Supramolecular gels from sugar-linked triazole amphiphiles for drug entrapment and release for topical application

Article abstract of DOI:10.1039/c9ra02868d

A simple molecular framework obtained by cross-linking a hydrophobic chain with S,S- and R,R-tetritol by the copper-catalysed azide-alkyne cycloaddition reaction is found to serve as an excellent bioisostere for self-assembly. The hexadecyl-linked triazolyl tetritol composite spontaneously self-assembles in n-hepane and methanol to form hierarchical organogels. Microscopic analyses and X-ray diffraction studies demonstrate eventual formation of nanotubes through lamellar assembly of the amphiphiles. A rheological investigation shows solvent-dictated mechanical properties that obey power law behavior similar to other low molecular weight gelators (LMOGs). The gel network was then utilized for the entrapment of drugs e.g. ibuprofen and 5-fluorouracil, with tunable mechanical behaviour under applied stress. The differential release profiles of the drugs over a period of a few hours as a result of the relative spatio-temporal location in the supramolecular network can be utilized for topical formulations.

Full text of DOI:10.1039/c9ra02868d

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PAPER
Supramolecular gels from sugar-linked triazole
amphiphiles for drug entrapment and release for
Cite this: RSC Adv., 2019, 9, 19819
topical application†
a
Komal Sharma,a Jojo P. Joseph,b Adarsh Sahu,
Narender Yadav,a Mohit Tyagi,a
b
a
Ashmeet Singh,b Asish Pal
and K. P. Ravindranathan Kartha
*
*
A simple molecular framework obtained by cross-linking a hydrophobic chain with S,S- and R,R-tetritol by
the copper-catalysed azide–alkyne cycloaddition reaction is found to serve as an excellent bioisostere for
self-assembly. The hexadecyl-linked triazolyl tetritol composite spontaneously self-assembles in n-hepane
and methanol to form hierarchical organogels. Microscopic analyses and X-ray diffraction studies
demonstrate eventual formation of nanotubes through lamellar assembly of the amphiphiles.
A
rheological investigation shows solvent-dictated mechanical properties that obey power law behavior
similar to other low molecular weight gelators (LMOGs). The gel network was then utilized for the
entrapment of drugs e.g. ibuprofen and 5-fluorouracil, with tunable mechanical behaviour under applied
stress. The differential release profiles of the drugs over a period of a few hours as a result of the relative
spatio-temporal location in the supramolecular network can be utilized for topical formulations.
Received 16th April 2019
Accepted 14th June 2019
DOI: 10.1039/c9ra02868d
rsc.li/rsc-advances
regenerative medicine,10 and oil spill recovery.3d–e,11 Controlled
and sustained release of a drug meditated by LMOGs for dermal
Introduction
or transdermal application is an excellent approach in drug
delivery, which requires local administration and circumvents
specic side effects occurred in oral delivery and subsequent
metabolism process.12 In such topical formulations involving
organogel with entrapped drug, the organic media being anti-
microbial and moisture insensitive, plays a crucial role.13
Carbohydrates are versatile building blocks for self-assembly
as they encompass simple sugar units to complex granular
starch-structure-like organization of (1,4)-a-linked glucans.
Among the carbohydrate-based low molecular weight gelators,
dialkanoate derivatives of mannitol and sorbitol have found
interesting application in combating marine oil spills3d,e,11,14
and self-healing mediated so optical devices.15 Triazole-linked
carbohydrate-based self-assembling materials are envisaged as
an interesting class of materials owing to the antimicrobial,
antiviral and antitumor effects of the 1,2,3-triazole moiety.16a
Moreover, its structural features such as polarity, rigidity and
ability to act as both hydrogen bond donor and acceptors make
it a relevant bioisostere for designing a number of biologically
important molecules e.g. glycerotriazolophanes and glyco-
triazololipids.16 Cu(I)-assisted azide–alkyne cycloaddition reac-
tion (click reaction) has been used widely in the synthesis of
several structures of varying complexities in the area of
synthetic carbohydrate chemistry e.g. glycomimetics, glyco-
dendrimers, glycorotaxanes etc.17
Self-assembly exists at both macroscopic and microscopic level
in almost every aspect of nature, e.g., arrangement of nucleo-
tides in the double helical structure of DNA, formation of lipid
tubules from phospholipids, generation of silk from mono-
meric silk broin, crystal growth by crystal engineering etc.1
Molecular self-assemblies, formed by spontaneous aggregation
of molecules under thermodynamic equilibrium conditions, are
mediated by a number of non-covalent interactions such as
hydrogen bonds, ionic bonds, metal–ligand interactions, p–p
stacking, electrostatic forces, hydrophobic forces and strong
dipole–dipole associations and pave the way to realizing the
formation of molecular crystals, colloids, nanobrils, nano-
tubes, phase separated polymers, self-assembled monolayers
and cross-linked gels in a bottom-up approach.2 Self-assembled
brillar network (SAFIN)-mediated formation of low molecular
weight gelators (LMOGs) employs a wide class of compounds
from carbohydrates,3 and amino acid derivatives,4 to organo-
metal complexes5 etc. resulting in a number of interesting
applications such as drug delivery and release,6 gene delivery,7
biomineralization,8 anion binding,9 tissue engineering,
aDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research (NIPER), S. A. S. Nagar, Punjab-160062, India. E-mail: rkartha@niper.
