vaccines. The nanorod-shaped
viromimetic particles are a powerful and modular platform for the
development of fully synthetic vaccines, that effectively target
antigen-presenting cells and are capable of inducing a strong
immune response.
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Acknowledgements
We gratefully acknowledge the support from the DFG via the
collaborative research center SFB 1066 and thank Prof. H. Kunz
for stimulating discussions and critical reading of the manuscript.
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Keywords: supramolecular polymer • multicomponent
biomaterials • self-assembly • mannose receptor-targeting •
immune cells
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ChemBioChem
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
A modular route is presented to
prepare multifunctional
supramolecular polymers based on
self-assembled dendritic peptide
amphiphiles decorated with
D. Straßburger, N. Stergiou, M.
Urschbach, H. Yurugi, D. Spitzer, D.
Schollmeyer, E. Schmitt*, P. Besenius*
Page No. – Page No.
mannosides to effectively target
antigen-presenting cells such as
macrophages. The multicomponent
co-assembly protocol is a powerful
platform for the development of fully
synthetic multifunctional vaccines.
Mannose-Decorated Multicomponent
Supramolecular Polymers Trigger
Effective Uptake into Antigen-
Presenting Cells
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