Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5445_Библиотеки_им_академика_М_И_Перельмана.pdf
267
transverse, and descending colons, each having its own specic physiological fea-
tures (Mead 2009). The colon has a unique capacity to absorb water, which signi-
cantly increases the viscosity compared to that of the upper parts of the gastrointestinal
tract. Consequently, a dense mucus layer forms on the inner walls of the colon,
impeding the dissolution and absorption of medications. Goblet cells, which are
specialized epithelial cells, create mucus in the colon’s lamina propria connective
layer, resulting in the formation of a single mucus layer (Arévalo-Pérez etal. 2020).
The mucus consists of mucin glycoprotein, which provides its structure and adhe-
siveness, along with water, inorganic ions, and fat.
The pH values vary across different sections of the gastrointestinal system, with
notable differences between the upper sections and the colon, as well as within dif-
ferent regions of the large intestine itself. The pH levels in the ascending colon may
vary between 5.26 and 6.72, mostly because of the many bacteria present in the
colon. These microorganisms digest carbohydrates, resulting in the production of
short-chain fatty acids (Falsa etal. 2022). While passing through the transverse
and descending colons, the absorption of fatty acids occurs, and the release of
H
2
CO
3
is stimulated, resulting in an increase in the alkalinity of the environment.
The pH value in the distal region of the colon is 6.6, and this pH may be inuenced
and potentially decreased by intestinal bowel illnesses such as ulcerative colitis
(Arévalo-Pérez etal. 2020). The colon has a substantial population of microorgan-
isms, ranging from 10^11 to 10^12CFU/mL, which is accountable for a signicant
level of enzymatic activity (Turner etal. 2003). The microbiomes in the colon may
initiate a range of processes, including decarboxylation, deglucuronidation, reduc-
tion of double bonds, ester hydrolysis, amide hydrolysis, and dihydroxylation.
These processes facilitate the breakdown of peptides and polymers in the colon,
which hinders the effective use of polymers in medication administration targeted to
the colon.
However, inulin is a naturally existing polysaccharide that has resistance to deg-
radation in the intestinal tract (Teferra 2021). Hence, it attracted the scientic frater-
nity to utilize it as a viable drug delivery carrier for colon targeting. It is a naturally
occurring complex polymeric carbohydrate that is hydrophilic, cheap, and available
as a rich source of ber in the diet. Since it cannot be broken down by intestinal or
gastric enzymes, it can pass through to the colon undamaged. Enzymes such as
galactosidase, glucosidase, pectinase, dextranase, amylase, and xylosidase, pro-
duced by various bacteria in the colon, effectively degrade inulin. This characteris-
tic qualies inulin as an effective vehicle for delivering drugs specically to the
colon. Additionally, inulin is widely used in both the pharmaceutical and food
industries due to its benecial physical and chemical characteristics, such as gel
formation and water solubility (Giri etal. 2021).
12.3 Inulin Degradation intheColon Environment
Inulin is a type of nondigestible ber regarded as a prebiotic due to its ability to
selectively stimulate the growth and/or activity of benecial gut bacteria, thereby
promoting host health. Found naturally in various plants like banana, chicory root,
12 Inulin: AVersatile Polymer inColon Drug Targeting
268
Jerusalem artichoke, and garlic, inulin is a nonstructural polysaccharide consisting
of β–1,2-linked D-fructosyl residues with a terminal α–1,2-linked D-glucose moiety
(Riva etal. 2023).
Upon consumption, inulin reaches the colon intact, as it is resistant to gastric
acidity, mammalian enzyme hydrolysis, and absorption in the upper gastrointestinal
tract. In the colon, it serves as a substrate for fermentation by the resident gut micro-
biota. The microbial degradation of inulin is primarily catalyzed by inulinases,
enzymes that hydrolyze inulin to produce fructooligosaccharides (FOS) and mono-
saccharides like glucose and fructose (Mutanda et al. 2014). While most of the
identied inulinases are of fungal origin and are utilized in industrial food produc-
tion, some gut bacteria have also been found to possess inulinase activity. These
include members of the genera Bacteroides, Lactobacillus, Bidobacterium, and
Arabiibacter massiliensis (Singh etal. 2017).