ac.in
bInstitute of Nano Science and Technology, Phase 10, Sector 64, Mohali, Punjab-
160062, India. E-mail: apal@inst.ac.in; Web: http://www.twitter.com/pal_asish
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra02868d
The glycerotriazolophanes with triazole ring-substituted
carbohydrates, are highly metabolically stable as compared to
the unsubstituted ones and possess the ability of p-stacking
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interaction thereby, facilitating the formation of self-assembled of n-hexane/water and methanol/water in 2 mL glass vials with
structures.18 However, the cyclic glycerotriazolophanes, 1–2 gradual heating. Aer complete dissolution, solutions were
(Scheme 1) have rotational and exibility constraints which may allowed to remain undisturbed at room temperature for 10 min
severely affect its solubility in various solvents. However, in its to obtain the organogels.
acyclic analogue, the exibility of the lipid chains and the
presence of the triazole ring make the molecule amphiphilic in
nature, thereby widening its applications in designing articial
molecular receptors, chemical sensors, drug carrier systems,
enzyme inhibitors etc.19 We postulated design of acyclic struc-
tures with tetritol unit, 3 as the platform to anchor the alkyne
residue (4) for click chemistry with a fatty acid-based alkyl azide
moiety (5).
Microscopic analysis
The gels (0.7% w/v) were carefully scooped onto the carbon
tapes on the aluminium stubs and were allowed to freeze dry.
The dried gels were coated with gold for 20 seconds under high
vacuum using BAL-TEC SSD-500 sputter coater instrument.
Finally the morphology of the gels was imaged on a Hitachi
S3400N SEM operated at 10 kV.
Thus, we report the design of a new class of tetritol-based
triazole-linked acyclic lipid derivatives and their self-assembly
behaviour in different solvents to form supramolecular
network and phase-selective gel. The structural features of the
hierarchical self-assembled network starting from lamellar
assembly of the building blocks to nanotubes and physically
cross-linked network were deciphered with microscopy and X-
ray diffraction. Detailed mechanical properties and ow
behaviour of the gels were investigated to establish the thixo-
tropic nature of the gel. The gelators, owing to the amphiphilic
nature and network structures, were utilized to entrap both
hydrophobic (ibuprofen) and hydrophilic (5-uorouracil) drugs
with the spatial selection, modulating the mechanical strength
of the drug entrapped gel. The differential in vitro release
proles of the drugs spatially located in the self-assembled
Diluted gel samples (0.35% w/v) were placed on a silicon
wafer and were allowed to dry in air overnight. AFM Images of
the dried samples were recorded with scan rate of 1 Hz in
tapping mode analysis on a Bruker Multimode 8 scanning
probe microscope with Bruker made antimony doped silicon
cantilever of resonance frequency of 300 kHz and spring
constant of 40 N mꢀ1
5 mL aliquot of the diluted gel ber (0.02% w/v) in n-hexane/
n-heptane/n-octane/methanol was drop-casted on clean
.
a
copper grid followed by room temperature drying. The samples
were observed under TECNAI G2 F-20 high resolution trans-
mission electron microscopy (HR-TEM) from FEI.
