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Potential Applications of Chitosan-Based Nanomaterials to Surpass the Gastrointestinal Physiological Obstacles and Enhance the Intestinal Drug Absorption

Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli 10540, Samut Prakan, Thailand
Author to whom correspondence should be addressed.
Pharmaceutics 2021, 13(6), 887;
Received: 7 May 2021 / Revised: 6 June 2021 / Accepted: 11 June 2021 / Published: 15 June 2021
(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery)


The small intestine provides the major site for the absorption of numerous orally administered drugs. However, before reaching to the systemic circulation to exert beneficial pharmacological activities, the oral drug delivery is hindered by poor absorption/metabolic instability of the drugs in gastrointestinal (GI) tract and the presence of the mucus layer overlying intestinal epithelium. Therefore, a polymeric drug delivery system has emerged as a robust approach to enhance oral drug bioavailability and intestinal drug absorption. Chitosan, a cationic polymer derived from chitin, and its derivatives have received remarkable attention to serve as a promising drug carrier, chiefly owing to their versatile, biocompatible, biodegradable, and non-toxic properties. Several types of chitosan-based drug delivery systems have been developed, including chemical modification, conjugates, capsules, and hybrids. They have been shown to be effective in improving intestinal assimilation of several types of drugs, e.g., antidiabetic, anticancer, antimicrobial, and anti-inflammatory drugs. In this review, the physiological challenges affecting intestinal drug absorption and the effects of chitosan on those parameters impacting on oral bioavailability are summarized. More appreciably, types of chitosan-based nanomaterials enhancing intestinal drug absorption and their mechanisms, as well as potential applications in diabetes, cancers, infections, and inflammation, are highlighted. The future perspective of chitosan applications is also discussed.

1. Introduction

Oral entry route is the most favorable and frequently used pathway for drug administration owing to its simplicity, feasibility, convenience, low-cost manufacturing process, non-invasiveness, and safety for most patients [1,2]. After intake of medication, the orally administered drugs travel down to the stomach and they are majorly absorbed at the proximal part of small intestine before entering the systemic circulation. However, the drug substances have to challenge with the harsh environment of the gastrointestinal (GI) tract, including gastric pH, digestive enzymes, bile salts, GI motility, and intestinal mucosal layers, ameliorating the drug absorption or drug assimilation and leading to poor oral bioavailability [3,4]. In order to overcome these physiological obstacles, the drug delivery system has been designed and developed. The ideal characteristics of nano-drug carriers are safe, biocompatible, biodegradable, acid-tolerant, and GI enzyme-stable [5,6,7]. Moreover, to deliver the drugs to the systemic circulation, the carriers should help to penetrate the mucosal microenvironment and prolong the drug-mucosa contact time for extent duration of drug absorption [8,9]. In response to the fluctuation of pH along the GI tract, the suitable carriers should be able to control the drug release in each GI segment. In recent times, the investigators have taken the advantages of these properties found in the natural polymers, particularly chitosan [2,4].
Chitosan is a cationic linear heteropolysaccharide, consisting of β-(1,4)-linked D-glucosamine (GlcN, deacetylated monomer) and N-acetyl-D-glucosamine (GlcNAc, acetylated monomer) [10,11]. It is obtained from chitin, containing β-(1,4)-linked 2-acetamido-2-deoxy-β-D-glucose, which is the second-most abundant natural polymer in the world and is mostly found in the structural component of exoskeletons of crustaceans (e.g., shrimps, lobsters, and crabs), insects, and arthropods as well as in the cell wall of fungi [10,11]. The outstanding features of chitosan, including natural abundance, water solubility, non-toxicity, biodegradability, and chemical modifiability, make this natural biomaterial attractive as an ideal candidate for adopting in pharmacological and biotechnological applications [8]. In the drug delivery system, the chitosan-based nanoparticles have been formulated by several techniques, such as chemical modification, ionic gelation, and polyelectrolyte complexation methods [12,13]. These nanomaterials can boost up the oral drug absorption by improving mucoadhesion, the permeation-enhancing effect, and controlled drug release [2,4,8,9].
Herein, the aims of this review are (i) to provide the comprehensive knowledge involving GI physiological challenge-modulated intestinal drug absorption and oral bioavailability, as well as (ii), to address the implication of chitosan and various types of emerged chitosan-based nanomaterials in the improvement of intestinal drug assimilation.

2. The GI Challenges of Intestinal Drug Absorption

In any given patients, the orally taken drugs must encounter a ruthless GI environment, which is influenced by multiple determinants, such as the age, gender, and ethnicity of the treated patients [14,15,16,17]. These factors can affect the physiologically challenging variables involved in the drug absorption, including intraluminal pH, gastric emptying time, intestinal transit time, GI motility, intestinal transporter proteins, gut microbiota, and disease conditions (Figure 1).
Age-dependent alteration of oral drug absorption gives rise to the adjustment of drug dosing to meet the medical requirement, particularly in childhood, due to the immaturity of the GI tract [14,18]. Therefore, tailor-made pediatric dosage at a specific age is necessary. In addition, poor cooperation in pediatric patients makes it more difficult. For the elderly, the frailty is associated with the progressive impairment of organ structures and functions, which affects the GI physiology and oral drug bioavailability [15,19]. Additionally, polypharmacy in advancing age brings about the increased risk of adverse drug reactions and poor drug compliance [19]. Gender-based changes in GI function also needs to be considered. The difference in occupational exposures, behavior, lifestyle, and medications between men and women leads to the dissimilarity in body weight, body surface area, and the amount of water, contributing to sex-divergent pharmacokinetics [20,21]. Ethnicity/race-related differences in body response to medications has been documented due to the interaction of genetic variation and the environmental factors [17,22]. In particular, the racial genetic difference is resulted from the variance in genetic polymorphisms [23,24].
The GI physiological challenges limit the capability of absorption of orally taken drugs and thus affect their oral bioavailability. The amount of drugs that are assimilated at the absorption site will reflect the alteration of the pharmacokinetics in the patients, compared with normal subjects. A synopsis of the physiological challenges impacting on oral drug bioavailability is recapitulated as below and is depicted in Figure 1. In addition, the effect of chitosan on those parameters and disease states are included.

2.1. Gastric pH

The gastric pH is acidic, with a pH between 1.5 and 3.5. When passing down to the small intestine, the pH slowly increases to 5–6 in the duodenum and 7–8 in the jejunum and terminal ileum. Meanwhile, the pH falls to 5.7–6.4 in the caecum and rises again at the range of 6.1–7.5 in the descending colon and rectum [14,25]. Therefore, the drugs have to expose to the variation of the pH along the GI tract, which may cause the deactivation of the drugs, particularly in protein and peptide drugs by the modulation of differential oxidation, hydrolysis, or deamination of these drugs [26]. In the drug delivery system, the environmental pH determines the drug dissolution and drug absorption by affecting the degree of ionization (pKa) of the drug substrates [27]. The water-insoluble weakly alkaline drugs are ionized and dissolved in the low-pH stomach lumen, but have poor drug absorption at the small intestine [28]. Impaired drug absorption of weak basic drug can occur in the stomach of the patients with achlorhydria or hypochlorhydria, which have no or decreased gastric acid secretion, respectively [29]. In addition, the patients who took weakly basic drugs with antacids, which could cause a rise in gastric pH, were reported to reduce the drug absorption of those basic drugs by the chelation with polyvalent cations (e.g., Ca2+, Mg2+, and Al3+) and subsequent formation of insoluble complex [30,31].
At birth, the gastric pH is neutral due to the presence of amniotic fluid in the stomach. It then gradually decreases until the age of two years, reaching to the adult-equivalent pH [32,33]. In the elderly, the gastric pH is increased, resulting in the slight decrease in drug absorption [19,33]. In women, smaller gastric secretion is found with pH ~ 0.5 units higher than in men. Therefore, the drugs that require the acidic gastric pH have a poorer bioavailability in women [20,34,35].
Chitosan has the amino group with the pKa of ~6.5, relating to the degree of N-deacetylation, and is fully protonated at the pH of ~4, resulting in the increase in acidity of chitosan [36,37]. Therefore, the chitosan-loaded drug has better mucoadhesive and permeation-enhancing properties, promoting drug absorption at proximal part of GI tract, including stomach and duodenum, when compared with the chitosan-free group [4,8,37,38]. The problem is that chitosan precipitates at the pH of >6.5 in the jejunum, ileum, and colon, and thus chitosan has less adhesion to the mucus layer of GI tract, leading to the ineffective drug absorption [38,39]. Interestingly, this drawback is solved by the modification of chitosan, such as thiolated chitosan, which will be addressed in a later section [40,41,42].

