Supramolecular Self-Assembly of Histidine-Capped-Dialkoxy-Anthracene: A Visible-Light-Triggered Platform for Facile siRNA Delivery

Article abstract of DOI:10.1002/chem.201601442

Supramolecular self-assembly of histidine-capped-dialkoxy-anthracene (HDA) results in the formation of light-responsive nanostructures. Single-crystal X-ray diffraction analysis of HDA shows two types of hydrogen bonding. The first hydrogen bond is established between the imidazole moieties while the second involves the oxygen atom of one amide group and the hydrogen atom of a second amide group. When protonated in acidic aqueous media, HDA successfully complexes siRNA yielding spherical nanostructures. This biocompatible platform controllably delivers siRNA with high efficacy upon visible-light irradiation leading up to 90 % of gene silencing in live cells.

Full text of DOI:10.1002/chem.201601442

A Journal of
Accepted Article
Title: Supramolecular Self-Assembly of Histidine-Capped-Dialkoxy-Anthracene: A
Visible Light Triggered Platform for facile siRNA Delivery
Authors: Sachin Patil; Basem Moosa; Shahad Alsaiari; Kholod Alamoudi; Aws Als-
hamsan; Abdulaziz Almailk; Karim Adil; Mohamed Eddaoudi; Niveen Khashab
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To be cited as: Chem. Eur. J. 10.1002/chem.201601442
Link to VoR: http://dx.doi.org/10.1002/chem.201601442
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Chemistry - A European Journal
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COMMUNICATION
Supramolecular Self-Assembly of Histidine-Capped-Dialkoxy-
Anthracene: A Visible Light Triggered Platform for facile siRNA
Delivery
Sachin P. Patil, Basem A. Moosa, Shahad Alsaiari, Kholod Alamoudi, Aws Alshamsan, Abdulaziz
AlMalik, Karim Adil, Mohamed Eddaoudi, and Niveen M. Khashab*
ABSTRACT: Supramolecular self-assembly of histidine-capped-
dialkoxy-anthracene (HDA) results in the formation of light
responsive nanostructures. Single-crystal X-ray diffraction analysis
of HDA shows two types of hydrogen bonding. The first hydrogen
bond is established between the imidazole moieties while the
second involves the oxygen atom of one amide group and the
hydrogen atom of a second amide group. When protonated in acidic
aqueous media, HDA successfully complexes siRNA yielding
spherical nanostructures. This biocompatible platform controllably
delivers siRNA with high efficacy upon visible light irradiation leading
up to 90% of gene silencing in live cells.
their potential use in clinical settings.
Visible light responsive (VLR) moieties such as 9-
alkoxyanthracene, 9,10- dialkoxyanthracene (DA), amino
acrylate and cis-oxo- or thioether were developed as a safer
alternative with an improved penetration capability. VLR
systems can also be coupled with nano-transducers to covert
7
8
deeply penetrating near-infrared light to visible light.
Specifically, DA group showed favorable green light