XRD analysis
brillar network were investigated towards topical application. The organogels in n-heptane were heated to sol, and 100 mL of
the sols were individually transferred carefully on to a pre-
cleaned glass slide and le to air dry for 8 h to form the self-
supported cast lms on which measurements were performed
using a Model-D8 Advance X-ray diffractometer. The X-ray beam
generated with a Cu anode at the wavelength of Ka1 beam at
Experimental
Gelation study
R,R- and S,S- tetritol-based lipid derivatives were dissolved in
1 mL of HPLC grade solvents viz. n-hexane, n-heptane, n-octane,
methanol, dichloromethane, toluene, water and 1 : 1 mixtures
˚
1.5418 A was directed toward the lm edge, and scanning was
done unto a 2q value of 22ꢁ. Data were analysed and interpreted
in terms of higher order reections.
Rheological studies
Rheological studies were performed on an Anton Paar MCR 302
rheometer with an adjustable Peltier temperature controlling
system using a cone and plate geometry of CP-50-1. The gap
distance between the cone and the plate was xed at 0.1 mm.
Oscillatory frequency sweep experiments were performed at
constant amplitude of 0.05% strain which corresponds to the
linear viscoelastic region of gel samples for an angular
frequency range 200 to 0.001 rad sꢀ1 at 20 ꢁC. Stress amplitude
sweep experiments were performed at a constant oscillation
frequency of 10 rad sꢀ1 for the strain range 0.001 to 100 at 20 ꢁC.
Temperature ramp measurements were performed at a constant
oscillation frequency of 10 rad sꢀ1 and constant oscillation
amplitude of 0.05% strain for a temperatuꢀre1 range of 20 to 50 ꢁC
at a heating and cooling rate of 5 ꢁC min
.
Drug entrapment study & release study
Scheme 1 Rationale of designing acyclic tetritol-based lipids from
triazolophanes and their general chemical structure along with the
cartoon representation.
Drug-entrapped gel was prepared by simultaneously dissolving
the gelator (0.7%, w/v) and drug (ibuprofen or 5-uorouracil)
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ꢁ
(1.5%, w/v) in 1 mL of methanol and heating it to 50 C. The
uorescence emission spectra of ibuprofen and ibuprofen-
entrapped gel/sol were obtained in the range of 270–400 nm
upon excitation at 263 nm with excitation and emission slit
width of 5 nm and 10 nm, respectively. The uorescence
emission spectra of 5-uorouracil and 5-uorouracil entrapped
gel/sol were obtained in the range of 250–600 nm upon excita-
tion at 230 nm with excitation and emission slit width of 5 nm
each by using CARY-Eclipse uorescence spectrophotometer,
Varian. The uorescence emission spectra and relative
enhancement was compared to ascertain the entrapment of
drug in the gel.
Entrapment efficiency helps in determining the amount of
drug that has actually been entrapped inside the gel matrix. It
was determined by centrifuging the drug-entrapped gel at
10 000 rpm for 5 min so that any free drug present comes up in
the supernatant while the entrapped drug remain at the bottom
within the gel. The collected supernatant was analyzed by HPLC
to determine the drug content. The entrapment efficiency was
then calculated by the formula:
% EE ¼ [(total amount of drug ꢀ amount of free drug)/total
amount of drug] ꢂ 100
Scheme 2 Synthesis of triazolyl lipids (12–16) cross-linked with tetritol
(a) I2, acetone, rt, 12 h, 77%; (b) NaBH4, THF, 70 ꢁC, reflux, 4 h, 78%; (c)
propargyl bromide, NaH, DMF, 0 ꢁC to >rt, 1 h, 71%; (d) CuSO4, sodium
ascorbate, Ball mill (PM 100), 450 rpm, 85%.
In vitro drug release behavior of the drugs entrapped in gel
was determined by the dialysis bag method. The study was done
on methanolic gel loaded with 0.5% w/v drug. The drug-
entrapped gel was loaded in a dialysis bag suspended in
a dissolution media comprising 50 mL water or phosphate
buffer saline of pH 7.4. The dissolution media was kept at 37 ꢁC
with stirring at 100 rpm for 24–36 h. Aliquots of 1 mL each from
the dissolution media were withdrawn at predetermined time
intervals each time being replaced by an equal volume of fresh
dissolution media (in order to keep the volume unchanged).
The samples were analyzed using HPLC analytical technique.
exhibited a singlet of two protons at d 7.58 ppm, characteristics of
the two triazolyl hydrogens (one on each of the two triazole units)
in the structure (cf. ESI†).