2.2. GI Motility

The GI motility is defined as the contraction and relaxation of GI smooth muscles to propel the contents along the GI tract with the change in intraluminal pressure and it is a causal determinant for the drug absorption. The gastric emptying, which is a process of removing the content from the stomach and moving it into the duodenum, also has an impact on the intestinal assimilation [43,44]. The increasing rate of gastric emptying, found in the case of solutions or suspensions, may lead to a rise in the drug absorption rate [25,45,46]. However, medications for gastric ulcer need delayed gastric emptying in order to prolong in the stomach. After reaching the small intestine, the content of drugs in the bowel needs a sufficient residence time and a long intestinal transit time in order to facilitate the opportunity of drug absorption at this site, owing to the enormous surface area of the small intestine [47,48,49]. Peristaltic contraction also enhances the capacity of drug absorption, as it promotes drug dissolution and membrane–drug contact [50]. In addition, the volume of GI luminal fluids may contribute to drug assimilation by affecting drug dissolution and providing the driving force for drug permeation [51,52]. In adults, the rate of gastric emptying is varied, relating to fasted and fed conditions [33,53]. At the age of 6–8 months, the gastric emptying is much slower than that in adults, owing to the immature development of neural control for GI motility [54]. Moreover, in the elderly, there is the delayed gastric emptying and a decrease in GI motility [19]. Indeed, women have slower gastric emptying than men, which gives rise to a longer gastric retention time and attenuates drug absorption [34,55,56]. Therefore, in women, a longer interval between having meals and taking drugs is required [56].
Chitosan-poly(acrylic) acid (PAA) polyionic complex was fabricated and was shown to prolong gastric retention of ampicillin, an antibiotic used for the treatment of Helicobacter pylori infection-induced gastric ulcer, in swelling and drug release studies, suggesting a role in drug absorption enhancement of this complex [57]. Furthermore, chitosan-based nanoparticles using sodium tripolyphosphate (TPP) as a cross-linking agent were revealed to delay gastric emptying, as well as to improve the absorption and oral bioavailability of ketoconazole, an antifungal drug with poor absorption due to rapid gastric emptying and a short gastric residence time [58]. In addition, in ex vivo porcine gastric mucosa, ketoconazole-loaded chitosan/TPP was demonstrated to adhere to negatively charged mucin layers, implicating good mucoadhesive properties of this nanoparticle formulation [58].

2.3. Transport Proteins and Enzymes

The drug substances reaching to the small intestine, where the major site for drug absorption is taken, can be transported across the enterocytes by several mechanisms, such as simple diffusion, active transport, facilitated transport, and pinocytosis, via the paracellular or transcellular route. However, the drugs can be pumped out of enterocytes by the ATP-binding cassette (ABC) efflux transporters, which are a major hindrance for the drug assimilation. The drug transporter proteins located at the apical side of the intestinal epithelial cells include P-glycoprotein (P-gp) multidrug resistance protein-2 (MRP-2) and breast cancer resistance protein (BCRP) [59,60,61,62,63]. These transporters are responsible for the drug efflux into the intestinal lumen. In addition, they can bind to some unspecific compounds other than drug substrates; therefore, they may attenuate the absorption of some drugs, such as antibiotics, lipid-lowering agents, and anti-cancer drugs. Meanwhile, the other transporters located at basolateral side of enterocytes comprise MRP-1, -3, and -5, which are for pumping the drug into the blood circulation [63,64,65,66,67,68]. In the small bowel, the drugs also encounter bile salts and pancreatic enzymes secreted into the intestinal lumen. These bile salts and pancreatic enzymes contribute to the drug dissolution and solubility in the GI tract [69,70]. The intestine-absorbed drugs will pass into the liver via the portal vein in order to undergo drug metabolism. The drug-metabolizing enzymes (DMEs), including cytochrome P450 (CYP450) and CYP3A, also modulate the drug absorption and oral bioavailability [71,72,73]. The immaturity of the GI function in pediatric patients causes the increase in epithelial permeability [33,74]. The intestinal drug absorption in newborns might be variable due to irregular peristalsis. The expressions and functions of efflux transporter protein (i.e., P-gp) and tight junction may increase with age, as the early infancy relies on the passive diffusion [75,76]. However, Toornvliet and colleagues revealed the decreased activity of P-gp efflux transporter in the elderly [77]. For ethnicity-based drug assimilation, the genetic polymorphisms are variedly distributed to a gene product related to drug metabolism enzymes, including CYP450 superfamilies, and transport proteins, including P-gp and organic anion transporting polypeptides [OATPs] [17,78,79]. Several studies have suggested that the P-gp expression is abundantly found in Africans, compared with Caucasians [80,81,82,83].
Interestingly, chitosan can attenuate the P-gp expression in dose-dependent manner, and thereby enhance the oral bioavailability of norfloxacin, an antibacterial agent used for the treatment of gram-negative bacteria infection, in Grass Carp [84]. For the chitosan conjugates, curcumin-carboxymethyl chitosan was developed, serving as an inhibitor of P-gp and an enhancer of drug absorption [85]. In addition, quercetin-chitosan (QT-CS) conjugate was synthesized as an enhancer of drug absorption of doxorubicin by inhibiting P-gp, opening tight junction, and enhancing the water solubility [86]. Carboxymethyl chitosan-quercetin conjugate also helped to improve oral drug delivery and oral bioavailability of paclitaxel by inhibiting P-gp and increasing its water solubility [87].

2.4. Gut Microbiota

The human gut microbiota, containing >1014 microbes and their genome, resides in the distal segment of the GI tract, particularly in the ileum and colon [88]. For the small intestine, there is less gut microbiota due to its lower luminal pH, higher levels of oxygen delivery, and higher concentrations of antimicrobial agents [89,90,91,92]. The gut microbiota helps to regulate the immune system and to maintain physiological conditions. Importantly, it can ferment the indigested carbohydrates and proteins, giving rise to the byproducts as short-chain fatty acids (SCFAs) [93,94]. Moreover, the gut microbiota and microbial metabolites can metabolize endogenous substances such as amino acids, cholesterol, and bile acids, by various enzymes (e.g., glucuronidases and glucosidases), and modulate the pharmacokinetics (i.e., drug absorption and drug metabolism) [95]. The study of the drugs affected by gut microbiota sheds the light on personalized medicine to predict the drug pharmacokinetics for individual patients. The human microbiome can alter drug-induced pharmacological and toxicological effects. For example, the gut microbiota can alter the oral bioavailability and activity of insulin, as it is susceptible to proteolysis [92,96]. Additionally, it may increase acetaminophen-induced hepatotoxicity, involved with p-cresol, a microbial metabolite [97]. The enhanced toxicity of diclofenac by gut microbiota is associated with the deglucuronidation and delayed excretion [98]. The decrease in firs pass a metabolism effect and high levels of intestinal β-glucuronidase activity were documented in neonates [99]. The gender difference contributing to the gut microbiota compositions has not been well-addressed due to its inconsistency. However, several lines of evidence related to the sex difference in gut microbiota have been documented [100]. Ethnicity-, dietary-, and lifestyle-specific variations in gut microbiota composition are also observed [101,102].
Several studies have reported that chitosan and its derivatives can modulate the gut microbiota imbalance. For instance, carboxymethyl chitosan has revealed to alter the gut microbiota in Escherichia coli (E. coli)-treated mice, affecting to fat and glucose metabolism, as well as the inflammatory profile [103,104]. It was also found that chitosan-chelated zinc has reduced the intestinal inflammatory process and mucosal injury in E. coli-infected rats by reversing the gut bacterial composition [105]. In addition, chitosan oligosaccharide (COS), a derivative of chitosan, has been exhibited to restore the gut microbial imbalance in diabetic mice [106].

2.5. Disease Conditions

The disease conditions can influence the drug absorption of orally administered drugs, as they impact on the structures and functions of GI tract organs, including esophagus, stomach, small intestine, and large intestine. The change in drug absorption is associated with the alteration of the aforementioned physiological characteristics.
In diabetic patients, they secrete less gastric acid than healthy individuals [107]. Therefore, the gastric pH is increased, resulting in the poor absorption of basic drugs. However, the delayed gastric emptying and prolonged transit times have been impressed in diabetes [108,109,110]. Importantly, owing to the microvascular complications, the gastric blood flow is declined, leading to further delayed gastric emptying and affect to the drug absorption in the small bowel. The alterations of P-gp expression and function under diabetic conditions were decreased in diabetic rats [111]. However, some evidence has mentioned that the P-gp expression is temporally induced and then restored to a baseline level [112]. In addition, it has been shown that the level of the CYP3A4 enzyme is reduced, leading to the change in the oral bioavailability of some drugs related to CYP3A4 activity, such as carbamazepine, anti-retroviral drugs and some statins [113,114]. In obesity, a larger gastric volumes and lower gastric pH have been reported, compared with lean subjects [115]. The gastric emptying time in obese patients is controversial [25]. For the intestinal transporter proteins, the inhibition of P-gp could result in hepatic steatosis and obesity using P-gp deficiency mice fed a high-fat diet model [116]. The CYP34A enzyme activity was found to be reduced in obese individuals; therefore, it needs to be cautious when using CYP3A4 substrates, inhibitors, or inducers in these patients [117]. For the treatment of diabetic patients, oral insulin is applied due to its greater convenience and its less adverse drug reaction than subcutaneously injected insulin. However, it still interferes with proteolytic degradation and mucosal layers in the GI tract. Insulin-loaded chitosan nanoparticles increase residence time to retain in the GI tract and enhance mucoadhesion, therefore promoting drug assimilation [118,119].
In patients with gastric cancer, the gastric pH is 6–7, which results from the gastric atrophy and decreased gastric secretion [120,121]. The gastric emptying is slower than in healthy subjects, and is further decreased after gastrectomy [122,123]. However, the oral anticancer drugs may improve their efficacy as they retain in the stomach for a longer duration, thus providing sufficient time for gastric tumor to expose with drugs [124]. For colorectal cancer, the transit time is not clear, although the colon motility change in this type of cancer is well-known [25]. Of note, the efflux transporters (e.g., P-gp, MRP-2, BCRP) were reported to be altered in cancer cells and were still the big concern for the drug resistance in the cancers [125,126]. Doxorubicin is an oral chemotherapy used in the treatment of considerable cancers, including lung, gastric, breast, thyroid, and ovarian cancers, by acting on the nucleus of target cells [127,128,129]. Doxorubicin was documented to have a low bioavailability because it was abolished by the first-pass metabolism of CYP450 and the overexpression of P-gp [130,131,132,133]. It was shown that doxorubicin-loaded chitosan nanoparticles increased the permeation across intestinal epithelium. Moreover, when conjugating with quercetin, it inhibited the P-gp efflux transporter. Collectively, chitosan was claimed to relieve the poor absorption of doxorubicin [87,131].
The effect of GI tract infections on oral drug assimilation is unpredictable, as the GI membrane damage induced by infections can cause both the increase and decrease in drug intestinal absorption. The delayed gastric emptying may be associated with an increasing chance of experiencing nausea and vomiting and a longer onset of medications, resulting in uncontrolled drug plasma concentrations. H. pylori infection leads to the decrease in gastric secretion and the impairment of drug absorption. The poor absorption of some antibacterial drugs (e.g., gentamicin, metronidazole) were alleviated by the drug-chitosan complex [134,135]. For pain and stress, the alterations of GI physiology are relevant to the gut–brain axis, such as the reduction in GI motility, gastric secretion, and mucosal blood being low [136]. It was demonstrated that chitosan-based hydrogels could manipulate the drug release of paracetamol in the intestine [137]. Besides, a chitosan complex could regulate the drug release properties of ibuprofen, a non-steroidal anti-inflammatory drug (NSAID) [138].
The altered kinetics of drug absorption in these disease states have been partially acknowledged. Further investigations involving pharmacokinetics towards personalized and precision medicines should be considered.