Research has indicated a rise in the relative abundance of Bidobacterium in
response to inulin intake in human treatments. Nevertheless, little is known about
the precise gut microbes and entire metabolic pathways involved in inulin con-
sumption. Numerous techniques, including as whole-genome sequencing, uores-
cence in situ hybridization (FISH), multimodal sorting methods, and exvivo gut
microbiota incubations, have been used to study the relationship between inulin
and the gut microbiota (Riva etal. 2023). Studies were performed on inulin-grafted
mesoporous silica nanoparticle (MSNs) where the MSNs were tagged uorescence
to be identied in the gut when the inulin was attached to the inulin-binding bacte-
ria of microbiota. The investigations were also performed on human stools which
were incubated anaerobically with inulin-grafted MSNs to identify the microbiota
which include Ruminococcus, Bacteroides, Roseburia, and Balutia (Riva
etal. 2023).
The stools were also identied for the high translational activity in the presence
of inulin. Bioorthogonal noncanonical amino acid tagging (BONCAT) was utilized
to identify these translationally active cells. The results showed that Lachnospiraceae,
Prevotellaceae, Bacteroidaceae, and Ruminococcaceae were identied to be in a
sizable population exhibiting the translational activity. In addition to the identica-
tion of translational activity, the bacteria were also isolated by using Raman-
activated cell sorting (RACS) which was specic to the inulin stimulation.
Ruminococcus, Parabacteroides, Weissella, Bacteroides, Bidobacterium,
Enterococcus, Alistipes, and Phocaeicola were the bacterial taxa being isolated
which exhibited the ability to break down the inulin.
Thereby, inulin is primarily acted upon by the gut microbiota for its degradation
in the gut, specically residing in the colon, and is not being acted upon by the
human digestive enzymes. The inulin acted upon by the gut microbiota produces
metabolites such as fructooligosaccharides and monosaccharides and is utilized by
the same microbiota for their metabolic activity (Roberfroid 1993). However, more
research is to be performed in studying the degradation path of inulin and its metab-
olites in the colon which is specically acted upon by specic microbiomes present
in the colon.
N. Desai et al.
269
12.4 Different Modifications ofInulin
Inulin undergoes breakdown in the colon by gut microbes, resulting in the produc-
tion of short-chain fatty acids. However, recent research is focused on the derivatiza-
tion of inulin to enhance its functionality and to broaden its application. A
hydrophobic derivative of inulin was synthetized which is commercially recognized
as Inutec SP1. The inulin dodecyl carbamate was synthesized by reacting with
dodecyl isocyanate in an aprotic solvent. The molecular weight of Inutec SP1 was
determined to be 5000g/mol. The implementation of this technology is extensively
seen in diverse industrial sectors and has been successfully utilized for the stabiliza-
tion of emulsions and dispersions (Muley etal. 2016).
Numerous types of hydrophobic derivatives were reported in the literature where
most of the inulin derivatives were synthetized using organic solvent reacting with
the methyl esters, fatty acid chlorides, alkyl isocyanates, and alkyl epoxides
(Exerowa etal. 2009; Gochev etal. 2011). A research was conducted to synthesize
an inulin derivative using a green technique. The reaction took place in water, where
inulin was reacted with succinic anhydrides under moderate alkaline conditions.
The inulin derivatives exhibited different alkenyl chain lengths and degrees of sub-
stitution. The inulin surfactants have shown the ability to adhere to the boundary
between air and water, and at concentrations over a certain threshold, they may form
clusters resembling micelles when dissolved (Kokubun etal. 2015).
