Glucose-triggered dissolution of phenylboronic acid-functionalized cholesterol-based niosomal self-assembly for tuneable drug release

Article abstract of DOI:10.1039/c9nj00798a

The present study described the design and development of a new class of non-ionic vesicular self-aggregates and their utilization as glyco-responsive drug release vehicles. Cholesterol-based phenylboronic acid (PBA)-functionalized amphiphile was synthesi

Full text of DOI:10.1039/c9nj00798a

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Glucose triggered dissolution of phenylboronic acid functionalized
cholesterol based niosomal self-assembly for tuneable drug release
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Deep Mandal and Suman Das*
Department of Chemistry
Jadavpur University
Raja S. C. Mullick Road, Jadavpur
Kolkata 700 032
India
*Corresponding authors
Address for Correspondence
Tel.: +91 94 3437 3164, +91033 2457 2349
Fax: +91 33 2414 6266
E-mail:
SD: sumandas10@yahoo.com
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Abstract
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The present study described the design and development of a new class of non-ionic vesicular
self-aggregates and its utilization as glyco-responsive drug release vehicle. Cholesterol based
phenylboronic acid (PBA) functionalized amphiphile was synthesized that formed non ionic
spherical vesicular aggregates in aqueous milieu and hence termed as ‘niosome’. Various non-
covalent forces involved in the formation of niosome were thoroughly investigated by
microscopic and spectroscopic techniques. The PBA group in the amphiphilic backbone rendered
di-ol sensitivity in the niosome due to which it showed morphological and physicochemical
change in response to external glucose stimuli. Fascinatingly, the niosomes underwent
dissolution on addition of glucose owing to the formation of reversible boronate-diol adduct.
This unique diol-sensitivity of the niosomes was utilized in initiation of enzymatic reaction using
glucose as a switch. Substrate entrapped within niosome interacted with enzyme in presence of
glucose as a consequence of glucose triggered dissipation of the niosome encapsulation followed
by accessibility of the substrate to the enzyme. However, in absence of glucose the enzymatic
reaction failed as enzyme can’t have close proximity to the substrate. This glyco-responsive
behaviour of the niosome was further employed in the field of tuneable drug release. Insulin was
entrapped within the niosome without disconcerting the stability of the self-assembly. When
external glucose was introduced to the drug-niosome conjugate the niosomal encapsulation
destroyed followed by release of the insulin. This unique glyco-sensitivity, drug encapsulation
efficacy and sustained drug release ability of the niosomal self-assembly make this soft-material
highly promising in the hunt of developing cutting edge drug delivery vehicles.
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1. Introduction
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In the race of designing smart soft-materials, material chemists across the world faced a major
challenge to develop stimuli responsive supramolecular self-assemblies that can gratify our
contemporary needs. Supramolecular chemistry is a powerful tool to construct diversified task-
specific soft-materials that is witnessing enormous attention due to its budding importance in
various domains ranging from advanced materials to drug delivery.1-7 Low molecular mass
amphiphilic gels, micelles, bilayers, vesicles etc. are the beautiful expressions of supramolecular
self-assembly where small molecules held together to form vast well-defined structures by means
of non-covalent dynamic forces like hydrogen bonding, - stacking, hydrophobic interactions
etc.8-11 Non-ionic surfactant vesicle or niosome belongs to a special class of supramolecular self-
assembly which is composed of uncharged single-chain surfactant where cholesterol is one of the
integral part.12-14 Niosome is morphologically analogous with vesicle or liposome, although
liposome is usually prepared from double-chain phospholipids (neutral or charged molecules).13
Niosome has great drug regulation prospective towards targeted delivery of cellular probes,
DNA, anticancer and anti-infective cargos. Fascinatingly, it can encapsulate large amount of
drug and control their release by interacting with external stimuli.14-17 In past few years, different
carriers have been used as drug regulatory vehicle such as immunoglobulin, serum proteins,
synthetic polymers, liposome, microsphere, niosome and so on.18-20 However, niosome is
considered to be a superior drug delivery vehicle over other carriers owing to its better stability,
capability to encapsulate both water soluble and lipid soluble drugs in its pocket, bio-
compatibility, bio-degradability and cost effectiveness.18-20 In this regard, at the initial stage of
development of niosome, methotrexate-loaded niosomes were utilized as a drug delivery system
in substitution of liposomes, to modify the therapeutic index of the anticancer drug.21 In another
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study, Polysorbate 80 niosomes were used to encapsulate a high amount of AZT, that rendered
prolonged drug release efficacy upon addition of dicetyl phosphate.22 Rifampicin, an anti-
tuberculosis drug, encapsulated in Sorbitane trioleate niosomes was found to be most effective
for the lungs of mice that raised the possibility of improving anti-tuberculosis therapy.23
According to the structure, nonionic surfactants can be catagorized to alkyl ethers (Hexadecyl
diglycerol ether (C16G2), Brij), alkyl esters (Span, Tween), alkyl amides (C-Glycoside
derivative surfactant, Octyl-decyl polyglucoside), fatty alcohols or fatty acids (stearyl alcohol,
cetyl alcohol, stearic acid, myristic acid).16,24 These were extensively used to develop
commercial niosomes for drug regulation purpose and so on. However, development of newer
synthetic niosome that can encapsulate and release drug in response to external stimuli and other
desirable advantages is a challenging job. In this regard, Damera et al have carried out
systematic synthetic and spectroscopic study of niosome about drug entrapment upon structural
variation of the niosomes.25 Swain et al had shown temperature-dependent water penetration in
synthesized Tween20:cholesterol niosome membrane.26 Our primary objective of this study was
to design a task specific niosomal self-assembly that can encapsulate drug molecules and
undergo dissipation in response of external stimuli accompanied by release of the cargo
entrapped in it. In addition, we also intend to use this stimuli sensitive niosomal aggregate in
initiation of bio-catalytic reaction by the help of an external stimuli.
