Synthesis, Characterization and Evaluation of Nanocellulose- based Nanogels from Local Sources for Sustained Drug Delivery
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Date
2022-03
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Addis Ababa University
Abstract
Polysaccharides possess great potential advantages in the development of drug delivery vehicles
due to their biocompatibility, biodegradability, and amenability for modifications. Cellulose, a
well-known ubiquitous polysaccharide on Earth, and its derivatives are among the most promising
and versatile materials with special chemical structure providing a good platform for the synthesis
of hydrogel networks. Woody plants and cotton are the major sources of cellulose and its
derivatives such as cellulose nanocrystals (CNCs) and carboxymethyl cellulose (CMC), but
overutilization of these sources has raised huge economic and environmental concerns forcing
researchers and stakeholders to look for other potential substitutes. Nanogels, three-dimensional
hydrogel nanomaterials, based on natural biodegradable polymers have recently got considerable
attention as effective drug delivery nanocarriers as they include the advantages of hydrogels and
nanoparticles. However, the longer preparation time and usage of large amounts of organic
solvents and surfactants have limited their applications.
The objectives of this study were to explore teff straw (TS), enset fiber (EF), sugarcane bagasse
(SB) and coffee hull (CH) as alternative sources of cellulose, CNCs and CMC as well as to prepare
nanocellulose-based nanogels following a simple and green ecofriendly approach, and evaluate
the nanogels for sustained delivery of various model BCS class drugs: acyclovir, carbamazepine
and furosemide.
Cellulose fibers were extracted from the aforementioned lignocellulosic sources following various
eco-friendly chlorine-free extraction conditions comprising alkaline pretreatment, delignification
(using formic acid, acetic acid and hydrogen peroxide) and bleaching (using alkaline hydrogen
peroxide) to obtain an optimum condition. CNCs were obtained following sulfuric acid (64% w/w)
hydrolysis of cellulose fibers extracted using 5%, 10% and 17.5% sodium hydroxide at the
pretreatment stage. CMC was obtained from the as-extracted cellulose fibers, following mercerization and etherification steps using sodium hydroxide and monochloroacetic acid in
isopropyl alcohol. The as-obtained cellulose fibers, CNCs and CMC were investigated and
characterized in terms of yield, crystallinity, chemical functionality, morphology, particle
diameter/size, and thermal stability.
EF yielded the highest cellulose content (60.0%), whereas CH the least (35.5%). FTIR spectra and
SEM morphological studies of the celluloses indicated progressive removal of non-cellulosic
constituents. XRD analyses showed EF cellulose had the highest crystallinity index (CrI)
(85.56%), crystallite size (5.52 nm), and proportion of crystallite interior chains of 200 plane
(0.629), exhibiting unique physicochemical properties. TGA studies revealed enhanced stability
of the as-extracted celluloses. All as-isolated cellulose fibers and CNCs maintained a typical
Cellulose Iβ
crystalline structure, but Cellulose I and II allomorphs coexisted in CNCs
isolated
from TS, EF, and SB pretreated with 17.5% sodium hydroxide. The highest yield (~ 70%), CrI (~
86%), and crystal size (~ 6 nm) were observed in EF–CNCs, and the least in CH–CNCs (yield:
~25%, crystal size: ~4 nm) and SB-CNCs (CrI: ~65.4%). FTIR spectra of all CNCs indicated
typical chemical composition of cellulose. TEM analyses revealed that CNCs
isolated from all
byproducts pretreated with 5% sodium hydroxide had higher aspect ratios (17.32-36.67) with
elongated needle-shaped nanoscale structures than CNCs obtained with 17.5% sodium hydroxide
at the pretreatment stage (8.95-16.38). The thermal studies by TGA/DTG revealed the CNCs had
a two-step decomposition process at Tmax
ranging from 215–225 °C and 340–355 °C. The CNCs
obtained using 5% sodium hydroxide at the pretreatment stage also exhibited high yield, crystal
size, crystallinity, length, aspect ratio and colloidal stability. The high alkaline condition, 17.5%
sodium hydroxide, might not necessarily contribute to the polymorphic transition in lignocellulosic
materials with higher lignin content as evidenced in CH. By and large, the formation of Cellulose
I and II allomorphs in the as-obtained CNCs were dependent on the cellulose source and cellulose
extraction condition, and less influenced by sulfuric acid hydrolysis. The as-obtained CMC from
all plant sources had DS in the range of 0.71‐1.18, and with a yield of 1.28‐1.55 g/g. The
appearance of new bands around 1600 and 1412 cm
‐1
in the FTIR spectra of as‐obtained CMC
showed efficient attachment of carboxymethyl groups to the cellulose chains. The XRD analyses
of the as‐obtained CMC samples showed a significant reduction in crystallinity with the main
diffraction signal at 2θ=20°, showing polymorphic transition to Cellulose II too. From the TGA
results, the Tmax
of the as‐obtained CMC ranged from 285‐296 °C. The SEM results indicated that
the CMC samples existed as more granular and corroded structure. At similar modification
condition, CMC obtained from EF had the highest DS, %carboxymethyl, yield and purity.
Based on its unique and superior properties such as yield, purity, and crystallinity, EF was selected
for preparation of carboxymethyl (nano)cellulose (CM(N)C) to be included as anionic
polysaccharide in the nanogel formulations. CMNC was obtained from EF-CNCs following a
similar etherification approach for CMC. The DS and yield of EF-CMNC were 0.56 and 1.11 g/g.
The nanogels were prepared from self-assembled anionic CMC- or CMNC- and cationic-lysozyme
blends via electrostatic complexation for sustained drug delivery. Three model drugs from
different classes of Biopharmaceutics Classification System (BCS): acyclovir (BCS III),
carbamazepine (BCS II), and furosemide (BCS IV) were evaluated. The influence of weight ratios
of CMNC-lysozyme, pH, sonication and heating times, and storage conditions on the size and
polydispersity index (PDI) of the nanogels was studied. The nanogels were characterized by PCS,
UV/Vis spectrophotometry, FTIR spectroscopy, TEM, XRD, TGA, and DSC techniques, and also
evaluated for drug loading and in vitro drug release. Spherical nanogels of small sizes (75-110 nm)
and PDI (< 0.2) as well as large zeta potential (-38 to -55 mV) were prepared at optimal condition
(at 1:1 weight ratio of CMNC:lysozyme, pH 7.4, and 30-min heating time). CMNC-based nanogels
exhibited lower particle size than CMC-based nanogels at all pH points (5.3-10.5) investigated.
The results demonstrated high encapsulation efficiency (62-94%) and loading capacity (18-27%),
and sustained release profiles of the model drugs from the loaded nanogels for 12 h.
On the basis of the physicochemical characteristics, all the byproducts studied could be considered
as alternative sources of cellulose, CNCs, and CMC for potential value-added industrial
applications although differences were observed due to variations in cellulose sources. EF showed
unique and superior physicochemical properties. From the findings, nanocellulose-based nanogels
with potential applications as sustained release nanocarriers for various BCS class drugs were
developed following a simple and green approach.
Description
Keywords
Teff straw, Enset fiber, Sugarcane bagasse, Coffee hull, Cellulose, Chlorine-free extraction, Cellulose nanocrystals, Cellulose I and II allomorphs, Crystallinity, Polymorphic transition, Carboxymethyl cellulose, Physicochemical characterization, Etherification, Synthesis, Nanogels, Carboxymethyl nanocellulose, Lysozyme, Electrostatic complexation, Sustained drug delivery.