Solvent Adaptive Dynamic Metal-Organic Soft Hybrid for Imaging and Biological Delivery

Article abstract of DOI:10.1002/anie.201900692

A solvent responsive dynamic nanoscale metal-organic framework (NMOF) [Zn(1 a)(H₂O)₂] has been devised based on the self-assembly of Zn^II and asymmetric bola-amphiphilic oligo-(p-phenyleneethynylene) (OPE) dicarboxylate linker 1 a having dodecyl and triethyleneglycolmonomethylether (TEG, polar) side chains. In THF solvent, NMOF showed nanovesicular morphology (NMOF-1) with surface decorated dodecyl chains. In water and methanol, NMOF exhibited inverse-nanovesicle (NMOF-2) and nanoscroll (NMOF-3) morphology, respectively, with surface projected TEG chains. The pre-formed NMOFs also unveiled reversible solvent responsive transformation of different morphologies. The flexible NMOF showed cyan emission and no cytotoxicity, allowing live cell imaging. Cisplatin (14.4 wt %) and doxorubicin (4.1 wt %) were encapsulated in NMOF-1 by non-covalent interactions and, in vitro and in vivo drug release was studied. The drug loaded NMOFs exhibited micromolar cytotoxicity.

Full text of DOI:10.1002/anie.201900692

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Solvent adaptive dynamic metal-organic soft hybrid for imaging
and biological delivery
Authors: Debabrata Samanta, Syamantak Roy, Ranjan Sasmal,
Nilanjana Das Saha, Pradeep K R, Ranjani Viswanatha, Sarit
S. Agasti, and Tapas Kumar Maji
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900692
Angew. Chem. 10.1002/ange.201900692
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http://dx.doi.org/10.1002/ange.201900692

10.1002/anie.201900692
Angewandte Chemie International Edition
COMMUNICATION
Solvent adaptive dynamic metal-organic soft hybrid for imaging
and biological delivery
Debabrata Samanta,a Syamantak Roy,a Ranjan Sasmal,b Nilanjana Das Saha,b Pradeep K R,b Ranjani
Viswanatha,bc Sarit S. Agasti,ab Tapas Kumar Maji*abc
Abstract: A solvent responsive dynamic nanoscale metal-organic
framework (NMOF) [Zn(1a)(H2O)2] has been devised based on the
self-assembly of ZnII and asymmetric bola-amphiphilic oligo-(p-
phenyleneethynylene) (OPE) dicarboxylate linker 1a having dodecyl
and triethyleneglycolmonomethylether (TEG, polar) side chains. In
THF solvent, NMOF showed nanovesicular morphology (NMOF-1)
with surface decorated dodecyl chains. In water and methanol, NMOF
exhibited inverse-nanovesicle (NMOF-2) and nanoscroll (NMOF-3)
morphology, respectively, with surface projected TEG chains. The
pre-formed NMOFs also unveiled reversible solvent responsive
transformation of different morphologies. The flexible NMOF showed
cyan emission and no cytotoxicity, allowing live cell imaging. Cisplatin
(14.4 wt%) and doxorubicin (4.1 wt%) were encapsulated in NMOF-1
by non-covalent interactions and, in-vitro and in-vivo drug release was
studied. The drug loaded NMOFs exhibited micromolar cytotoxicity.
ZnII, THF
ZnII, MeOH 1a
1a
ZnII, H2O
1a
H2O
THF
MeOH
H2O
Nanovesicle
NMOF-1
Inverse-nanovesicle
NMOF-2
Nanoscroll
NMOF-3
Scheme 1. Schematic representation of synthesis and morphology
transformation of NMOFs.