responsiveness in the presence of singlet oxygen, which can
cleave DA derivatives into 9,10-anthraquinone (AQ). Despite
the remarkable progress made in the design and assembly of
9
10
VLR polymeric
and host-guest
assemblies,
a
self-
organization-based small molecule VLR assembly has, so far,
proved to be elusive. Herein, supramolecular self-assembly of
histidine-capped-9,10-dialkoxy-anthracene (HDA) to form visible
light responsive platform is reported. Single-crystal X-ray
diffraction analysis of HDA shows two types of hydrogen
bonding in the assembly comprising imidazole and amide
moieties.
Self-assembly of macromolecules or small molecules through
non-covalent bonds to generate supramolecular complexes is a
prevalent process in nature. From a research perspective, this
principle is commonly used to build up supramolecular nano-
and microstructures that are developed for
a variety of
applications including drug/ gene delivery, cell imaging, and
1
tissue regeneration. Self-assembly in water has received major
attention because it can generate dynamic materials starting
from versatile building blocks such as block copolymers,
2
peptides, liposomes, and dendrimers. Such assemblies are
mainly reported in the form of supramolecular hydrogels or host-
3
guest complexes based on macrocyclic receptors.
These
systems are also stimuli responsive by nature and can be easily
tailored to respond to a variety of triggers including pH, heat,
4
light, enzymes, and redox. Among a plethora of stimuli, light is a
clean, easy to control, and low cost trigger that can be easily
5
applied. The known majority of light-responsive scaffolds such
as azobenzene, o-nitrobenzyl and spiropyran, are responsive to
6
ultraviolet irradiation. Unfortunately, the high-energy light (∼6
eV) is harmful and can hardly penetrate tissues, which hampers
[
†]
[†]
[
a] Dr. S. P. Patil , Dr. B. A. Moosa , S. Alsaiari, K. Alamoudi, Prof. N.
M. Khashab
Smart Hybrid Materials (SHMs) Laboratory,
King Abdullah University of Science and Technology (KAUST),
Thuwal, Makkah 23955-6900, Kingdom of Saudi Arabia.
Dr. Aws Alshamsan
Department of Pharmaceutics, College of Pharmacy and King
Abdullah Institute of Nanotechnology, King Saud University, KSA
Dr. Abdulaziz Almalik
Center of Excellence in Nanomedicine, King Abdulaziz City for
Science and Technology (KACST), Riyadh, KSA
Dr. K. Adil, Prof. M. Eddaoudi,
Functional Materials Design, Discovery and Development Research
King Abdullah University of Science and Technology(KAUST),
Thuwal, Makkah 23955-6900, Kingdom of Saudi Arabia.
†] These authors contributed equally.
Scheme 1. Schematic representation: (A) No assembly of HDA with siRNA at
pH 7.36; (B) Formation of spherical nanostructures of HDA with siRNA at pH
6; (C) siRNA-HDA complex disassembled after green light exposure in the
presence of eosin (visible light sensitizer).
[
Supporting information for this article is given via a link at the end of
the document.

