key: cord-0897199-k3c96ut7 authors: Usman, Muhammad; Zhang, Chengnan; Patil, Prasanna Jagannath; Mehmood, Arshad; Li, Xiuting; Bilal, Muhammad; Haider, Junaid; Ahmad, Shabbir title: Potential applications of hydrophobically modified inulin as an active ingredient in functional foods and drugs - A review date: 2020-10-06 journal: Carbohydr Polym DOI: 10.1016/j.carbpol.2020.117176 sha: 31a52c98d50d501b3343140ddd5cb73a56d94b98 doc_id: 897199 cord_uid: k3c96ut7 Over the past few years, hydrophobically modified inulin (HMI) has gained considerable attention due to its multitudinous features. The targeted release of drugs remains a subject of research interest. Moreover, it is important to explore the properties of short-chain fatty acids (SCFAs) inulin esters because they are less studied. Additionally, HMI has been used to stabilize various dispersion formulations, which have been observed to be safe because inulin is generally recognized as safe (GRAS). However, the results regarding HMI-based dispersion products are dispersed throughout the literature. This comprehensive review is discussed the possible limitations regarding SCFAs inulin esters, real food dispersion formulations, and HMI drugs. The results revealed that SCFAs inulin esters can regulate the human gut microbiota and increase the biological half-life of SCFAs in the human body. This comprehensive review discusses the versatility of HMI as a promising excipient for the production of hydrophobic drugs. Inulin, which was discovered as a fructan-type oligosaccharide, is distributed in more than 36,000 vegetables and herbs. Jerusalem artichokes, leeks, oats, onion, and garlic are abundant sources of inulin, while it is obtained commercially from members of the Asteraceae family, such as chicory (Kokubun, Ratcliffe, & Williams, 2018; Afinjuomo et al., 2019) . Inulin is made up of d-fructose units that are linked by β-2,1 glycosidic bonds with a wide range of degrees of polymerization (between 2 and 60) and commonly combined with a glucose residue at the terminus (L'opez- Molina et al., 2015) . In addition, inulin has received generally recognized as safe (GRAS) status by the Food and Drug Administration (FDA) due to its several outstanding properties including J o u r n a l P r e -p r o o f biodegradability, renewability, nontoxicity, etc., compared to those of many other polysaccharides (Afinjuomo et al., 2019) . It is an undigested polysaccharide and is classified as a dietary fiber that escapes small intestinal digestion but is degraded (partial or complete) by colonic microbiota. Its degradation subsequently produces short-chain fatty acids (SCFAs), which may improve human health (Tripodo and Mandracchia 2019a) . Inutec ® SP1 is a commercially available graft copolymer that is synthesized by the reaction of inulin with dodecyl isocyanate in an aprotic solvent to obtain inulin dodecyl carbamate (Stevens et al., 2001b; Nestor et al., 2007; Exerowa et al., 2007 Exerowa et al., , 2009a Exerowa et al., , 2009b and has been widely used to provide steric stabilization for various dispersions, improve the biological half-life of SCFAs and control the release of drugs (Tadros, 2017; Chambers et al., 2019; Tripodo et al., 2019b; Tripodo, 2016) . Moreover, various types of inulin derivatives have been produced by the reaction of inulin with fatty acid methyl esters (FAMEs), fatty acid chlorides, alkyl epoxides, and alkyl isocyanates (Exerowa et al., 2009a (Exerowa et al., , 2009b Gotchev et al., 2011; Khristov & Czarnecki, 2010; Stevens, Merigii & Booten, 2001) . In consideration of environmental issues with the development of industrialization, a green methodology has been established to synthesize different types of inulin derivatives with varying alkenyl chain lengths and varying degrees of substitution (DSs) by using alkenyl succinic anhydrides in an aqueous environment under mild alkaline conditions (Morros et al., 2010a; Morros, Levecke, & Infante, 2011; Kokubun, Ratcliffe, & Williams, 2013; Kokubun, Ratcliffe, Williams, 2015; Kokubun, Ratcliffe, & Williams, 2018; Han, Ratcliffe, & Williams, 2015; Han, Ratcliffe, & Williams, 2017) . It was revealed that these types of inulin derivatives adsorbed at the liquid-liquid interface, solid-liquid interface, and air-water interface and produced micellar-like structures in the solution above a critical concentration. Moreover, the HMI derivatives contributed excellent encapsulation efficiency, reaching up to 100%, and nearspherical drug-loaded micellar aggregates of ∼250 nm, resulting in prolonged drug and vaccine release (Walz, Hagemann, Trentzsch, Weber, & Henle, 2018 Han et al., 2020 Kesharwani, Dachineni, Bhat, & Tummala, 2019) . The commercially available Inutec ® SP1 has been widely used for the targeted release of anticancer drugs, particularly paclitaxel (Muley, Kumar, El Kourati, Kesharwani, & Tummala, 2016) . Furthermore, Tripodo et al. (2015a) and Tripodo et al. (2015b) prepared INVITE bioconjugates with varying DS and designed a drug delivery system based on mesenchymal stromal cells (MSCs) for the therapy of neurodegenerative diseases, which obtained practical achievements regarding the drug delivery profile. In addition, HMI such as amine J o u r n a l P r e -p r o o f derivatives have been grafted with biotin, retinoic acid, and vitamin E to produce mucoadhesive micelles, which exhibit transcorneal permeation properties, as well as long-circulating carriers for receptor-mediated targeted drug delivery (Di Prima et al., 2017; Mandracchia et al., 2018) . Studies have revealed that inulin serves as a promising transporter for colonic drug delivery because it is not digested in the stomach and small intestine . SCFAs play an important physiological role in combating colon-related diseases and altering gut microbiota compositions. Moreover, the amount of SCFAs can be regulated exogenously and endogenously (Zhu et al., 2018; Xu, Zhu, Li, & Sun, 2020) . It was confirmed that the therapeutic value of exogenously administered SCFAs is limited due to the minimum biological half-life (Polyviou et al., 2016) . Experimental studies have revealed that SCFA inulin esters, mainly inulin propionate ester (IPE), can enhance the biological half-life of SCFAs, which improves overall human health. In addition, a number of inulin derivatives have been widely produced by using different anhydrides to improve the antimicrobial abilities and antioxidant activities of inulin (Chen, Mi, Li, Dong, & Guo, 2020; Ren et al., 2012) . HMI derivatives have been shown to minimize plant fungi that damage fruits and vegetable crops (6-48%) worldwide, particularly in developing countries (Li, Qiu, Tan, Gu, & Guo, 2017; Chen et al., 2018 Chen et al., , 2019b Tripodo et al., 2019b) . Similarly, hydrophobic inulin derivatives have been shown to exhibit greater antioxidant activity than native inulin (Chen et al., , 2019b . Based on the scientific literature, it has been observed that HMI derivatives were more studied as emulsion stabilizers than as foam and wetting film stabilizers. Furthermore, reports on the application of modified inulin in real food dispersions are scarce. Likewise, HMI derivativemediated vaccines have been less elucidated than their drug counterparts. The functional properties of SCFA inulin esters have shown excellent findings, but systematic knowledge is scattered throughout the literature. Therefore, this comprehensive review summarizes the recent information on the use of HMI in the controlled release of drugs and functional foods as well as antimicrobial abilities and antioxidant activities. Additionally, the evaluation of emulsions, suspensions, and wetting films has been deeply discussed in this article. Over the past few decades, keen attention has been paid to the chemical modification of inulin, which depends on the charge of the final products. Thus, Stevens, Meriggi, & Booten (2001a) J o u r n a l P r e -p r o o f described the chemical modification of inulin, which was a great leap forward to develop novel industrial products. The chemical modification of inulin is classified into three types: anionic, cationic, and neutral modification (Stevens, Meriggi, & Booten 2001a) . Moreover, highperformance liquid chromatography (HPLC), Raman spectroscopy, nuclear magnetic resonance [(NMR) H-NMR, C-NMR] spectroscopy and Fourier transform infrared (FTIR) spectroscopy have been used to reveal the changes in the inulin conformation structure. The significant difference in the chemical modification of inulin can be divided according to the type of reaction medium and reaction conditions, and the most important is the anhydride type, which is combined on the inulin backbone. Initially, the graft copolymer, i.e., Inutec ® SP1, has been synthesized commercially by using dodecyl isocyanate in an aprotic solvent (which cannot donate protons) to obtain inulin dodecyl carbamate (Figure 1a ). This graft copolymer has widely been used as an emulsifier due to the multipoint attachment of its particles or droplets and high degree of hydration, with more than 97% purity of the end product (Stevens, Meriggi, & Booten 2001; Tadros, 2017; Gotchev et al., 2007; Exerowa et al., 2007 Exerowa et al., , 2009a Exerowa et al., 2009b Nestor et al., 2007) . Consequently, several authors have documented the modification of inulin by esterification, etherification, and carboxymethylation using fatty acid methyl esters (FAMEs), fatty acid acyl chlorides, alkyl epoxides, and alkyl isocyanates or by alkenyl succinic anhydrides, mainly in organic solvents and environmentally friendly aqueous solvents (Stevens, Meriggi, & Booten 2001; Nestor et al., 2007; Morros, Infante, & Pons; Morros, Levecke, & Infante, 2011; Morros, Levecke, & Infante, 2010; Exerowa et al., 2009a Exerowa et al., , 2009b Gotchev et al., 2011; Khristov & Czarnecki, 2010; Zhu et al., 2018; Hartzell, Maldonado-Gómez, Yang, Hutkins, & Rose; Han, Ratcliffe, & Williams, 2015; Han, Ratcliffe, & Williams, 2017; Kokubun, Ratcliffe, & Williams, 2013) . Thus, it is important to divide the chemical modification reactions of inulin based on the types of anhydride and types of reaction medium, which will be discussed below. There has been surging interest in modifying inulin in environmentally friendly solvents because environmentalists have expressed enormous concerns about the environmental impacts of chemical processes, particularly in the development of industrialization. A number of research groups have developed strategies to modify inulin ethers and inulin esters by using water as a solvent in the presence of different catalysts. However, in this organic chemical reaction, the J o u r n a l P r e -p r o o f production yield may be affected because two different chemical species participate in the chemical reaction, which have different polarities, such as a hydrophilic polymer and a hydrophobic reactant. Therefore, the rate of the reaction is essential to obtain specific end products with high DSs. For this purpose, different types of basic and acidic catalysts, including sodium hydroxide, potassium carbonate, 4-(dimethylamino) benzene, 4-(dimethylamino) pyridine, 4-(dimethylamino) benzaldehyde, ion-exchange resins, stearoyl chloride, acrylonitrile, sodium acetate, etc., were used to enhance the chemical reaction rate. Moreover, the basic ion-exchange resin could be used to obtain high DSs compared with the fundamental catalyst because it is not essential to neutralize before reaction. Recently, an environmentally friendly approach was used to synthesize novel inulin derivatives by the reaction of inulin with alkenyl succinic anhydrides [(octenyl succinic anhydride (OSA) and dodecenyl succinic anhydride (DDSA)] in an aqueous solution under mild alkaline conditions ( Figure 1b) (Kokubun, Ratcliffe, & Williams 2013) . Overall, this environmentally friendly mechanism has exhibited excellent reaction efficiency ranging from 59 to 95% for OSA-inulin derivatives and DDSA-inulin derivatives (Kokubun et al., 2013) . Moreover, the results revealed that the reaction efficiency was too high for the OSA-inulin derivative compared to the DDSAinulin derivative. Normally, the high reaction efficiency is very desirable. Furthermore, the same research group has produced different types of HMI derivatives (Han, Ratcliffe, & Williams 2017) and alkenylated inulin samples (OSA, DDSA, TDSA, HDSA, and ODSA) (Han, Ratcliffe, & Williams 2015) . The former derivatives were synthesized using fatty acid acyl chlorides with varying alkyl chain lengths (C10-C16), while the latter samples were formed using alkenyl succinic anhydrides (ASAs) with a wide range of alkenyl chain lengths (C8-C18) in aqueous solution. Both types of compounds were characterized by NMR spectroscopy and FTIR spectroscopy, and the DS was calculated under the same reaction conditions (temperature, time) and with the same chemicals, washing steps, and end-product drying steps. The findings revealed that the alkenylated inulin samples were successfully modified with a high degree of substitution; thus, they can be used for the encapsulation of β-carotene as a natural biomaterial for pharmaceutical, nutraceutical, and personal care applications. Moreover, the DS was observed to decrease with increasing amounts of fatty acid acyl chlorides. Morros, Levecke, & Infante (2011) J o u r n a l P r e -p r o o f found approximately similar results regarding the reaction efficiency, reaction time, and DS of pure and end products. The authors prepared DDSA-inulin derivatives and OSA-inulin derivatives through ASA in environmentally friendly surfactant aqueous media and aqueous media, respectively. The results revealed that the reaction time was noticeably decreased up to 1 hour, obtaining a 65% reaction efficiency using cationic surfactants such as dodecyl trimethylammonium bromide (DTAB). The profound differences in reaction efficiency may be due to the utilization of different anhydrides, catalysts, and experimental conditions. Polyviou et al. (2016) synthesized inulin propionate ester (IPE) by reaction of inulin with propionic anhydride in aqueous solution, with up to 70% yield and a 1.25% degree of esterification. Moreover, Liu, Lu, Kan, Wen, & Jin (2014) grafted inulin with catechin by hydrogen peroxide and ascorbic acid in aqueous medium, which was utilized as a functional ingredient for patients with liver disease and diabetes ( Figure 1c ). In etherification, the fundamental catalyst typically used is sodium hydroxide, which is added in a sufficient amount to perform the chemical reaction and promote the hydroxylation of inulin. Initially, Tomecko and Adams (1923) described the etherification of inulin by the reaction of inulin with epichlorohydrin in basic aqueous solution. Later, Remon, Duncan, & Schacht (1984) developed a method to explore inulin ethers by reacting allyl bromide in aqueous medium. However, the reaction efficiency was too low in these aqueous solutions. Therefore, evidencebased studies have focused on producing a neutral hydrophobic β-hydroxyalkyl inulin ether in environmentally friendly aqueous media with a high DS. It was confirmed that by using alkyl epoxides such as ethylene and propylene oxide, the reaction efficiency could be improved up to 70%, while butyl epoxide or 1,2-hexyl epoxide exhibited less reaction efficiency, at most 40%, owing to their lower solubility in the solution (Morros, Levecke, & Infante, 2010a) . It is important to emphasize that the reaction efficiency is directly proportional to the solubility of the alkyl epoxides. However, insoluble alkyl epoxides have shown a partial response to hydrophobic effects that depend on the alkyl chain lengths of the epoxides, which was not able to modify the required amount of solubilizer. Further, the reaction efficiency was found to be low in water-isopropyl alcohol mixtures with long-chain epoxides, such as C12 and C14. Quite the reverse, Morros, Levecke, & Infante (2010b) also formed hydrophobic β-hydroxyalkyl inulin ether in an aqueous J o u r n a l P r e -p r o o f reaction medium consisting of 1 M KOH and 40% inulin at 80 °C. The authors described that the nonionic surfactant β-hydroxydodecyl inulin ether had no effects on the etherification reaction, although cationic surfactants such as DTAB and hexadecyltrimethylammonium bromide (CTAB) noticeably improved the reaction efficiency up to 50% as described in Figure 1d . The findings have stated that during the etherification of inulin, the reaction efficacy was dependent on the types and nature of surfactants, particularly in an aqueous environment using 1,2-dodecylepoxide. Moreover, β-hydroxydodecyl inulin ethers including InEC8, InEC12, and InEC14 were synthesized using 1,2-alkylepoxides, namely, 1,2-octylepoxide, 1,2-dodecylepoxide, and 1,2tetradecylepoxide, respectively, in aqueous media, and their properties were compared with those of commercially available Inutec ® N25 and Inutec ® SPI. Potassium hydroxide and DTAB were introduced as an excellent micellar-like catalyst. The catalyst reduced the reaction time and increased the total reaction yield and reaction efficiencies, i.e., 80% and 50%, respectively, from 4 to 24 h (Morros, Infante, & Pons, 2012) . These outstanding inulin ethers have found use in several industrial applications, such as in pharmaceuticals as a stabilizing agent for aqueous solutions that contain poorly soluble molecules or as carriers for water-insoluble substances. The cyanoethylation of polysaccharides is a dynamic approach that has been prevalent in the last few decades (Tripodo, & Mandracchia 2019a; Verraest, Peters, Kuzee, Raaijmakers, & van Bekkum, 1997) . Cyanoethylated starch was used in the textile industry due to its high dispersing and emulsifying properties. However, the modified starch resulted in high-viscosity solutions and exhibited low solubility, significantly decreasing the applicability. It was believed that inulin showed lower solution viscosities and exquisite solubility due to its low molecular weight (Verraest, Peters, Kuzee, Raaijmakers, & van Bekkum, 1997) . Hence, the cyanoethylation of inulin has been performed by reaction of inulin with Michael-type addition in an analogous manner, mainly in an aqueous environment, by using stearoyl chloride and acrylonitrile as a catalyst ( Figure 1e ) (Stevens, Meriggi, & Booten 2001) . Cyanoethyl inulin and its derivatives showed multiple industrial applications, including as a crystallization inhibitor for calcium carbonate, in detergent formulations and as a dispersing agent. Nevertheless, 3-amino-3-oxopropyl and carboxyethyl cyanoethyl inulin derivatives can be mixed and substantially used as hair fixatives, metal ion carriers, and dispersing agents. It is also observed that when the cyanoethyl inulin derivatives J o u r n a l P r e -p r o o f exhibit a low DS (viz., DS < 1.5), they are soluble in water, while when the products exhibit a high DS (viz., DS > 1.5), they are insoluble in water. Thus, it was concluded that an appropriate DS is critical to determine the quality of nonionic polymeric surfactants. It is well known that inulin can be reduced to avoid intense color formation and side chain products before further modification. The reduction process is completed by employing many reducing agents, such as primary amine, sodium borohydride, and molecular hydrogen, or by electrochemical reduction (Stevens, Meriggi, & Booten 2001) . In the early 19 th century, most scientists focused on the preparation of triacetyl inulin by the reaction of native inulin with pyridine at 40-140°C (Haworth and Streight, 1932) . As a result, a good amount of unpurified end product was obtained, ranging from 57-99%, whereas the amount of purified end product obtained ranged from 73% to 80%. However, this modification may not be applicable on an industrial scale due to the low rate of the chemical reaction, which makes the process expensive and time-consuming. Therefore, in 1932, Haworth and Streight produced acetylated inulin using methyl alcohol and obtained high amounts of the purified end product (approximately 95%). Recently, Hartzell, Maldonado-Gómez, Yang, Hutkins, & Rose (2013) synthesized butyrylated, propionylated, and acetylated inulin derivatives by reaction of inulin with dimethylsulfoxide 1-methylimidazole and acetic anhydride in pyridine solvent. It was noted that a foamy precipitate was produced during the production of propionylated inulin, whereas it was not observed during the formation of butyrylated and acetylated inulin. This phenomenon occurred due to the high concentrations of unreacted acid and depolymerization of the inulin units, particularly in the aqueous environment. It was confirmed that inulin is extremely susceptible to acid hydrolysis (Courtin, Swennen, Verjans, & Delcour, 2009) , which may affect the DS of the end product. However, Zhu et al. (2018) synthesized propionylated inulin by the reaction of inulin with propionic anhydride using pyridine as the solvent (Figure 1f ). Further, the authors evaluated the effect of the anhydride ratio, inulin concentration and temperature on the DS of IPE. The findings revealed that the DS was high with increasing propionic anhydride ratio, while it was decreased as the temperature and concentration of inulin increased. Moreover, Tripodo et al. Figure 1g . The H-NMR and FTIR studies confirmed that with sufficient DS, polymeric micelles were produced upon water dispersion. Ren et al. (2011a) synthesized O-aminoethyl inulin in water, NMP, and benzene using NaOH, Et3N, and AlCl3 as catalysts, respectively. The inulin derivative produced in NMP/Et3N exhibited better yield or reaction efficiency than other inulin derivatives produced in water/NaOH. To date, a few groups have also synthesized 6-azido-6-deoxy-3,4-di-O-acetyl inulin (AAIL), 6-bromo-6-deoxy-3,4-di-O-acetyl inulin (BAIL), and chloracetyl inulin (CAIL) to improve their antimicrobial abilities and antioxidant activities as illustrated in Figure 3 and Figure 4 (Hu, et al., 2014; Guo et al., 2014; Chen et al, 2020 Chen et al, , 2019 Chen et al, , 2018 . Subsequently, a number of functional groups such as aminopyridine, benzaldehydes, aromatic aldehydes, quaternary ammonium salts, triphenylphosphonium salts and trialkylphosphonium salts have been grafted onto the backbone of inulin with the addition of organic solvents. A series of inulin derivatives were conveniently produced, and their chemical structures were characterized by FTIR, C-NMR, and H-NMR spectroscopy. The results showed that the chemical structures of inulin derivatives differed in number and substitution position on the hydroxyl phenolic groups on the aromatic and benzene aldehydes as well as quaternary ammonium salts, triphenylphosphonium salts and trialkylphosphonium salts. Moreover, Dong et al. (2014) formed amphiphilic aminated inulins via click chemistry by introducing triazolyl functional groups and evaluated their chemical structure by C-NMR and FTIR spectroscopy. To the best of our knowledge, this is the first study to modify inulin via click chemistry. In this mechanism, first, a 6-Br inulin derivative was synthesized by the reaction between the primary hydroxyl group of inulin with N-bromosuccinimide (NBS) and triphenylphosphine (Ph3P). Afterwards, the secondary hydroxyl group of the 6-Br inulin derivative was reacted with acetic anhydride; as a result, the amphiphilic aminated inulin was used as a potential biomaterial. Further advancement in the development of HMI derivative techniques is J o u r n a l P r e -p r o o f essential, which should be unique, convenient, relatively less expensive, and environmentally friendly owing to the increased demands of modified natural products. Many industrial products are composed of dispersions including liquid/liquid (emulsions) and solid/liquid (suspensions) dispersions. These dispersions require stabilization against coalescence and flocculation, which is needed to produce an energy barrier between two particles to ultimately prevent them from coming into close proximity, where the van der Waals attraction is large (Tadros, 2017) . The two basic mechanisms of stabilization are reported to include steric and electrostatic stabilization. Electrostatic stabilization works to provide charge separation and production of electric double layers whose extension is influenced by valency and electrolyte concentration. This stabilization mechanism of dispersions is commonly known as 'Deryaguin-Landau-Verwey-Overbeek' (DLVO theory or colloid stability theory). However, electrostatic stabilization of dispersions has not been commonly used due to the high electrolyte concentration, which can destabilize industrial products. One study revealed that ionic emulsifiers in solutions do not easily adsorb at the liquid/liquid and solid/liquid interfaces (Tadros, 2017) . Thus, nonionic surfactants have gained considerable attention due to the excellent stabilization properties of dispersions at high temperature or at high electrolyte concentrations and against high volume fractions, which is also frequently referred to as steric stabilization. It is essential to specify that destabilization difficulties may occur using customary surfactants even in the presence of nonionic stabilizers due to a reduction in the thickness of the adsorbed layer. As a