The ability of hydrophobic derivative of inulin to form micellar aggregates has
attracted the interest in designing novel colon targeted drug delivery systems. Inutec
SP1 was studied to encapsulate the anticancer drug paclitaxel and achieved the con-
trolled release. The micelles were characterized by dynamic light scattering and
transmission electron microscope and revealed the size of the micellar aggregate to
be 250nm exhibiting nearly spherical shaped. These micellar structures of hydro-
phobic derivates of inulin were widely studied by researchers to encapsulate differ-
ent drugs (Muley etal. 2016). Di Prima et al. generated the amine derivative of
inulin to encapsulate retinoic acid and produced the mucoadhesive micelles which
augmented the permeation across the cornea (Di Prima etal. 2017). In another study
led by Mandracchia etal., the inulin-derived micelles encapsulating vitamin E and
biotin were synthetized which exhibited long circulating carriers for receptor-
mediated targeted drug delivery (Mandracchia etal. 2017).
A recent research examined the derivatives of inulin known as octenyl and dode-
cenyl succinic anhydride (OSA, DDSA). The interfacial and solution characteristics
of these derivatives were examined and compared with those of Inutec SP1. The
release of beta-carotene was studied between the anionic succinylated derivatives
and the non-ionic Inutec SP1. The ndings indicated that both OSA and DDSA
inulin, as well as Inutec SP1, exhibited micelle formation in solution after a thresh-
old concentration was reached. These micellar aggregates had a favorable impact on
decreasing the interfacial tension at both the air-water and oil-water interfaces,
therefore enhancing the stability of oil in water emulsions (Kokubun etal. 2018).
In another study, cinnamoylated derivative of chicory inulin was generated and
studied for the colon targeting. Methotrexate was chosen as a model drug for the
12 Inulin: AVersatile Polymer inColon Drug Targeting
270
study where methotrexate was encapsulated in vesicles of cinnamoylated derivative
of chicory inulin. The study was designed to assess the stability of inulin derivative
against the inulinase enzyme produced by a specic bacterium that resides in the
colon. Microspheres of the inulin derivate were synthetized using Tween 20 and
were tested for the inulinase enzyme activity. Irrespective of the activity of the
enzyme, the microspheres retained the ability of encapsulation of methotrexate.
Thus, the study supported the ability of cinnamoylated inulin in targeting the colon
drug delivery and aids in treating various colonic diseases including cancer and
Crohn’s diseases (López-Molina etal. 2015). Thus, the chemically modied inulin
derivatives were shown to be a viable carrier for colon targeting of numerous com-
pounds including drugs, antimicrobials, and vitamins which had a wide applicabil-
ity in pharmaceuticals and nutraceuticals.
12.5 Inulin-Based Formulations forColon Targeting
12.5.1 Hydrogels
Hydrogels represent intricate three-dimensional networks of hydrophilic polymers
adept at absorbing and retaining substantial volumes of water or biological uids
(Wang etal. 2020; Damiri etal. 2024; Rana etal. 2022, 2023b; Desai etal. 2023a).
Their distinctive swelling behavior in aqueous environments stems from the abun-
dant presence of hydrophilic moieties within the polymer matrix (Bashir et al.
2020). Synthetic iterations of hydrogels, synthesized from compounds like polyeth-
ylene glycol (PEG) or polyvinyl alcohol (PVA), afford meticulous control over
composition and properties, thereby enhancing reproducibility and scalability dur-
ing fabrication (Madduma-Bandarage and Madihally 2021). Conversely, natural
hydrogels, sourced from biocompatible polymers inherent to living organisms, such
as proteins (e.g., collagen, gelatin) or polysaccharides (e.g., alginate, hyaluronic
acid), exhibit exceptional biocompatibility and bioactivity, rendering them particu-
larly apt for engagements with biological systems (Rana etal. 2023b; Jaipan etal.