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When protonated in water at pH 6, this supramolecular
assembly can efficiently complex siRNA forming spherical
nanostructures, whereas no complexation could be achieved at
neutral conditions (pH 7.36) (Scheme 1). Electrostatic interaction
between the positively charged HDA and negatively charged
RNA is the major driving force of this assembly where we
hypothize that the two protonated HDA arms are curving to
complex RNA and thus yielding spherical nanostructures. Upon
green light irradiation in the presence of eosin (photosensitizer),
the spherical nanostructures disassembled releasing the trapped
siRNA (Scheme 1). To the best of our knowledge, this is the first
example of VLR small molecule self-assembly for externally
controlled siRNA delivery. The histidine moiety not only provides
a positive corona for electrostatically binding siRNA but also
proves effective in improving siRNA efficacy by promoting
1
1
endosomal escape.
Fluorescent HDA was synthesized starting from non-
1
13
fluorescent anthraquinone (AQ) (Scheme S1). The H, and
C
spectra of HDA revealed the formation of a pure organic building
block. Colorless block single crystals of HDA were obtained by
recrystallization from N,N-dimethyl formamide. Single-crystal X-
ray diffraction (SCXRD) analysis showed that HDA crystallized
1
in monoclinic space group P2 (Table S1). Figure 1 shows the
packing of molecules through two types of hydrogen bonding.
The first hydrogen bond (2.067(1) Å) occurs between imidazole
moieties (Figure 1B) while the second (2.202(1) Å) involves the
oxygen atom of one amide group and the hydrogen atom of a
second amide group (Figure 1C).
The photolysis of HDA was performed and monitored via NMR
1
spectroscopy (Figure 2 and S1). All HNMR measurements were
6 2
done in DMSO-d instead of D O as unwanted intermolecular
Figure 1. Crystal structure of (A) HDA; (B) Hydrogen bonding between
imidazole moieties (2.067 Å); (C) HDA along the b axis showing hydrogen
bonding between amide moieties (2.202 Å).
aggregation drastically broadens the signals making them
unidentifiable. AQ is the major product of visible light
decomposition of HDA-composite (HDA-C) which contains HDA
with 1 mol % of eosin and 1% of TFA (Figure 2A). Proton peaks
a h
of HDA-C (H –H ; Figure 2B and S1B) shifted downfield
compared to pure HDA (Figure S1A) due to the presence of TFA.
Upon green light irradiation (>500 nm for 10 min.), HDA-C peaks
started to decrease while new peaks that are assigned to AQ
’
’
(
H
1
2
–H ) were observed (Figure 2C and S1C–E). Increasing
light exposure duration to 40 mins resulted in more prominent
AQ peaks, which supports the successful photolysis of HDA
(
Figure 2D and S1D).
Transmission electron microscopy (TEM) was employed to
further study HDA assembly (Figure S2). HDA self-assembled
into uniformly dispersed nanorods (30–60 nm width and 90–120
nm height; Figure S2A). Upon visible light exposure (40 mins),
the rod-like nanostructures disappeared and random fragments
were observed (Figure S2B).
All self-assembly studies were originally conducted at neutral
conditions however, protonation of the imidazole moieties at pH
6
increased the charge of the assembly to +39 compared to -11
at pH 7.36 (Figure S3). This pH-driven charge reversal prompted
us to test this assembly for encapsulation of negatively charged
cargo such as siRNA. The RNA interference machinery can be
exploited to silence nearly any gene in the body, giving it a very
broad therapeutic potential. However, naked siRNA is subject to
degradation by endogenous enzymes, and is too large and too
1
Figure 2. (A) Photolysis of HDA; Aromatic region of HNMR spectra (DMSO-
6
d )
of (B) HDA-Eosin-CF
3
COOH (HDA-C); (C) after 10 min green light
exposure; (D) after 40 min green light exposure.
1
2
negatively charged to cross cellular membranes. A variety of