3. Chitosan-Based Nanomaterials for Improving Intestinal Drug Absorption and Their Pharmacological Applications

Since one of our goals of this review is to summarize the types of fabricated chitosan-based nanomaterials in the aspect of the drug absorption enhancer, the literature search was performed on the full-text articles published in English, with date limits of 2010 up to 8 February 2021, assessed in the PubMed database by using the search term of “chitosan” AND “intestine” AND “drug delivery”. As a result, a total of 106 articles were collected by EndNote and further selected for relevant topics. Additional articles that provided specific evidence and information (e.g., diabetes, cancers, infections, inflammation, polyelectrolyte complex, thiolated chitosan, trimethyl chitosan, carboxymethyl chitosan, alginate, Eudragit etc.) were included.
Chitosan-based nanomaterials have received tremendous attention from many investigators over the past decade as the enhancer of drug delivery, particularly drug absorption, based on their marvelous properties, which are (i) protection against GI luminal degradation (ii) mucoadhesion, (iii) permeation enhancement, (iv) controlled drug release, and (v) efflux inhibition (Figure 2). The significance of chitosan-based nanomaterials is indicated and discussed in detail as below. In addition, the types of chitosan-based nanomaterials are summarized in Table 1.

3.1. Chitosan-Based Polymeric Nanoparticles with Chemical Modifications

Although chitosan is well-soluble in acidic medium, it has poor solubility in the basic environment, as in the duodenum. Fortunately, chitosan is easy to chemically modify at its functional groups, including an amino group (-NH2) and two hydroxyl groups (-OH), in order to improve its physical and biological properties [139].
Thiolated chitosan is a favorable derivative of chitosan with the immobilized sulfhydryl- or thiol-bearing groups onto the primary amine groups of chitosan. The disulfide bond formation with cysteine-rich subdomains of mucus glycoprotein by a thiol-disulfide interchange reaction leads to the close contact between the thiomer and mucosal layers, hence making this modified chitosan have a better mucus entrapment efficiency, compared with conventional chitosan [139]. The increased mucoadhesivity retains the nanoparticles at the site of absorption, giving rise to the enhanced drug oral bioavailability. Fabiano and colleagues revealed the importance of thiol groups on drug oral bioavailability by comparing quaternary ammonium-chitosan with S-protected thiol groups (NP QA-Ch-S-pro) and without thiol ones (NP QA-Ch) [140]. Moreover, thiolated chitosan provides a beneficial effect as a permeation enhancer by inhibiting the protein tyrosine phosphatase (PTP) enzyme, which in turn dephosphorylates the tyrosine subunits of occluding protein and further promotes the opening of tight junctions [141,142]. The enhancement of permeation depends on the degree of the thiolation and the physiochemical properties of the drug [143]. The utilizations of thiolated chitosan were denoted in diabetes treatment. In the insulin delivery, oral insulin-loaded thiolated chitosan nanoparticles (Ins-TCNPs) could be prepared with pentaerythritol tetrakis (3-mercaptoproprionate) or PETMP, which was used for penetrating the cell membrane, while the thiomer inhibited the PTP enzyme and enhanced the opening tight junctions, promoting the drug absorption [118]. In addition, Ins-TCNPs was shown to reduce blood glucose as well as enhance the level of plasma insulin and prolong its duration in rats [118,144]. Insulin was released from thiolated chitosan-based nanoparticles at two phases, which were a rapid initial release or burst release at pH 2 and a sustained release at pH 5.3 [145,146]. It also improved the mucus adhesion between the polymer and the intestinal mucosa and prolonged drug gastric residence time, improving the oral bioavailability and thus implicating the potential role of thiolated chitosan in oral delivery of insulin [118]. Besides mucoadhesive and permeation-enhancing features, thiomers could inhibit the ATP-dependent drug efflux pumps, including P-gp and MRP-2, which were able to pump the drug molecules out of the cells, causing the attenuated drug efficiency and the poor oral drug bioavailability. Recently, it has been shown that both anionic and cationic thiolated chitosans could inhibit these efflux pumps and promote intestinal transcellular drug uptake [147]. For their applications in cancers, docetaxel (DTX), an anticancer drug for metastatic breast, lung, and gastric cancers, was carried by thiolated chitosan with the improvement of cellular internalization, the augmentation of mucoadhesivity, and the inhibition of P-gp [148]. Aside from DTX, α-mangostin, a natural xanthonoid extracted from mangosteen, was loaded by thiolated chitosan with pH-dependent Eudragit L100 and cross-linking genipin and this xanthonoid-bearing nanoparticle exhibited the mucoadhesive and controlled drug release properties in colorectal cancer [149]. Besides, thiolated chitosan could provide to increase the stability of low-molecular weight heparin (LMWH) in a gastric environment by ionic cross-linking with hydroxypropyl methylcellulose phthalate (HPMCP) [150]. Mechanistically, thiolated chitosan improved mucoadhesion, increased paracellular permeability of LMWH at the absorption site, and controlled the release of LMWH in the circulation [150]. Moreover, S-protected chitosan-thioglycolic acid using 6-mercaptonicotinamide (TGA-MNA) had better mucoadhesive, permeation-enhancing, and efflux pump-inhibiting properties than chitosan-thioglycolic acid (chitosan-TGA) with thiol-free groups [151,152,153]. Thiolated chitosan with reduced glutathione (GSH) enhanced the oral drug delivery of leuprolide, a poor-permeable peptide drug using as a gonadotropin-releasing hormone (GnRH) analogue, by preventing it from enzyme degradation and promoting its absorption [154,155].
Trimethyl chitosan (TMC) is a water-soluble quaternized chitosan derivative produced from the methylation of chitosan with iodomethane in the presence of sodium hydroxide (NaOH) at the elevated temperature [156,157]. TMC has the potential for augmenting the membrane-penetrating features for hydrophilic macromolecular drugs, which are poorly absorbed owing to rapid hydrolytic degradation by gastrointestinal juices [158]. For the treatment of diabetes, encapsulated insulin-incorporated TMCs exerted mucoadhesive and permeation-enhancing effects and stimulated the intestinal absorption by mediating the intestinal barrier integrity and promoted the insulin transport via the paracellular route. The self-assembly of chitosan nanoparticles with negatively charged fucoidan was anticipated to have the hypoglycemic effects and avoid diabetic complications [159]. Moreover, it was documented that oral insulin-loaded TMC nanoparticles provided a better therapeutic outcome, compared with injected insulin in type 1 diabetes (T1D) [160]. In the field of cancers, TMC could be applied in the drug delivery of paclitaxel (PTX), an anti-microtubule agent using the treatment of gastrointestinal tumors. TMC-loaded PTX enhanced the internalization of the nanoparticles and exerted the cytotoxic effect to cancer cells without the systemic adverse effects [161]. Interestingly, when TMC-loaded peptides were coated with liposome, they prolonged the residence time and increased the mucoadhesivity in the GI tract [162]. TMCs were also utilized in peptide drug delivery in cancer immunotherapy. For instance, the Oral PD-L1 Binding Peptide 1 (OPBP-1)-loaded TMC was shown to increase the oral bioavailability of the peptide drug and impede the tumor cell growth [163]. In addition, it has been reported that TMCs could carry curcumin, which plays a vital role in the signaling cascades related to cancers and inflammation, as curcumin-loaded TMC provided the controlled release and enhanced the oral bioavailability of curcumin [164,165]. Interestingly, TMC-coated solid lipid nanoparticles (SLNs) incorporated the curcumin displayed in the sustained release of curcumin and elevated its oral bioavailability, compared with free curcumin and non-coating chitosan nanoparticles [166].
Carboxymethyl chitosan (CMS or CMCS) is a pH-sensitive chitosan derivative with the carboxymethyl substituent that improves the water solubility in a neutral and basic pH, based on the degree of substitution, as well as enhancing the mucoadhesive properties [167]. CMCS can be produced by direct or reductive alkylation. For the treatment of diabetes, insulin-loaded chitosan/CMCS nanogels increased mucoadhesion and permeation in a rat jejunal ex vivo model, even though it had no differences in the duodenum [168]. CMCS has a negative charge, which can interact with positively charged chitosan to obtain the polyelectrolyte complex through electrostatic interaction, which provides the pH responsive stability and thus controls the drug release [133]. This will be included in the later section “chitosan-based polyelectrolyte complex nanoparticles”. Several lines of evidence have shown that doxorubicin, an anti-neoplastic drug used for treating solid tumors, can be loaded with chitosan/O-carboxymethyl chitosan (OCMCS) by simple ionic gelation. Doxorubicin-loaded chitosan/CMCS nanoparticles had better mucoadhesive properties and helped to improve oral bioavailability in ex vivo intestine [133,169,170]. Furthermore, CMCS was employed in the delivery of clarithromycin for the treatment of H. pylori. infection in the gastric environment. CMCS was grafted with stearic acid and conjugated with urea to obtain ureido-modified CMCS-graft-stearic acid (U-CMCS-g-SA). This nanopolymer was claimed to have a gastric retention property and a drug-controlled release with a target specificity [171]. For the inflammation, pH-responsive OCMCS/fucoidan nanoparticles were potentially used for the delivery of curcumin, as they controlled the release of curcumin and promoted the cellular uptake and endocytosis of curcumin Caco-2 cells [165]. In addition, gum Arabic (GA)-CMCS microcapsules enhanced the oral bioavailability of omeprazole, an antacid and a proton-pump inhibitor, to augment GI-targeted delivery [172].

