A pH-Responsive DNAsome from the Self-Assembly of DNA–Phenyleneethynylene Hybrid Amphiphile

Article abstract of DOI:10.1002/chem.201701446

A pH-responsive DNAsome derived from the amphiphilicity-driven self-assembly of DNA amphiphile containing C-rich DNA sequence is reported. The acidification of DNAsome induces a structural change of C-rich DNA from random coil to an i-motif structure that

Full text of DOI:10.1002/chem.201701446

A Journal of
Accepted Article
Title: A pH-responsive DNAsome from the self-assembly of DNA-
phenyleneethynylene hybrid amphiphile
Authors: Reji Varghese, Shine K Albert, Murali Golla, Hari Veera
Prasad Thelu, and Nithiyanandan Krishnan
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201701446
Link to VoR: http://dx.doi.org/10.1002/chem.201701446
Supported by

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A pH-responsive DNAsome from the self-assembly of DNA-
phenyleneethynylene hybrid amphiphile
Shine K. Albert, Murali Golla, Hari Veera Prasad Thelu, Nithiyanandan Krishnan and Reji Varghese*
Abstract:
A
pH-responsive DNAsome derived from the
O
DNA-PE
N
amphiphilicity-driven self-assembly of DNA amphiphile containing C-
rich DNA sequence is reported. The acidification of DNAsome
induces a structural change of C-rich DNA from random coil to an i-
motif structure that triggers the disassembly of DNAsome and its
subsequent morphological transformation into an open entangled
O
N
N
hydrophilic DNA
hydrophobic segment
3’-CCCCAATCCCC-PE-5’ (DNA amphiphile)
amphiphilicity-driven self-assembly at pH 7.3
Nile red
network. The encapsulation of
a hydrophobic guest into the
membrane of DNAsome and its pH-triggered release upon
acidification of DNAsome is also demonstrated.
Stimuli-responsive DNA nanostructures have found potential
applications in several fields including medicine[1] and
nanotechnology.[2,3] Among the various DNA nanostructures,
DNAsomes (vesicular nanostructures made of DNA) is
particularly attractive due to their remarkable ability to act as
nanocarrier in drug delivery applications.[4] The salient structural
features of DNAsomes include DNA based corona, hydrophilic
internal cavity and hydrophobic membrane. Hence, DNAsomes
are capable of encapsulating both hydrophilic and hydrophobic
drugs in the internal cavity and membrane, respectively. More
importantly, DNA shell of DNAsomes offers the unique
opportunity for targeted drug delivery either by incorporating
specific cell targeting ligands onto their surface through DNA
hybridization[5] or by replacing the random DNA sequence with
DNA aptamer for a specific target.[6] Another desirable property
that needs to be maintained in DNAsomes for drug delivery
applications is the stimuli-responsive nature, which allow them to
respond to different stimuli in a predictable manner. Hence the
design and synthesis of stimuli-responsive DNAsomes are
extremely important for drug delivery applications.
Amphiphilicity-driven self-assembly is an efficient bottom-
up approach for the crafting of stimuli-responsive soft molecular
assemblies that has been extensively explored in
supramolecular chemistry.[7] Very recently, amphiphiles derived
from DNA (DNA amphiphiles) have emerged as a promising
candidate for the design of soft DNA nanostructures.[8] In an
interesting report, Liu et al. have shown pH-induced morphology
switching between spherical micelle and cylindrical micelle in the
self-assembly of a DNA amphiphile containing i-motif forming
DNA as the hydrophilic segment.[9] Motivated from this report,
we envisioned that the replacement of random DNA sequence of
DNAsome forming amphiphile reported by us recently[10] with an
i-motif forming DNA could lead to a pH-responsive DNAsome.
pH-responsive DNAsome
pH 5 (i-motif formation at pH 5)
pH 7.3
i-motif
5’
C
C
C
C
C
C
C
C
3’
5’
3’
C
C
C
C
C
C
C
C
3’
C
C
C
C
C
C C
C
C C C
C
5’
C C 3’
C
C
C
C C
C
C
C
5’
C C
C
C
C
C
5’
C
C
C
C
3’
open entangled network
Scheme 1. Chemical structure of DNA-PE and its amphiphilicity-driven self-
assembly into pH-responsive DNAsome. The encapsulation of Nile red into
DNAsome and its release upon i-motif formation with acidification is also
shown.
structure through intermolecular cytosine–protonated cytosine
(C:CH+) base-pairing at low pH (acidic) and a random coil single
stranded DNA (ssDNA) at high pH (neutral or basic).[9] This
secondary structural changes of DNA with the change in pH
could result in the formation of a pH-responsive DNAsome.