result, coalescence and flocculation are observed in such dispersions (Tadros, 2011) . This instability can be avoided by the utilization of graft (BAn) and block (A-B or A-B-A) nonionic copolymers owing to their considerable physical properties and specific chemical structure (A and B chains). The A chain is referred to as the stabilizing chain (usually with a molar mass > 1000 Daltons), which is hydrophilic and should be soluble in the medium and strongly solvated based on its molecular Flory-Huggins interaction parameter χ (< 0.5), whereas the B chain is considered the "anchor" chain, which is hydrophobic in the medium and highly adsorbed on the surface of droplets or particles (Tadros, 2003) . The steric stabilization of oil-in-water (O/W) emulsions has been achieved through nonionic surfactants, namely, HMI, at higher concentrations of electrolyte and different temperatures, as summarized in Table 1 . Recently, O/W emulsions were prepared by mixing MCT oil and DDSA, OSA, and Inutec ® SP1 solution in a mixer for 3 min at 24,000 rpm. Subsequently, the emulsification properties were evaluated by using zeta potential (Zetasizer) and droplet size measurements (Mastersizer) at various pH values and up to 21 days of storage at room temperature and 50°C. The zeta potential of the OSA inulin derivative was observed to increase (-4.8 mV to -60.8 mV) with increasing pH (1.9 to 9.7), whereas that of the DDSA-inulin derivative was found to increase (2.2 mV to 55.5 mV) within a pH range of 1.8 to 10.2. The results of droplet size as a function of time and temperature were assessed for the DDSA-inulin derivative, OSA inulin derivative, and Inutec ® SP1, and it was observed that the DDSA-inulin derivative showed the greatest emulsification properties (smaller droplet size) of the three compounds (Kokubun, Ratcliffe, & Williams 2018) . The same research group studied the emulsification properties of OSA inulin derivatives and DDSA-inulin derivatives in the presence of electrolytes and during storage. It was also revealed that the ~2% DDSA inulin derivative exhibited a smaller droplet size and produced stronger medium-chain triglyceride emulsions than the OSA inulin derivatives and Inutec ® SP1 (Kokubun, Ratcliffe, & Williams 2015) . The high emulsion stability of OSA and DDSA inulin derivatives has been achieved due to the significantly shorter inulin chain and formation of electrostatic repulsive forces owing to the presence of carboxylate ions in the head group. Tadros et al. (2004) also found similar droplet sizes that were stable, and there was no oil separation for one year against extreme temperature (up to 50°C) and a particular concentration of NaCl and MgSO4 (1 mol dm -3 ). The stability of the Inutec ® SP1 emulsion was also evaluated through cloud-point measurements. There was no sign of cloudiness up to 100°C for the emulsion containing 1 mol dm -3 NaCl and MgSO4. In contrast, the polyethylene glycol surfactant did not demonstrate that ability and exhibited coalescence and flocculation in the solution. The difference in zeta potential among OSA-inulin derivative, DDSA-inulin derivative, and Inutec ® SPI was due to the absence or presence of the ionic group. The OSA inulin derivative and DDSA inulin derivative contain an ionic group that dissociates from alkaline succinic anhydride as the pH increases; on the other hand, Inutec ® SP1 J o u r n a l P r e -p r o o f lacks an ionic group (Nestor et al., 2005) and thus does not exhibit similar trends. The increase in the zeta potential of Inutec ® SP1 is due to the adsorption of the molecules on the surface of oil droplets, which can be formed because of covalent attachment of hydrophobic chains to the modified inulin (Xin et al., 2013; Liu, Sun, Li, Liu, & Xu 2006) . Nestor et al. (2005) and Stevens et al. (2001b) found that Inutec ® SPI droplet aggregation prevented steric repulsive forces produced at the interfaces of carbohydrate moieties. Moreover, Czarnecki (2010) and Gotchev et al. (2011) revealed that the size of the loops of inulin molecules at the interface depended on the alkyl chains attached to it. Furthermore, the experimental results regarding the stabilization of emulsions motivated the interrogation of O/W and W/O emulsions, which were prepared through varying concentrations of oils (Han, Ratcliffe, & Williams 2017) . The stability of the emulsions was evaluated for several inulin derivatives, which were synthesized with various alkyl chain lengths (C10-C16). The inulin derivatives including DS2C10, DS2C12, and DS2C14 were able to stabilize O/W emulsions, whereas DS2C16 did not stabilize O/W emulsions at either 25°C or 50°C. It is important to mention that inulin derivatives such as DS2C16 were only able to stabilize the W/O emulsions. The results obtained from photomicrographs were unambiguous; the droplet size dramatically decreased (~8 µm to ~1 µm) as the DS2C16 concentration increased (0.5%-1.5%). In a preliminary study, the authors also observed the properties of the emulsions immediately after preparation and after 21 days of storage. The emulsion properties of the alkenyl succinylated inulin derivatives (C8-C18) were explained, and Tween 20 was used for comparison. The findings of this work demonstrated that except Tween 20 and the C8-alkenyl succinylated inulin derivative, all the inulin derivatives noticeably stabilized the O/W emulsions. In addition, a slight variation occurred in the droplet size after storage for 21 days (Han, Ratcliffe, & Williams, 2015) . As is known, foods are the prime energy source for humans and help to prevent diseases and live a healthy life. Consequently, it is important to evaluate the stability of emulsions against intestinal lipolysis and gastric proteolysis because the complex sequences of biochemical and physical processes in the human body alter the stability of both O/W and W/O emulsions. Experimental results have shown that HMI increases the stability and functionality of emulsions within a range of CaCl2 concentrations (0-40 mM) and pH values (2.0 INUTEC ® SP1 >HMI-B >HMI-C. The film thickness was markedly decreased with increasing NaCl concentration at a certain level (5×10 -2 mol dm -3 ). In all cases, these NBFs are very stable and have a constant thickness up to the highest possible measured capillary pressure of 45 kPa. With the polymeric surfactant possessing the highest DS, the transition to an NBF of thickness 7 nm occurs even at a low capillary pressure of 36 Pa. With a reduction in DS, the loop size increases, and the transition to an NBF of 7 nm occurs at a higher capillary pressure of 0.5 kPa Exerowa, et al., 2009c . The microinterferometric technique of Scheludko-Exerowa was designed to find the stability of O/W emulsion films against different types of electrolytes (Na2SO4 NaCl and Mg2SO4). The film thickness significantly decreased and produced NBFs in all types of electrolyte at a specific capillary pressure, with no observed influence of electrolyte types on the Gotchev, et al., 2007a. equivalent film thickness, the formation of NBF and disjoining pressure-equivalent film thickness isotherms. The microinterferometric technique of Scheludko-Exerowa was used to measure the stability of wetting films produced on a hydrophilic silica surface. The stability was evaluated against different Inutec ® SP1 concentrations in the presence or absence of Na2SO4 and NaCl. The equilibrium film thickness varied with increasing electrolyte and polymeric surfactant concentrations. The reduction pattern in the equilibrium film thickness can be observed at 10 −1 mol dm −3 NaCl, 10 −6 mol dm −3 Inutec ® SP1 and 10 −2 or 1 mol dm −3 Na2SO4. Nedyalkov, et al., 2007 . The microinterferometric technique of Scheludko-Exerowa was used to measure the stability of wetting films against different types of polymeric surfactants at varying DSs. Gotchev, et al., 2011. O/W = oil-in-water, NBF = Newton black film, HMI-A, HMI-B, HMI-C and 1HMI, 2HMI, 3HMI = Different types of inulin derivatives with different DSs. DS = degree of substitution. In a previous section, we described the stabilization of emulsions by biocompatible polymeric surfactants, i.e., HMI. Consequently, there is a surging interest in exploring the stabilization of suspensions through nonionic polymeric surfactants. Thus, several types of latexes such as butyl acrylate, polystyrene (PS) and poly-(methyl methacrylate) (PMMA) have been developed by emulsion polymerization using potassium persulfate as an initiator, which was determined by turbidimetry measurements and expressed in terms of critical coagulation concentration (CCC) against different types of electrolytes (Table 3 ). In a significant study, Nestor et al. (2005) prepared emulsion polymerization of PS and PMMA particles using an optimum ratio of polymer and monomer. It was reported that Inutec ® SP1 is the best option to stabilize the suspensions owing to an increase in its CCC with an increasing Inutec ® SP1 amount even at a high concentration of CaCl2. However, the latex particles prepared without surfactants showed a low CCC value of approximately 0.0175 -0.05 mol dm -3 . The superior Inutec ® SP1 was shown to stabilize the latex particles at up to 20% monomer content, with a relatively low ratio of surfactant/monomer of approximately 0.002. Esquena et al. (2003) also reported similar results and prepared PS and PMMA particles using surfactant-free and Inutec ® SP1 emulsion polymerization, respectively. The CCC values of the three types of electrolytes were 0.0004 mol dm -3 for Al2(SO4)3, 0.375 mol dm -3 for NaCl, and 0.007 mol dm -3 for CaCl2. As mentioned in the previous report, Inutec ® SP1 can remarkably improve the stability of latex particles due to the higher CCC above a critical polymer concentration, producing a hydrated layer with a thickness of almost 4 nm. The high stability of these latex particles depends on the production of hydrated tails and loops and ample adsorption of Inutec ® SP1 on the latex particles. In 2008, Nestor et al. measured the steric repulsive forces of these latexes, which were adsorbed on glass spheres and plates, by atomic force microscopy (AFM) in the presence of water and varying Na2SO4 concentrations. In the force-distance curve, it was found that the repulsion interactions persisted even against a higher concentration of Na2SO4. Moreover, the layer thickness was significantly decreased from 10 nm to 3 nm with increasing electrolyte concentration from 0.3 mol dm −3 to 1.5 mol dm −3 . The findings of this report were consistent with those of Obiols-Rabasa et al. Recently, Singh, Esquena, Solans, Booten, & Tadros. (2014) stabilized vulcanized natural rubber using HMI determined by measuring the CCC of calcium nitrite. The CCC of vulcanized natural rubber particles significantly increased as the HMI concentration increased; however, high concentrations of calcium nitrite above 0.002 M produced flocs that were observed through optical micrographs. Furthermore, the adsorption conformation in response to the steric repulsive force was evaluated by light scattering and zeta potential measurements, which confirmed that the HMI could improve the colloidal stability of latex particles. Thus, during the stability of latex particles, three types of stability regions can be observed, namely, a stable dispersion region, coagulation region, and weak flocculation region. The development of a more uniform layer of latex was achieved in the weak flocculation region, which has been utilized in the glove manufacturing industry. It is essential to mention that flocculation appeared gradually in the suspensions and showed dramatic behavior, which made it hard to estimate the real CCC values. Thus, the polyethylene oxide does not provide steric stabilization for suspensions at extreme electrolyte concentrations compared to HMI. Nestor, et al. (2005) suspensions was determined by turbidimetry measurements and expressed in terms of CCC using different types of electrolytes. Inutec ® SP1 PMMA and PS The PS and PMMA were prepared using surfactantfree emulsion polymerization and by the addition of Inutec ® SP1, respectively. The stability of these latex suspensions was determined by CCC using Al2(SO4)3, NaCl and CaCl2 as electrolytes. HMI can markedly improve the stability of latex particles due to the higher CCC above a critical polymer concentration and produced a hydrated layer with a thickness of almost 4 nm. Esquena, et al. (2003) Inutec ® SP1, Synperonic A, Synperonic NP PS was formed using emulsion polymerization of Inutec ® SP1, Synperonic A, and Synperonic NP. The stability was measured using AFM in the presence of water and varying Na2SO4 