2017; Li and Lin 2021). Integration of inulin as a constituent in hydrogels amalgam-
ates the advantageous attributes of synthetic and natural elements, focusing on opti-
mizing traits like mechanical robustness, biocompatibility, and degradation kinetics.
This strategic blending aims to tailor hydrogel properties for efcacious delivery of
encapsulated therapeutics, especially targeting the colon (Jain etal. 2024).
Maris etal. (2001) stated the synthesis of inulin-azo hydrogels tailored speci-
cally for colon targeting. The researchers incorporated bis(methacryloylamino)azo-
benzene (BMAAB) into methacrylated inulin (MA-IN) hydrogels to improve the
degradation of the hydrogels in the colon environment. Adding BMAAB resulted in
a reduction in hydrophilicity and an increase in crosslinking density, as shown by
the equilibrium degree of swelling. In addition, the researchers also explored the
possibility of copolymerization with hydrophilic monomers like 2-hydroxyethyl
methacrylate (HEMA) and methacrylic acid (MA). Surprisingly, the addition of
these monomers did not lead to an increase in the equilibrium degree of swelling,
N. Desai et al.
271
despite initial expectations. It is probable that the increased network density is a
result of copolymerization with these monomers, which may be further strength-
ened by enhanced hydrogen bonding. The pH independence of gels containing MA
indicates that changes in pH have minimal impact on the behavior of the polymer
network. A study using prednisolone as a model drug found that more than 80% of
the drug was released within the rst 3 h from hydrogels made of
MA-IN:HEMA. Although there was a signicant decrease in drug release in
MA-IN:HEMA:BMAAB hydrogels, a considerable amount of the drug was still
released, with 50% being released within 5h. The ndings highlight the complex
task of achieving the right balance between swelling, promoting degradation in the
colon, and minimizing early drug release before reaching the desired colonic
environment.
In a different investigation, Stubbe etal. (2001) explored the development of inu-
lin-based “azo-containing polysaccharide gels” tailored for targeted drug delivery to
the colon. The research distinguished between two categories of gels: azo-inulin gels
and azo-dextran gels. Thorough characterization elucidated substantial discrepancies
in the swelling behavior and mechanical characteristics of these gels, primarily mod-
ulated by crosslinker concentration and polysaccharide substitution degree. Azo-
dextran gels manifested signicant susceptibility to degradation by dextranase
enzymes, contrasting with the limited degradation observed in azo- inulin gels due to
hindered enzyme access resulting from the high degree of substitution typical of
inulin-based gels. The study underscored the signicance of cofactors such as
NADP
+
and FAD in the degradation mechanism. Notably, the investigation revealed
a potential impediment to enzymatic degradation in azo- inulin gels attributed to the
diminished afnity of NADP
+
, while FAD exhibited enhanced penetration. This
observation provides insights into the intricacies of achieving efcient enzymatic
degradation within the intricate matrix of inulin- based gels.
Van den Mooter etal. (2003) conducted a thorough analysis of methacrylated
inulin (MA-IN) hydrogels tailored for targeted drug delivery to the colon. Employing
a systematic screening methodology, the study unraveled the intricate relationship
between various parameters of hydrogel formulation and the kinetics of drug
release. The results underscored the pivotal role played by the method of loading
hydrogels and the attributes of the model protein, such as its molecular weight and
loading concentration, in dictating invitro release kinetics. Furthermore, the com-
position of the feed for MA-IN hydrogels, including factors like the degree of sub-
stitution and feed concentration, emerged as a critical determinant inuencing
protein release, affording precise manipulation of the release prole. Integration of
inulinase into the release medium was identied as a strategy to augment protein
release from the hydrogels, presenting a promising avenue for modulating drug
release kinetics. Notably, two specic formulations of MA-IN hydrogels, distin-
guished by their unique feed compositions, demonstrated optimal lag times for drug
release. This feature ensures minimal premature release in the small intestine while
facilitating enhanced release in the colon through inulinase-mediated degradation.