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According to the said objective, we have developed a new class of cholesterol based
phenylboronic acid (PBA) functionalized amphiphile that formed vesicular self-assemblies in
aqueous milieu. The aggregates were devoid of any surface charge and hence they were termed
as ‘niosome’. The morphological characteristics, various intermolecular non-covalent forces
acting during vesiculation process, dye entrapment ability were thoroughly characterized by
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microscopic and spectroscopic techniques. Interestingly, these niosomes showed high sensitivity
towards glucose and underwent morphological and physicochemical change in response. The
well defined niosomal structure was destroyed in presence of glucose owing to the formation of
boronate-diol adduct. This glucose triggered dissolution of self-assembly was utilized in
initiation of bio-catalytic reaction using glucose as a switch. Moreover this glucose responsive
dissipation phenomenon of niosome was further employed in the drug (insulin) encapsulation
and glyco-responsive drug release from it.
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2. Experimental procedures
2.1. Materials
tert-butyloxycarbonyl (Boc) anhydride, dicyclohexylcarbodiimide (DCC), 4-N,N-
(dimethyl)aminopyridine (DMAP), 1-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide
(NHS), 4-carboxyphenylboronic acid, Silica gel of 100-200 mesh and solvents were procured
from SRL, India. Trifluoroacetic acid (TFA) and sodium hydroxide (NaOH) were procured from
Spectrochem, India. Cholesterylchloroformate, 2,2’-(ethylenedioxy)bis(ethylamine), deuterated
solvents for NMR and FTIR spectroscopic experiments were obtained from Sigma-Aldrich
Chemical Co. Milli-Q water and phosphate-buffered saline (PBS) was used throughout the study.
Thin layer chromatography was performed on Merck precoated silica gel 60-F254 plates.
Chromobacterium viscosum lipase (E.C.3.1.1.3 type XII) was purchased from Millipore, India.
2.2. Synthesis of amphiphile-1
Cholesterol based phenylboronic acid tethered amphiphiles (1) were synthesized by following
the method as described in the Scheme S1. Briefly, Cholesterolchloroformate (i) was coupled
with mono Boc protected 2,2-(ethylenedioxy)bis(ethylamine) taken in dichloromethane (DCM)
by stirring in presence of trielthyl amine (NEt3). Then Boc protection (ii) was removed by
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stirring the compound with trifluoroacetic acid (TFA) for 6h and the obtained amine (iii) was
column purified in 100-200 mesh silica gel (eluent: 10 % methanol in chloroform (v/v)) . On the
other hand, the NHS linked activated 4-carboxyphenylboronic acid was prepared by reaction of
4-carboxyphenylboronic acid, DCC (1.5 equiv), and NHS (1.1 equiv) in dry DMF (8 mL) and
stirring overnight under a N2 atmosphere. To the former amine (iii) compound, NHS coupled
activated 4-carboxyphenylboronic acid was added in presence of dry pyridine. The residue
mixture was column purified by using 100-200 mesh silica gel and 7% methanol in chloroform
was used as the eluent to obtain pure amphiphile-1. The synthesized amphile was characterized
by 1H-NMR and HRMS (Fig. S1, S2, Supplementary Information (ESI)).
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2.3. Critical Aggregation Concentration (CAC) measurement
The critical aggregation concentration (CAC) of niosome solution formed by 1 (N1) in
respective solvent was measured using a du Noüy tensiometer (Krüss, Germany) by applying the
Du Noüy ring method at 25 °C in water. From surface tension (γ) versus concentration plot the
inflection point was obtained which indicated the CAC.
2.4. Preparation of niosomal solutions
Requisite amount of amphiphile-1 (4 mg) was dissolved in 400 L DMSO to prepare stock
solution. From the stock solution, 5 L added in 2 mL aqueous phosphate-buffered saline (PBS)
solution of pH = 7.4 to obtain the niosome solution of 1 (35 M). As the fraction of DMSO in
the niosome solution of 1 was very small (DMSO: aqueous buffer 1:400 (v/v)), hence the
niosome solution-1 was mentioned as aqueous solution of 1 throughout the all experiments. The
concentration of niosome solution throughout all the experiments was maintained 10 times
higher than CAC (in some cases concentration was kept 20 times higher).