The self-assembly of the compounds 12–16 was investigated
by dissolving them in the desired solvent by warming to obtain
a saturated solution which upon gradual cooling led to the
formation of certain loosely assembled structural units via
stochastic nucleation, further interactions among which
resulting in tightly packed gels. The formation of gel was
ascertained by the inverted vial method, in which a perfect gel
immobilise all the solvent such a way that it does not ooze out
on inversion of the vial (cf. ESI, Fig. S1†). The properties of gels
depend on the nature of the solvent, amphiphilicity and the
concentration of the gelator. Compounds 12–16 were tested for
gelation in non-polar solvents, e.g. n-hexane, n-heptane, octane,
toluene and dichloromethane, in polar solvents, e.g. methanol,
ethanol, dimethyl sulfoxide (DMSO) and water, and mixtures of
solvents, i.e. n-heptane/water and methanol/water (Table 1). For
the series of molecules in non-polar solvents, an increase in the
hydrophobic lipid chain length (from C10 to C18) was observed
to lead to a gradual change in the gelation tendency. Thus, while
an aggregate or weak gel was obtained for 12a/b, a stable gel was
obtained for 15a/b (with low mgc values, 0.21%, w/v), whereas
the octadecyl-linked molecules (16a/b) gave a precipitate,
whereby indicating the requirement of an optimally tuned
hydrophilic/hydrophobic balance in the compounds for the
desired gel to be formed. On the other hand, in polar solvents
such as methanol, ethanol and DMSO, opaque gels were ob-
tained with 15a/b and 16a/b as the gelator (mgc 0.3–0.5%, w/v).
However, these compounds remained insoluble in water and
Result & discussion
Multistep synthesis of tetritol-based triazole-linked lipid deriva-
tives was achieved using the Cu(I)-assisted azide–alkyne cyclo-
addition (CuAAC) reaction with S,S- and R,R-diethyl tartrate (6a
and 6b) as the starting materials. The protection of the diol
residues was performed with acetone in the presence of molec-
ular iodine to obtain the desired isopropylidene acetal derivatives
(7a/b). The acetonide-protected ester (7a/b) was then reduced
with NaBH4 and the derived 1,4-diol (8a/b) was then propargy-
lated with propargyl bromide in the presence of NaH to obtain
the dipropargyl ether 9a/b (Scheme 2). A series of alkyl azides, 11
were prepared from the commercially available bromides 10 by
a standard bimolecular nucleophilic substitution and were
reacted with 9a/b under solvent-free click reaction conditions by
grinding in a ball mill. The 1,4-di-O-triazolylated tetritol deriva-
tives (12a/b–16a/b) having carbon chain length varying from C10
to C18, were obtained in good yields with improved solubility in
CH2Cl2, CHCl3 and toluene (unlike the rather insoluble tri-
1
azolophanes 1 and 2). The H NMR spectrum of the compound
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Table 1 Gelation ability of tetritol-based triazole-linked lipid derivatives 12–16 in different solvents at 25 ꢁCa
CH2Cl2 &
toluene
Entry
n-Hexane
n-Heptane
n-Octane
MeOH
EtOH
DMSO
12a
13a
14a
15a
16a
12b
13b
14b
15b
16b
A
A
A
A
A
A
A
A
A
S
S
S
S
S
S
A
A
W
G (0.30)
G (0.36)
A
W
W
S
S
S
S
S
S
S
S
S
S
G (0.25)
P
A
W
G (0.72)
G (0.32)
P
G (0.21)
P
A
W
G (0.62)
G (0.25)
P
G (0.20)
P
A
W
G (0.66)
G (0.21)
P
G (0.34)
G (0.30)
S
S
G (0.40)
G (0.45)
S
S
S
S
G (0.38)
G (0.35)
G (0.42)
G (0.50)
G (0.34)
G (0.38)
a
A (aggregate), G (gel), P (precipitate), S (solution) and W (weak gel) denote the result of dissolution of the particular compound in the solvent
indicated; the values in parenthesis show the minimum gelator concentration (mgc) in % w/v.
dissolved completely in dichloromethane and toluene even at applications e.g. chemosensing, biological evaluation and
room temperature, thus, forming a clear solution. A study of the selective trapping of metal ions. Upon adding metal ions, e.g.
gelation property of these compounds in various solvents using Cu2+ and Zn2+, the gel network broke down to yield clear solu-
a gelator concentration in the range 0.2–1% w/v manifested tion (Fig. 1c) indicating the metal-responsive nature of the gel
similar self-assembly behaviour for the S,S-derivatives to their presumably due to the ligation of the respective metal ions to
corresponding R,R-analogues. The gels exhibited reversible gel- the triazole rings in the molecule.