Herein, we demonstrate the amphiphilicity-driven self-assembly
of DNA-PE into DNAsomes and its reversible pH-induced
morphological switching between DNAsome and entangled
nanostructure (Scheme 1). The potential of pH-responsive
DNAsome as a nanocarrier for drug delivery applications is also
demonstrated with the encapsulation and pH-triggered release
of Nile red, a hydrophobic dye, as a representative example.
Synthesis of DNA-PE was achieved through copper(I)-
catalyzed azide-Alkyne cycloaddition (CuAAC) following
reported procedures[11] and the details are provided in the
Supporting Information (SI). Self-assembly of DNA-PE was
initially studied at pH 7.3 by annealing DNA-PE (Tris-HCl buffer,
50 mM) at 90 °C for 5 minutes followed by slow cooling to room
temperature. Optical properties of DNA-PE aggregates are
provided in SI (Figure S29). Denaturing polyacrylamide gel
electrophoresis (PAGE) analysis shows no migration of DNA-PE
on PAGE gel (Figure 1a). The retardation of migration of DNA-
PE on PAGE gel can be attributed to the spontaneous formation
of DNA-PE nanostructures having dense display of DNA on its
surface, as observed in similar systems.[12] DLS analysis of
DNA-PE at 20 °C shows unimodal distribution of spherical
particles with sizes ranging from 44 nm to 460 nm (σ = 0.189)
with an average diameter of 142 nm (Figure 1b). Since the
Keeping this in mind, we have designed
a
DNA-
phenyleneethynylene (PE) based amphiphile (DNA-PE). The
DNA sequence used in our design is 5’-PE-CCCCTAACCCC-3’,
which can undergo reversible structural change between i-motif
[a]
S. K. Albert, M. Golla, H. V. P. Thelu, N. Krishnan, Dr. R. Varghese
School of Chemistry, Indian Institute of Science Education and
Research-Thiruvananthapuram (IISER-TVM)
CET campus, Trivandrum-695016 (India)
E-mail: reji@iisertvm.ac.in
Supporting information for this article is given via a link at the end of
the document.
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a)
b)
a)
b)
DNA-PE
100 nm
1 µm
c)
d)
Figure 1. a) Denaturing PAGE (20%) of DNA-PE. b) Size distribution graphs
from the DLS analyses of DNA-PE at pH 7.3 and 5, and the inset shows the
pH induced cycling of random coil ss-DNA and i-motif structures monitored
using the changes in the average diameter (d) of the nanostructures (c = 1 μM,
Tris-HCl buffer, 50 mM).
10 µm
Figure 2. a) T-AFM (height), b) TEM and c) fluorescence microscopic images
of DNA-PE DNAsome. d) Fluorescence spectra of Calcein encapsulated in
DNA-PE DNAsome and Calcein in DNAsome-free solution (c = 1 μM, Tris-HCl
buffer, λex = 470 nm).
diameter of the smallest particle (44 nm) is significantly larger
than the calculated bilayer distance of DNA-PE (∼16 nm), it can
be inferred that the spherical aggregates are vesicular
(DNAsomes) and not micellar in nature.[13] As expected, zeta
potential measurement shows −39.5 mV for DNA-PE
aggregates, indicating the negatively charged surfaces of the
DNAsome (Figure S30).
interaction of the alkyl chains and π-stacking of PE, which
constitute the membrane of DNAsome, whereas hydrophilic C-
rich DNA is exposed to the polar medium on either side of the
membrane as shown in Scheme 1.
