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Fig. 12.2 (a) Inulin-coated MNCs coupled with RNAi to reverse intestinal tumorigenesis.
Subgure (i) shows the TEM image of INU-shRNA-Arg@MNCs. Subgure (ii) displays the nd-
ings of a cytotoxic assay study, which indicates that INU-shRNA-Arg@MNCs treated for 48h did
not cause any harm to HEK293 or HCT-116 cells at increasing doses. Subgure (iii) depicts the
evaluation of hepatic functions (ALP, SGOT, and SGPT) to determine the toxicity status in the
treated mice, whereas subgure (iv) depicts the immunohistochemistry for Ephb4 and c-Myc pro-
tein in the treated cohort. Adapted with permission from (Kourani etal. 2022), Copyright Elsevier
2022. (b) Double-layered nanoparticles modied with inulin and containing PTX for the treatment
of colon cancer. Subgure (i) displays the patterns of absorption of free DiD, DiD/PP NPs, and
DiD/PPHI NPs (with a DiD concentration of 10μg/mL) in colon cancer tissue after being co-
incubated for 5h. Subgure (ii) displays the invivo distribution of oral Dir and Dir/PPHI NPs in
orthotopic colon cancer animals. Fluorescent photographs of mice were captured at time intervals
of 1, 2, 4, 6, 8, and 24h. Adapted with permission from (Hou etal. 2022), Copyright Elsevier 2022
12 Inulin: AVersatile Polymer inColon Drug Targeting
278
tissue, thereby augmenting therapeutic efcacy. The efcacy of these nanoparticles
in alleviating UC symptoms, notably inammation and oxidative stress, was dis-
cerned through marked improvements in the levels of inammatory mediators and
oxidative stress indicators. Moreover, the nanoparticles exhibited promising capa-
bilities in restoring the integrity of the intestinal mucosal barrier, a pivotal factor in
impeding disease progression in UC.The investigation also revealed a signicant
alteration in the composition of the intestinal microbiota upon nanoparticle treat-
ment, suggesting the potential of this therapeutic modality in rectifying dysbiosis, a
hallmark of UC pathogenesis. Notably, the nanoparticles’ targeted approach toward
mitochondria, recognized as a primary site of oxidative stress in UC pathology,
underscores their promise in addressing the underlying molecular mechanisms fuel-
ing disease advancement.
12.5.4 Inulin Conjugates
In the realm of drug delivery, the term “conjugates” denotes molecules synthesized
through the chemical linkage of two or more components, typically comprising a
therapeutic agent and a carrier molecule or targeting ligand. Inulin-based conjugates
are designed to use the targeted delivery properties of inulin in order to enhance the
effectiveness of drugs while reducing negative side effects. The process of combin-
ing inulin with CoB12 vitamin, cysteine, and noradrenaline has been shown to
increase the durability of the medications that are included, making them more
resistant to many types of environmental stressors such as light exposure, hydroly-
sis, chemical agents, and temperature changes. Inulin conjugates may be supplied
alone or in combination with other excipients or biomaterials to create nanostruc-
tured carriers. The following are some fascinating research articles on inulin
conjugates.
In a rst-of-its-kind study, Schoener etal. (2013) attempted to improve cancer
therapy efcacy by developing an inulin-doxorubicin conjugate. Utilizing doxoru-
bicin’s primary amine group, they chemically linked it to inulin. Through meticu-
lous experimentation, including cytotoxicity assays, DNA binding studies, confocal
imaging, and transport studies, the researchers demonstrated the superior potency
and toxicity of the inulin-doxorubicin conjugate compared to free doxorubicin.
Notably, the conjugate exhibited enhanced cellular uptake, potentially due to its
larger molecular size hindering efux pumps, and demonstrated increased DNA
binding afnity. Moreover, the conjugate’s enzymatically degradable nature and
suitability for oral delivery offer promising avenues for safer and more effective
cancer therapy.