3.2. Conjugated Chitosan

Chitosan can conjugate or form the complex with other superporous networks and (SPNs)-based polymers, which have numerous interconnected pores in three-dimensional structures with water-soluble agents, such as poly(vinyl alcohol) (PVA) and alginate [173]. The rapid swelling of SPNs could occur since the porous space of SPNs provide the water absorption, extending the gastric retention of the drug in the GI tract [174]. For the applications of conjugated chitosan, cross-linked chitosan/PVA was revealed to enhance the delivery of ascorbic acid with the formulated hydroxypropyl methylcellulose (HPMC), a hydrophilic and polymer and glyoxal, which was used for a crosslinking reagent, by prolonging the gastric retention time and promoting sustained release [173]. Additionally, for the diabetes therapy, the conjugation of cationic charged chitosan and anionic charged poly(γ-glutamic acid) (PGA) ameliorated the oral insulin delivery to adhere to the GI mucosal surface and transiently stimulated to open the tight junctions of the intestinal epithelial cells [175,176]. Moreover, in the treatment of cancer, Caco-2 cell monolayers treated with antiangiogenic, protein-loaded chitosan-N-arginine/PGA-taurine conjugated nanoparticles exhibited the enhancement of the cell permeation of antiangiogenic protein [177]. Not only chitosan alone, but chemically modified chitosans could take part in the conjugation process. For example, CMCS was prepared with poly(ethylene glycol) (PEG) to load doxorubicin hydrochloride in tumor cells. This nanoparticle was able to serve as a candidate for drug delivery of the antitumor drug [178]. Besides, thiolated chitosan could be conjugated with PEG to generate the thiol group bearing PEGylated chitosan (Chito-PEG-SH) with magnified mucoadhesive and permeation-enhancing properties, in isolated porcine and rat intestines [179]. In addition to drug delivery, chitosan-based nanoparticles are employed in a protein delivery system by inventing spherical PEG-grafted (chitosan-g-PEG), using TPP or PGA as a cross-linking agent [180].

3.3. Chitosan-Based Polyelectrolyte Complex Nanoparticles/Nanocapsules

To improve the drug stability in the GI tract and to lessen the systemic toxicity, the nanoencapsulation of the drugs is generated as the drug molecule loading into nanocarriers (e.g., nanoparticles, liposomes, micelles, and microemulsions) [130,132,181,182,183,184]. However, the encapsulated drugs confront the site-dependent pH change along the GI tract as the pH increases from the stomach (pH 1.2–3.7) to the small intestine (pH 6–7.4). Therefore, pH-sensitive/responsive polymers containing ionizable acidic and basic residues regarding the environmental pH are produced. The formations of the polyelectrolytes by non-covalent electrostatic interactions between polycations and polyanions are known as polyelectrolyte complex nanoparticles (PECNs). In response to the pH variation, these complex polymers could be adapted as swelling or shrinking, relying on the different degree of ionization of functional groups of PECNs [185]. The multishell structures in hollow nanocapsules were made from the dissolution of the core from the epitaxial core-shell structure of the nanoparticles [185,186]. A polyelectrolyte sphere was developed by the layer-by-layer (LbL) assembly method, employing a positively charged chitosan as the pH-responsive outer layer. The shrinking process of the chitosan-based nanoparticle might occur in the acidic surroundings [187,188].
Apart from chitosan, other biocompatible polymers, such as alginate, tripolyphosphate (TPP), and Eudragit, can serve as the outer membrane of nanocapsules. Alginate, consisting of 1,4-linked β-D-mannuronic acid and α-L-guluronic acid, was also a water-soluble and biodegradable natural polymer derived from seaweed [137,189]. It was able to crosslink with divalent/polyvalent cations (e.g., calcium, zinc, and copper) to form a network structure for use in sustaining drug release [137,189]. The carboxyl groups of alginate provided the negative charge and interact with the positively charged amino group of chitosan in the polyelectrolyte complex gel. Methoxy poly(ethylene glycol) or poly(ethylene glycol) monomethyl ether (mPEG)-grafted-CMCS (mPEG-g-CMCS) was synthesized with alginate to increase the loading capacity and provide a well-controlled drug release, particularly in the basic environment. In other words, mPEG-g-CMCS was a promising pH-sensitive nanoparticle for site-specific drug delivery in the intestine [190]. It was demonstrated that the fabricated core-shell nanoparticles, containing the curcumin at the core and the chitosan/alginate multilayer shell, could exhibit controlled release of the curcumin nanocrystal to target the inflamed colon in mice with ulcerative colitis (UC) [191]. In addition to alginate, TPP has been well-recognized. It had a negative charge and was used as a cross-linking agent with chitosan for the application of a chitosan-based hybrid system, such as quercetin-loaded and 5-Flurouracil (5-FU)-encapsulated chitosan/TPP nanoparticles [192,193,194]. Apart from that, a Eudragit polymer could be used for coating the nanoparticles in order to prevent the rapid release of curcumin and theophylline in the stomach and small intestine [195,196].
Chitosan-based PECNs are prepared from the interaction between the opposite charges of copolymers. For instance, chitosan/insulin PECNs could be obtained by positively charged chitosan-g-mPEG copolymers and negatively charged insulin [197]. These PECNs were used for improving the oral insulin to cross the mucus and epithelial membrane barriers in the GI tract [197,198]. mPEGylation is the process to enhance mucus-penetrating properties of chitosan-based nanomaterials. Recently, mPEG10%-chitosan glyceryl monocaprylate (GMC)10% copolymers have been modified to add the feature of hydrophobicity onto their surface, which helped to impale the epithelial membrane [197]. However, the differential advantages of hydrophilicity/hydrophobicity were still controversial for preferable usage of nanoparticles, since the hydrophilic surface was better permeable in the mucus layer, while the hydrophobic exterior was preferred to penetrate the cell membrane.
In addition, pH-sensitive PECNs were generated for improving doxorubicin to overcome the obstacles both in the GI tract and the intracellular tumor cell regulation, such as multidrug resistance (MDR) [199]. Chitosan/doxorubicin PECNs contained two polyelectrolytes, including positively charged chitosan and negatively charged poly(L-glutamic acid) grafted polyethylene glycol-doxorubicin conjugate nanoparticles (PG-g-PEG-hyd-DOX NPs) [132]. These PECNs prolonged duration in the blood circulation and tumor tissue accumulation with rapid drug release at target cells; therefore, these PECNs might serve as the ideal nanocarriers for the anticancer field [132]. Additionally, chitosan-based PECNs could be synthesized by the electrostatic interactions between positively charged chitosan and negatively charged CMCS, which was a water soluble derivative of chitosan, as previously mentioned, and produce the nanoparticles by the ionic gelation using CaCl2 as a cross-linking agent [131]. Doxorubicin was also prepared as DOX-loaded chitosan/carboxymethyl chitosan-based nanoparticles (DOX:CS/CMCS-NPs) with the porous-core nanoparticle and coacervate microcapsules-immobilized multilayer sodium alginate beads (NPs-M-ALG-Beads and CMs-M-ALG-Beads) in order to stabilize the drug in the GI tract [133,169,170].
Furthermore, the delivery of several antimicrobial agents was enhanced by the PECNs. For example, delafloxacin, a broad-spectrum fluoroquinolone used for both Gram-positive and negative aerobic and anaerobic bacteria, was loaded with positively charged chitosan and negatively charged stearic acid. The hybrid nanoparticles could increase the bioavailability and sustain the drug release via the electrostatic interaction of the polymer and lipid [200]. Another fluoroquinolone ciprofloxacin was carried by an embelin-chitosan gold nanoparticle (Emb-Chi-Au). This complex nanoparticle could enhance antipseudomonal activities by inhibiting the MDR efflux pump [201]. Tobramycin, an aminoglycoside antibiotic used for inhibiting biofilm formation by Pseudomonas aeruginosa, also relied on PECNs using N,O-[N,N-diethylaminomethyl(diethyldimethylene ammonium)n methyl]chitosan (QAL) nanoparticles and GENUVISCO type CSW-2 carrageenin (CG) [202]. Moreover, to achieve a better anti-inflammatory effect, curcumin was loaded with chitosan/GA and it was found that this nanoparticle helped control the release of curcumin [165]. Another example of CMCS-based application was the drug delivery of omeprazole using gum Arabic (GA)-O-carboxymethyl chitosan LbL microcapsules, which were able to enhance the oral bioavailability of omeprazole [172].
Table 1. Summary of chitosan-based nanocarriers used for improving the absorption of indicated drugs and their pharmacologic effects. This table summarizes the chitosan-based nanomaterials that carry the considerable drugs for better drug assimilation. The nanocarriers, loading drugs, and their exerting pharmacological effects are listed with their attainable references. Abbreviations: LMWH, low-molecular weight heparin; OPBP-1, Oral PD-L1 Binding Peptide 1; 5-FU, 5-flurouracil; BSA, bovine serum albumin.
Table 1. Summary of chitosan-based nanocarriers used for improving the absorption of indicated drugs and their pharmacologic effects. This table summarizes the chitosan-based nanomaterials that carry the considerable drugs for better drug assimilation. The nanocarriers, loading drugs, and their exerting pharmacological effects are listed with their attainable references. Abbreviations: LMWH, low-molecular weight heparin; OPBP-1, Oral PD-L1 Binding Peptide 1; 5-FU, 5-flurouracil; BSA, bovine serum albumin.
NanocarrierDrugPharmacological Effect(s)Reference(s)
1. Chemical modification
1.1 Thiolated chitosanInsulinmucoadhesion, permeation enhancement,
controlled drug release
Docetaxelmucoadhesion, permeation enhancement,
controlled drug release, efflux inhibition
α-mangostinmucoadhesion, controlled drug release[149]
LMWHprotection against GI luminal degradation,
mucoadhesion, permeation enhancement,
controlled drug release
Leuprolidemucoadhesion, permeation enhancement[154]
1.2 Trimethyl chitosan (TMC)Insulinmucoadhesion, permeation enhancement,
controlled drug release
Paclitaxelmucoadhesion, permeation enhancement,
controlled drug release
Calcitoninmucoadhesion, permeation enhancement,
prolongation of residence time
OPBP-1mucoadhesion, permeation enhancement,
controlled drug release
Curcuminmucoadhesion, permeation enhancement,
controlled drug release
1.3 Carboxymethyl chitosanDoxorubicinmucoadhesion, permeation enhancement,
controlled drug release, efflux inhibition
Clarithromycincontrolled drug release,
prolongation of residence time
5-FUcontrolled drug release[192]
Curcuminmucoadhesion, controlled drug release,
efflux inhibition
Omeprazoleprotection against gastric degradation,
controlled drug release
2. Conjugation
Poly(vinyl alcohol) (PVA)Ascorbic acidcontrolled drug release[173]
Poly(γ-glutamic acid) (PGAInsulinprotection against GI luminal degradation,
mucoadhsion, permeation enhancement
Poly(ethylene glycol) (PEG)Insulinmucoadhsion, permeation enhancement,
controlled drug release
BSAmucoadhsion, permeation enhancement,
controlled drug release
3. Polyelectrolyte complexationInsulinprotection against GI luminal degradation,
mucoadhesion, permeation enhancement,
controlled drug release
Doxorubicinmucoadhesion, permeation enhancement,
controlled drug release, efflux inhibition
5-FUcontrolled drug release[192]
Quercetinprotection against GI luminal degradation,
controlled drug release
Curcuminmucoadhesion, controlled drug release[165,191,195]
Rutinmucoadhesion, permeation enhancement,
controlled drug release
Gentamicinmucoadhesion, permeation enhancement,
controlled drug release
Paracetamolpermeation enhancement,
controlled drug release
Ibuprofencontrolled drug release[138]
Omeprazoleprotection against GI luminal degradation,
controlled drug release
Furosemidemucoadhesion, permeation enhancement,
controlled drug release
Theophyllinecontrolled drug release[196]
Delafloxacincontrolled drug release[200]
Ciprofloxacinefflux inhibition[201]
Tobramycinmucoadhesion, permeation enhancement[202]