Pitarresi etal. (2008) synthesized INUDVSA-TT hydrogels for colon-specic
drug delivery. Their study entailed the modication of inulin through a reaction
12 Inulin: AVersatile Polymer inColon Drug Targeting
272
involving divinyl sulfone (DV) and succinic anhydride (SA), yielding the INUDVSA
derivative. Subsequent crosslinking of this derivative with trimethylolpropane tris
(3-mercaptopropionate) (TT) led to the formation of the desired hydrogel network.
Characterized by a distinct chemical composition, these hydrogels exhibited pH-
responsive swelling behavior. Notably, they demonstrated resilience in simulated
gastric uid, ensuring the integrity of encapsulated drugs until they reach the colon.
Crucially, the hydrogels displayed biodegradability upon exposure to colon-resident
enzymes, specically inulinase and esterase, underscoring their appropriateness for
colon-targeted drug delivery applications. Furthermore, the study explored the
incorporation of 2-methoxyestradiol (2-ME), an anticancer agent, into the hydrogel
matrices. Subsequent assessment encompassed the elucidation of its release kinetics
and apoptotic efcacy on Caco-2 cells, a pertinent model system in colorectal can-
cer research.
12.5.2 Microparticles
Microparticles (also referred to as microspheres or microcapsules) constitute solid
entities typically within the size range of 1–1000μm (Salave etal. 2022c, 2023b;
Khunt etal. 2023; Jindal etal. 2023; Longre etal. 2024). Primarily fashioned to
entrap drugs, proteins, or other bioactive agents within a polymeric or lipidic frame-
work, they afford a means for the controlled release of their cargo over prolonged
intervals, thereby engendering sustained therapeutic effects and mitigating dosing
frequency (Lengyel et al. 2019). The modulation of microparticle composition,
dimensions, and morphology affords customization of the kinetics and pathways
governing drug liberation (Singh etal. 2010). Notably, microparticles furnish safe-
guarding to encapsulated cargo against degradation, enzymatic attenuation, or
untimely discharge, a facet particularly advantageous for safeguarding delicate or
susceptible compounds necessitating stabilization during transit or storage (García
2020). Continuous advancements in microparticle engineering have fostered the
emergence of novel drug delivery modalities boasting heightened efcacy and clini-
cal applicability (Kállai-Szabó et al. 2024). Subsequent sections elaborate on
instances wherein inulin has been employed for targeted drug delivery to the colon.
In a pioneering exploration, Poulain etal. (2003) scrutinized the utility of inulin-
derived microspheres as a vehicle for the controlled release of serine protease inhib-
itors, with a specic focus on (E,E)-bis(amidinobenzylidene)cycloheptanone
((E,E)-BABCH) as a representative drug model. Employing rigorous analytical
methodologies such as NMR, infrared spectroscopy, and differential scanning calo-
rimetry, the authors elucidated the formation of inulin acetate and its complexation
with 1,12-dodecane dicarboxylic acid, delineating signicant disparities in their
thermal behavior and structural attributes. The manufactured microspheres demon-
strated uniform dimensions ranging from 0.5 to 5μm, achieving encapsulation ef-
ciencies of up to 65% subsequent to optimization via screening designs. Notably,
analysis of drug release kinetics unveiled distinctive proles contingent upon micro-
sphere composition, with formulations incorporating inulin acetate associated with
N. Desai et al.
273
1,12-dodecane-dicarboxylic acid manifesting prolonged and controlled release
characteristics. This is attributed to intermolecular interactions between the diacid
and inulin acetate matrix. These ndings underscore the promising prospect of
employing inulin-based microspheres as efcacious carriers for serine protease
inhibitors, offering potential avenues for enhancing therapeutic strategies in condi-
tions such as thrombosis, cancer, and neurological disorders.