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2.5. FTIR Study
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FTIR measurements were conduted in a Perkin-Elmer Spectrum 100 FTIR spectrometer with
amphiphile-1 in non-self-assembled state (in DMSO-D6) and self-assembled (in DMSO-D6-D2O
(1:400 v/v) but mentioned as ‘in D2O as the DMSO-D6 content was very little) state both.
2.6. Field-emission scanning electron microscopy (FESEM)
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FE-SEM images were obtained using FEI INSPECT F50 FESEM instrument. 6 µL niosome
solutions of 1 (35 M) taken in respective solvent was placed on a piece of cover slip and dried
overnight. It was then kept few hours under vacuum before imaging. The morphologies of
samples were also observed under FE-SEM. Similar procedure was followed for the insulin
included niosome solution of 1 in absence and presence of glucose (6mM).
2.7. High Resolution Transmission Electron Microscopy (HRTEM)
For HRTEM studies, 4 μL of each sample solutions of 1 (35 M) was deposited on a 300-mesh
carbon coated copper grid and dried. The HR-TEM images were obtained in a JEOL JEM 2010
microscope.
2.8. UV-vis study
UV-vis spectra of Coumarin-153 (C153) doped solution of 1 was taken on Schimadzu model
UV-1800 spectrophotometer (Schimadzu Corporation Kyoto Japan) in non-self-aggregating
solvent (DMSO) and aggregating solvent (DMSO-aqueous buffer (1:400 v/v)).
2.9. Fluorescence spectroscopy
The emission spectra of Coumarin-153 (C153) in presence of amphiphile-1 were recorded in
Schimadzu RF5301PC spectrofluoremeter (Schimadzu Corporation Kyoto Japan). The vesicular
solution-1 was excited at 420 nm (λex). The excitation and emission slit widths were kept 3 nm.
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2.10. X-ray diffraction (XRD)
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XRD spectra of the dried sample of niosome solution of 1 (and glucose treated solution of 1 were
obtained from Bruker D8 Advance diffractometer and the source used was CuKα radiation (λ =
0.15406 nm) with a voltage 40kV and current 30mA.
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2.11. Dynamic Light Scattering (DLS) measurements
Mean hydrodynamic diameter of the aggregates of 1 (35 M) in DMSO-water (1:400v/v)
mixtures in absence and presence of glucose was analyzed by DLS using a fixed-angle apparatus
(Model DLS-nano ZS90, Zetasizer Nanoseries, Malvern Instruments). The scattering intensity
was measured at an angle of 175°.
2.12. Monitoring Chromobacterium viscosum (CV) lipase catalyzed hydrolysis within
niosomal self-assembly
The lipase catalyzed hydrolysis of p-nitrophenyl-n-octanoate was examined in Schimadzu model
UV-1800 spectrophotometer (Schimadzu Corporation Kyoto Japan). The substrate p-
nitrophenyl-n-octanoate (1 mM) was included in niosome (500 L) without disturbing the
internal stability of the niosome (35  . To the substrate entrapped niosomal solution
aqueous lipase solution (1.02 gmL-1) was added in absence and presence of glucose. Now
absorbance of liberated p-nitrophenol owing to the enzymatic reaction was measured at 310 nm
with regular time interval.
2.13. Model drug (Insulin) entrapment efficiency of niosomal self-assembly
The insulin loading efficiency of the niosome was measured following the reported protocol.26
Insulin (0.030 mgmL-1) was stirred overnight with niosomal solution of N1 (35 M). The drug-
included niosome conjugate obtained was then centrifuged at 5000 rpm for 30 min and the
absorbance intensity of the supernatant solution (i.e. un-entrapped drug) was measured. Finally,
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the concentration of the drug in the supernatant solution was calculated from the standard
calibration curve of absorbance versus concentration (Fig. S3, ESI). The amount of the un-
entrapped drug was subtracted from the initial amount drug used. It provided the amount of drug
entrapped in the niosomal pocket. The insulin loading efficiency of the niosome was measured
following the equation
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Entrapment efficiency = (Concentration of drug entrapped within the niosome / Concentration of
drug used initially) ×100
2.14. Monitoring release of insulin entrapped within niosomal self-assembly
The model drug insulin (0.012 mgmL-1) was integrated in niosomal solution N1 (35 ) without
disturbing the internal stability of the niosome. The absorbance maxima of native N1, free
insulin and insulin loaded N1 in absence and presence of glucose (with varying concentration)
was monitored from UV-vis spectra.
2.15. Circular dichroism study
The conformational change of the native insulin and released insulin from niosomal self-
assembly was compared by recording circular dichroism spectra using JASCO J815
spectropolarimeter (Jasco International Co., Japan) affixed to a thermal programmer model PFD-
425L/15.
3. Results and discussion
3.1. Designing of amphiphile
Supramolecular chemistry is a powerful tool to construct task specific soft-materials that can
satisfy our contemporary requirements. Small amphiphilic molecules assemble to form self-
organized vast supramolecular nanostructures. Low molecular mass amphiphiles generally
consist of hydrophobic and hydrophilic group at two opposite terminals.27 An optimal
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hydrophilic lipophilic balance (HLB) in the amphiphilc backbone may yield well defined
supramolecular structures such as micelles, gels, vesicles etc.28 Hence, choice of hydrophobic
and hydrophilic moiety is the most decisive factor to develop a task specific amphiphile that can
produce well defined nanostructures as well as serve the ultimate purpose of our need. In the
present study, we aimed to develop low molecular mass amphiphilic self-assembly that can
undergo physicochemical and morphological change in response to glucose stimuli and the
glyco-sensitivity of the soft-materials may be utilized in tunable drug regulation. Accordingly,
cholesterol based phenylboronic acid (PBA) tailored amphiphile-1 (Fig. 1a) was synthesized.