concentrations. For 5 wt % latex, the Inutec ® SP1 concentration was kept constant at 0.0165 wt %, and the initiator concentration was also kept constant at 0.0125 wt %, whereas the cosurfactant concentration was varied between 0.1 and 0.5 wt %. Nestor, et al. (2008) Inutec ® NRA VNR The stability of VNR using HMI was determined by measuring the CCC of calcium nitrite. The adsorption values of steric repulsive force were also studied and determined through dynamic light scattering and zeta potential measurements The CCC of vulcanized natural rubber particles significantly increased with increasing HMI concentrations in up to 0.002 M calcium nitrite. In other cases, flocs are produced in the suspensions. The dynamic light scattering and zeta potential experiments revealed that HMI could stabilize the latex particles. Singh, et al. J o u r n a l P r e -p r o o f modulus was markedly maintained in the presence of up to 0.05 mol dm −3 Na2SO4. PMMA = polymethyl methacrylate, PS = polystyrene, AFM = atomic force microscopy, VNR = vulcanized natural rubber, BuA = butyl acrylate, CCC = critical coagulation concentration. Determining the aggregation behavior of nonionic polymers is a meticulous process, and its importance in drug delivery and nanotechnological systems is undeniable. It is important to mention that the critical micelle concentration (CMC) is a point at which hydrophobic polymers self-assemble into substantial globular aggregates, although the critical aggregation concentration (CAC) measures the concentration at which premicellar aggregates emerge. Moreover, the CAC is an attractive parameter for tuning the formation of micellar-like structures by one or more selfassembling polymer chains and is determined using light scattering spectroscopy, UV/vis spectrometry, self-diffusion coefficients and steady-state fluorescence quenching (Han, Ratcliffe, & Williams 2017) . Furthermore, the hierarchy of surfactants has been expressed at three levels, namely, precipitates (>500 nm), flocks (<100 nm), and aggregates (<20 nm) (Morros, Infante, & Pons, 2012) . It is noted that the solubilization of HMI depends on the CAC or CMC value; for example, a smaller value indicates the excellent solubilization properties of HMI derivatives in the colloidal system. Han, Ratcliffe, & Williams (2017) recently documented the CAC value of synthesized inulin derivatives through surface tension and dye solubilization measurements. The results showed that Sudan IV dye dissolved in the hydrophobic region of the derivatives, confirming that the absorbance value of esterified inulins increased above a critical concentration; as a result, a micellar-like structure was formed, as summarized in Figure 2a . Moreover, the surface tension is measured by using the Du Nouy ring method and is expressed as a function of concentration. The surface tension was found to be low (45 mN/m) for DS2C10 and high (62 mN/m) for DS2C14. The surface tension of esterified inulins dramatically decreased as the alkyl chain length increased, and one would expect that this behavior may be due to the position of chain attachment and varying DSs. Moreover, this effect has been elucidated based on the interplay between the intramolecular and intermolecular interactions of nonionic polymeric surfactants in solutions and at the air-water interface. It was concluded that the amphiphilic inulin derivatives succeeded in forming micellar-like aggregates in the solutions. Likewise, the same group reported that the ASA inulin derivatives also produced micellartype aggregates, with successful dissolution of the tested dye (Han, Ratcliffe, & Williams 2015) . The abovementioned findings are in agreement with the results of Kokubun, Ratcliffe, & Williams (2013) . The authors reported the CAC values of OSA and DDSA inulin derivatives in comparison with Tween 20 and ASA-inulin samples using dynamic light scattering, dye solubilization, conductivity, and surface tension measurements. The results revealed that the CAC value of DDSA decreased from 12 to 6% as the amount of hydrophobic dye increased. Moreover, the surface tension ranged from ∼35−40 mN/m using concentrations of 0.05% and 0.6% for DDSA and OSA inulin derivatives, respectively, as shown in Figure 2c . In contrast, Tween 20 and ASA exhibited less interaction with the hydrophobic dye than OSA and DDSA. In addition, the conductivity results were not presentable because the authors did not find inflexion of the head groups, which did not pack close together. Recently, another study reported the surface tension values of Inutec ® SPI, DDSA, and OSA, which were 49 mN/m, 42 mN/m, and 38 mN/m, with noted inflexions of 0.0025%, 0.020%, and 0.70%, respectively. Though it is not surprising that the CAC values for DDSA and OSA were higher regarding Inutec ® SPI, OSA exhibited higher CAC values than DDSA (Kokubun, Ratcliffe, & Williams, 2018) . Moreover, the results regarding dye solubilization were consistent with the surface tension values. Nestor et al. (2005) and Srinarong et al. (2011) presented similar tendencies concerning surface tension that decreased with increasing concentration, i.e., 0.00035% and 0.009% from ∼68 to ∼45 mN/m and ∼55 mN/m, respectively, for Inutec ® SP1. Moreover, the surface excess (air/water interface) reached 1.44 nm 2 , 0.74 nm 2 , and 0.87 nm 2 for OSA, DDSA, and Inutec ® SP1, respectively (Kokubun, Ratcliffe, & Williams, 2018) . In contrast, Stevens et al. (2001b) documented surface excess values of approximately 0.9 nm 2 for Inutec ® SP1. Furthermore, the interfacial tension at the interface between aqueous solutions of the abovementioned inulin derivatives and MCT oil was graphed as a function of concentration and found to be reduced as the concentration increased; however, no evident inflexion was observed (Figure 2b ). This effect may be due to the heterogeneous nature of the modified inulin samples (Kokubun, Ratcliffe, & Williams 2015) . However, the interfacial tension has been reported to be approximately 13 mN/m, 16 mN/m, and 8 mN/m for the Inutec ® SPI, DDSA, and OSA inulin derivatives, respectively. Although the value was almost close to that of Stevens et al. (2001b) , it was 6.8 mN/m for Inutec ® SPI at the Isopar/M oil/water interface. Furthermore, Morros J o u r n a l P r e -p r o o f et al. (2012) synthesized HMIs including InEC8, InEC12, and InEC14 and discussed the surface tension compared to that with Inutec ® SP1. In all cases, the surface tension was decreased, reaching 72.0 mNm -1 at 1 mM (~0.5% (w/w)) for water, but drastically was reduced to approximately 66 mNm -1 for 10% inulin solution, whereas it was nearly 40 mNm -1 for the InEC8 derivative and between 30 and 20 mNm -1 for InEC14, InEC12, and Inutec ® SP1. The results indicated the correlation between surface tension reduction, concentration, and equilibrium. Archetypal equilibration times can last for more than two hours, with reductions in surface tension up to 20 mNm -1 . The documented findings showed that the HMI derivatives are attractive contenders, with equilibrium surface tension values as low as 30 mNm -1 . Another study described the CMC of commercially available Inutec ® SP1, which was used for encapsulation of anticancer drugs. The emission spectrum was measured at 375 nm (I1) and 384 nm (I3), whereas the excitation wavelength was fixed at 334 nm. Accordingly, the CMC was measured by taking the midpoint of the Inutec ® SP1 concentration at which the relative fluorescence intensity ratio of I3/I1 was varied. The CMC of Inutec ® SP1 reached 27.8 µg/ml, which made it possible to stabilize the O/W emulsions, films, and foams (Muley, Kumar, Kourati, Kesharwani, & Tummala 2016) . This result was consistent with a previous report in which inulin was used for film formation (Kurečič et al., the CAC for the formation of self-assembling inulin-LA conjugate micelles was demonstrated to be 0.0669 mg/ml (Wang et al., 2018) . In 2014, Licciardi, Scialabba, Sardo, Cavallaro, & Giammona reported the self-assembled micelle structure of graft copolymers including inulinceramide and inulin-ceramide PEG2000 in water. The results revealed that the CAC values were very consistent for both inulin ceramide and inulin-ceramide PEG2000, achieving 6×10 -2 and 5×10 -2 mg/ml, respectively. By contrast, the CAC value was measured by determining the crossover point of two straight lines, which reached 3.0 × 10 −4 g/L in an aqueous environment, which means that the formation of nanoparticles occurred (Zhang, Li, Wang, Li, Zhao, & Yang 2014) . It is important to mention that the HMI derivatives showed more ability to form a micellar-like structure than HMP derivatives, with CAC values ranging from 24.5 × 10 −2 to 24 × 10 −2 mg/ml in the different solutions Wu et al., 2014; Zhu et al., 2011) . This exceptional performance of HMI derivatives regarding aggregation behavior can enhance the research interest in exploring notable critical aggregation values. As a type of organic polysaccharide, inulin plays imperative roles in any living creature. It has been rapidly gaining great attention due to its increased applications as a biomaterial attributable to its biodegradability, low immunogenicity, high availability, and biocompatibility cucumerium Owen. The findings showed that all modified inulin derivatives had the potential to degrade the fungi due to their broad-spectrum antifungal activity. Thus, at 1.6 mg/ml, the inhibitory rates of 3-HBSAIL were excellent, i.e., 82%, 93%, and 83%, against Phomopsis asparagi, Botrytis cinerea, and Fusarium oxysporum f. sp. cucumerium Owen, respectively (Chen et al., 2020) . Another study performed by the same group, who prepared seven inulin derivatives with aromatic Schiff bases, found complete inhibition of the growth of plant pathogens such as Fusarium oxysporum f., (sp. cucumerium Owen, sp. Niveum), Phomopsis asparagi and Botrytis cinerea at 1.0 mg/ml (Chen et al., 2019b) . Moreover, the inhibitory indices of 3,4DCBSAIL were 100% at 1.0 mg/ml, and Botrytis cinerea showed more sensitivity to all inulin derivatives; F. oxysporum f. sp. niveum was more vulnerable to derivatives containing chlorine; and, F. Additionally, Guo et al. (2014) reported the antifungal spectrum of inulin derivatives prepared by The results showed that all the developed inulin derivatives, particularly dichlorobenzylideneamino pyridyl acetyl inulin chloride, inhibited the activity of the phytopathogens Fusarium oxysporum, Colletotrichum lagenarium and Phomopsis asparagi, with inhibitory rates of approximately 43%, 67%, and 47%, respectively, at 1.0 mg/ml. Another research group synthesized triazole (4a˗4d) and triazolium (5a-5d) inulin derivatives and tested them against the plant pathogens C. lagenarium and Gibberella zeae (Li, Qiu, Tan, and Gu, 2017) . The findings suggested that the triazolium derivatives at 1.0 mg/ml had excellent antifungal indices, ranging from 45.31% to 57.93% for C. lagenarium and 43.10% to 82.56% for Gibberella zeae. The results revealed that the antifungal ability of triazolium may be largely attributed to the alkylation of the 1,2,3-triazole moiety. The substantial effect of the triazolium inulin derivatives may be due to their cationic nature, which interacts with anionic components on the cell wall of fungi. In contrast, 'click chemistry' is an attractive platform for the chemical modification of inulin, with a significant inhibitory rate of approximately 58% against Staphylococcus aureus at 1 mg/ml . The reports, as mentioned earlier, were almost consistent with the findings of Ren et al. (2012) , who synthesized the 6-amino-6-deoxy-inulin derivative using radical, and hydroxyl radical scavenging assays. Hydroxyl radicals are very strong oxidative free radicals that can cause cell death by damaging pyrimidines and purines in DNA (Chen et al., 2019b) . DPPH radicals are very persistent nitrogen-centered free radicals by virtue of their steric and conjugation barrier effects. Additionally, superoxide anion free radicals are a type of free radical formed during the metabolic process of all living organisms. Consequently, these free radicals attack biological macromolecules, further act as a precursor of hydrogen peroxide and hydroxyl radicals, and as a result, damage cell function and structure. In other words, the superoxide anion is one of the most destructive molecules for aerobic life owing to its toxic nature and large production (Chen et al., 2019b; Liochev, 2013) . The reduction ability of polysaccharides, including inulin, is also a prevalent mechanism corresponding to antioxidant activity (Chen et al., 2020) . The reductive mechanism of inulin is dynamic, producing K4Fe (CN6) using the abovementioned methods. Compared to that of native inulin, the antioxidant activity of all inulin derivatives was effectively increased. The documented results demonstrated that the 3-HBSAIL-inulin derivative at 1.6 mg/ml significantly scavenged DPPH and hydroxyl radicals. Moreover, 2,3,4-THBSAIL and 3,4-DHBSAIL-inulin derivatives at 1.6 mg/ml exhibited exquisite antioxidant activity toward DPPH and superoxide radicals, with scavenging indices of approximately 100% and 90%, respectively. These two inulin derivatives also exhibited excellent antioxidant activity, even at a low concentration, i.e., at 0.1 mg/ml. In a deep analysis, it was found that scavenging ability against hydroxyl radicals decreased as the number of phenolic hydroxyl groups on the benzene ring decreased, in the order 2,3,4-THBSAIL> 3,4-DHBSAIL> 4-HBSAIL> 3-HBSAIL, with scavenging rates ranging from 79% to 100%. The same trend was also observed in the case of DPPH and superoxide radicals, with the order 3-HBSAIL> 4-HBSAIL> 2-HBSAIL> BSAIL. The results further proved the importance of phenolic hydroxyl groups in the case of radical scavenging ability. Moreover, the position of the phenolic hydroxyl groups on the benzene J o u r n a l P r e -p r o o f ring influences the scavenging ability. In general, the meta-position is more advantageous. It is worth mentioning that the number of phenolic hydroxyl groups did not influence the two inulin derivatives 2,3,4-THBSAIL and 3,4-DHBSAIL regarding superoxide and DPPH radical scavenging ability. The results of the reductive ability were nearly in agreement with the findings of DPPH and superoxide radicals. The inulin derivatives such as 2,3,4-THBSAIL and 3,4-DHBSAIL demonstrated better reductive abilities of approximately 3.9 and 3.7, respectively, at 1.6 mg/ml. Moreover, the 4-HBSAIL 3-HBSAIL, 2-HBSAIL, and BSAIL inulin derivatives showed better reductive ability than native inulin. Accordingly, the reductive ability of inulin derivatives is affected by the numbers of phenolic hydroxyl groups on the benzene ring. The same group found the antioxidant activity of inulin derivatives that were prepared with quaternary ammonium salts. The findings showed that 1.6 mg/ml 2-imidazoleacetyl inulin chloride (IAIL) had great scavenging rates of approximately 67.8% for superoxide radicals and 86.7% for hydroxyl radicals compared to those of the 2-triethylamine acetyl inulin chloride (TAIL) and 2- (1-methylimidazole) acetyl inulin chloride (MAIL) derivatives. In general, the results demonstrated that imidazole and quaternary ammonium salt enhanced the antioxidant activity of inulin derivatives compared with native inulin. The results also revealed that the antioxidant rates may be increased due to the hydrophobic moiety of the prepared inulin derivatives . The profound alteration of IAIL and MAIL regarding antioxidant ability may be due to the substitution of 1-H by ethyl groups in the imidazole molecule. Moreover, a novel series of inulin derivatives were synthesized by using 1,2,3-triazole quaternization, and their antioxidant activity was assessed at different concentrations . The DPPH, hydroxyl, and superoxide radical scavenging activity of the inulin derivative triazolium (5a to 5d) was better than that of the triazoles (4a to 4d). It is important to mention that the 5a to 5d and 4a to 4d inulin derivatives were characterized by H-NMR spectroscopy. The antioxidant ability was reported in the order of 5a-5d (IC50 0.16-0.32 mg/ml) ˃ 4a-4d (IC50 0.34-0.59 mg/ml) ˃ inulin. Moreover, another research group elucidated the antioxidant activity of native inulin and modified inulin through DPPH, hydroxyl, and superoxide radical scavenging activity assays. The inulin derivatives, i.e., 4-APAIL and 3,4-DAPAIL, exhibited exquisite antioxidant activity up to 80% at 0.4 mg/ml, reaching 85% at 1.6 mg/ml. The results suggested that the number of amino groups on pyridine significantly affected the antioxidant activity of inulin derivatives against the aforementioned radical scavenging models (Hu et al., 2014) . Furthermore, Ren, Liu, Dong, & Guo (2011) and Ren, Liu, J o u r n a l P r e -p r o o f derivatives by using superoxide and hydroxyl radical scavenging activity assays. The results revealed that the inulin derivatives demonstrated excellent antioxidant activity compared to unmodified inulin (Figure 4 ). In addition, the modified inulin derivatives presented an average hydroxyl radical scavenging activity of approximately 35%, whereas the superoxide radical scavenging activity ranged from 72.08-83.74% at varying concentration levels (0.1-1 mg/ml) and DSs (0.14, 0.20, 0.54, 0.70, and 0.76). The antioxidant activity of modified inulin could be improved with increasing DS. Furthermore, it is noted that the attached -NH2 group might be conducive to the superoxide radical scavenging ability. Thus, the antioxidant activity is a significant property describing the functional attributes of HMI, which will be presented below. The development of functional foods and their acceptance by consumers have escalated the demands of producing healthy food products. These functional foods contain a variety of health compounds, specifically polyphenols, whose ingestion is beneficial to the prevention of certain conditions, including hyperuricemia, hepatic injury, cancer, cardiovascular diseases (CVDs) and oxidative stress (Manach, Scalbert, Morand, Rémésy, & Jiménez 2004; Mehmood et al., 2020; Mehmood et al., 2019) . Thus, several studies have focused on the modification of inulin and the production of SCFA inulin esters. It is important to note that these esters have transformed the gut microbiota and improved the biological half-life of SCFAs due to the biotransformation of beneficial metabolites and increase the beneficial metabolites in the gut microbiota as reported in Figure 5b (Polyviou et al., 2016; Flint, Scott, Louis, & Duncan 2012) . It was found that the biological life cycle of SCFAs is shallow in the human gut microbiota, which has been well documented in various studies, reaching 13.5 minutes (Daniel et al., 1989) . Further, SCFAs participate in energy metabolism, strengthen immunity, and help stimulate anorectic gut hormones (Bjerkeng, Storebakken, & Wathne 1999) . Several findings have confirmed that the utilization of drugs for the treatment of hepatic injury may be imperfect and exhibits partial therapeutic effects due to the variability of humans. Henceforth, there has been surging interest in exploring advanced strategies that can ameliorate hepatic injury risk, diabetes mellitus, and management of body weight ( Figure 5a ). Interestingly, bioavailable propionates have been found to promote the release of gastrointestinal hormones, such as glucagon in the form of peptide-1 and peptide YY (PYY), to lower body weight and regulate appetite. Furthermore, these compounds were associated with reduced lipid and cholesterol levels. Similar to propionate, acetate can reduce appetite and induce apoptosis in colorectal cancer cells by increasing the amount of anorectic gut hormones including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), and it also inhibits the production of TNF-alpha, which mediates hyperinsulinemia (Freeland and Wolever, 2010; Frost et al., 2014) . The basic mechanism behind lowering the glycemic index is to impede the absorption of glucose using hydrolyzing enzymes, such as α-amylase and α-glucosidase. Like acetate and propionate, butyrate plays an important physiological role in reducing the risk of colon cancer by taking advantage of the substantial functions of the colonic epithelium (Pingitore et al., 2017; Roshanravan et al., 2017) . decreased food intake, confirming that propionate plays a significant role in appetite modulation in the colon. The outcomes of this study were consistent with those of Chambers et al. (2014) , who prepared IPE and proved that IPE inhibited food ingestion in adults by stimulating the release of GLP-1 and PYY from human colonic cells. Moreover, the stable isotope technique revealed the release of propionate from IPE. This result indicated that more than 80% of propionate was released in the colon, suggesting that only a small quantity of esterified propionate was enzymatically degraded in the small intestine. Thus, the optimum levels of SCFAs, particularly propionate in the colon, can regulate body weight management on a large scale. However, the optimum percentage of SCFAs in the human gut microbiota is still unknown (Xu et al., 2020) . Additionally, the physiological impact of IPE was evaluated on 21 obese or healthy overweight humans. For this purpose, IPE was added to food products, such as fruit smoothies and bread rolls. The findings showed that IPE-food products dramatically regulated appetite and augmented resting energy expenditure (REE), whereas the results regarding metabolic and hormone analysis were nonsignificant. To date, this is perhaps the first study concerning the direct addition of IPE into palatable food products in order to obtain practical results due to its lack of side effects on the GIT . The same research group has explored the effect of IPE and inulin on insulin sensitivity, systemic inflammatory responses, gut microbiota, and plasma metabolome in obese adults. It is important to emphasize that the molar and total percentages of SCFAs were insignificant in fasting and stool serum. However, IPE and inulin diet intervention markedly enhanced insulin resistance, reaching 1.23 and 1.17, respectively, compared to 1.59 for cellulose using homeostatic model assessment 2. A similar trend was observed in adipose tissue insulin resistance and was found to be approximately 6.5, 6.3, and 8.3 mmol/L×µU/ml for IPE, inulin, and cellulose, respectively. In addition, IPE and inulin altered the bacterial strains in the gut microbiome at the order, class, and species levels. However, there was no difference observed at the phylum level. For example, compared to cellulose supplementation, IPE supplementation enhanced the amount of It is important to point out that the results regarding the systemic inflammatory response were significantly different between IPE and inulin diet intervention . Likewise, Malkova et al. (2019) reported the physiological impact of 4-week IPE diet intervention under a normal exercise training schedule on plasma satiety hormones (viz., PYY and GLP-1) and body weight management. In total, 20 healthy overweight women volunteers contributed to this study and were divided into two groups, i.e., EX/placebo and EX/IPE. The results revealed that the EX/IPE group had decreases in body fat mass from 37.7 to 36.9% and body weight from 77.3 to 76.6 kg. This effect was achieved due to increased intra-abdominal fat oxidation. The abovementioned in vivo studies have documented that supplementation with 10 g/day and 20 g/day IPE or IPE-food products is essential to manage body weight and body fat mass by reducing ad libitum energy intake and improving fat oxidation. Moreover, IPE diet intervention could increase the REE, but further research is required to understand whether IPE has the potential to enhance the REE. It has been confirmed that IPE supplementation also regulates appetite by anorectic gut hormones. Therefore, the essential mechanism for IPE appetite reduction remains to be elucidated. It is well known that the oral administration of SCFAs is unstable and unpalatable as a dietary mediation strategy. However, other pathways such as encapsulation of the duodenal supply are conceivable, but whether large or small intestinal SCFAs facilitate the aforementioned outcomes in a physiologically identical manner remains unknown. Moreover, valerate and caproate inulin esters remain to be studied. Valerate and caproate also have essential health effects but have drawn less attention. These two SCFAs are beneficial for glucose and lipid metabolism and reduce nonhigh-density lipoprotein cholesterol levels. They were also shown to increase the microbial abundance of Coprococcus spp. and Prevotella spp (Tap et al., 2015; Zhao et al., 2017) . J o u r n a l P r e -p r o o f Microencapsulation is a robust technology involving the physical entrapment of delicate elements in a homogeneous or heterogeneous matrix, leading to their protection. This technology comprises several types of methodologies, for instance, freeze-drying, spray-cooling, spraychilling, spray-drying, coacervation, polymerization, and evaporation. Most of them are solventbased and involve expensive manufacturing and purification steps to obtain the desired product. According to the targeted properties of the substance, application, and