The recent upsurge in design and synthesis of meso/nanoscale
metal-organic frameworks (MOFs) stems from their solution
processability.[1] This has magnified the landscape of application
of MOFs in several interdisciplinary areas, particularly in biology[2]
and device fabrication.[3] Several synthetic methodologies and
approaches have been adopted to fabricate nanoscale MOFs
(NMOFs) with varied shape, size and morphologies.[4] However,
fabrication of solvent responsive chromophoric NMOFs with
flexible and dynamic morphologies, based on a suitable linker, is
yet to be explored. Such tailoring of MOF nanostructure will find
potential applications in drug delivery,[5] molecular recognition and
sensing[6] or separation of specific molecules.[7] So far, Fe, Zr, and
Zn MOFs have been found to be bio-compatible and frequently
utilized as nanocarriers for drug delivery.[8] Recently, our group
has adopted a strategy towards the synthesis of nano/mesoscale
MOFs with varied morphologies by self-assembly of bola-
amphiphilic oligo-p-phenyleneethynylene carboxylate (OPE)
based chromophoric linker with different metal ions.[9] The
dynamic nanostructures obtained by tuning the length of alkyl
chains in OPE linkers showed applications in light harvesting,
bimodal imaging, sensing, photocatalysis and also as
a
superhydrophobic self-cleaning material.[9] The introduction of
different polarity like glycol and alkyl chain on the OPE backbone,
will result in asymmetric bola-amphiphilicity and we envisioned
that self-assembly of such linker with specific metal ions will result
in NMOFs with omniphilic pore surfaces. Such modulation of the
polarity of pore surfaces is of paramount importance for
encapsulation of suitable molecular species or drug molecules.[10]
Furthermore, polarity and philicity of the outer surface of the
preformed NMOFs can also be tuned based on the polarity of the
solvent media. Fabrication of such luminescent, reversible shape
shifting dynamic NMOFs are yet to be documented and can be
applied in bioimaging and drug delivery.
In this communication, we report the self-assembly of bola-
amphiphilic asymmetric organic linker (OPE, 1a) with ZnII to form
three reversibly shape shifting and non-toxic NMOFs with
nanovesicle (NMOF-1), inverse nanovesicle (NMOF-2) and
nanoscroll (NMOF-3) morphologies. The emissive nature of the
NMOFs allowed for bio-imaging applications. Furthermore, the
omniphilicity of the pores of NMOF-1 was utilized for cisplatin and
doxorubicin drug loading and their subsequent in vitro and in vivo
release study.
[a]
[b]
[c]
Dr. D. Samanta, Dr. S. Roy, Prof. Dr. S. S. Agasti, Prof. Dr. T. K. Maji,
Chemistry and Physics of Materials Unit, School of Advanced
Materials (SAMat), Jawaharlal Nehru Centre for Advanced Scientific
Research (JNCASR), Jakkur, Bangalore-560064, India. E-mail:
tmaji@jncasr.ac.in
The nanoscale metal-organic framework, NMOF-1 was
prepared by mixing ZnII and the linker 1a (1:1) in THF under basic
condition. Inductively coupled plasma atomic emission
spectroscopy
(ICP-AES)
and
energy-dispersive
X-ray
R. Sasmal, Pradeep K. R., Dr. N. D. Saha, Prof. Dr. S. S. Agasti, Prof.
spectroscopy (EDAX) showed the presence of 8.12 wt% and 7.91
wt% of Zn, respectively (Figure S1). Fourier transform IR
spectroscopy (FT-IR) showed the signature of ZnII coordinated
water molecules at 3400 cm-1 (Figure S2). The symmetric and
asymmetric stretching frequencies of carboxylate were found at
1592 and 1399 cm-1, respectively, indicating coordination of
carboxylate with ZnII. Thermogravimetric analysis (TGA) revealed
an initial weight loss of 4.5 wt% which continued upto 210 °C
Dr.
R.
Viswanatha,
Prof.
Dr.
T.
K.
Maji,
New Chemistry Unit and School of Advanced Materials (SAMat),
Jawaharlal Nehru Centre for Advanced Scientific Research
(JNCASR), Jakkur, Bangalore-560064, India
Prof. Dr. T. K. Maji, Prof. Dr. R. Viswanatha, International Centre for
Materials Science, School of Advanced Materials (SAMat) Jawaharlal
Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore -
560064, India
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201900692
Angewandte Chemie International Edition
COMMUNICATION
a)
d)
b)
c)
(a)
(c)
Hydro-
philic
pore
(012)
Hydro-
phobic
pore
3 mm
172
1 mm
500 nm
(011)
e)
f)
(b)
(d)
(010)
(010)
(011)
18.5 Å
11.8 Å
scroll
belt
(012)
9.12 Å
(134)
200 nm
250 nm
200 nm
4.29 Å
Figure 2. a) FESEM and b) TEM images of NMOF-1. c) FESEM and TEM (inset,
scale bar: 2 µm) images of NMOF-2, d) FESEM and e) TEM images of NMOF-
3. f) FESEM images of NMOF-3 (1h).