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Fig. 1 (a) Structure of amphiphile-1; (b) HR-TEM, and (c) FE-SEM images of the 1 taken in
DMSO-aqueous buffer (1:400 v/v).
Here cholesterol and PBA was integrated as hydrophobic and hydrophilic units respectively.
These two functionalities were further coupled by 2,2′-(ethylenedioxy)bis(ethylamine) linker to
obtain amphiphile-1. We included PBA moiety within the structure specially to render di-ol
sensitivity in the amphiphilic backbone.29,30 PBA shows high affinity towards di-ol (such as
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glucose, catechol etc.) due to its unique ability to form reversible cyclic boronate-diol adducts.
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It is also expected that PBA-diol interaction may also assist physicochemical and
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morphological change to the self-assemblies formed by molecule-1. Cholesterol was included in
the structure considering its crucial role in the formation of vesicular membrane particularly the
bilayer structure. Cholesterol has been termed as the ‘‘mortar’’ of bilayers because, by virtue of
its rigid structure, molecular shape and solubility properties, it compels the amphiphiles to
anchor more strongly into the bilayer arrangement.13,31 Cholesterol in niosomes is reported to
enhance membrane stability, decrease the fluidity of the membrane and alter membrane
permeability.12,13,31-33 In addition, the steroidal backbone may also be supportive to maintain
optimal HLB required for self-aggregation. Now, the synthesized amphiphile was characterized
by 1H-NMR, high resolution mass spectrometry (HRMS) (Fig. S1-S2, ESI).
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3.2. Self-assembling behaviour and microscopic investigations of aggregates
The self-organisation behaviour of the synthesized amphiphile was examined in aqueous solution
of phosphate-buffered saline (PBS) of pH=7.4, dimethyl sulphoxide (DMSO) and DMSO-
aqueous buffer binary solvent mixtures. The amphiphile-1 showed poor solubility in aqueous
buffer (pH= 7.4) forming turbid suspension where as it was completely dissolved in DMSO
generating a clear solution. Now, to the aqueous turbid suspension of 1 (in PBS buffer solution
of pH= 7.4), little amount of DMSO was added gradually. Amphiphile-1 formed viscous
translucent solution in DMSO-water (up to DMSO: water  1:400 v/v). It might be a primary
indication of the formation of self-aggregated structures in that solution at a particular DMSO-
water ratio. With further adding DMSO, translucent solution of 1 gradually turned clear.
Actually, we tried to maintain DMSO content minimum as much as possible considering its
future biological application. For simplicity, we will mention the solution of 1 taken in DMSO-
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aqueous buffer (1:400 v/v) as aqueous solution of 1 since the portion of DMSO content in that
binary solvent was very little. The morphological properties of the aqueous translucent solution
of 1 were investigated by means of high resolution transmission electron microscope (HR-TEM)
and field emission scanning electron microscope (FE-SEM). According to the HR-TEM images,
the viscous translucent solution of 1 showed well defined spherical vesicular structures having a
thin wall (vesicular membrane thickness 2-3 nm) and a hollow core. The sizes of the aggregates
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were ranging from 500-600 nm (Fig. 1b). The magnified HR-TEM image (Fig.S4, ESI) showed
that a dark band of 2-3 nm thickness (i.e. the vesicular wall) encircled a spherical core region
(comparatively brighter part). It indicated that the spherical aggregates were hollow internally.
The thickness of the vesicular membrane of 1 (2-3 nm) might be correlated to the unilamellar
nature of the wall that was composed of bi-layered molecular arrangement of the amphiphilic
building blocks. FESEM images of the sample showed analogous spherical aggregates (Fig. 1c).
The average diameters of the vesicular self-assemblies were noted to be 600 nm. From the
microscopic investigations it can be understood that amphiphile-1 uphold the suitable HLB to
form self-organised vesicular structures in the binary solvent at a particular composition
(DMSO-aqueous buffer 1:400 v/v).
3.3. Characterization of the niosomal self-assemblies
The critical aggregation concentration (CAC) at which the amphiphile-1 started to form self-
aggregated vesicular structures in aqueous solution was noted to be 3.5 M following the Du
Noüy ring method (Fig. S5, ESI). Interestingly, the translucent vesicular solution of 1 showed
zeta potential value -3.2 mV. It indicates that the vesicular aggregates were devoid of any
charged surface. Hence these vesicular self-assemblies can be termed as ‘non-ionic liposomes’ or
in brief ‘niosome’ (the niosome self-assemblies formed by amphiphile-1 are now abbreviated as
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N1). The pKa value of PBA group is 8.8.34 It was expected that at pH = 7.4, PBA group would
be in neutral form (B(OH)2 , sp2 hybridized state) and it will not exist as boronate form (B(OH)3
, sp3 hybridized). This would be probable reason due to which the vesicular aggregates did not
contain any charged surface showing zeta potential very small negative value (i.e. almost in
neutral range).