material, the development of novel formulations requires different encapsulation or particle formation techniques. Nevertheless, the most frequently applied technology is 'spray-drying', which is substantially due to the cost-effectiveness and equipment availability (Beirao-da-Costa et al., Walz, Hagemann, Trentzsch, Weber, & Henle, 2018 . The formation of micellar aggregates by HMI derivatives has attracted much interest in recent years (Kokubun, Ratcliffe, & Williams 2018) . Several studies have been conducted on the encapsulation of HMI for drug delivery and release, as summarized in Table 4 . Walz, Hirth, & Weber (2018) studied the encapsulation of dexpanthenol with inulin alone and acetylated as well as propionylated inulin by spray-drying. By the esterification of acetic anhydride and propionic anhydride with free hydroxyl groups, inulin was chemically modified. The yields of inulin alone, acetylated inulin and propionylated inulin were 78%, 82%, and 60%, respectively, indicating that acetylated inulin had the maximum yield among them. Additionally, the particles displayed a great encapsulation efficiency of approximately 100% for all polymeric materials. In another study published that year, the same group scrutinized the degradation of modified inulin as a prospective encapsulation material for the release of mesalamine and colon targeting (Walz, Hagemann, Trentzsch, Weber, & Henle, 2018) . Encapsulation of mesalamine with inulin and acetylated inulin was accomplished by spray-drying, and analysis of the release behavior was performed. The encapsulation efficiency of inulin was higher, i.e., 109% ± 10%, than that of AcIn (84% ± 5%). In addition, the particle yield was 82% for inulin and 87% for acetylated inulin. HMI, i.e., octenyl-and dodecenyl succinic anhydride derivatives (OSA-and DDSA-) of inulin have also been manufactured; their properties such as solution and interfacial properties were compared with those of a commercially available alkylated inulin, Inutec ® SP1, along with the study of their emulsification as well as encapsulation properties (Kokubun, Ratcliffe, & Williams, 2018) . The encapsulation of beta-carotene with HMI was performed using the solvent evaporation method. Encapsulation using anionic succinylated J o u r n a l P r e -p r o o f derivatives had amazing benefits in the controlled release of beta-carotene in comparison with commercial nonionic Inutec ® SP1. The DDSA-inulin sample was more effective in encapsulation, with a higher degree of modification than OSA-inulin and Inutec ® SP1. These materials exhibit promising applicability in the encapsulation of active compounds, including antimicrobials, drugs, vitamins, aromas, etc. Furthermore, the drug delivery application of HMI-based doxorubicin (DOX) and paclitaxel (PTX) micelles for breast cancer treatment was studied to assess the transport mechanisms (Kesharwani, Dachineni, Bhat, and Tummala, 2019) . INT micelles encapsulated with doxorubicin (DOX) and paclitaxel (PTX) were produced by a thin-film hydration method. INT-micelles represent an exclusive delivery system for one or more chemotherapeutic agents, with very high drug encapsulation efficiency (89.5% with DOX and 76.6% for PTX). EPB and loading contents were calculated to be 81.3% and 8.1%, respectively, with increased tumor inhibition and decreased systemic toxicity. It was expected that the encapsulation efficiency of OSA-and DDSA-inulin derivatives is similar to that of graft and block copolymers; however, the encapsulated properties of graft and block copolymers remain to be studied. Here, it is important to stipulate that there is still a plethora of research needed for the optimization of encapsulation methodologies for several inulin derivatives to augment the encapsulation efficiency, which would serve as a tool to design novel encapsulated drugs or vaccines in controlled delivery systems. Natural biomolecule-based drug delivery systems have recently emerged as a novel approach to protect, release or encapsulate hydrophobic therapeutics or bioactive compounds or drugs to increase their biological potency. These macromolecules comprise proteins, including zein, gelatin, etc., polysaccharides including inulin, starch, chitosan, etc., and lipids, including lipid nanocarriers such as lipid-drug conjugates (LDCs), solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) (Chen, Miao, Campanella, Jiang, & Jin 2016 . Due to their many favorable characteristics such as cost-effectiveness, nontoxicity, nonreactivity, availability at a large scale, biodegradability and biocompatibility, the most wellknown choice for targeted nutraceuticals or drug delivery systems is polysaccharides. Polysaccharides also possess physicochemical characteristics, offering suitable sites for chemical modification as needed and permitting informal fabrication of particles and hydrogels for delivery or release purposes. These compounds also promote adapted cellular physiology, which is responsible for several aforementioned properties. Overall, polysaccharides are the paramount choice for the creation of drug delivery vehicles (Barclay, Day, Petrovsky, & Garg, 2019) . Recently, cellulose derivatives have commonly been used as essential ingredients in the manufacturing of cosmetics, production of functional foods, and formulation of pharmaceutical Zhang et al. (2016) products (Abbaspoor et al., 2019) . Moreover, many other considerable examples, such as dextran (Anirudhan, 2016) , hyaluronic acid (Tripodo et al., 2015c; Huang and Chen, 2019a) , chitosan (Sahariah and Masson, 2017) , pullulan (Alhaique, Matricardi, Di Meo, Coviello, & Montanari, 2015) , and starch (Chen, Hao, Ting, Li, & Gao, 2019) , have widely been applicable in the field of pharmaceuticals. However, these compounds have some potential disadvantages as drug delivery vehicles including their mixed molecular weights, variable chemistry, lack of solubility in most organic solvents, and slow enzymatic degradation, which makes it hard to precisely define the delivery vehicle (Barclay, Day, Petrovsky, & Garg, 2019) . The fact that inulin is not digested or absorbed by humans in the small intestine makes this polymer an alluring transporter for gastrointestinal drug delivery. Thus, inulin has been demonstrated to be a versatile substance for application as a drug vehicle. Moreover, inulin may serve as a perfect model for microbially activated drug delivery to the colon, which leads to sole applications such as identification of kidney function and colonic targeting, where metabolization by microbiota present in the colon has been utilized (L´opez-Molina et al., 2015) . Compared with other saccharides, inulin varies in terms of the type of glycosidic bond between monomers as well as molecular weight. It possesses a higher molecular weight than saccharides, which is relevant to a lower solubility, along with a higher glass transition and melting temperature as well as higher viscosity. Inulin also has high molecular flexibility because of its (2→1) linked d-fructosyl backbone in comparison with other saccharides (L´opez-Molina et al., 2015 , Kokubun, Ratcliffe, & Williams, 2018 . Reducing groups of saccharides are undesired for various pharmaceutical applications. Therefore, inulin is more suitable as an excipient than other saccharides when there is concern about reducing groups (Mensink et al., 2015) . It also received generally recognized as safe (GRAS) status by the Food and Drug Administration (FDA) due to its several outstanding properties including biodegradability, renewability, nontoxicity, etc., compared to many other polysaccharides as described in Figure 6 (Afinjuomo et al., 2019) . Over the past few years, hydrophobically modified polysaccharides (HMPs), especially hydrophobically modified inulins (HMIs), have been gaining greater attention in numerous drug delivery systems owing to their capability to produce self-assembling micelles and alleviate safety concerns (Kokubun, Ratcliffe, & Williams, 2018 , Kesharwani, Dachineni, Bhat, & Tummala, 2019 . Polymeric micelles have also received substantial interest as versatile drug delivery J o u r n a l P r e -p r o o f platforms. Micelles are self-assembling colloidal particles comprising two chief parts, namely, a hydrophilic shell and a hydrophobic core, which play a key role in the pharmacokinetic behavior of the delivery system. A hydrophilic shell interacts with aqueous biological fluids, while the hydrophobic core acts as a repository for poorly water-soluble drugs (Kesharwani, Dachineni, Bhat, & Tummala, 2019) . The application of inulin alone as a hydrophobic drug delivery vehicle is inadequate due to its high water solubility. For its application as a gastrointestinal drug carrier material, the physicochemical characteristics of inulin can be altered by the replacement of hydroxyl groups with hydrophobic functional groups. Thus, inulin derivatives have been manufactured to acquire suitable systems for various applications including hydrogels, surfactants, microspheres, etc. (Sun et al., 2017 . Recently, inulin has been fabricated with many hydrophobic functional groups including methyl esters, fatty acid chlorides, alkyl epoxides, alkyl isocyanates, etc., in organic solvents to obtain several hydrophobic derivatives. HMI has numerous benefits, such as biodegradability, biocompatibility, renewability, and strong stability at extreme electrolyte concentrations and under highly acidic conditions as well as extreme temperatures (Doost, Dewettinck, Devlieghere, & Van der Meeren et al., 2018) . Drug targeting can be defined as the targeted delivery of a drug to the site of action. The reproducible and continuous release rate of the pharmaceutical or targeted compound is the benefit of drug targeting, which helps to prevent overdose and in turn alleviates the side effects and drug toxicity. In the recent few decades, an upsurge in the global frequency of colonic diseases has resulted in the increased urgency for operational local treatment of colonic diseases, for instance, Crohn's disease, ulcerative colitis, amebiasis, colonic cancer, colorectal cancer (CRC), inflammatory bowel disease (IBD), etc., for more effective and safer drug therapies. There is an extreme need for targeted drug delivery into the colon for local treatment of a range of bowel diseases and colonic pathologies through the systemic delivery of protein and peptide drugs (Walz et al., 2017 , Philip and Philip, 2010 . Colon targeting has developed increasing interest over the past few decades because of its ability to treat colon-specific diseases with fewer side effects. Colon-targeted drug delivery systems, in addition to contemporary delivery, are advantageous for improving the bioavailability of drugs that are at risk of enzymatic or acidic disruption in the upper gastrointestinal (GI) tract, specifically macromolecules such as proteins and peptides, because of lower protease activity in the colon. This approach of transporting a hydrophobic drug into the lower intestinal tract might emerge as an effective plan to achieve local drug release and a targeted therapy for various intestinal diseases (Walz et al., 2017 , Mandracchia et al., 2017 . For decades, there has been rising interest in inulin-coated metallic nanoparticles, inulinbased hydrogels, inulin-based nanomicelles, and inulin-conjugated polymeric nanoparticles for drug delivery applications (Figure 7 ). Inulin has been chemically modified to obtain new photocrosslinkable derivatives. UV-photocrosslinking of inulin derivatives resulted in the formation of hydrogels that were applied for the drug delivery of ibuprofen (Tripodo et al., 2005) . swelling and degradation data. In contrast, the INU-MA1 hydrogel acted as a drug delivery system after oral administration, even though the release of the drug was not dependent on alterations in physiological pH. HMIs such as Inutec ® SP1 present a safe, low-cost, and natural alternative to broadly used PEG-modified polymers for the formulation of micellar delivery systems for paclitaxel. Inutec ® SP1 possesses outstanding tensioactive properties and is an emulsifier in the pharmaceutical industry. Thus, for micellar delivery of paclitaxel, it has been utilized as an amphiphilic carbohydrate polymer through the intravenous route. The paclitaxel (PTX)-embedded micelles showed high drug encapsulation efficiency (95.66±2.25%) and loading (8.69±0.22%); moreover, they displayed low toxicity and exceptional hemo-compatibility toward cultured cells as well as the continued release of PTX and greater anticancer efficiency in vitro in mouse melanoma cells (B16F10) and equivalent in