4. Future Perspectives and Conclusions

The oral route is the most promising for drug administration; however, it is essential to overcome various physiological barriers along the GI tract (i.e., gastric pH, GI enzymes, mucus layer, efflux pump) before reaching the systemic circulation and exerting its effects at the action site. These challenges limit the absorption of multitudinous drugs, including antidiabetic, anticancer, antimicrobial, and anti-inflammatory drugs and hence their oral drug bioavailability. To surpass these GI obstacles, the drug delivery carriers have been designed and developed. Chitosan is chosen to be a potentially unique candidate that meets the ideal properties for bioinspired drug delivery. Chitosan is a natural origin-based polymer with its versatile functional groups, and hence it is feasible to be chemically modified to improve the chitosan’s physiochemical properties, including mucoadhesive capabilities, the permeating-enhancing effect, controlled drug release, and efflux inhibition. Several types of chitosan-based nanomaterials are fabricated and they are investigated for the potential to be the enhancer for drug assimilation. Even though the drug can reach the blood circulation, the fluctuations in drug concentrations can occur and may result in the increased incidence of either the drug adverse reaction or subtherapeutic treatment. Therefore, the sustained delivery system has been introduced to solve this problem [9,203]. Thiolated chitosan can be applied for the sustained delivery, but the maintenance of the drug remaining for longer period of time is required. Moreover, particularly in the elderly, polypharmacy is increasingly occupied in many cases. For the effective treatment, the co-delivery systems will assist to carry multiple drugs to differential targets at the same time [204,205,206]. Aging-, gender-, and race-dependent physiological factors related to drug absorption are still unclear. A better understanding in the study of personalized medicine will help to clarify these variations. The state-of-art technology related to personalized medicine is needed to be developed. Considering the novelty of theranostics, the combination of the therapeutics and diagnostics, chitosan and chitosan-based nanocarriers have been emerged in the biomedical engineering field. The large varieties of chitosan derivatives and modifications, as well as their versatilities, allow them to be the ideal carriers that can reach the specific site of such diseases. Theranostics and imaging-guided therapies will help instantaneously keep track of chitosan-based drug delivery and direct them to the target site [207]. The development of personalized nanomedicine will provide the information of an individualized drug response in order to adjust it to an optimal dosage and proper management for each patient [208]. Moreover, since chitosan could be applied with other polymers to fabricate various chitosan formulations, the studies of toxicity and safety of chitosan-based nanoparticles need to be further explored in vivo to ascertain the appropriate dose selection in humans [209]. The in-depth in vivo studies for chitosan nanoparticles may include the types of utilized polymer, size, shape, surface, morphology, and electrokinetic potential, which are significant determinants for the toxicity and safety and are associated with the nanotoxicity of these nanoparticles [207]. It is possible that the cytotoxicity of chitosan-based nanocarriers is resulted from the electrostatic interaction between chitosan and cell membrane, as well as the cellular uptake of chitosan and subsequent activation of intracellular signaling cascades [210]. Unfortunately, for the biocompatibility studies in the animal models, the short duration after the intravenous injection of nanoparticles might be insufficient [207]. Therefore, the clinical efficiency and in vivo efficacy of these nanoparticles should be stepped up. Another concern in the use of chitosan-based nanomaterials is that the antimicrobial activity of chitosan may be disrupted by interaction with food (e.g., fruits and vegetables). Besides, the patients who take warfarin, an anticoagulant, with chitosan, may have a potential risk of bleeding due to the effect of chitosan on intrinsic coagulation and fat-soluble vitamin absorption [211]. In addition, for the pharmaceutically industrial and commercial scales, the technology for the high-throughput level may be integrated. Recent advances in the development and application of chitosan-based nanomaterials have been brought up in this review. The implementations of the nanomaterials in diabetes, cancers, infections, and inflammation are specific; therefore, the further research for polymeric drug delivery in such individual diseases are encouraged toward a new paradigm in the future treatment based on nanotechnology.

Author Contributions

Conceptualization, N.P. and C.M.; writing, N.P.; review and editing, N.P. and C.M., supervision, C.M.; project administration, N.P. and C.M.; funding acquisition, N.P. and C.M. All authors have read and agreed to the published version of the manuscript.