Figure 1. a) Possible packing and b) PXRD pattern of the NMOF-1. c) Benzene
and water vapour adsorption isotherms of NMOF-1 (295 K) (inset: water contact
angle), and d) CO2 adsorption profile of NMOF-1 at 195 K.
diameter range of 100 – 400 nm (Figure 2a,b,S7,S8). An
approximate wall thickness of the nanovesicles was found to be
5.7 ± 0.6 nm from the peripheral dark regions of TEM images
(Figure S8), suggesting that the walls of the nanovesicles consist
of 5 - 6 interdigitated layers (Figure 1a). As the NMOF is
assembled by weak supramolecular interactions like π-stacking,
H-bonding and van der Waals interactions, the morphology varied
greatly on the polarity of solvent used for synthesis. For example,
in polar water and moderately polar methanol medium, the formed
NMOFs, namely NMOF-2 and NMOF-3, showed inverse-
nanovesicular and nanoscroll morphology, respectively, as
observed in FESEM and TEM study (Figure 2, S9-S12). NMOF-2
has diameter upto 700 nm and NMOF-3 has wide distribution of
length starting from 100 nm to 500 nm and diameter 50-60 nm.
Sharp contrast for the openings of the nanoscroll was also
observed (Figure 2f/S12). FT-IR spectroscopy, TGA, EDAX, ICP
and elemental analysis concluded the molecular formula of
NMOF-2 and NMOF-3 to be Zn(1a)(H2O)2 which is the same as
NMOF-1 (Figure S2,S3,S13,S14). Notably, PXRD of NMOF-2&3
are similar to that of NMOF-1, suggesting that the repeating OPE
backbone and interdigitation are similar in all cases (Figure S15).
The CO2 uptake (195 K, p = 1) of NMOF-2 and NMOF-3 was
found to be 44.6 cc/g and 46.4 cc/g, respectively, indicating their
similarity in packing and pore structure (Figure S16).
As the linker 1a contains mixed polar side chains, either
dodecyl chains or TEG chains can be present on the outer surface
of vesicles, depending on polarity of the solvent used for NMOF
synthesis, and this arrangement was corroborated by comparing
nonpolar and polar solvent vapor adsorption isotherms as well as
water contact angle measurement. Benzene and water vapor
adsorptions (at 295 K) were measured with activated samples of
all three NMOFs. NMOF-1-3 showed gradual uptake of both the
solvents, indicating the presence of omniphilic pore surface
(Figure 1c, S17/18). Strikingly, in the case of NMOF-1, benzene
uptake is higher than water in the low pressure region p = 0 - 0.63,
this may be due to hydrophobic nature of the exterior surface. The
NMOF-1 coated glass surface also showed superhydrophobic
water contact angle of 172° whereas hexane droplet was found to
be immediately spreading over the surface. As the synthesis of
NMOF-1 was performed in THF, the dodecyl chains got exposed
on the outer surface of the nanovesicles, resulting in the
possibly due to removal of Zn(II)-coordinated two water molecules
(Figure S3). In combination with elemental analysis, EDAX, ICP
and TGA, the molecular formula of the MOF was determined to
be Zn(1a)•2H2O i.e. linker 1a and ZnII are complexed in 1:1 ratio
and two water molecules are seemingly coordinated to each ZnII.
To understand the coordination environment of NMOF-1, Zn K-
edge EXAFS study was performed and quick shell fitting showed
that the coordination number of ZnII is ~4 (Figure S4, Table S1).