Jain etal. (2014) reported inulin microparticles tailored for targeted delivery to
the colon in response to microbiota stimuli. This innovation involved the acetylation
of inulin to produce inulin acetate (INA), rendering it amenable to electrospraying.
The successful acetylation of inulin was validated through comprehensive charac-
terization studies employing FTIR spectroscopy, which exhibited characteristic
peaks indicative of the presence of acetyl groups. Gel permeation chromatography
further conrmed the uniformity of acetylation by revealing a unimodal mass distri-
bution of INA.SEM analysis elucidated the inuence of electrospraying parameters
on the morphology of INA microparticles, with optimized conditions identied as
employing a 24G needle gauge, a 20cm electrospraying distance, a 20kV electro-
spraying voltage, and a 15% polymer concentration. Subsequent optimization of the
formulation for indomethacin (IDM)-loaded INA microparticles yielded spherical
microparticles with an average diameter of approximately 3 μm, exhibiting an
entrapment efciency of 35.39±1.63%. Notably, IDM was found to be molecularly
dispersed within the INA matrix in an amorphous state. In vitro release studies
demonstrated IDM release solely in simulated colonic uid (SCF) containing inu-
linase, thereby conrming the microbiota-triggered targeting mechanism
(Fig.12.1a). Mathematical modeling of the release kinetics suggested a combina-
tion of concentration-dependent diffusion and polymer erosion as the underlying
mechanisms governing drug release.
In a parallel investigation, Saud etal. (2023) investigated the application of elec-
trosprayed inulin-based microparticles as a medium for the targeted delivery of pre-
biotics to the colon. Utilizing electrospraying techniques, microparticles
incorporating inulin were successfully synthesized through the amalgamation with
poly(vinyl) alcohol (PVA), thereby augmenting their processability and mucoadhe-
sive characteristics. Confocal microscopy and FTIR spectroscopy corroborated the
uniform encapsulation of inulin within the PVA matrix. In vivo experimentation
conducted on murine models showcased a notable extension in the retention of inu-
lin within the colon when administered via microparticles compared to conventional
formulations, as conrmed by fecal quantication and real-time animal imaging.
Furthermore, rheological assessments unveiled heightened viscoelastic moduli and
shear-rate-dependent viscosity in samples containing inulin, indicative of modied
rheological attributes upon hydration.
In a recent study, Johnson etal. (2020) delved into the application of ferulic acid-
grafted self-assembled fructo-oligosaccharide (FA FOS) microparticles for targeted
colon delivery. Systematic experimentation enabled the authors to pinpoint the opti-
mal conditions for ferulic acid grafting onto fructo-oligosaccharide, yielding a
weight percentage composition of 20.93% (wt/wt) with a degree of substitution of
0.2206. Analysis via solid-state NMR spectroscopy unveiled distinct peaks
12 Inulin: AVersatile Polymer inColon Drug Targeting
274
Fig. 12.1 (a) Electrosprayed inulin microparticles for targeted delivery to the colon in response
to microbiota. Subgure (i) shows the chemical structure of synthesized inulin acetate. Observe
subgure (ii) for a SEM micrograph of INA microparticles (5000×, scale bar= 10μm) and the
inset for a single microparticle (33,000×, scale bar=1.5μm). Subgure (iii) depicts INA micropar-
ticle IDM release kinetics invitro under simulated GI circumstances. SGF, SIF, and SCF are simu-
lated stomach, intestinal, and colonic uids. Adapted with permission from (Jain etal. 2014),
Copyright Elsevier 2014. (b) FA FOS microparticles for targeted colon delivery. Subgure (i)
shows an SEM photograph of disc-shaped FA FOS. Subgure (ii) shows the results from the
TUNEL assay using HT-29 and LoVo cell lines. Adapted with permission from (Johnson etal.