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materials have been explored to package siRNA including,
liposomes, polymeric systems, and inorganic nanoparticles.
600 nm on the concentration of HDA. In the absence of siRNA,
the optical transmittance of HDA at 600 nm showed no
appreciable change as the concentration increased until 0.15
mM (Figure S5E, Supporting Information). However, at fixed
HDA concentration (0.10 mM), the optical transmittance
decreased gradually as the concentration of siRNA increased
because of the formation of the large amphiphilic assembly.
Figure S5 showed that the HDA/siRNA complex critical
aggregation concentration was obtained as 4.5−7.5 M (Figures
S5F).
CCK-8 assay was used to assess the biocompatibility of HDA
assembly. As shown in Figure S7 HDA did not exhibit significant
toxicity at their optimal concentrations for transfection in HeLa
cells. Approximately 95% of the cells survived at each
concentration of HDA. Cellular uptake by HeLa cells and
controlled disassembly of siRNA-HDA complex (Figure 4A–C
and S8–9) was monitored by confocal microscopy. Figures 4B
and S8 reveal the presence of blue fluorescence in HeLa cells
treated with cy3 labeled siRNA-HDA complex, indicating the
uptake of the assembly. Upon visible light irradiation (40
minutes), the blue fluorescence disappeared confirming the
photo-degradation of HDA while the green fluorescence of
cy3siRNA was monitored supporting the successful delivery to
cells. As a control, cells were treated with naked cy3siRNA
under the same conditions but no green fluorescence could be
detected in cells (Figure S9).
13
However, these “conventional” systems are heterogeneous in
size, composition, and surface chemistry, which can lead to
substandard performance, low efficacy, and possible toxicity.
Thus, self-assembled small molecules can potentially succeed in
1
4
siRNA delivery. Interestingly, HDA readily complexed siRNA
and assembled into stable spherical nanostructures (≈500 nm;
Figure 3A, S2C and S2D), whereas it cannot form further
assembly at neutral pH. DLS study supports the increase in the
size of the assembly after siRNA complexation (Figure S4).
Upon visible light irradiation, the spherical nanostructures of
siRNA-HDA complex readily disassembled supporting the photo-
responsiveness of the supramolecular assembly (Figure 3B).
To examine the gene silencing effect of siRNA-HDA complex,
we analyzed the Bcl-2 mRNA expression level by quantitative
real-time PCR (qRT-PCR). The siBcl2–HDA could remarkably
enhance the gene-silencing efficacy, resulting in more than 90%
of gene knockdown after visible–light exposure (Figure 4D). As
negative controls, Hela cells were also transfected by HDA
complex with scramble/nonspecific sequence (siNS-HDA),
showing no down regulation of Bcl-2 mRNA level, supporting the
specific gene regulation effect of Bcl-2 siRNA.
Figure 3. TEM images of (A) spherical siRNA-HDA assembly; (B) siRNA-
HDA complex disassembly after green light (Black ray® B-100YP lamp,
>
500nm) irradiation for 40 min. in the presence of photosensitizer.
We then carried out fluorescence spectral titration to
determine the interaction and binding constant between HDA
and siRNA (Figure S5). Variation in fluorescence intensity of
Cy3 (cyanine3) labeled siRNA in the presence of HDA was
measured. In the absence of HDA, the fluorescence of
Cy3siRNA showed no considerable change however upon
addition of HDA, the fluorescence intensity at 564 nm decreased
gradually (Figure S5A) and a growing new peak at 548 nm
(
Figure S5C) was seen as the concentration of HDA increased.
The increase in the intensity of the peak at 548 nm could be due
to the formation of a higher-order complex of cy3siRNA with
HDA. The fluorescence of the complexing HDA with Cy3siRNA
was correlated with a Job’s plot that indicated a 1:1 (which
equals 20 N/P ratio; N/P = No. of protonated amines from HDA/
No. of phosphate group from siRNA) stoichiometry (Figure S5D).
The association constant for the complexation process was
5
-1
estimated to be 5.09 x 10
M
(error < 10%) following the
1
5
modified Benesi–Hildebrand equation. Gel electrophoresis was
further employed to verify the ability of HDA to complex siRNA
and then controllably release it upon exposure to green light
(
(
Figure S6). HDA complexed siRNA in acidic pH at N/P ratio 20
Figure S6, lane 6) whereas it cannot complex siRNA in neutral
pH at identical N/P ratio (Figure S6, Lane 4). The siRNA was
released from HDA after green light exposure for 40 min in the
presence of eosin (Figure S6, lane 7). The critical aggregation
concentration of HDA in the presence of siRNA was measured
by monitoring the dependence of the optical transmittance at

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Figure 4. Confocal images of live HeLa cells after incubation with siRNA-HDA
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In summary, a visible light responsive supramolecular assembly
was prepared employing histidine–capped–dialkoxy-anthracene
building blocks. SCXRD revealed two types of hydrogen bonding
involving the imidazole and amide moieties. When protonated in
acidic aqueous solution, this assembly can successfully complex
negatively charged siRNA and controllably release it upon
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Keywords: Self-assembly • Photo-responsive • Hydrogen
bonding • Supramolecular • siRNA delivery
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COMMUNICATION
A “Smart Assembly”: Visible light
responsive small molecule self-
assembly was developed employing
histidine-capped-9,10-dialkoxy-
anthracene. When protonated, this
biocompatible platform could
Sachin P. Patil, Basem A. Moosa,
Shahad Alsaiari, Kholod Alamoudi,
Karim Adil, Mohamed Eddaoudi, and
Niveen M. Khashab *
Page No. – Page No.
successfully complex siRNA and
deliver it with high efficacy, upon
visible light irradiation, leading up to
Supramolecular Self-assembly of
Histidine-Capped-Dialkoxy-
Anthracene: A Visible Light Triggered
Platform for facile siRNA Delivery
90% of gene silencing in live cells.