This suggests ZnII is in a tetrahedral geometry with two water and
two carboxylate oxygen atoms in NMOF-1. Powder X-ray
diffraction (PXRD) measurement of NMOF-1 showed high degree
of crystallinity with several intense peaks corresponding to the d-
spacing of 18.5 Å, 11.8 Å, 9.12 Å and 4.29 Å (Figure 1b). For
instance, the most intense peak with a d-spacing at 18.5 Å
indicates the repeating OPE-backbone that complexed with ZnII
forming a linear polymer (Figure 1a and Scheme S4). The broad
pattern at 4.29 Å, represents that the linear 1D chains are
extended in two-dimension via weak π-stacking. Another two
peaks at 11.8 Å and 9.12 Å, can be understood as repeating units
formed alternatively by dispersive interaction between dodecyl
chains and hydrogen bonding between TEG chains, respectively
(Figure 1a). The interdigitation between 2D layers resulted in a
3D supramolecular framework of NMOF-1. Indexing of the PXRD
patterns showed an orthorhombic crystal system with cell
parameters of a = 9.67(2) Å, b = 18.26(4) Å, c = 31.38(7) Å and
cell volume of 5544 Å3 (Table S2). The permanent porosity of
NMOF-1 was identified by the adsorption isotherms of N2 (at 77
K) and CO2 (at 195 K) with a final uptake of 26 cc/g and 55 cc/g,
respectively, at p = 1 (Figure 1d/S5). N2 adsorption showed type-
II profile whereas CO2 adsorption exhibited typical type-I profile
which suggested microporosity in NMOF-1. Thus CO2 adsorption
occurred in the pore channel but N2 adsorption took place in the
inter-particle void space. The CO2 adsorption profile validated 3D
supramolecular arrangement of NMOF-1.
Morphology of NMOF-1 was investigated by field emission
scanning electron microscopy (FESEM) and transmission
electron microscopy (TEM). All the microscopic analyses support
nanovesicular morphology of NMOF-1 with
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10.1002/anie.201900692
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superhydrophobic surface. The measured water contact angle on
NMOF-2 and NMOF-3 coated glass surfaces are 55 and 74°,
respectively, representing hydrophilic exterior surface due the
projection of TEG chains in both the NMOFs. It is interesting to
note that increasing solvent polarity from THF→MeOH→water,
the morphology of the NMOF can be regulated among
nanovesicle (NMOF-1) → nanoscroll (NMOF-3) → inverse-
nanovesicle (NMOF-2). In control experiments, synthesized
MOFs, using linker 1b and 1c, did not show any regular nanoscale
morphology (Figure S19,S20), therefore, signifying the
importance of mixed polar side chain for fabrication of vesicular
NMOF with dynamic morphologies.
allowed us to perform cellular uptake for bioimaging. We have
tested the cell uptake by structured illumination microscopy (SR-
SIM) after treating the HeLa cells with NMOF-1, suspended in
DMEM culture media (0.2 mg ml-1). The SR–SIM image of the
cells, which was recorded after 48 h of incubation at 37 °C showed
the presence of cyan emission from the cells, indicating efficient
uptake of the NMOF-1 by HeLa cell (Figure S27,S28).
The nanovesicular NMOF-1 has surface decorated dodecyl
chains and the inner TEG chains create hydrophilic cavity which
can offer multiple H-bonding interactions toward encapsulation of
cisplatin and doxorubicin drug molecules. Morphological flexibility
of NMOF could also allow drug release by changing the solvent.
As expected, cisplatin was successfully loaded into NMOF-1,
from a saturated solution of
In order to study morphological flexibility and dynamicity
with solvent polarity, NMOF-1 (nanovesicle), synthesized in THF,
a)
“drug loading”
“drug release”
HeLa cell
or
water
MeOH
cisplatin@NMOF-1
NMOF-1
(b)
c)
(d)
(c)
Scheme 4. a) Schematic representation of drug loading and release by NMOFs.
b) Drug release profile of cisplatin@NMOF-1 and DOX@NMOF-1 in 1xPBS
buffer. (c) SR-SIM image of HeLa cells after treatment with cisplatin@NMOF-
1 (scale bar: 5 µm).
Figure 3. a) Normalized UV-Vis and PL spectra (λex = 433 nm) of NMOF-1.