2020), Copyright Elsevier 2020
corresponding to ferulic acid and fructo-oligosaccharide constituents, afrming
successful conjugation. Utilizing SEM, morphological examination revealed the
microparticles’ discoidal architecture, boasting an average diameter of approxi-
mately 2 μm, indicative of their self-assembling propensity. Impressively, these
microparticles demonstrated robust stability under simulated gastrointestinal condi-
tions and exhibited uniform dispersibility in aqueous media. Signicantly, the mic-
roparticles showcased potent anticancer efcacy against human colon cancer cell
lines HT-29 and LoVo, presenting a superior selectivity index relative to conven-
tional chemotherapeutic agents (Fig.12.1b). Moreover, the conjugation of ferulic
acid conferred augmented antioxidant properties to the microparticles, potentially
offering a shield against oxidative stress within the intestinal milieu.
12.5.3 Nanoparticles
Nanoparticles represent intricate nanostructures spanning dimensions typically
within the range of 1 to 100 nanometers (nm), engineered from diverse materials
N. Desai et al.
275
encompassing polymers, lipids, metals, and ceramics (Desai etal. 2023a, b; Salave
etal. 2021, 2022c, d, e, f, g, 2023b, c; Rana etal. 2023c, d, e, f, 2024; Rawat etal.
2023; Jadhav etal. 2023; Karunakaran etal. 2023; Gupta etal. 2023). Their diminu-
tive size and amplied surface area-to-volume ratio engender distinctive physical,
chemical, and biological attributes (Mitchell etal. 2021). These properties render
nanoparticles procient as conveyors of therapeutic payloads, facilitating precise
delivery to designated cells or tissues within the organism. A paramount advantage
of nanoparticles lies in their capability to shield drugs from enzymatic degradation
and immune surveillance, thereby extending their systemic circulation duration and
augmenting therapeutic efcacy (Liu etal. 2023). This protective shield proves par-
ticularly benecial for drugs prone to poor solubility or stability issues, often con-
straining their therapeutic potential. Through encapsulation within nanoparticles,
these drugs are safeguarded from degradation and witness-enhanced solubility, con-
sequently fostering elevated bioavailability (Polaka etal. 2021). Moreover, nanopar-
ticles derived from inulin have garnered signicant attention for their prociency in
colon targeting. Capitalizing on inulin’s biodegradability and its responsiveness to
colonic pH, these nanocarriers demonstrate promise in delivering therapeutic agents
to the colon, thereby addressing specic gastrointestinal disorders or conditions
with enhanced precision (Nikezić etal. 2020).
Sun et al. (2018) achieved targeted delivery of budesonide (BSD) to address
inammatory bowel diseases (IBD) by employing redox-sensitive nanoparticles
derived from 4-aminothiophenol-carboxymethyl inulin (ATP-CMI). Synthesis of
ATP-CMI, an amphiphilic inulin derivative, showcased its potential for selective
BSD delivery to inamed mucosa typical of IBD.The nanoparticles exhibited pH/
redox-responsive swelling behavior, expanding in size in response to pH alterations
and the presence of reducing agents like glutathione (GSH). In vitro investigations
demonstrated that BSD release from ATP-CMI nanoparticles was triggered explic-
itly by the redox environment, with notably accelerated release rates observed in the
presence of GSH, akin to conditions encountered in the inamed colon. In vivo
studies employing a dextran sulfate sodium (DSS)-induced colitis mouse model
revealed the superior therapeutic efcacy of BSD-loaded ATP-CMI nanoparticles
compared to alternative formulations. The nanoparticles exhibited a propensity to
accumulate at inamed sites, possibly attributed to their mucoadhesive properties
and the formation of disulde bonds with mucin. Moreover, the redox-responsive
BSD release facilitated enhanced intracellular drug delivery, contributing to
improved therapeutic outcomes.