Wang etal. (2018) reported a glutathione-responsive inulin-based micelle for the
targeted treatment of colorectal cancer. Inulin was conjugated with lipoic acid, and
tanshinone IIA (TAN), an anticancer agent derived from Salvia miltiorrhiza, was
incorporated during micelle assembly via cross-linking. Through meticulous exper-
imentation, the researchers demonstrated the effectiveness of their delivery system
in targeting colorectal cancer cells while promoting the growth of benecial colonic
N. Desai et al.
279
microora. Drug-loaded cross-linked carriers exhibited enhanced cytotoxic activity
against human colon carcinoma cells (HT29) compared to free drugs, particularly
after 48h of co-culture, indicating improved drug delivery and release within the
tumor microenvironment. Additionally, the micelles were found to promote the pro-
liferation of Bidobacterium longum, a common bacterium in the human colon,
which could contribute to the breakdown of inulin within the colon. This dual thera-
peutic approach not only highlights the potential of inulin-based micelles for tar-
geted drug delivery but also underscores their role in supporting the health of the gut
microbiome.
Shivhare etal. (2018) synthesized a novel amphiphilic inulin-dehydropeptide
conjugate capable of self-assembling into nanostructures in aqueous media. This
conjugate was meticulously engineered with the purpose of encapsulating ornida-
zole, a hydrophobic drug widely employed in treating colonic ailments. The hydro-
phobic peptide moiety within the conjugate acts as a pivotal physical crosslinker,
orchestrating the self-assembly phenomenon, thereby yielding core-shell nano-
structures. Employing sophisticated spectroscopic methodologies alongside rigor-
ous cytotoxicity assays, the authors meticulously validated the successful formation
and inherent biocompatibility of these nanostructures. Notably, in vitro release
investigations unveiled an expedited release prole of ornidazole, particularly in an
enzymatically enriched milieu resembling the colonic environment.
In a recent investigation, Catenacci etal. (2020) integrated the attributes of inulin
and β-cyclodextrin to engineer a colon-specic platform for delivery of hydropho-
bic drugs. Through comprehensive characterization employing thermal analysis,
FTIR spectroscopy, and 1H NMR, they conrmed the successful synthesis of the
INUCD bioconjugate, highlighting its stability and structural integrity. Their system
exhibited remarkable colloidal properties, with a nely tuned size distribution aver-
aging 381nm and a zeta potential of −9.4mV.The bioconjugate showcased excep-
tional solubilization capacity for hydrophobic compounds, demonstrated by the
formation of a robust inclusion complex with curcumin, a representative hydropho-
bic drug model, with a binding constant (Kc) of approximately 300M
−1
. Enzymatic
degradation studies underscored the bioconjugate’s susceptibility to complete deg-
radation by inulinase, afrming its potential for precise colon-specic drug release
mediated by intestinal microora. Further assessments on Caco-2 cells revealed the
high cytocompatibility of the bioconjugate and its inability to traverse an intestinal
barrier model, suggesting its propensity for localized drug activity within the colon
while mitigating systemic absorption.
12.5.5 Miscellaneous
In the realm of formulations, inulin is a highly adaptable and exible excipient that
may serve several functions. It can work as a functional excipient or as a coating
material for oral dosage forms. The purpose of this is to facilitate the deliberate
administration of medications, particularly at the location of the colon, in order to
enhance the effectiveness of treatment. Karrout et al. (2010) developed
12 Inulin: AVersatile Polymer inColon Drug Targeting
280
enzymatically activated coated multiparticulates containing theophylline. Various
polymer blends were meticulously examined for their potential to provide targeted
drug release to the colon. Among the components studied, inulin played a crucial
role as one of the “targeting compounds,” selected for its propensity to undergo
preferential degradation by bacterial enzymes present in the colons of patients with
inammatory bowel disease. The authors aimed to leverage inulin’s enzymatic sus-
ceptibility to design multiparticulate systems that could effectively deliver theoph-
ylline to the colon. Through systematic variations in the blend ratio of inulin to
ethylcellulose, a water-insoluble polymer chosen to prevent premature dissolution
in the upper gastrointestinal tract, the researchers sought to optimize the formula-
tion for enhanced drug permeability and controlled release kinetics. Their ndings
indicated that upon exposure to fecal samples from patients with inammatory
bowel disease, the inulin- containing multiparticulates exhibited signicant water
uptake, dry mass loss, and increased drug permeability, suggesting promising pros-
pects for colon- specic drug delivery.