vivo antitumor activity in a B16F10 allograft mouse model (Muley, Kumar, El Kourati, Kesharwani, & Tummala, 2016) . The chemical modification of inulin results in a decline in enzymatic degradation capability by enzymes, which can be expressed by the colon microbial flora. Degradation studies of modified inulin as a potential encapsulation material and release of mesalamine in the colon have been conducted. Different degrees of substitution of acetylated inulin were obtained. Microparticles synthesized from inulin and acetylated inulin were loaded with the colon-specific drug mesalamine by spray-drying. Acetylated inulin microparticles presented less burst release of mesalamine than inulin particles within 6 hours, followed by a continuous drug release phase (Walz, Hagemann, Trentzsch, Weber, & Henle, 2018) . Further, the applicability of inulin as a drug vehicle system for dexpanthenol in particles has been explored. By esterification of free hydroxyl groups with propionic anhydride and acetic anhydride, chemically modified inulin was prepared using a spray-drying technique, resulting in smooth and spherical particles. Dexpanthenol (1%) was encapsulated, and release behavior studies were conducted. Overall, chemically modified inulin derivatives showed a longer drug release; i.e., after 24 hours, acetylated inulin particles released 60% of the drug, and only 10% of the drug was released by propionylated inulin. On the other hand, inulin particles released 100% dexpanthenol after 6 hours (Walz, Hirth, & Weber, 2018) . For the transport of the highly J o u r n a l P r e -p r o o f hydrophobic drug celecoxib, INVITE-SA, a pH-sensitive micelle prepared from a succinylated inulin-vitamin E polymer, has been proven to be the best choice for targeted site-specific intestinal drug delivery. Mandracchia et al. (2018) synthesized pH-sensitive inulin-based nanomicelles INVITE-SA for intestinal site-specific and controlled release of celecoxib. The resulting INVITE-SA micelles were nanosized, with a pronounced pH-dependent release profile. The micelles were stabilized against acidic hydrolysis, and drug release was strongly dependent on the pH. At pH 1.2 in PBS, only 1% of the drug was released after 2 h in PBS; however, at pH 6.8 in PBS, a controlled and quick release occurred for nearly 10 h. Inulin-based micelles embedded with curcumin or celecoxib, which are highly hydrophobic drugs, display prominent antiangiogenic activity (Mandracchia et al., 2016) . This study was the first to report angiogenesis suppression triggered by CLX-loaded polymeric micelles. CUR or CLX were introduced to INVITE micelles by the dialysis method. Not only CUR-loaded but also CLX-loaded INVITE micelles showed notable antiangiogenic activity, as proven by in vivo CAM experiments. Additionally, there was a rise in the water solubility of CUR and CLX by using this INVITE nanotechnology. These results have opened the doors in regenerative medicine as well as anticancer or diabetic maculopathy therapy based on the antiangiogenesis strategy. For cancer therapy, the inulin-based glutathione-receptive delivery system was found to be productive in colorectal cancer and promoted the growth and development of useful commensal microbiota in the gut. Inulin esterified with lipoic acid and a novel delivery system for tanshinone IIA for the treatment of colorectal cancer in vitro were established. It was observed that in tumor cells, the drug-loaded CR micelles discharged the loaded drug along with the addition of 10 mM DTT, and the release of tanshinone IIA in the system was highly receptive to glutathione (Wang et al., 2018) . Further, a rifampicin (RIF)-loaded antituberculosis drug (Tripodo et al., 2019b) . During the last decade, regarding deteriorating pathologies of the retina, corticosteroid therapy has arisen as a propitious treatment. Nevertheless, it is essential to discover an alternative promising ocular delivery system J o u r n a l P r e -p r o o f that can release corticosteroids very effectively. An amphiphilic derivative of inulin (INU-EDA-RA) was synthesized by fabrication with ethylenediamine (EDA) and retinoic acid (RA) to form micelles in aqueous media using the solvent casting method. Three corticosteroid drugs, viz., dexamethasone (DEX), triamcinolone (T), and triamcinolone acetonide (TA), loaded with INU-EDA-RA micelles were selected for the treatment of degenerative pathologies of the retina. It was observed that INU-EDA-RA micelles quickly released a high percentage of the entrapped drug based on the drug release profiles. Owing to the mucoadhesive properties, capability to release encapsulated drugs, and suitable particle size, this drug delivery system is ideal for ocular drug delivery (Di Prima et al., 2017) . For the delivery of single or amalgamated therapeutics in breast cancer treatment, HMIbased micelles are inexpensive, efficient, and safe alternatives. Nanomicelles of lauryl carbamate HMI (Inutec SP1) used to transport a combination of chemotherapeutic drugs (PTX and DOX) for breast cancer treatment were synthesized by the thin-film hydration technique. The drug encapsulation efficiency was found to be very high with INT nanomicelles (89.5% with DOX and 76.6% for PTX). At pH 7.4, the in vitro drug release from the micelles was constant for more than 72 h, and PTX was released at a lower rate than DOX (approximately 50%) from INT-D within the initial 24 h because PTX is more hydrophobic than DOX (Kesharwani, Dachineni, Bhat, & Tummala, 2019) . Very recently, octenyl-succinylated inulin (OSA-inulin) particles produced by freeze-drying were studied for the entrapment and release of beta-carotene. Beta-carotene was easily dissolved in the hydrophobic cores of the micelles, and alterations in pH activated its release. When administered into gastric fluid at pH 2.5, the encapsulated beta-carotene was not released from the freeze-dried particles. Conversely, it was readily released in small intestinal fluid at pH year, using the same INVITE micelles as nanocarriers for effective intravenous injection of curcumin to develop the biopharmaceutical characteristics of hydrophobic drugs (Tripodo et al., 2015b) . The authors prepared INVITE bioconjugates with different degrees of derivatization, i.e., INVITE 1, 2, and 3, and further evaluated their drug release profile. INVITE 3MC was able to release 42% curcumin in PBS at pH 7.4 in 48 h and 53% at pH 5.5, while INVITE 2MC released 23% curcumin in PBS at pH 7.4 in 48 h and 33% at pH 5.5. In the case of INVITE 1MC, 15% of curcumin was released in PBS at pH 7.4 and 25% at pH 5.5. It was observed that curcumin release for all of the INVITE micelles at pH 5.5 was ≈10% higher than that at pH 7.4 and was controlled by penetration through the cellular membrane. The synthesis of self-assembling micelles based on amphiphilic inulin graft copolymers for anticancer model drug doxorubicin delivery was reported by Licciardi, Scialabba, Sardo, Cavallaro, & Giammona, (2014) . The micelles based on two graft copolymers, INU-ceramide and INU ceramide-PEG2000, were loaded with the drug doxorubicin, and its release was studied in different media; the micelles were able to release DOXO in the complete form for a longer time without burst release with 16-17 wt % of drug loading. A study was conducted to assess whether cinnamoylated inulin is inhibited by the enzyme inulinase to reveal its potential in colonic drug delivery. Microspheres of cinnamoylated derivatives of inulin were synthesized in the presence of Tween 20, and it was found that these microspheres were proficiently hydrolyzed by the inulinase enzyme and were successfully embedded with MTX. The MTX release by these microspheres was controlled, and the observation was made that MTX release from the microspheres was triggered by enzymatic hydrolysis of the polymer by inulinase (Lopez-Molina et al., 2015) . Small interfering RNAs (siRNAs) have also been found to possess therapeutic value for many human diseases such as cancer, metabolic diseases, neurodegenerative diseases, and cardiovascular diseases in comparison with traditional drugs, which epitomize an evolving model for the treatment of many human diseases. Sardo et al. (2015) designed a novel inulin-diethylenetriamine (Inu-DETA)-based siRNA transporting system that effectively delivered functional siRNAs and was highly cytocompatible with no cytotoxicity, opening the way for the treatment of these aforementioned diseases. Magnetic nanoparticles represent an advanced group of nanocarrier materials that can deliver target anticancer drugs, and this ability of magnetic nanoparticles has been utilized by Scialabba et al. (2014) . The authors designed a novel self-assembly based on inulin-polymer (PEGylated squalene grafted inulin amphiphile)-coated superparamagnetic iron oxide J o u r n a l P r e -p r o o f nanoparticles (SPIONs) for targeted cancer therapy, which were able to self-organize into nanocarriers to deliver the drug doxorubicin. The nanoparticles liberated doxorubicin in the intact form for a prolonged time without a first burst effect and displayed higher anticancer activity than the free drug, exhibiting excellent magnetic targeting. Further, self-assembling core-shell-type nanostructures of enzyme-sensitive inulin-dehydropeptide conjugates were analyzed for targeted delivery of ornidazole as a remedy for gastrointestinal diseases (Shivhare et al., 2017) . Dehydrophenylalanine was introduced in the peptide to stabilize it over a broad spectrum of pH values and proteases. In addition to drug delivery, the effect of the inulinase enzyme on inulin peptide degradation has been studied, and it was concluded that the discharge was controlled in the presence of the inulinase enzyme, where ~93% of ornidazole was liberated. The semicrystalline form of inulin, i.e., delta inulin or AdvaxT, induces the development of cellular as well as humoral immune responses to a wide spectrum of antigens after interacting with the immune system. This property of nanostructured delta inulin particles to boost the immunogenicity of injected protein antigens has been utilized as a vaccine adjuvant . It was observed that the administered delta inulin particles were transported to the liver as well as secondary lymphoid tissue after being primarily taken up by macrophages, hydrolyzed to be dispersed into the bloodstream and finally eliminated into the urine. Furthermore, delta inulin was modified by coating doxorubicin on its nanostructured surface for application in targeted drug delivery for anticancer therapy . The authors used the property of delta inulin in which it is endocytosed by monocytes to design a platform to transport doxorubicin to lymphoid organs. The study showed that 2.48 ± 0.12% w/w doxorubicin was loaded onto the surface of the delta inulin. The drug release profile revealed pH-dependent controlled drug discharge in artificial lysosomal fluid (ALF), reflecting the applicability of delta inulin-doxorubicin particles for the treatment of cancer. J o u r n a l P r e -p r o o f Vaccines have been considered to be one of the most vital scientific breakthroughs for the prevention and treatment of numerous infectious diseases. For several diseases, including cancer, AIDS, Ebola, malaria, influenza, etc., the unavailability of current vaccine technologies is attributable to their inability to adequately stimulate both cellular and humoral immune responses at safe doses. Hence, before any severe pandemic or epidemic disease outbreaks such as COVID-19, there is a medical necessity to investigate new vaccine adjuvants or technologies on an immediate basis (Kumar, Kesharwani, Kuppast, Bakkari, & Tummala, 2017; Gallovic et al., 2015) . A novel pathogen simulating a vaccine transporting system was developed by targeting specific signaling pathways of the innate immune system. To overcome alum's numerous J o u r n a l P r e -p r o o f inadequacies, chemically modified inulin, Ace-IN, was used to provide numerous characteristics that have benefits for a vaccine delivery vehicle when encapsulated into microparticles (MPs), playing dual roles as an immune-stimulatory adjuvant and antigen delivery vehicle (Gallovic et al., 2015) . Naturally occurring inulin polysaccharides have been chemically modified to produce acid-sensitive hydrophobic microparticles (MPs) (acetylated inulin, Ace-IN) by oil-in-water emulsions followed by solvent evaporation. Texas Red-labeled OVA (TR-OVA) antigen was encapsulated in Ace-IN MPs using the W/O/W homogenization procedure. At pH 7.4, TR-OVA was released slowly from Ace-IN MPs, with just 20% release at 168 hours, while after optimization, 