This research was funded by Mahidol University, Thailand Research Fund and National Research Council of Thailand (grant number DBG6180029 and grant number NFS6300233)”.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Khafagy, E.-S.; Morishita, M. Oral biodrug delivery using cell-penetrating peptide. Adv. Drug Deliv. Rev. 2012, 64, 531–539. [Google Scholar] [CrossRef]
  2. Chen, M.C.; Mi, F.L.; Liao, Z.X.; Hsiao, C.W.; Sonaje, K.; Chung, M.F.; Hsu, L.W.; Sung, H.W. Recent advances in chitosan-based nanoparticles for oral delivery of macromolecules. Adv. Drug Deliv. Rev. 2013, 65, 865–879. [Google Scholar] [CrossRef]
  3. Hatton, G.B.; Madla, C.M.; Rabbie, S.C.; Basit, A.W. Gut reaction: Impact of systemic diseases on gastrointestinal physiology and drug absorption. Drug Discov. Today 2019, 24, 417–427. [Google Scholar] [CrossRef]
  4. Lang, X.; Wang, T.; Sun, M.; Chen, X.; Liu, Y. Advances and applications of chitosan-based nanomaterials as oral delivery carriers: A review. Int. J. Biol. Macromol. 2020, 154, 433–445. [Google Scholar] [CrossRef] [PubMed]
  5. Patra, J.K.; Das, G.; Fraceto, L.F.; Campos, E.V.R.; Rodriguez-Torres, M.D.P.; Acosta-Torres, L.S.; Diaz-Torres, L.A.; Grillo, R.; Swamy, M.K.; Sharma, S.; et al. Nano based drug delivery systems: Recent developments and future prospects. J. Nanobiotechnol. 2018, 16, 71. [Google Scholar] [CrossRef] [PubMed][Green Version]
  6. Bajracharya, R.; Song, J.G.; Back, S.Y.; Han, H.K. Recent Advancements in Non-Invasive Formulations for Protein Drug Delivery. Comput. Struct. Biotechnol. J. 2019, 17, 1290–1308. [Google Scholar] [CrossRef]
  7. Sung, Y.K.; Kim, S.W. Recent advances in polymeric drug delivery systems. Biomater. Res. 2020, 24, 12. [Google Scholar] [CrossRef] [PubMed]
  8. Bernkop-Schnürch, A.; Dünnhaupt, S. Chitosan-based drug delivery systems. Eur. J. Pharm. Biopharm. Off. J. Arb. Pharm. Verfahr. EV 2012, 81, 463–469. [Google Scholar] [CrossRef] [PubMed]
  9. Homayun, B.; Lin, X.; Choi, H.J. Challenges and Recent Progress in Oral Drug Delivery Systems for Biopharmaceuticals. Pharmaceutics 2019, 11, 129. [Google Scholar] [CrossRef][Green Version]
  10. Thadathil, N.; Velappan, S.P. Recent developments in chitosanase research and its biotechnological applications: A review. Food Chem. 2014, 150, 392–399. [Google Scholar] [CrossRef]
  11. Muanprasat, C.; Chatsudthipong, V. Chitosan oligosaccharide: Biological activities and potential therapeutic applications. Pharmacol. Ther. 2017, 170, 80–97. [Google Scholar] [CrossRef] [PubMed]
  12. Grenha, A. Chitosan nanoparticles: A survey of preparation methods. J. Drug Target. 2012, 20, 291–300. [Google Scholar] [CrossRef] [PubMed]
  13. Hu, L.; Sun, Y.; Wu, Y. Advances in chitosan-based drug delivery vehicles. Nanoscale 2013, 5, 3103–3111. [Google Scholar] [CrossRef]
  14. Debotton, N.; Dahan, A. A mechanistic approach to understanding oral drug absorption in pediatrics: An overview of fundamentals. Drug Discov. Today 2014, 19, 1322–1336. [Google Scholar] [CrossRef] [PubMed]
  15. Khan, M.S.; Roberts, M.S. Challenges and innovations of drug delivery in older age. Adv. Drug Deliv. Rev. 2018, 135, 3–38. [Google Scholar] [CrossRef]
  16. Soldin, O.P.; Chung, S.H.; Mattison, D.R. Sex differences in drug disposition. J. Biomed. Biotechnol. 2011, 2011, 187103. [Google Scholar] [CrossRef] [PubMed]
  17. Cazzola, M.; Calzetta, L.; Matera, M.G.; Hanania, N.A.; Rogliani, P. How does race/ethnicity influence pharmacological response to asthma therapies? Expert Opin. Drug Metab. Toxicol. 2018, 14, 435–446. [Google Scholar] [CrossRef]
  18. Williams, K.; Thomson, D.; Seto, I.; Contopoulos-Ioannidis, D.G.; Ioannidis, J.P.; Curtis, S.; Constantin, E.; Batmanabane, G.; Hartling, L.; Klassen, T. Standard 6: Age groups for pediatric trials. Pediatrics 2012, 129 (Suppl. 3), S153–S160. [Google Scholar] [CrossRef][Green Version]
  19. Klotz, U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab. Rev. 2009, 41, 67–76. [Google Scholar] [CrossRef] [PubMed]
  20. Soldin, O.P.; Mattison, D.R. Sex differences in pharmacokinetics and pharmacodynamics. Clin. Pharmacokinet. 2009, 48, 143–157. [Google Scholar] [CrossRef][Green Version]
  21. Messing, K.; Mager Stellman, J. Sex, gender and women’s occupational health: The importance of considering mechanism. Environ. Res. 2006, 101, 149–162. [Google Scholar] [CrossRef]
  22. Yasuda, S.U.; Zhang, L.; Huang, S.M. The role of ethnicity in variability in response to drugs: Focus on clinical pharmacology studies. Clin. Pharmacol. Ther. 2008, 84, 417–423. [Google Scholar] [CrossRef]
  23. Huang, T.; Shu, Y.; Cai, Y.D. Genetic differences among ethnic groups. BMC Genom. 2015, 16, 1093. [Google Scholar] [CrossRef][Green Version]
  24. Pontoriero, A.C.; Trinks, J.; Hulaniuk, M.L.; Caputo, M.; Fortuny, L.; Pratx, L.B.; Frías, A.; Torres, O.; Nuñez, F.; Gadano, A.; et al. Influence of ethnicity on the distribution of genetic polymorphisms associated with risk of chronic liver disease in South American populations. BMC Genet. 2015, 16, 93. [Google Scholar] [CrossRef][Green Version]
  25. Stillhart, C.; Vučićević, K.; Augustijns, P.; Basit, A.W.; Batchelor, H.; Flanagan, T.R.; Gesquiere, I.; Greupink, R.; Keszthelyi, D.; Koskinen, M.; et al. Impact of gastrointestinal physiology on drug absorption in special populations—An UNGAP review. Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci. 2020, 147, 105280. [Google Scholar] [CrossRef]
  26. Liu, L.; Yao, W.; Rao, Y.; Lu, X.; Gao, J. pH-Responsive carriers for oral drug delivery: Challenges and opportunities of current platforms. Drug Deliv. 2017, 24, 569–581. [Google Scholar] [CrossRef] [PubMed][Green Version]
  27. Manallack, D.T. The pK(a) Distribution of Drugs: Application to Drug Discovery. Perspect. Med. Chem. 2007, 1, 25–38. [Google Scholar]
  28. Kataoka, M.; Fukahori, M.; Ikemura, A.; Kubota, A.; Higashino, H.; Sakuma, S.; Yamashita, S. Effects of gastric pH on oral drug absorption: In vitro assessment using a dissolution/permeation system reflecting the gastric dissolution process. Eur. J. Pharm. Biopharm. Off. J. Arb. Pharm. Verfahr. EV 2016, 101, 103–111. [Google Scholar] [CrossRef] [PubMed]
  29. Mitra, A.; Kesisoglou, F. Impaired drug absorption due to high stomach pH: A review of strategies for mitigation of such effect to enable pharmaceutical product development. Mol. Pharm. 2013, 10, 3970–3979. [Google Scholar] [CrossRef] [PubMed]
  30. Patel, D.; Bertz, R.; Ren, S.; Boulton, D.W.; Någård, M. A Systematic Review of Gastric Acid-Reducing Agent-Mediated Drug-Drug Interactions with Orally Administered Medications. Clin. Pharmacokinet. 2020, 59, 447–462. [Google Scholar] [CrossRef] [PubMed][Green Version]
  31. Zhang, L.; Wu, F.; Lee, S.C.; Zhao, H.; Zhang, L. pH-dependent drug-drug interactions for weak base drugs: Potential implications for new drug development. Clin. Pharmacol. Ther. 2014, 96, 266–277. [Google Scholar] [CrossRef] [PubMed]
  32. Neal-Kluever, A.; Fisher, J.; Grylack, L.; Kakiuchi-Kiyota, S.; Halpern, W. Physiology of the Neonatal Gastrointestinal System Relevant to the Disposition of Orally Administered Medications. Drug Metab. Dispos. Biol. Fate Chem. 2019, 47, 296–313. [Google Scholar] [CrossRef]
  33. van den Anker, J.; Reed, M.D.; Allegaert, K.; Kearns, G.L. Developmental Changes in Pharmacokinetics and Pharmacodynamics. J. Clin. Pharmacol. 2018, 58 (Suppl. 10), S10–S25. [Google Scholar] [CrossRef] [PubMed][Green Version]