De Mohac etal. (2019) conducted a study focused on enhancing the oral absorp-
tion of irinotecan (IRN), an anticancer drug, through the formulation of multicom-
ponent solid dispersions (MSDs) using the Spray-Drying technique. The aim was to
improve IRN solubility and permeability in the intestinal tract, which is crucial for
its therapeutic efcacy. By incorporating inulin along with other polymers like poly
(methyl methacrylate-co-methacrylic) acid (PMMA) and cellulose acetate phthalate
(CAP), the researchers aimed to optimize drug release and absorption proles. The
study involved rigorous characterization of the MSDs, including particle size analy-
sis, water content determination, and examination of drug-polymer interactions
through techniques like FTIR and DSC.The formulated MSDs exhibited enhanced
drug dissolution rates under gastrointestinal conditions, indicating improved drug
solubility. Furthermore, exvivo experiments demonstrated increased drug perme-
ation through colon specimens, suggesting the potential for enhanced oral absorp-
tion of IRN.
In a different study, Sardou etal. (2019) investigated the suitability of different
polysaccharides, including inulin, as components of composite lms based on
Eudragit RS for delivering 5-ASA to the colon. Various invitro tests were employed
to evaluate mechanical properties, swelling behavior, loss of lm mass, and drug
permeability in simulated gastrointestinal uids. Among the polysaccharides stud-
ied, inulin demonstrated favorable characteristics for colonic drug delivery. Films
containing inulin exhibited desirable mechanical properties, limited swelling, and
minimal changes in weight in the upper gastrointestinal tract, indicating stability in
the stomach and small intestine. Importantly, these lms were susceptible to enzy-
matic degradation in simulated colonic uid, suggesting their potential for targeted
drug release in the colon. Inulin outperformed other polysaccharides examined,
which included pectin, chitosan, guar, and dextran.
Recently, Zhu etal. (2024) conducted a comprehensive study aimed at address-
ing Fusobacterium nucleatum (F. nucleatum) in colorectal cancer (CRC) tissues
through a novel therapeutic approach. They meticulously screened a probiotic
strain, Enterococcus faecium (EF47), known for its potent antibacterial activity
N. Desai et al.
281
against F. nucleatum. To enhance its efcacy and ensure targeted delivery, they
developed an innovative oral delivery system involving a double-layer coating of
EF47 with hyaluronic acid (HA) and inulin. This coating not only shielded EF47
from the harsh gastrointestinal environment but also facilitated its precise delivery
to CRC tissues. Importantly, HA facilitated mucosal adhesion, prolonging EF47
retention in CRC tissues, while inulin bolstered EF47 viability in simulated gastro-
intestinal conditions. Consequently, the system effectively inhibited F. nucleatum
growth. Safety evaluations conrmed the lack of toxic effects associated with the
system, establishing it as a safe and efcient drug delivery method.
12.6 Toxicity Consideration ofInulin-Based Formulations
Inulin is a nonstructural polysaccharide that is generated by plants and commonly
used as a prebiotic in the food and supplement industry. The structure consists of
around 60 D-fructosyl residues that are linked together in a linear manner by β–1,2
bonds, with a terminal D-glucose moiety attached through an α–1,2 bond. Banana,
chicory root, Jerusalem artichoke, wheat, barley, rye, onions, leeks, and garlic are
abundant in inulin (Riva etal. 2023). In the upper gastrointestinal (GI) tract, inulin
is not easily digested, but it is fermented by the bacteria in the colon (Riva et al.