Tapping-mode atomic force microscopic (T-AFM) analyses
of DNA-PE on mica surface reveal the formation of spherical
particles with size ranging 50 nm to 800 nm (Figure 2a). The
average diameter of the spheres of DNA-PE assemblies, which
were estimated from the fitted histograms of the size distribution
curve, is 250 nm. In this case also, it can be seen that the
diameter of the smallest particle (~50 nm) is considerably larger
than the calculated bilayer distance of DNA-PE, confirming the
formation of DNAsome for DNA-PE. In addition, the section
analysis of DNAsomes reveals an average height of ~15 nm,
which is considerably smaller when compared with the
respective average diameter of the DNAsomes. This clearly
indicates that the DNAsomes are “soft” in nature and hence are
flattened on the mica surface, as observed for similar
systems.[14] Furthermore, transmission electron microscopic
(Figure 2b) and fluorescence microscopic analyses (Figure 2c)
show the formation of DNAsomes. We have also carried out dye
encapsulation experiments to further confirm the DNAsome
structure for the DNA-PE aggregates using Calcein. Calcein is a
fluorescent hydrophilic dye, and hence would be encapsulated in
the hydrophilic interior of the DNAsome. Significant quenching is
observed for the emission intensity of Calcein encapsulated
inside the DNA-PE DNAsome when compared with the emission
of an absorption matched solution of Calcein in a DNAsome-free
solution (λex = 470 nm, Figure 2d). This quenching of emission
can be attributed to the self-quenching of the dye emission due
to the high encapsulation of Calcein inside the hydrophilic cavity
of DNAsome. These results unequivocally confirm that DNA-PE
self-assembles into DNAsomes through van der Walls
In order to investigate the pH-responsiveness of DNAsome,
self-assembly of DNAsomes was studied at pH 5 (c = 1 μM, Tris-
HCl buffer). Circular dichroism (CD) studies of DNAsome (pH
7.3) show a CD signal with positive Cotton effect at 280 nm and
a negative Cotton effect at 250 nm, which is a characteristic CD
signal of random C-rich ssDNA present on the surface of
DNAsomes.[9] Interestingly, a red-shift of CD signal to 290 nm
with an increase in CD signal intensity is observed upon
acidifying the DNAsome to pH 5 (Figure 3a). The CD signal
observed at pH 5 is a characteristic spectral feature for the
formation of i-motif structure through C-CH+ hydrogen bonding
as shown in Scheme 1. More interestingly, pH-induced structural
transformation between the random ssDNA and i-motif
structures is completely reversible for several cycles as evident
from the CD studies (Figure 3a inset). At pH 5, the absorption
spectrum of DNAsome shows
a decrease in absorbance
corresponds to DNA region with a red-shift to 272 nm, further
supporting the i-motif formation at pH 5 (Figure S29).[9] DLS
analysis of DNAsome at pH 5 shows a decrease in the average
size of the aggregates to 91 nm (σ = 0.13, Figure 1b).
Interestingly, DLS analyses also reveal that the switching of size
distribution upon acidification is reversible for several cycles, in
agreement with the CD studies (Figure 1b, inset). These
experiments obviously indicate that the DNAsomes are
undergoing reversible morphological transformation with the
change in pH. AFM and scanning electron microscopic (SEM)
analyses of DNAsomes at pH 5 show the formation of
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a)
b)
250 nm
c)
d)
Figure 4. Fluorescence spectra of Nile red encapsulated in DNA-PE
DNAsome at pH 7.3 (black trace), DNAsome-free solution at pH 7.3 (red trace)
and at pH 5 (blue trace). (c = 1 µM, Tris-HCl buffer, λex = 514 nm).
study the encapsulation and release of the dye (λex = 514 nm).
Initially, Nile red was encapsulated into the membrane of
DNAsome by annealing DNA-PE in the presence of Nile red.
Nile red is nearly non-emissive in buffer (Tris-HCl buffer) at pH
7.3 (c = 2 μM). The emission intensity of Nile red encapsulated
in the membrane of the DNAsome was compared with the
emission intensity of Nile red alone in buffer at pH 7.3 (Figure 4).
A significant fluorescence enhancement is observed for Nile red
emission after its encapsulation into the DNAsome membrane,
which clearly indicates that the dye is encapsulated into the
hydrophobic membrane of DNAsome. Interestingly, a decrease
in the fluorescence intensity is observed upon acidification of
DNAsome to pH 5. On the other hand, control experiments of
effect of pH on the fluorescence of Nile red show a slight
increase in fluorescence intensity with the change in pH from 7.3
to 5 (Figure S38). Hence the observed decrease in fluorescence
intensity of Nile red encapsulated inside the DNAsome with the
change in pH from 7.3 to 5 is indeed due to the disassembly and
transformation of DNAsome into an open entangled network and
the subsequent release of Nile red to a more polar medium.