Inset: NMOF-1 dispersion under UV light, b) cytotoxicity profile of NMOF-1,
cisplatin@NMOF-1 and DOX@NMOF-1. (c) Contact angle measurement of
the transformed NMOFs.
methanol/water (v/v 11:1, SI), and the loading amount was
quantified to be 14.4 wt% by detecting Pt in ICP and EDAX
analyses (Figure S29). The TGA analysis of the
cisplatin@NMOF-1 showed an additional step of weight loss in
the range 200-300 °C due to the early decomposition of cisplatin
(Figure S30). FT-IR spectrum also revealed the presence of N-H
stretching of the encapsulated cisplatin at 3283cm-1 (Figure S31).
Indeed, cisplatin@NMOF-1 showed drastically reduced CO2
uptake (195 K, p = 1) of 26.1 cc/g compared with NMOF-1 (55.5
cc/g, Figure S32). The encapsulation also resulted in 20 nm blue-
shift and 7 nm red-shift in the UV-Vis and PL maximum,
respectively, further suggesting encapsulation of cisplatin within
the NMOF-1 (Figure S33). All these studies supported that
cisplatin encapsulation occurred inside the vesicles. FESEM
analysis of the cisplatin@NMOF-1 showed nanoscroll
morphology which is similar to NMOF-3 (Figure S34). Moreover,
elemental mapping revealed that the encapsulated cisplatin is
distributed homogeneously into the nanoscroll (Figure S34). The
in-vitro drug release was studied by dialysis and quantified by
detecting Pt via ICP analysis (Figure 4b). In 1xPBS buffer (pH 7.4),
67% drug was released within 8 h and then release kinetics
became slow providing 82% of drug release in 48 h. The kinetics
was also found to be similar in 10xPBS (pH ~ 6.8, Figure S37).
Absence of ZnII in the solution is indicative of the structural
integrity of the NMOF. We have tested the delivery potential of
cisplatin@NMOF-1 via HeLa cell culture studies (Figure
4c,d,S38-S40). The cells (~30,000 cells/100µL culture medium)
was dipped in water for 3 h and the morphology was studied.
FESEM images showed nanovesicular morphology and PXRD
patterns (Figure S21,S22) were found to be similar to that of
NMOF-2. In contrast, the measured water contact angle
drastically dropped down to 51° from 172°, indicating hydrophilic
outer surface decorated by TEG chains (Figure 3c, S23).
Therefore, nanovesicle (NMOF-1) was converted to inverse-
nanovesicle (NMOF-2) upon treatment with water. Similarly,
NMOF-2 was also converted to NMOF-3 when dispersed in
methanol and kept for 3 h. The transformation was supported by
FESEM (nanoscroll morphology), PXRD and water contact angle
(71°) measurement (Figure S23-S25). To understand the
intermediate for NMOF-2→NMOF-3 transformation, NMOF-2 was
charged in methanol for 1 h only and FESEM analysis revealed
nanobelt morphology as an intermediate along with nanoscale
semi-scrolls (Figure 2f). Dispersion of NMOF-2 and NMOF-3 in
THF resulted in NMOF-1 with superhydrophobic water contact
angle of 156° and 162°, respectively (Figure S23/S26). Therefore,
NMOF, synthesized from asymmetric bola-amphiphilic 1a and ZnII,
showed solvent responsive dynamic shape and size shifting
morphology transformation which is unprecedented in nanoscale
MOF system.