2023). Microbial enzymes known as inulinases facilitate the process of hydrolyzing
inulin, resulting in the formation of fructooligosaccharides (FOS) as well as glucose
and fructose monomers. The majority of known inulinases are derived from fungi
and are commonly employed in the context of industrial food production (Riva
etal. 2023).
Inulin has been designated as a “Generally Recognized as Safe (GRAS)” sub-
stance by the United States Food and Drug Administration (FDA), as shown by the
issuance of GRAS Notice No. GRN 849. The FDA’s GRAS classication signies
that inulin does not provide any substantial hazard to human health when used
according to instructions and in the stated quantities (Riva etal. 2023). Extensive
research has delved into the realm of inulin consumption, revealing compelling evi-
dence that supports its safety for human consumption.
The study conducted by Carabin and Flamm assessed the safety of inulin and
oligofructose as dietary ber. The study concluded that elevated quantities of these
bers do not provide any health hazards, as determined through toxicological tests.
The gastrointestinal tolerance up to 20g/day was demonstrated in clinical trials.
Inulin and oligofructose have the potential to address the ber consumption dispar-
ity in the United States, as their transparent labeling enables consumers to make
well-informed decisions regarding their dietary intake. The research emphasizes the
safety and health advantages associated with the utilization of inulin as a functional
dietary component (Carabin and Flamm 1999).
According to the evaluation conducted by the European Food Safety Authority
(EFSA), inulin has been found to be non-allergenic. This means that it is generally
safe for the majority of individuals, even those with allergies (European Food Safety
Authority 2015; Akram etal. 2024). The regulatory classication of inulin varies
12 Inulin: AVersatile Polymer inColon Drug Targeting
282
across different countries and regions. In the United States, inulin, which is a kind of
dietary ber, is used in a variety of goods including meals, dietary supplements, and
medicinal foods (as dened by 21 CFR 101.81). It has a vital function in improving
the nutritional content of these goods. As previously stated, it has Generally
Recognized as Safe (GRAS) classication, allowing it to be used in many culinary
applications. Regulation (EU) 2015/2283 has authorized the use of inulin as a novel
food component in the European Union (EU). The EU’s clearance indicates a thor-
ough assessment of inulin, guaranteeing its compliance with all necessary safety
criteria for human consumption (Carabin and Flamm 1999; Akram etal. 2024).
To summarize, the toxicity factors associated with inulin-based formulations are
complex and necessitate thorough assessment to guarantee their safety and effec-
tiveness in clinical settings. It is important to consider potential gastrointestinal dis-
turbances, hypersensitivity reactions, and impacts on the gut microbiota when
evaluating the biocompatibility and toxicity of inulin, despite its good characteris-
tics. Researchers can enhance the eld of colon-targeted medication delivery and
personalized medicine by including these factors into the design and clinical devel-
opment of inulin-based formulations. This approach allows them to utilize the ther-
apeutic benets of inulin while minimizing any potential negative effects.
12.7 Conclusion
In conclusion, the comprehensive examination of inulin-based formulations for
medication delivery specically targeting the colon showcases its promise as a ex-
ible and efcacious strategy to improve treatment results in diverse gastrointestinal
illnesses. Numerous investigations have been conducted to examine the biocompat-
ibility, biodegradability, and enzymatic degradation of inulin. These studies have
resulted in the creation of formulations that exhibit accurate drug release kinetics,
enhanced targeting efciency, and diminished systemic adverse effects. Inulin’s
adaptability has been demonstrated by its application in diverse delivery systems,
providing tailored medication administration alternatives to address unique thera-
peutic requirements. Potential areas for future research encompass enhancing for-
mulation parameters, investigating novel nanoparticles, tackling gastrointestinal
disorders, and giving priority to safety evaluations. The imperative for advancing
inulin-based delivery methods and enhancing the well-being of patients with gastro-
intestinal illnesses necessitates the imperative collaboration among researchers hail-
ing from many domains. Colon targeting based on inulin exhibits potential for
revolutionizing drug delivery, augmenting personalized medicine, and expanding
therapeutic approaches for gastrointestinal disorders.
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