100% release of OVA occurred in only 16 hours at pH 7.4. Moreover, higher production of anti-OVA IgG antibody levels was identified when mice were immunized with Ace-IN MPs embedded with ovalbumin (OVA) antigen. To target antigen-presenting cells (APCs), a unique particle-based pathogen-mimicking vaccine delivery system (PMVDS) was designed by Kumar, Kesharwani, Kuppast, Bakkari, & Tummala (2017) using inulin acetate (InAc), which triggered innate immunity. PMVDS delivered improved, prolonged antigen delivery to APCs very efficiently and concurrently as an immune-adjuvant, activating Toll-like receptor-4 (TLR-4) on APCs to release cytokines. The release of the OVA antigen was controlled to less than 25% of the total embedded antigen and was constant for a more extended period than the control. This technology has broad applications in developing a new generation of vaccines against both intracellular and extracellular pathogens. The encapsulated hydrophobic inulin-loaded drugs have been much better studied than vaccines, which may be due to the wider availability of drugs as therapeutic compounds. However, it is imperative to develop new vaccines loaded with natural materials, such as hydrophobic inulin. Currently, nanotechnology is at the cutting edge of drug delivery and pharmaceutical research. Recently, due to their noteworthy superiority in increasing antitumor efficiency and attenuating toxicity, especially in cancer treatment, nanoparticle-based drug delivery systems have attracted growing attention. When the formulation is meticulously injected or entrapped, the nanoparticles gradually release the anticancer drugs inside solid tumors with the appropriate sizes and surface properties. Due to the subcellular and nanoscale size, this nanoparticle drug delivery system can simply permeate deeply through tissues and delicate capillaries (Kesharwani, J o u r n a l P r e -p r o o f Dachineni, Bhat, & Tummala, 2019; Zhang, Li, Wang, Li, Zhao, & Yang, 2014) . The application of methylprednisolone-loaded ibuprofen-modified inulin-based nanoparticles prepared by selfassembly for drug delivery in the treatment of spinal cord injury was studied. The synthesis of ibuprofen-modified inulin was achieved by in situ activation of the carboxylic acid with N,N′carbonyldiimidazole through a direct esterification linkage. Methylprednisolone-loaded nanoparticles did not display evident cytotoxic effects when assessed against RSC-96 cells. The drug encapsulation and loading amounts were found to be 91.2 ± 1.2% and 14.9 ± 0.8%, respectively. A drug release study showed that approximately 94.9% of the loaded methylprednisolone was released from the nanoparticles within 96 h. (Zhang, Li, Wang, Li, Zhao, & Yang, 2014) . Two years later, the same research group employed RGD peptide-modified inulinibuprofen nanoparticles for targeted delivery of epirubicin, which was used against several types of cancers. For targeted drug delivery, RGD-coupled EPB-based nanoparticles were fabricated by the self-assembly of inulin-ibuprofen polymer and in situ entrapment of EPB. It was observed that the RGD-coupled EPB-loaded nanoparticles increased cellular uptake and lowered cytotoxicity. More importantly, they exhibited better tumor growth suppression and decreased systemic toxicity. The EPB release exhibited a speedy burst release profile; the EPB release profile at pH 5.0 was found to have a slower release speed, with approximately 67% of the total EPB released before 24 h in comparison with that at pH 7.4, where 87% of the EPB was released from EPB-loaded nanoparticles after 48 h (Zhang et al., 2016) . Redox-sensitive nanoparticles coupled with 4aminothiophenol-carboxymethyl inulin (ATP-CMI) were prepared for the specific delivery of budesonide (BDS) to the swollen mucosa in inflammatory bowel diseases. The ATP-CMI-based nanoparticles (NPs) were obtained by embedding 4-aminothiophenol onto carboxymethyl inulin (CMI). The NPs displayed a high release rate (80 wt %) in GSH containing 20 mM GSH. In contrast, GSH-free media showed a low release rate (45 wt %) (Sun et al., 2017) . Currently, it is essential to seek a way to boost the transcorneal entry of drugs to effectively treat chronic ocular diseases. Di Prima et al. (2019) recently developed an inulin-based mucoadhesive PEGylated selfassembling nanoparticle INU-EDA-RA-PEG drug delivery system for improved transcorneal penetration of corticosteroids. INU-EDA-RA-PEG was utilized to synthesize self-assembling nanoparticles and corticosteroid-loaded self-assembling nanoparticles by the film rehydration technique. The self-assembling nanoparticles demonstrated suitable particle size values, J o u r n a l P r e -p r o o f mucoadhesiveness, and cytocompatibility and were capable of loading and discharging a high quantity of triamcinolone (T), dexamethasone (DEX), and triamcinolone acetonide (TA). As a result, the inulin-based self-assembling nanoparticles displayed substantial potential for ocular topic drug delivery. Inulin is a popular natural polysaccharide owing to its (ⅰ) high molecular flexibility, (ⅱ) easy availability, (ⅲ) high biodegradability, biocompatibility, (ⅵ) low toxicity, and (ⅴ) nonreactogenicity. In other words, its modification is very easy and tends to be used to provide steric stabilization for various dispersion formulations. Moreover, hydrophobic inulin has a wide range of functions as a targeted drug delivery vehicle in the human body, encompassing (ⅰ) a range of targeting approaches appropriate for gastrointestinal fate, (ⅱ) a potential prospect to enhance the biological half-life of loaded therapeutics, and (ⅲ) improvement of the circulation of phagocyte cells that ingest damaging particles, dead cells, and bacteria. One drawback of this natural polysaccharide as a drug excipient is that it is hard to define the structure of this polysaccharide regarding chemistry and molecular weight owing to its environmental and seasonal variations. The above-emphasized disadvantage of inulin in drug vehicles is that it is not a permanent solution for all self-healing drug applications. Notwithstanding, the advantages of inulin more often outweigh the disadvantages, and thus, in the future, it is expected to be utilized on a large scale in pharmaceutical science in drug vehicles through normal biological and physical processes. It is an enticing fact that the derivatization of inulin can enhance the functionalities in a single simple system and can further provide magnificent solutions to the intricate problems facing encapsulated hydrophobic inulin-mediated drugs. It is clear that these meticulous studies have promoted the application of hydrophobic inulin in various drugs and even in vaccines in the future. The The authors confirm that they have no known competing financial interests or personal relationship that could have appeared to influence the manuscript. The authors declare no conflict of interests. 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Carbohydrate polymers Synthesis and hydroxyl radicals scavenging activity of N-(aminoethyl) inulin. Carbohydrate polymers Synthesis and antifungal properties of 6-amino-6-deoxyinulin, a kind of precursors for facile chemical modifications of inulin Facilitated synthesis of inulin esters by transesterification Use of acyl phosphonates for the synthesis of inulin esters and their use as emulsion stabilizing agents Effect of butyrate and inulin supplementation on glycemic status, lipid profile and glucagon-like peptide 1 level in patients with type 2 diabetes: a randomized doubleblind, placebo-controlled trial Antimicrobial chitosan and chitosan derivatives: a review of the structure-activity relationship Development of a simple, biocompatible and cost-effective Inulin-Diethylenetriamine based siRNA delivery system Inulinbased polymer coated SPIONs as potential drug delivery systems for targeted cancer therapy Lipid nanocarriers: Preparation, characterization and absorption mechanism and applications to improve oral bioavailability of poorly water-soluble drugs Enzyme sensitive smart inulin-dehydropeptide conjugate self-assembles into nanostructures useful for targeted delivery of ornidazole Influence of hydrophobically modified inulin (INUTEC NRA) on the stability of vulcanized natural rubber latex Simple Method for Rheological Determination of Surfactant Layer Thickness Surface-active derivative of inulin (Inutec® SP1) is a superior carrier for solid dispersions with a high drug load Chemical modification of inulin, a valuable renewable resource, and its industrial applications Polymeric surfactants based on inulin, a polysaccharide extracted from chicory. 1. Synthesis and interfacial properties Cationic curdlan: Synthesis, characterization and application of quaternary ammonium salts of curdlan. Carbohydrate polymers Redox-sensitive nanoparticles based on 4-aminothiophenol-carboxymethyl inulin conjugate for budesonide delivery in inflammatory bowel diseases Interaction forces between particles containing grafted or adsorbed polymer layers Interaction forces between adsorbed polymer layers Stabilisation of dispersions using a graft copolymer of hydrophobically modified polyfructose Stabilisation of emulsions using hydrophobically modified inulin (polyfructose) Gut microbiota richness promotes its stability upon increased dietary fibre intake in healthy adults The allyl ethers of various carbohydrates Inulin as a multifaceted (active) substance and its chemical functionalization: From plant extraction to applications in pharmacy, cosmetics and food Mesenchymal stromal cells loading curcumin-INVITE-micelles: A drug delivery system for neurodegenerative diseases Inulin-d-α-tocopherol succinate (INVITE) nanomicelles as a platform for effective intravenous administration of curcumin Drug delivery of rifampicin by natural micelles based on inulin: Physicochemical properties, antibacterial activity and human macrophages uptake UVphotocrosslinking of inulin derivatives to produce hydrogels for drug delivery application Hyaluronic acid and its derivatives in drug delivery and imaging: recent advances and challenges Ulvan, a bioactive marine sulphated polysaccharide as a key constituent of hybrid biomaterials: A review. Carbohydrate polymers Distribution of substituents in O-carboxymethyl and O-cyanoethyl ethers of inulin Degradation studies of modified inulin as potential encapsulation material for colon targeting and release of mesalamine. Carbohydrate polymers Investigation of chemically modified inulin as encapsulation material for pharmaceutical substances by spray-drying Inulin based glutathione-responsive delivery system for colon cancer treatment Synthesis, antimicrobial activity of Schiff base compounds of cinnamaldehyde and amino acids Investigation of the biodistribution, breakdown and excretion of delta inulin adjuvant Doxorubicin-Loaded Delta Inulin Conjugates for Controlled and Targeted Drug Delivery: Development, Characterization, and In Vitro Evaluation In vitro evaluation of polymeric micelles based on hydrophobically-modified sulfated chitosan as a carrier of doxorubicin The influence of common free radicals and antioxidants on development of Alzheimer's Disease In vitro drug release and biological evaluation of biomimetic polymeric micelles self-assembled from amphiphilic deoxycholic acid-phosphorylcholine-chitosan conjugate Influence of CTAB and SDS on the properties of oil-in-water nano-emulsion with paraffin and span 20/Tween 20 Chemically modified polysaccharides: Synthesis, characterization, structure activity relationships of action Dynamic balancing of intestinal short-chain fatty acids: The crucial role of bacterial metabolism Biological activities and pharmaceutical applications of polysaccharide from natural resources: A review. Carbohydrate polymers RGD-peptide conjugated inulin-ibuprofen nanoparticles for targeted delivery of Epirubicin Synthesis of methylprednisolone loaded ibuprofen modified inulin based nanoparticles and their application for drug delivery Preparation, characterization and antibacterial activity of octenyl succinic anhydride modified inulin Structure-specific effects of short-chain fatty acids on plasma cholesterol concentration in male syrian hamsters Folate-modified chitosan micelles with enhanced tumor targeting evaluated by near infrared imaging system Synthesis, Characterization of Inulin Propionate Ester, and Evaluation of its in Vitro Effect on SCFA Production The authors wish to express their deep gratitude and appreciation for the support obtained from the National Key Research and Development Program of China (2017YFD0400206). Mandracchia et al. (2016)