However, the reasonable emission of Nile red after its release
from the DNAsome implies that the released dye still finds the
hydrophobic domains available in the 3D network. These results
suggest that the modulation of the hydrophobicity of the
amphiphile may allow the efficient release of the encapsulated
guest molecules, and could be a potential nanocarrier for drug
delivery applications in cancer therapy.
250 nm
1 µm
Figure 3. a) CD spectral changes of DNA-PE with the change in pH and the
inset shows the cycling of random coil ssDNA and i-motif structures monitored
using the CD spectral changes. b) AFM and c) SEM images of entangled
DNA-PE network at pH 5. d) AFM image of reformed DNAsome with the
increase of pH to 7.3 (c = 1 µM, Tris-HCl buffer).
highly entangled network that are extended over several
micrometers (Figure 3b, c). Zoom-in AFM images reveals that
the network is made of thin fibers that are grown in 3D to form
the network. Section analysis of the fibrous structures shows
that fiber has a width of ~35 nm (after reducing the tip
broadening factor)[15] and a height of ~2 nm (Figure 3b inset).
More interestingly, the morphological transition of DNAsome to
the entangled network is fully reversible. DNAsomes are
reformed upon increasing the pH of the solution of intertwined
structure to pH 7.3 as evident from the AFM analysis (Figure 3d).
Based on these results, it is proposed that DNA-PE undergoes
amphiphilicity-driven self-assembly into DNAsome at pH 7.3.
Acidification of DNAsome to pH
5 induces a structural
transformation of random-coil C-rich ssDNA on the surface of
DNAsome into i-motif structure through intermolecular C-CH+
base pairing. Since there is no directionality for the i-motif
formation it leads to highly entangled 3D networks with the
bilayer packing of the amphiphile intact as schematically shown
in Scheme 1.
In conclusion, we have demonstrated, for the first time, a
pH-responsive DNAsome from the self-assembly of DNA
amphiphile. Spectroscopic, light scattering and microscopic
studies have shown that DNA-PE undergone amphiphilicity-
driven self-assembly into nano-to-micro sized DNAsome at pH
One of the potential applications of pH-responsive
DNAsomes is to act as a nanocarrier in drug delivery application,
particularly in cancer therapy. Drugs could easily be loaded
either into the hydrophobic membrane (hydrophobic drugs) or
hydrophilic cavity (hydrophilic drugs) of the DNAsome during the
self-assembly, and by taking the advantage of acidic pH of
cancerous cell, the loaded drugs can be released upon entry
into the cancerous cell. As a proof-of-concept, we demonstrate
the encapsulation of Nile red, a hydrophobic dye, into the
membrane of DNAsome, and its release upon acidification.
Fluorescence changes of Nile red were monitored in order to
7.3. DNAsomes consists of
a
hydrophobic membrane
constituting of self-assembled alkyl chains tethered PE, and a
shell made of hydrophilic C-rich DNA. The C-rich DNA segment
undergoes a structural change from random coil ssDNA to an i-
motif structure upon acidification that triggered the opening of
DNAsomes and its subsequent morphological transformation
into entangled 3D network structure in a reversible manner. We
have also shown the potential of our system in the encapsulation
of a hydrophobic guest into the membrane of DNAsome and its
release upon acidification of DNAsome. We hope the unique
structural features of DNAsome and its pH-responsiveness may
find potential applications in drug delivery, particularly in cancer
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and N. K. thank UGC for Research Fellowships. We thank MGU
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schematic drawing is acknowledged.
Keywords: self-assembly • amphiphiles • DNA nanostructures •
vesicles • responsive systems
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S. K. Albert, M. Golla, H. V. P. Thelu, N.
Krishnan, R. Varghese*
Page No. – Page No.
A pH-responsive DNAsome from the
self-assembly of DNA-
phenyleneethynylene hybrid
amphiphile
Amphiphilicitty-driven self-assembly of DNA amphiphile containing C-rich DNA as
the hydrophilic segment leads to the formation of DNAsome at basic pH (7.3). The
acidification of DNAsome induces a structural change of C-rich DNA from random
coil to an i-motif structure that triggers the disassembly of DNAsome and its
subsequent morphological transformation into an open entangled network in a
reversible manner.
This article is protected by copyright. All rights reserved.