  34. Donovan, M.D. Sex and racial differences in pharmacological response: Effect of route of administration and drug delivery system on pharmacokinetics. J. Women Health 2005, 14, 30–37. [Google Scholar] [CrossRef] [PubMed][Green Version]
  35. Sansone-Parsons, A.; Krishna, G.; Simon, J.; Soni, P.; Kantesaria, B.; Herron, J.; Stoltz, R. Effects of age, gender, and race/ethnicity on the pharmacokinetics of posaconazole in healthy volunteers. Antimicrob. Agents Chemother. 2007, 51, 495–502. [Google Scholar] [CrossRef] [PubMed][Green Version]
  36. Yuan, Y.; Chesnutt, B.M.; Haggard, W.O.; Bumgardner, J.D. Deacetylation of Chitosan: Material Characterization and in vitro Evaluation via Albumin Adsorption and Pre-Osteoblastic Cell Cultures. Materials 2011, 4, 1399–1416. [Google Scholar] [CrossRef] [PubMed][Green Version]
  37. Mohammed, M.A.; Syeda, J.T.M.; Wasan, K.M.; Wasan, E.K. An Overview of Chitosan Nanoparticles and Its Application in Non-Parenteral Drug Delivery. Pharmaceutics 2017, 9, 53. [Google Scholar] [CrossRef][Green Version]
  38. TM, M.W.; Lau, W.M.; Khutoryanskiy, V.V. Chitosan and Its Derivatives for Application in Mucoadhesive Drug Delivery Systems. Polymers 2018, 10, 267. [Google Scholar] [CrossRef][Green Version]
  39. Botelho da Silva, S.; Krolicka, M.; van den Broek, L.A.M.; Frissen, A.E.; Boeriu, C.G. Water-soluble chitosan derivatives and pH-responsive hydrogels by selective C-6 oxidation mediated by TEMPO-laccase redox system. Carbohydr. Polym. 2018, 186, 299–309. [Google Scholar] [CrossRef]
  40. Dhaliwal, S.; Jain, S.; Singh, H.P.; Tiwary, A.K. Mucoadhesive microspheres for gastroretentive delivery of acyclovir: In vitro and in vivo evaluation. AAPS J. 2008, 10, 322–330. [Google Scholar] [CrossRef][Green Version]
  41. Bonengel, S.; Bernkop-Schnürch, A. Thiomers—From bench to market. J. Control Release Off. J. Control Release Soc. 2014, 195, 120–129. [Google Scholar] [CrossRef] [PubMed]
  42. Islam, M.A.; Park, T.E.; Reesor, E.; Cherukula, K.; Hasan, A.; Firdous, J.; Singh, B.; Kang, S.K.; Choi, Y.J.; Park, I.K.; et al. Mucoadhesive Chitosan Derivatives as Novel Drug Carriers. Curr. Pharm. Des. 2015, 21, 4285–4309. [Google Scholar] [CrossRef]
  43. Kuo, P.; Rayner, C.K.; Jones, K.L.; Horowitz, M. Pathophysiology and management of diabetic gastropathy: A guide for endocrinologists. Drugs 2007, 67, 1671–1687. [Google Scholar] [CrossRef]
  44. Huang, W.; Lee, S.L.; Yu, L.X. Mechanistic approaches to predicting oral drug absorption. AAPS J. 2009, 11, 217–224. [Google Scholar] [CrossRef][Green Version]
  45. Shekhawat, P.B.; Pokharkar, V.B. Understanding peroral absorption: Regulatory aspects and contemporary approaches to tackling solubility and permeability hurdles. Acta Pharm. Sin. B 2017, 7, 260–280. [Google Scholar] [CrossRef] [PubMed][Green Version]
  46. Back, H.M.; Song, B.; Pradhan, S.; Chae, J.W.; Han, N.; Kang, W.; Chang, M.J.; Zheng, J.; Kwon, K.I.; Karlsson, M.O.; et al. A mechanism-based pharmacokinetic model of fenofibrate for explaining increased drug absorption after food consumption. BMC Pharmacol. Toxicol. 2018, 19, 4. [Google Scholar] [CrossRef] [PubMed][Green Version]
  47. Sarosiek, I.; Selover, K.H.; Katz, L.A.; Semler, J.R.; Wilding, G.E.; Lackner, J.M.; Sitrin, M.D.; Kuo, B.; Chey, W.D.; Hasler, W.L.; et al. The assessment of regional gut transit times in healthy controls and patients with gastroparesis using wireless motility technology. Aliment. Pharmacol. Ther. 2010, 31, 313–322. [Google Scholar] [CrossRef] [PubMed]
  48. Roland, B.C.; Ciarleglio, M.M.; Clarke, J.O.; Semler, J.R.; Tomakin, E.; Mullin, G.E.; Pasricha, P.J. Small Intestinal Transit Time Is Delayed in Small Intestinal Bacterial Overgrowth. J. Clin. Gastroenterol. 2015, 49, 571–576. [Google Scholar] [CrossRef]
  49. Koziolek, M.; Grimm, M.; Garbacz, G.; Kühn, J.P.; Weitschies, W. Intragastric volume changes after intake of a high-caloric, high-fat standard breakfast in healthy human subjects investigated by MRI. Mol. Pharm. 2014, 11, 1632–1639. [Google Scholar] [CrossRef]
  50. Koziolek, M.; Garbacz, G.; Neumann, M.; Weitschies, W. Simulating the postprandial stomach: Physiological considerations for dissolution and release testing. Mol. Pharm. 2013, 10, 1610–1622. [Google Scholar] [CrossRef]
  51. Grimm, M.; Koziolek, M.; Kühn, J.P.; Weitschies, W. Interindividual and intraindividual variability of fasted state gastric fluid volume and gastric emptying of water. Eur. J. Pharm. Biopharm. Off. J. Arb. Pharm. Verfahr. EV 2018, 127, 309–317. [Google Scholar] [CrossRef]
  52. Mudie, D.M.; Murray, K.; Hoad, C.L.; Pritchard, S.E.; Garnett, M.C.; Amidon, G.L.; Gowland, P.A.; Spiller, R.C.; Amidon, G.E.; Marciani, L. Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted state. Mol. Pharm. 2014, 11, 3039–3047. [Google Scholar] [CrossRef] [PubMed]
  53. Yu, G.; Zheng, Q.S.; Li, G.F. Similarities and differences in gastrointestinal physiology between neonates and adults: A physiologically based pharmacokinetic modeling perspective. AAPS J. 2014, 16, 1162–1166. [Google Scholar] [CrossRef] [PubMed][Green Version]
  54. Allegaert, K.; van den Anker, J. Neonatal drug therapy: The first frontier of therapeutics for children. Clin. Pharmacol. Ther. 2015, 98, 288–297. [Google Scholar] [CrossRef] [PubMed]
  55. Moyer, A.M.; Matey, E.T.; Miller, V.M. Individualized medicine: Sex, hormones, genetics, and adverse drug reactions. Pharmacol. Res. Perspect. 2019, 7, e00541. [Google Scholar] [CrossRef] [PubMed]
  56. Whitley, H.; Lindsey, W. Sex-based differences in drug activity. Am. Fam. Phys. 2009, 80, 1254–1258. [Google Scholar]
  57. Torrado, S.; Prada, P.; de la Torre, P.M.; Torrado, S. Chitosan-poly(acrylic) acid polyionic complex: In vivo study to demonstrate prolonged gastric retention. Biomaterials 2004, 25, 917–923. [Google Scholar] [CrossRef]
  58. Modi, J.; Joshi, G.; Sawant, K. Chitosan based mucoadhesive nanoparticles of ketoconazole for bioavailability enhancement: Formulation, optimization, in vitro and ex vivo evaluation. Drug Dev. Ind. Pharm. 2013, 39, 540–547. [Google Scholar] [CrossRef] [PubMed]
  59. Leslie, E.M.; Deeley, R.G.; Cole, S.P. Multidrug resistance proteins: Role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol. Appl. Pharmacol. 2005, 204, 216–237. [Google Scholar] [CrossRef]
  60. Gutmann, H.; Hruz, P.; Zimmermann, C.; Beglinger, C.; Drewe, J. Distribution of breast cancer resistance protein (BCRP/ABCG2) mRNA expression along the human GI tract. Biochem. Pharmacol. 2005, 70, 695–699. [Google Scholar] [CrossRef]
  61. Stappaerts, J.; Annaert, P.; Augustijns, P. Site dependent intestinal absorption of darunavir and its interaction with ketoconazole. Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci. 2013, 49, 51–56. [Google Scholar] [CrossRef] [PubMed]
  62. Peters, S.A.; Jones, C.R.; Ungell, A.L.; Hatley, O.J. Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models. Clin. Pharmacokinet. 2016, 55, 673–696. [Google Scholar] [CrossRef][Green Version]
  63. Gameiro, M.; Silva, R.; Rocha-Pereira, C.; Carmo, H.; Carvalho, F.; Bastos, M.L.; Remião, F. Cellular Models and In Vitro Assays for the Screening of modulators of P-gp, MRP1 and BCRP. Molecules 2017, 22, 600. [Google Scholar] [CrossRef] [PubMed][Green Version]
  64. Estudante, M.; Morais, J.G.; Soveral, G.; Benet, L.Z. Intestinal drug transporters: An overview. Adv. Drug Deliv. Rev. 2013, 65, 1340–1356. [Google Scholar] [CrossRef]
  65. Hilgendorf, C.; Ahlin, G.; Seithel, A.; Artursson, P.; Ungell, A.L.; Karlsson, J. Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines. Drug Metab. Dispos. Biol. Fate Chem. 2007, 35, 1333–1340. [Google Scholar] [CrossRef][Green Version]