to-sol transition on repeated heating (in the range of 40–45 ꢁC)
The hexadecyl-linked tetritol derivatives 15a–b were chosen
and cooling using the inverted vial method. However, the gels for further studies as they formed gels readily in almost all the
from methanol were found to have slightly higher gel-to-sol organic solvents examined. To discern the nature of the
transition temperature as compared to that from n-heptane.
microstructures and morphologies present in the gels, we
Tyndall effect typical of particles of the colloidal range i.e. thoroughly examined the gel samples of 15a–b by using
40 nm to 1 mm was also observed for these molecules (Fig. 1a). different microscopic techniques viz. SEM, TEM and AFM.
When the laser beam was passed through 0.1% w/v gelator in n- Representative SEM of the dried gel of 15a–b obtained from n-
heptane, scattering of the beam was observed as the self- heptane and methanol showed the presence of three dimen-
assembled structures grew to attain particle size of colloidal sional networks of bers with varying thickness and porous
range (Fig. 1a). Next, the phase selective gelation behaviour was structures that could entrap solvent molecules (Fig. 2). Atomic
investigated using a mixture of immiscible solvents, n-heptane force microscopic studies on the diluted gels (0.35%, w/v, from
and water. Compound 15a selectively gelated the n-heptane n-heptane) obtained from 15a revealed long bres of high
layer of the binary mixture of the solvents (Fig. 1b). The free aspect ratio with the height of 6–7 nm (Fig. 3a). On the other
triazole ring played an important role in the gelation process. In hand the gel from methanol consisted of relatively short bres
order to check the stimuli-responsive nature of the gel network,
we resorted to the use of different metal ions that binds with the
trizole rings as such interactions are efficiently exploited in
Fig. 1 (a) Tyndall scattering from the colloidal suspension of 0.1%, w/v
of 15a in n-heptane. (b) Phase selective gelation by 15a (0.7% w/v
gelator) in a mixture of n-heptane/n-hexane and water in 1 : 1 ratio. (c)
Metal-responsive gel-to-sol transition for the gel of 15a in methanol Fig. 2 Scanning electron micrograph of compound 15a (0.7%, w/v) in
on adding Cu2+ ions (0.02% w/v).
(a) n-heptane (b) methanol; 15b in (c) n-heptane (d) methanol.
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TEM images indicating a complete disruption of the straw
structure with the resultant formation of clusters of short
elongated assembled structures (Fig. 3e). However, the meth-
ꢁ
anol solution on standing at ambient temperature (25 C) for
a few minutes, led to complete restoration of the straw pattern
(Fig. 3f), thereby demonstrating the reversible nature of the
assembly.
Time-dependent TEM images were recorded by heating a gel
to sol followed by gradual cooling to ambient temperature till
complete immobilization of the solvent occurred. The micro-
graphs obtained at different time intervals viz. 5 min, 10 min,
15 min and 30 min demonstrate the formation of intermediate
structures (Fig. 4a–d). Initially, the molecules of the gelator
assemble themselves to give a thin helical ribbon-like structure,
which undergoes further intertwining. The nely intertwined
ribbons on further incubation condense to give compact
molecular straws. Each turn in the helical ribbon comes closer
to the previous turn by non-covalent interactions thereby,
leading to stacking over one another to form a tube like hollow
structure.21 Further, an examination of the assembly from 15a at
the initial stages, or in a dichloromethane solution, showed the
presence of right-handed turns in the ribbon which can be
compared with the origami structures made using the palm
leaves (cf. ESI, Fig S2†). Indeed, the analogous S,S-congured
15b did exhibit the matching le-handed turns in the structure
formed in CH2Cl2, which suggests that even though the
assembly is not strong enough to manifest in gel structures in
such solvents, ensembles with distinct patterns of distinct
shapes and dimensions, or properties, can be formed in the
process of attaining stable ordered arrangements by adapting to
the environment suitably.22a Additionally, in this particular
class of self-assembled structures the molecular chirality can be
extended to the net supramolecular chirality as conrmed from
the mirror image of the CD band in the wavelength of 215 to
260 nm for the diluted gels of 15a–b (cf. ESI, Fig. S3†).22b–c
Fig. 3 Atomic Force micrograph of tetritol-anchored triazolyl lipid 15a
in (a) n-heptane and (b) methanol, respectively. Transmission electron
micrographs of 15a depicting the assembly into bundles of molecular
straw in (c) n-heptane and (d) methanol. (e) and (f) demonstrate
complete disruption and restoration of the tubular nanostructures in
hot methanol and at 25 ꢁC, respectively.