All the NMOFs showed OPE based cyan emission with
~43% quantum yield (Figure 3a). NMOF-1 was chosen for live cell
imaging as it provides stable dispersion in different solvents
(Figure 3a inset). Inherent emissive nature of the OPE backbone
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10.1002/anie.201900692
Angewandte Chemie International Edition
COMMUNICATION
were incubated with different concentrations (20 µM to 1.25 µM)
of cisplatin@NMOF-1 and NMOF-1 (control). PrestoBlue cell
viability assay indicated that cisplatin@NMOF-1 is very toxic with
IC50 ~0.5 µM (Figure 3b,S41-S43). The control experiments with
only NMOF-1 into cells showed no appreciable cytotoxic behavior
thereby confirming the ability of the NMOF-1 as an efficient
payload carrier and delivery vehicle. Further, to study versatility of
NMOF-1 as a delivery vehicle, doxorubicin (DOX) was loaded in
NMOF-1 from THF medium. NMOF-1 showed 4.1 wt% loading of
DOX as confirmed from FT-IR, UV-Vis, TGA and elemental
analysis (Figure S44-S46). PXRD analysis of DOX@NMOF-1
showed the stability of the framework and drastic reduction in CO2
uptake (55.5 cc/g→12.8 cc/g) indicating encapsulation of DOX
inside NMOF-1 (Figure S47,S48). The in-vitro drug release study
in 1xPBS buffer exhibited 99% release of DOX within 48 h (Figure
4b, S49). Efficient payload delivery and corresponding cell death
were also observed upon treating HeLa cells with DOX@NMOF-
1 (Figure 3b) indicating general applicability and versatility of the
delivery vehicle.
Notably, the vesicular morphology and PXRD patterns of
NMOF-1 remained intact in DMEM culture media (Figure S50).
The NMOF-1 showed 3.3% and 18.8% hydrolysis in 1xPBS buffer
and 10% FBS protein containing DMEM culture media after 10
days (Figure S51). NMOF-C12 and NMOF-OMe, synthesized
from the linker 1b and 1c, respectively, decomposed by 0.2% and
27.1%, respectively, in 1xPBS buffer after 10 days (Figure S52).
This result indicated that the aqueous stability of NMOF-1
originated due to the presence of dodecyl chains, possibly by
reducing effective concentration of water molecules near the
inorganic building unit.
In conclusion, synthesis and characterization of a solvent
adaptive reversible shape-shifting luminescent nanoscale MOF
have been successfully demonstrated. The adapted design
principle for making such soft and smart material is based on the
utilization of mixed polar side chains containing bola-amphiphilic
OPE dicarboxylate linker and its self-assembly with ZnII in
solvents of different polarity. This dynamic and nontoxic NMOF
has been exploited for bioimaging. Furthermore, the material has
been exploited for anti-cancer drug loading and delivery in HeLa
cell with micromolar cytotoxicity. This study would open up a path
in designing flexible MOFs based on novel linker toward drug
delivery vehicles and other biomedical applications. Thus, our
findings could help in designing cargo that captures a targeted
molecule and release of it upon external stimuli.
Caliebe for assistance in EXAFS measurement at PETRAIII of
DESY, Helmholtz Association (HGF), (beamline P64) supported
by the DST.
Keywords: OPE• Nanovesicles• Nanoscroll• Inverse-
nanovesicle• Drug delivery
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Acknowledgements
TKM is grateful to the DST, India (Project No. MR-2015/001019;
TRC-DST/C.14.10/16-2724), and JNCASR for funding. TKM also
acknowledges Life science research, education and training at
JNCASR (BT/INF/22/SP27679/2018). We thank Dr. W. A.
This article is protected by copyright. All rights reserved.

10.1002/anie.201900692
Angewandte Chemie International Edition
COMMUNICATION
Table of Contents
COMMUNICATION
Solvent adaptive nanoscale MOF: A
solvent adaptive reversible nanoscale
MOF with dynamic morphology was
devised based on an asymmetric bola-
Debabrata Samanta, Syamantak Roy,
Ranjan Sasmal, Nilanjana Das Saha,
Pradeep K R, Ranjani Viswanatha, Sarit
S. Agasti, Tapas Kumar Maji*
amphiphilic
oligo-(p-
Page No. – Page No.
phenyleneethynylene)
(OPE)
dicarboxylate linker. The emissive and
non-toxic NMOF is cell permeable and
allowed live cell imaging. Cisplatin
(14.4 wt%) and doxorubicin (4.1 wt%)
were encapsulated in the polar cavity
of the NMOF and delivered to HeLa
cell with micromolar cytotoxicity.
Solvent adaptive dynamic metal-
organic soft hybrid for imaging and
biological delivery
This article is protected by copyright. All rights reserved.