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Various non-covalent intermolecular interactions operating within the niosomal self-
1
assemblies were scrutinized by FTIR, H-NMR, UV-vis and fluorescence spectroscopy. FTIR
spectra of 1 in non-self-assembled state (1 taken in DMSO-D6) gave sharp transmittance band at
1542, 1651 and ~3242-3306 cm-1 that were originated due to amide δN-H (amide II, bending),
νC=O (amide I, stretching) and co-existence of νN-H (amide A) with νO-H peaks, respectively (Fig.
2a). When translucent niosomal solution of 1 was taken in D2O (more accurately DMSO-D6-D2O
1:400 v/v, (in self-assembled state)), the transmittance signals appeared at 1553, 1642 and
3352-3476 cm-1 (broad band), respectively (Fig. 2a). These shifts in stretching and bending
frequencies clearly pointed out the participation of intermolecular hydrogen bonding between
1
carbonyl (C=O) and amide N-H moieties during vesiculation process.35 Solvent dependent H-
NMR was conducted with 1 in both non-self-assembled (in DMSO-D6) and self-assembled
1
condition (in DMSO-D6-D2O (1:400 v/v)). In DMSO-D6 (Fig. 2b) the H-NMR signals of
phenyl group (7.72-7.90 ppm), amide (6.97 ppm), vinyl proton (5.34 ppm), linker (3.31-3.76
ppm), -OH (2.29-2.68 ppm) and cholestenyl group protons (0.66-2.07 ppm) appeared to be
sharp. In contrast, when the solvent was changed to D2O, (more accurately DMSO-D6-D2O
1:400 v/v) as the DMSO-D6 content was very little it was mentioned as D2O solution for
1
simplicity) H-NMR signals were notably broadened as well as suppressed (Fig. 2b). The
broadening and suppression of NMR signal in the self-assembled state of the amphiphile
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indicated the contribution of intermolecular non-covalent forces (such as hydrogen bonding,
hydrophobic interactions etc.) between the amphiphiles during the self-aggregation process.36
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Fig. 2 (a) FTIR spectra of 1 in non-self-assembled state (in DMSO-D6) and in self-assembled
state (in DMSO-D6-D2O  1:400v/v); (b) 1H-NMR spectra of 1 in DMSO-D6 and in DMSO-D6-
D2O (1:400v/v); (c) normalized UV-vis and (d) normalized fluorescence spectra of coumarin-
153 (C153) in DMSO (dye in free state), in presence of amphiphile-1 (35 M, in non-self-
assembled state) in DMSO and entrapped within niosomal solution N1 (1 taken in DMSO-
aqueous buffer (1:400 v/v solution).
3.4. Dye entrapment study
We further conducted dye entrapment study of the niosomal aggregates. We recorded the UV-vis
spectra of a well known dye Coumarin-153 (C153) taken in DMSO, in presence of non-
aggregated amphiphile-1 (C153 and amphiphile-1 taken in DMSO where dye remains free) and
in entrapped condition within the niosomal self-assemblies (C153 doped N-1 taken in DMSO-aq.
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buffer  1:400 v/v where dye remains entrapped). Free C153 in DMSO gave absorbance peak at
430 nm (Fig.2c). In presence of amphiphile-1, C153 in DMSO (1 in non-self-aggregated state)
gave almost same absorbance maxima at 430 nm. However, C153 doped in the niosomal solution
of N1 showed blue shifted absorbance maxima at 419 nm (Fig.2c) compared to the previous
cases. On the other hand, fluorescence spectra of C153 included N1 displayed similar blue shift
(emission maxima changed from 528 to 501 nm) upon changing the solvent from DMSO to
aqueous buffer (more accurately DMSO-aq. buffer  1:400 v/v) when it was excited at 420 nm
(Fig. 2d). C153 is a hydrophobic dye that is believed to be localized at the hydrophobic domain
within the niosomal membrane (stacked in between bilayer).37,38 Due to the localization of the
dye at the hydrophobic domain and the change in polar environment surrounding the dye
probably causes hypsochromic shift in UV-Vis and fluorescence spectra of C153.
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3.5. Glucose responsive behaviour of the self-aggregates
As described earlier our primary objective of this study was to develop a glyco-responsive soft-
material that can be utilized as drug delivery vehicle, we checked the glucose sensitivity of this
newly developed niosomal soft-material. To the translucent niosomal solution of N1, 6 mM
glucose was added, aged for 6h and the resulting solution was placed under FE-SEM. We have
seen that the spherical vesicular aggregates that appeared for the native niosomal solution N1
was destroyed in presence of glucose (Fig. 3). No such well defined spherical aggregates were
observed for the gluconated solution of N1. Only small irregular shaped particulates were seen.