with 5–6 nm in height that aggregated to form mesh-like clus-
ters (Fig. 3b). AFM recorded for diluted gel samples also showed
a presence of polydispersed nanoparticles, as a result of initial
self-assembly of gelators, which might act as nucleation sites for
1-dimensional growth of bers with eventual formation of three
dimensional gel network.20 The difference in the morphologies
in polar and non-polar solvents might be due to the existence of
stochastic non-covalent interactions between the gelator and
the solvent molecules, paving way for a competition between
solvent–gelator and solvent–solvent interactions. TEM images
obtained for the diluted gel (0.02%, w/v) of 15a from n-heptane
and methanol showed the inner structures of the bres, which
were found to be hollow and thus straw-like in appearance
(Fig. 3c and d). The long nanotubes (“straws”, length ꢃ 5 mm)
from both n-heptane and methanol had the outer and the inner
diameters of 45 ꢄ 5 nm and 24 ꢄ 3 nm respectively with shell
thickness of 10 ꢄ 3 nm. This indicates spontaneous self-
organization in the presence of the solvents to form distinct
molecular straw-like tubular arrangement. The effect of
temperature was observed on the methanolic gel formed by 15a
by subjecting it to sequential heating and cooling cycles fol-
lowed by microscopic analysis at each of the stages. The gel on
heating dissolves completely and forms a clear solution with
Fig. 4 TEM showing time-dependent gel formation by 15a in meth-
anol after heating it to a sol followed by incubation at 25 ꢁC for (a)
5 min, (b) 10 min, (c) 15 min and (d) 30 min.
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The X-ray diffraction pattern of the cast lm from the gel the 15a-derived gels in n-heptane and methanol. The rota-
of 15a in methanol and n-heptane showed periodical tional ow curve experiment showed zero shear viscosity of
diffraction peaks, indicating an ordered layered structure. ꢃ20 000 Pa sꢀ1, which on applying increasing shear rate
The gel formed in methanol and n-heptane as in Fig. 5A(i–ii) exhibited the shear-thinning behaviour of the gel with
and Table S1† showed a predominantly intense peak at 2q ¼ a scaling decay, h f (dg/dt)ꢀ0.97 and a negative slope
2.97 that corresponds to periodicity of 2.9 nm in the struc- approaching ꢀ1, indicating the viscoelastic solid-like property
tures of the aggregates. This matches well with the extended of the gel (Fig. 6a). In an oscillatory frequency sweep experi-
length of the molecules (3 nm) in their energy-minimized ment for strong viscoelastic solid-like gels, the storage (G0)
structures. We propose a multiple lamellar bilayer of the moduli are usually a magnitude higher as compared to the loss
amphiphiles that folds into nanotubes. However, solvents (G00) moduli. The gels from 15a in methanol and n-heptane
such as n-heptane and methanol differ in polarity and the showed a frequency-independent behaviour for G0 and G00 over
effective gelator–solvent interactions mediated by chain two decades of the angular frequency with a G0/G00 value of 5.8
interdigitation. Hence, the solvents dictate the nature and (Fig. 6b). The oscillatory amplitude sweep showed (Fig. 6c)
the extent of exposure of the hydrophilic head groups and a linear viscoelastic region (LVR) with G0 > G00 till a critical
hydrophobic tails (Fig. 5B). The assembly obtained from stress beyond which the gel started to ow. The values for the
methanol solution of 15a and Cu2+ ions in 1 : 1 ratio showed corresponding stress, known as yield stress (sy), indicated
an intense peak at 2q ¼ 2.5 corresponding to a periodicity of a high degree of robustness of the gels. The gel made in
3.46 nm in the structures of the aggregates as in Fig. 5A(iii). It methanol had slightly higher value of G0 and G00 as compared
suggests signicant metal–triazole ligand complexation that to the gel obtained in n-heptane, hence, proving the meth-
in turn disrupts the packing and increases the dimension of anolic gel to be stronger. Also, the gel obtained in DMSO was
the bilayer assembly. This must also be accompanied by a net found to possess a G0 value of an order higher than that of the
change in the overall polarity of the assembled particles gels in ethanol and methanol (cf. ESI, Fig. S4A†). To verify the
eventually resulting in the observed dissolution of the gel power law behavior of the gel, (G0f cm), the logarithmic plot of
structure (Fig. 1c).