Mandracchia et al. (2018) reported pH-sensitive inulin-based nanomicelles
(termed INVITESA) for targeted release of celecoxib in the intestinal tract. The
platform was prepared through the succinylation of inulin-vitamin E bioconjugates,
introducing pH-responsive carboxyl groups to the system. The stability and size
dynamics of INVITESA nanomicelles were rigorously investigated under various
pH conditions mimicking the gastrointestinal environment. Under acidic pH condi-
tions mimicking the gastric environment, INVITESA nanomicelles exhibited
remarkable resistance to premature drug release, ensuring minimal leakage.
Conversely, at intestinal pH levels, a precisely modulated and sustained release of
12 Inulin: AVersatile Polymer inColon Drug Targeting
276
celecoxib was achieved, effectively aligning with transit time and mitigating the risk
of systemic absorption. Comprehensive biocompatibility assessments conducted on
Caco-2 cells afrmed the safety prole of INVITESA nanomicelles. Transport stud-
ies shed light on the cellular behavior of nanomicelles, demonstrating their capacity
to traverse cellular monolayers and undergo active re-transportation to the luminal
side. This phenomenon underscores the promising potential of INVITESA nanomi-
celles for localized drug delivery along the intestinal tract.
In a different study, Kourani etal. (2022) presented an innovative tactic in cancer
therapy, particularly in targeted colorectal cancer treatment, through the develop-
ment of inulin-coated manganese oxide nanocuboids (MNCs) coupled with RNA
interference (RNAi) to reverse intestinal tumorigenesis. The researchers success-
fully synthesized a multimodal bio-drug, INU-shRNA-Arg@MNCs, by carefully
developing the formulation. This was achieved by modifying the surface of MNCs
with arginine (Arg) to enhance stability and enable the loading of small hairpin
RNA (shRNA). Inulin coating was then applied to facilitate the pH-specic delivery
of the drug to the small intestine. The bio-drug was shown to be biocompatible and
nontoxic in laboratory trials conducted outside of a living organism. Analysis of
how the medication is distributed in the body showed that it accumulates speci-
cally at the intended target location and is eliminated from the body more ef-
ciently. Crucially, the effectiveness of the therapy was conrmed in living organisms
by employing Apc deletion mouse colon cancer models. The targeted delivery of the
bio-drug to specic sites successfully reduced the expression of target genes and led
to a longer median survival time in the treated groups (Fig.12.2a).
In a related study, Hou etal. (2022) examined the efcacy of oral inulin-modied
double-layered nanoparticles containing the chemotherapeutic agent paclitaxel
(PTX) against colon cancer. The nanoparticle architecture consists of an outer layer
of inulin, fullling a dual role: safeguarding the drug cargo within the acidic gastric
environment and facilitating targeted delivery to the colon. This outer inulin layer
not only shields the encapsulated drug from gastric degradation but also undergoes
enzymatic breakdown in the colon, revealing hyaluronic acid (HA) residues. These
exposed HA residues facilitate receptor-mediated endocytosis, thereby enhancing
drug uptake by colon cancer cells (Fig. 12.2b). Under simulated gastrointestinal
conditions, the nanoparticles exhibit robustness, suggesting their suitability for oral
administration. In vivo experiments employing orthotopic colon cancer models
have validated the therapeutic efcacy of the nanoparticle system. Encouragingly,
the nanoparticles demonstrate favorable therapeutic outcomes, emphasizing their
potential clinical utility in colon cancer treatment. Crucially, safety assessments
have determined that the blank nanoparticles themselves do not elicit cytotoxicity or
systemic toxic effects, thus afrming their safety prole as a drug delivery platform.
In a recent investigation, Zhang etal. (2024) introduced a novel therapeutic inter-
vention for ulcerative colitis (UC) by employing inulin-based nanoparticles loaded
with cannabidiol (CBD), aimed at multi-targeting. These nanoparticles were metic-
ulously engineered to possess dual functionality, characterized by redox responsive-
ness and the capacity for dual targeting of both mitochondria and the colon. Such
meticulous design ensures the selective transport of CBD to the inamed colon
N. Desai et al.