This observation intrigued us to further investigate the glucose responsive dissolution of the
niosome by conducting dynamic light scattering (DLS) experiment with the niosome solution in
absence and presence of glucose. DLS study provides a measure of average size of the self-
aggregated materials within the respective solvent systems.39 According to the DLS study, the
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Fig. 3 FESEM images of niosomal self-assembly-N1 (35 M) (a) in absence and (b) presence of
glucose.
native niosomal self-assemblies had average size 600 nm which was in well agreement with the
size found from microscopic images (Fig. 1b, c). However, upon adding glucose and aging up to
1 h, we observed two DLS peak at the range of 400 nm and 80 nm (Fig. 4a). Increasing the
incubation period of gluconated niosomal solution up to 6h, DLS signal appeared at 80 nm
only. It suggested that within 1 h, niosomal aggregates started to disassemble in presence of
glucose, forming irregular shaped particles (showing dual DLS peak). After 6 h incubation, the
glucose triggered dissolution of niosome was almost complete and the 600 nm sized self-
assemblies destroyed to form small irregular particles having average size 80 nm.
To confirm the glucose triggered dissipation, we further analyzed X-ray diffraction
(XRD) of dried sample of niosomal solution-N1 in absence and presence of glucose (Fig. 4b).
Dried sample of niosomal solution-N1 showed distinct XRD peaks at 2Ɵ  26.33° (d = 0.33 nm)
20.57° (d = 0.43 nm), 9.36° (d = 0.94nm), 4.04° (d = 2.18 nm) and 2.67° (d = 3.29 nm) (Fig. 4b).
These peaks may be correlated (roughly) to the spacing between the intermolecular steroidal
backbones and interlayer distance of the bi-layered vesicular membrane.40 Overall, the XRD
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Fig. 4 (a) Dynamic light scattering (DLS) study and (b) XRD plot of the niosomal self-assembly-
N1 (35 M) in absence and presence of glucose.
signals of native niosome-1 corresponded to the well organised molecular orientation.
Conversely, gluconated sample of niosome solution-1 (incubated for 6h and then dried) did not
show any discernible XRD peak (Fig. 4b). It means, in presence of glucose, spherical
morphology of N1 was destroyed. Consequently, no distinguishable XRD peak was observed.40
Now the obvious question came in to play that why niosomes underwent dissolution in
presence of glucose? The amphiphilic building blocks of the niosomal aggregates composed of
PBA terminals which may covalently interact with di-ol functionality such as glucose.
Presumably, the PBA tethered amphiphile-1 formed reversible boronate-diol adduct in presence
of glucose.41-43 Consequently, the HLB required for formation of vesicular self-organisation was
perturbed. The niosomal self-assemblies could not sustain its stability and its morphology in that
microenvironment. It went through dissolution in presence of glucose. Mass spectrometry
(MALDI) experiment further confirmed the expected formation of boronate-diol adduct
(1+glucose, Fig. S6, ESI).
3.6. Initiation of enzymatic reaction using glucose switch
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To this end, we intended to employ the glucose responsive dissolution of self-assembly
phenomenon to initiate a bio-catalytic reaction using glucose as a switch which may be relevant
in the field of pro-drug activation. For this purpose, enzyme catalyzed ester hydrolysis within the
niosomal self-assembly N1 was monitored (in absence and presence of glucose) and the reaction
was considered as a representative bio-catalytic reaction. We used the hydrolytic enzyme
Chromobacterium viscosum (CV) lipase and its substrate (p-nitrophenyl-n-octanoate) which on
hydrolysis produced n-octanoic acid and yellow colored p-nitrophenol.44,45 Accordingly, the
substrate (2 mM) was entrapped within the niosomal self-assembly (70 M, 20 times higher
than CAC) without disconcerting the stability of the system. To the substrate loaded niosome,
enzyme solution (1.0 gmL-1) was added and the system was incubated for hours. Photographic
images showed that color of the resulting solution was unaltered (Fig. 5a). On the other hand,
when the same experiment was repeated in presence of glucose, appearance of yellow colored
solution can be visualized through naked eye. Lipase catalyzed hydrolysis of p-nitrophenyl-n-
octanoate was further analyzed from UV-vis spectral study within the niosome system in absence
and presence of glucose. p-nitrophenyl-n-octanoate (1 mM) was again successfully included
within the niosome solution (35 M) In absence of glucose, the substrate entrapped within the
niosome showed an absorbance maximum at 304 nm characteristic to the p-nitrophenyl-n-
octanoate. Upon adding lipase (1.02 gmL-1) to the niosome-substrate conjugate the absorbance
intensity almost unaltered even after 30 min (absorbance intensity merely changed from 0.29 to
0.36, Fig. 5b). This mere change in absorbance intensity probably came from the hydrolysed
product (p-nitrophenol) of un-entrapped substrate that were scattered in the bulk solution in very
little amount. However, this little amount of p-nitrophenol production cannot be viewed through
naked eye. On the other hand, when substrate-niosome conjugate was treated with gluconated
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Fig. 5 (a) Photographic images of substrate (p-nitrophenyl-n-octanoate (2 mM)) entrapped
niosomal solution N1 (70 M) after treatment with enzyme (CV lipase (1.02 gmL-1))
solution in absence and presence of glucose; UV-vis spectra of the p-nitrophenyl-n-octanoate (1
mM) entrapped within the niosomal solution of N1 (35 M) after treatment of enzyme lipase
(1.02 gmL-1) (b) in absence of glucose at certain time interval and (c) in presence of glucose
with varying concentration (0-36 mM).