storage modulus of the gel vs. the gelator concentration was
Rheological studies were then carried out to gather infor- used to obtain the value of m (Fig. S4B†). The yield stress (sy)
mation on the mechanical strength and the ow behaviour of also increased with the gelator concentration, and scaled as
the power of the gelator concentration (sy f cm). The values of
the exponents (m and n) are 2.26 and 2.90, respectively, which
are in good agreement with the reported values for low
molecular mass gelling agents.23
Thixotropic nature of the organogel was investigated by
applying alternating 0.05% and 100% strain for three cycles,
which exhibited instantaneous self-recovery of the network aer
the removal of high strain. Real time temperature ramp study
Fig. 6 (a) Typical flow curve measurement of methanol gels 15a. (b)
Typical oscillatory frequency sweep and (c) oscillatory amplitude
Fig. 5 (A) X-ray diffraction intensities obtained for the gel formed by sweep measurement for the gel made in methanol and n-heptane
15a in (i) methanol and (ii) n-heptane; and (iii) the methanol gel of 15a with 15a (1% w/v). (d) Thixotropic behaviour by oscillatory rheology for
with Cu2+ ions in 1 : 1 ratio (B) possible assembly-pattern leading to the three cycles with strain variation from 0.05% to 100% in periodic
formation of nanotubes in methanol and in n-heptane.
manner for gel prepared from 15a in MeOH.
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with constant angular frequency (10 rad sꢀ1) and 0.05% strain loaded organogel network as compared to the native gel
for the gel made in methanol showed gel-to-sol transition with (Fig. 7b). Also, the deviation from the frequency-independent
abrupt decrease in G0 upon heating and sol-to-gel trans- behaviour for the drug-loaded organogels suggests relatively
formation during the cooling cycle, with recovery in G0 value weaker organogel strength due to incorporation of the drug
(see ESI, Fig. S4C†) suggesting reformation of the gel structures molecules. However, Ibu-loaded organogel did not show as
which is in agreement with the temperature dependent TEM much decrease in G0 values as the 5-FU-loaded gel. This is
investigation. The applied shear led to the intermittent presumably due to the weaken interaction among the con-
disruption of the straw structure as evident from the TEM formationally rigid polar head group due to the loading of 5-
images and upon removal of the shear stress the assembly FU, while the Ibu can be loaded in relatively exible long
recovered to its original straw structure (Fig. 4).
chain interior without compromising much of the interac-
In view of the amphiphilic nature of the compounds tions. The yield stress beyond which the gel starts to ow
described above, we explored the possibility of entrapping shows remarkable decrease in the case of the 5-FU-loaded gel
both hydrophobic and hydrophilic drugs in the gel network. as compared to that of the Ibu-loaded one (see ESI, Fig. S5B†).
Ibuprofen (Ibu) and 5-uorouracil (5-FU) were chosen as the
The in vitro drug release behaviour of the drugs entrapped in
model hydrophobic and hydrophilic drugs, respectively, the gel network was subsequently examined by the method of
because of their relatively small size, contrasting polarity dialysis. From the drug release prole of Ibu and 5-FU (Fig. 8a),
attributes and their applications as topical agents. Effective we observed that the maximum cumulative release of 5-FU up to
and successful transdermal delivery of such drugs circum- 95% occurred within the rst 8 h of the study when water was
vent possible side effects e.g. gastric irritation, mouth sores, used as the dissolution media, however, the Ibu release was
ulcers, diarrhoea, nausea and heartburn. The uorescence relatively slower, and aer 36 h only 62% of the drug was found
emission spectra of the two drugs were recorded individually released. This corroborate the relative positioning of the drugs in
and in the presence of the methanol gel of 15a, in both sol the hydrophilic exterior/hydrophobic interior, respectively, and
and the gel state. The uorescence of the hydrophobic drug, their subsequent release to (and the dissolution in) the dissolu-
Ibu increased nearly 2-fold in the presence of the gelator in tion media. Upon changing the dissolution media (from water) to
ꢁ
the sol state at 50 C and further to approximately 8-fold on phosphate buffer (pH 7.4), the release of Ibu took place much
cooling it to the gel state at 25 ꢁC (Fig. 7a). Such increases in faster, with 94% release occurring in 8 h, compared to the 30%