solution of enzyme, the hydrolysed product exhibited an absorbance maximum at 310 nm
(characteristic to the p-nitrophenol in that solvent system). A gradual increase in the absorbance
intensity was also recorded with increasing glucose concentration. Upon varying the glucose
concentration from 0 to 30 mM, absorbance intensity enhanced from 0.34 to 0.89 (2.6 fold
increment, Fig. 5c). From afore said observation it can be understood that glucose played a
crucial role in the dissolution of the niosomal self-assembly N1 and initiation of an enzymatic
reaction. In presence of glucose due to rupture of the niosome, substrate came out form the
niosomal pocket and interacted with the enzyme to produce yellow coloured p-nitrophenol
(Scheme 1). From Fig. 5a, formation of yellow colored p-nitrophenol in the enzyme (gluconated)
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Scheme 1 Schematic representation of glucose triggered initiation of lipase catalysed hydrolysis
reaction of p-nitrophenyl-n-octanoate after dissolution of niosomal self-assembly.
treated substrate-niosome solution can be visualized through naked eye. This observation
corroborated with the UV-vis spectral data also. More interestingly, the rate of degradation of the
niosomal self-assembly increased accordingly with the external glucose concentration. More
amount of glucose added, more will be the rupturing of the niosome followed by greater amount
of p-nitrophenol liberation. This may be the probable reason for gradual increment of absorbance
intensity with increasing glucose concentration. However, in absence of glucose, the substrate
(encapsulated within niosome) had no accessibility to the enzyme. As a result, the enzyme failed
to hydrolyze the substrate. To the best of our knowledge, this unique strategy to initiate such
bio-catalytic reaction within niosomal self-assembly using glucose as a switch was not explored
earlier. This new approach may be befitting for pro-drug activation and other pharmacological
application.
3.7. Insulin entrapment within niosome and glucose triggered release of insulin
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Diabetes is one of the common chronic disorders associated with glucose. In body, when insulin
production is hampered the blood glucose level is increased causing type-I diabetes.46 To
maintain appropriate blood glucose level, insulin is injected externally. Hence development of
soft material based insulin regulatory vehicle is of high demand. In particular employing
niosome as drug carrier would be more advantageous owing to its high drug loading efficiency,
capacity of including both hydrophilic/ hydrophobic drug and economic factor. At this instance
our primary objective was to examine the capability of the newly developed niosomal self-
assembly as relevant glyco-responsive drug regulatory vehicle. We have chosen insulin as a
model drug for this purpose considering its pharmacological significance in treatment of type-I
diabetes. Insulin was encapsulated successfully within the niosome. Starting from 0.030 mgmL-1
of insulin, 0.012 mgmL-1 can be loaded maximally within the niosome-N1 (35 M) without
perturbing the stability of the system. The insulin entrapment efficiency of N1 was measured to
be 40% following the equation: entrapment efficiency = (Concentration of drug within the
niosome / Concentration of drug used initially) ×100.25 According to the UV-vis study, insulin
taken in aqueous PBS buffer (pH= 7.4) solution showed absorbance maxima at 270 nm.
However, insulin entrapped within niosome showed absorbance peak at 274 nm (Fig. S7a, ESI).
To find out the localization of insulin within the niosomal pocket, UV-vis spectra was further
recorded in binary solvent mixture (1,4-dioxane (non-polar) and aqueous PBS buffer (polar)
mixture at different composition) with varying polarity. It was then compared with the
absorbance spectra of insulin, encapsulated within N1. In 1,4-dioxane included aqueous PBS
buffer (buffer: dioxane  9:1 (v/v)), absorbance peak of insulin appeared at 271 nm. Increase in
the dioxane content (i.e. decreasing the solvent polarity) in the binary solvent mixture the
absorbance maxima red shifted gradually. Up to buffer: dioxane  1: 9 (v/v), absorbance maxima
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shifted to 274 nm (Fig. S7b, ESI). This shift (270 nm to 274 nm) of insulin absorbance with
decreasing the solvent polarity suggested that insulin preferred less polar solvent. Now, the shift
in absorbance maxima of insulin moving from more polar to less polar solvent can be compared
to the shift of absorbance maxima owing to entrapment of insulin within niosome (Fig. S7, ESI).
From the above comparative study it can be assumed that insulin entrapped within niosome is
likely be localized at the less polar hydrophobic region of the niosomal wall.
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After successful inclusion of insulin within niosome-N1, glucose (with varying
concentration 6 to 30 mM) was added externally to the insulin-niosome conjugate. We observed
the FE-SEM images of the entrapped insulin in absence and presence glucose (Fig. S8a).
According to the FE-SEM image, insulin loaded niosome showed distinctive spherical
morphology which further suggested the stability of the insulin-niosome soft-composite even
after inclusion of the drug within niosome (Fig. S8a, ESI). Upon addition of glucose, the insulin
loaded niosomes lost its well-defined sphericular topologies (Fig. S8b, ESI) and tiny irregular
fragments were observed. It occurred probably due to the glucose responsive dissolution of the
niosomal aggregates as discussed earlier.
UV-vis spectra of the insulin loaded niosome-N1 were scrutinized in absence and
presence of glucose. We observed no discrete absorbance peak for the native niosomal solution.
Free insulin gave absorbance peak at 270 nm while entrapped insulin showed absorbance
maxima at 274 nm with reduced absorbance intensity.47 Probably, quenching in the absorbance
intensity of insulin arose due to entrapment within the niosome. Interestingly, when glucose
solution was added gradually to the insulin loaded niosome, the absorbance intensity at 274 nm
steadily enhanced (Fig. 6a).
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Fig. 6 (a) UV-vis spectra (b) fluorescence spectra (excited at 274 nm) of the native niosome N1
(35M), free insulin, insulin entrapped in niosome and the released insulin after addition of
glucose with varying concentration (6-30 mM).
Upon adding 30 mM of glucose solution intensity regained up to 66% compared to free insulin
of same concentration. The absorbance intensity of insulin remained unaltered beyond 30 mM
glucose concentration. The same experiment was carried out in fluorescence spectroscopy. In
fluorescent spectra, native solution of N1 gave emission maxima at 375 nm (Fig. 6b). Free
insulin gave emission maxima at 303 nm.47 insulin, entrapped within the niosome gave emission
maxima at 303 nm but its intensity notably reduced. This quenching in emission intensity was
probably due to encapsulation of the drug by niosomal self-assembly. Upon addition of glucose
(up to 30 mM) the emission intensity at 303 nm gradually enhanced. Here the emission intensity
was regained up to 62% compared to the free insulin. In addition, the emission intensity remain
unchanged at 375 nm region that appeared for native niosome N1. The above spectroscopic
observation clearly pointed out that insulin entrapped within the niosome get released when
external glucose was added as a consequence of dissolution of the niosomal encapsulation
(Scheme 2). More fascinatingly, the release rate of insulin can be tuned by varying the external
glucose concentration.
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Scheme 2 Schematic representation of the glucose responsive dissipation (owing to the
formation of boronate-diol adduct) of the niosome followed by release of the entrapped insulin
from it.
According to the CD spectra, free insulin displayed two negative bands at  = 208 and
220 nm that corresponded to the  and -helical structure of insulin, respectively (Fig. S9,
ESI).48 The ratio of the both bands ([F208/F220]) provides a qualitative measure of the overall
conformation of insulin. In this case of the native and released insulin [F208/F220] values were
found to be close to each other (1.19 and 1.16 respectively).48,49 It indicated that no major
conformational change took place for the released insulin from the niosome compared to that of
standard one. Thus, the above study endowed judicious employment of the niosomal self
aggregates as efficient drug carrier as well as glucose responsive insulin regulatory vehicle.
4. Conclusion
In summary, we developed cholesterol containing phenylboronic acid tethered amphiphile (1)
that formed vesicular nanostructures in aqueous (DMSO-water 1:400 v/v) solution. The spherical
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vesicular aggregates were devoid of charged surface due to which they were termed as of
‘niosomes’. Different intermolecular interaction forces contributing in the formation of niosomal
self-assemblies were thoroughly scrutinized by microscopic and spectroscopic techniques.
Interestingly, these niosomal self-assemblies underwent dissolution in presence of glucose owing
to reversible boronate-diol adduct formation. This unique gluose responsive dissipation feature
of the niosomes was judiciously employed in the initiation of enzymatic reaction using glucose
switch. Substrate entrapped within niosome can’t interact with external enzyme. However, in
presence of glucose the enzymatic reaction preceded through dissolution of the niosomal
aggregates followed by enzyme-substrate accessibility. Moreover, the glucose responsive
dissipation phenomenon was also utilized in the field of controlled drug release. The release of
the drug entrapped within the niosomal self-assemblies can be adjusted as required by varying
the external glucose content. This advantageous feature could be befitting for hyperglycemic
treatment. The present study described design and development of a new class of PBA
functionalized cholesterol based niosomal self-assemblies and its potential application in
programmed enzymatic reaction as well as controlled drug regulation. In fact, the unique glyco-
sensitivity, drug encapsulation efficacy and sustained drug release ability of these niosomal self-
assembly make this soft-material highly promising in the hunt of developing cutting edge drug
delivery vehicles.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the DST-SERB (PDF/2016/002123), University Grants
Commission (UGC), New Delhi, India [F. No. 43-243/2014 (SR), MRP-MAJORCHEM-2013-
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37991] and RUSA 2.0 Grant to Jadavpur University, Kolkata provided by MHRD, Government
of India (Reference No, R-11/101/19 dated 15(19)-02-2019).
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Glucose triggered dissolution of phenylboronic acid functionalized cholesterol
based niosomal self-assembly for tuneable drug release
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Deep Mandal and Suman Das*
Department of Chemistry, Jadavpur University, Kolkata-700 032, India.
GRAPHICAL ABSTRACT
Cholesterol containing phenylboronic acid based niosomal self-assemblies showed glucose
responsive dissolution and release of the encapsulated drug.
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