the uorescence suggest effective entrapment of the drug in release observed in water, owing to its higher solubility and
the hydrophobic pockets of the self-assembled structures intrinsic dissolution rate in the buffer media mediated by higher
mediated by the van der Waal's interaction among the pH and inclusion of salt in dissolution medium (see ESI,
hydrophobic chains.24 However, for the hydrophilic drug, 5- Fig. S6†).25 Thus, it can be concluded that using the gels derived
FU a uorescence intensity enhancement of only 3-fold was from 15a, drugs of varying hydrophilic/lipophilic balance could
observed in the gel state relative to that in sol, suggesting be incorporated in their structural cavities with varying resultant
localization of the drug towards relatively hydrophilic exte- drug release characteristics. Fig. 8b shows the effect of the three-
rior of the gelators engaging in hydrogen bonding interaction dimensional network of the gel on the release pattern for both
with the trizole moieties of the gelator (see ESI, Fig. S5A†). Ibu and 5-FU in comparison with the control (that is, without the
The entrapment efficiency of Ibu and 5-FU as determined presence of a gelator). In the absence of the gelator the drug
from the HPLC peak area calculation, was found out to be release was comparatively faster in both the drugs. Thus, it was
0.45% and 0.36% w/v with respect to the gelator and solvent, observed that aer 1 h of the study, 5-FU release was only 38%
respectively, indicating reasonably good extent of drug instead of the nearly 80% release observed in the absence of the
loading in the self-assembled network. The oscillatory gelator. Likewise, in the case of Ibu also the extent of the drug
frequency sweep for the native gel of 15a and the gel con- release observed was signicantly lower (18%) in the presence of
taining 5-FU (0.36%, w/v) and Ibu (0.45%, w/v) drugs in the gelator as against the nearly 50% value obtained in its
methanol suggests a decrease in the G0 values for the drug- absence.
Fig. 7 (a) Fluorescence emission spectra of ibuprofen in both gel and Fig. 8 Drug release profile for ibuprofen and 5-fluorouracil in (a) water
sol state. (b) Typical oscillatory frequency sweep for the methanol gels at 37 ꢁC. (b) Histogram profiles for the release of the drugs encapsu-
of 15a (1%, w/v) without any drug (control) and with of 5-FU (0.36% w/ lated in the methanol gel of 15a and in methanol as control using water
v) and Ibu (0.45% w/v).
as the dissolution media after 1 h.
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Conclusion
In summary, we have developed a new class of S,S-/R,R-tetritol-
based triazole-linked lipid derivatives as successful low molec-
ular weight organogelators suitable for a number of organic
solvents and biphasic solvent-mixtures. The self-assembly
pattern obtained by using microscopic techniques has
revealed generation of nanotubes in methanol and n-heptane
via gradual structural transformations. Rheological analyses
addressed the mechanical properties and self-healing nature of
the native gels as dictated by the solvent–gelator interaction.
Further, the amphiphilic domains of the nanostructures with
differential interaction with the drug molecules was efficiently
utilised as a distinct templates for entrapment and controlled
release of both hydrophobic (ibuprofen) and hydrophilic (5-
uorouracil) drugs. The spatial location of the drugs in the
amphiphilic domains modulate the mechanical strength of the
drug-entrapped gel based on the drug–gelator interactions.
Additionally, the gels can be utilized for small molecular drug
delivery platform and the release prole of the drugs can effi-
ciently be ne-tuned using the knowledge of spatial location
and interactions among the drug–gelator combinations. Such
rational correlations of structural and mechanical information
of the drug-entrapped gel network is a crucial addition in the
repertoire of gel-mediated drug entrapment and dual drug
release study for topical administration in future.
Conflicts of interest
´ ´
7 (a) P. Barthelemy and M. Camplo, MRS Bull., 2011, 30, 647–
There are no conicts to declare.
653; (b) N. Jain, V. Goldscmidt, S. Oncul, Y. Arntz,
´
G. Duportail, Y. Mely and A. S. Klymchenko, Int. J. Pharm.,
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Masters/Doctoral Fellowships awarded to them. A. P. acknowl-
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rheology facilities as well as the Department of Science &
Technology (DST, SERB project ECR/2016/000401), New Delhi
for nancial support.
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