  66. Murakami, T.; Takano, M. Intestinal efflux transporters and drug absorption. Expert Opin. Drug Metab. Toxicol. 2008, 4, 923–939. [Google Scholar] [CrossRef]
  67. Grandvuinet, A.S.; Steffansen, B. Interactions between organic anions on multiple transporters in Caco-2 cells. J. Pharm. Sci. 2011, 100, 3817–3830. [Google Scholar] [CrossRef] [PubMed]
  68. Fu, D.; Arias, I.M. Intracellular trafficking of P-glycoprotein. Int. J. Biochem. Cell Biol. 2012, 44, 461–464. [Google Scholar] [CrossRef] [PubMed][Green Version]
  69. Li, X.; Lindquist, S.; Lowe, M.; Noppa, L.; Hernell, O. Bile salt-stimulated lipase and pancreatic lipase-related protein 2 are the dominating lipases in neonatal fat digestion in mice and rats. Pediatric Res. 2007, 62, 537–541. [Google Scholar] [CrossRef][Green Version]
  70. Ianiro, G.; Pecere, S.; Giorgio, V.; Gasbarrini, A.; Cammarota, G. Digestive Enzyme Supplementation in Gastrointestinal Diseases. Curr. Drug Metab. 2016, 17, 187–193. [Google Scholar] [CrossRef] [PubMed][Green Version]
  71. Shi, S.; Li, Y. Interplay of Drug-Metabolizing Enzymes and Transporters in Drug Absorption and Disposition. Curr. Drug Metab. 2014, 15, 915–941. [Google Scholar] [CrossRef] [PubMed]
  72. Chen, Y.T.; Trzoss, L.; Yang, D.; Yan, B. Ontogenic expression of human carboxylesterase-2 and cytochrome P450 3A4 in liver and duodenum: Postnatal surge and organ-dependent regulation. Toxicology 2015, 330, 55–61. [Google Scholar] [CrossRef][Green Version]
  73. Brussee, J.M.; Yu, H.; Krekels, E.H.J.; de Roos, B.; Brill, M.J.E.; van den Anker, J.N.; Rostami-Hodjegan, A.; de Wildt, S.N.; Knibbe, C.A.J. First-Pass CYP3A-Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates. CPT Pharmacomet. Syst. Pharmacol. 2018, 7, 374–383. [Google Scholar] [CrossRef][Green Version]
  74. Kearns, G.L.; Abdel-Rahman, S.M.; Alander, S.W.; Blowey, D.L.; Leeder, J.S.; Kauffman, R.E. Developmental pharmacology--drug disposition, action, and therapy in infants and children. N. Engl. J. Med. 2003, 349, 1157–1167. [Google Scholar] [CrossRef]
  75. Takashima, T.; Yokoyama, C.; Mizuma, H.; Yamanaka, H.; Wada, Y.; Onoe, K.; Nagata, H.; Tazawa, S.; Doi, H.; Takahashi, K.; et al. Developmental changes in P-glycoprotein function in the blood-brain barrier of nonhuman primates: PET study with R-11C-verapamil and 11C-oseltamivir. J. Nucl. Med. Off. Publ. Soc. Nucl. Med. 2011, 52, 950–957. [Google Scholar] [CrossRef][Green Version]
  76. Lam, J.; Koren, G. P-glycoprotein in the developing human brain: A review of the effects of ontogeny on the safety of opioids in neonates. Ther. Drug Monit. 2014, 36, 699–705. [Google Scholar] [CrossRef]
  77. Toornvliet, R.; van Berckel, B.N.; Luurtsema, G.; Lubberink, M.; Geldof, A.A.; Bosch, T.M.; Oerlemans, R.; Lammertsma, A.A.; Franssen, E.J. Effect of age on functional P-glycoprotein in the blood-brain barrier measured by use of (R)-[(11)C]verapamil and positron emission tomography. Clin. Pharmacol. Ther. 2006, 79, 540–548. [Google Scholar] [CrossRef]
  78. Marzolini, C.; Tirona, R.G.; Kim, R.B. Pharmacogenomics of the OATP and OAT families. Pharmacogenomics 2004, 5, 273–282. [Google Scholar] [CrossRef]
  79. Shah, R.R.; Gaedigk, A.; LLerena, A.; Eichelbaum, M.; Stingl, J.; Smith, R.L. CYP450 genotype and pharmacogenetic association studies: A critical appraisal. Pharmacogenomics 2016, 17, 259–275. [Google Scholar] [CrossRef]
  80. Hoffmeyer, S.; Burk, O.; von Richter, O.; Arnold, H.P.; Brockmöller, J.; Johne, A.; Cascorbi, I.; Gerloff, T.; Roots, I.; Eichelbaum, M.; et al. Functional polymorphisms of the human multidrug-resistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl. Acad. Sci. USA 2000, 97, 3473–3478. [Google Scholar] [CrossRef] [PubMed]
  81. Cascorbi, I.; Gerloff, T.; Johne, A.; Meisel, C.; Hoffmeyer, S.; Schwab, M.; Schaeffeler, E.; Eichelbaum, M.; Brinkmann, U.; Roots, I. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin. Pharmacol. Ther. 2001, 69, 169–174. [Google Scholar] [CrossRef] [PubMed]
  82. Sansone-Parsons, A.; Krishna, G.; Calzetta, A.; Wexler, D.; Kantesaria, B.; Rosenberg, M.A.; Saltzman, M.A. Effect of a nutritional supplement on posaconazole pharmacokinetics following oral administration to healthy volunteers. Antimicrob. Agents Chemother. 2006, 50, 1881–1883. [Google Scholar] [CrossRef][Green Version]
  83. Vendelbo, J.; Olesen, R.H.; Lauridsen, J.K.; Rungby, J.; Kleinman, J.E.; Hyde, T.M.; Larsen, A. Increasing BMI is associated with reduced expression of P-glycoprotein (ABCB1 gene) in the human brain with a stronger association in African Americans than Caucasians. Pharm. J. 2018, 18, 121–126. [Google Scholar] [CrossRef][Green Version]
  84. Hu, K.; Xie, X.; Zhao, Y.N.; Li, Y.; Ruan, J.; Li, H.R.; Jin, T.; Yang, X.L. Chitosan Influences the Expression of P-gp and Metabolism of Norfloxacin in Grass Carp. J. Aquat. Anim. Health 2015, 27, 104–111. [Google Scholar] [CrossRef]
  85. Ni, J.; Tian, F.; Dahmani, F.Z.; Yang, H.; Yue, D.; He, S.; Zhou, J.; Yao, J. Curcumin-carboxymethyl chitosan (CNC) conjugate and CNC/LHR mixed polymeric micelles as new approaches to improve the oral absorption of P-gp substrate drugs. Drug Deliv. 2016, 23, 3424–3435. [Google Scholar] [CrossRef] [PubMed][Green Version]
  86. Mu, Y.; Fu, Y.; Li, J.; Yu, X.; Li, Y.; Wang, Y.; Wu, X.; Zhang, K.; Kong, M.; Feng, C.; et al. Multifunctional quercetin conjugated chitosan nano-micelles with P-gp inhibition and permeation enhancement of anticancer drug. Carbohydr. Polym. 2019, 203, 10–18. [Google Scholar] [CrossRef]
  87. Wang, X.; Chen, Y.; Dahmani, F.Z.; Yin, L.; Zhou, J.; Yao, J. Amphiphilic carboxymethyl chitosan-quercetin conjugate with P-gp inhibitory properties for oral delivery of paclitaxel. Biomaterials 2014, 35, 7654–7665. [Google Scholar] [CrossRef] [PubMed]
  88. Thursby, E.; Juge, N. Introduction to the human gut microbiota. Biochem. J. 2017, 474, 1823–1836. [Google Scholar] [CrossRef] [PubMed]
  89. Donaldson, G.P.; Lee, S.M.; Mazmanian, S.K. Gut biogeography of the bacterial microbiota. Nat. Rev. Microbiol. 2016, 14, 20–32. [Google Scholar] [CrossRef][Green Version]
  90. Kim, S.; Covington, A.; Pamer, E.G. The intestinal microbiota: Antibiotics, colonization resistance, and enteric pathogens. Immunol. Rev. 2017, 279, 90–105. [Google Scholar] [CrossRef]
  91. Noh, K.; Kang, Y.R.; Nepal, M.R.; Shakya, R.; Kang, M.J.; Kang, W.; Lee, S.; Jeong, H.G.; Jeong, T.C. Impact of gut microbiota on drug metabolism: An update for safe and effective use of drugs. Arch. Pharmacal Res. 2017, 40, 1345–1355. [Google Scholar] [CrossRef]
  92. Zhang, J.; Zhang, J.; Wang, R. Gut microbiota modulates drug pharmacokinetics. Drug Metab. Rev. 2018, 50, 357–368. [Google Scholar] [CrossRef]
  93. Morrison, D.J.; Preston, T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 2016, 7, 189–200. [Google Scholar] [CrossRef][Green Version]
  94. Parada Venegas, D.; De la Fuente, M.K.; Landskron, G.; González, M.J.; Quera, R.; Dijkstra, G.; Harmsen, H.J.M.; Faber, K.N.; Hermoso, M.A. Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases. Front. Immunol. 2019, 10, 277. [Google Scholar] [CrossRef][Green Version]
  95. Zhang, S.H.; Wang, Y.Z.; Meng, F.Y.; Li, Y.L.; Li, C.X.; Duan, F.P.; Wang, Q.; Zhang, X.T.; Zhang, C.N. Studies of the microbial metabolism of flavonoids extracted from the leaves of Diospyros kaki by intestinal bacteria. Arch. Pharmacal Res. 2015, 38, 614–619. [Google Scholar] [CrossRef] [PubMed]
  96. Tozaki, H.; Emi, Y.; Horisaka, E.; Fujita, T.; Yamamoto, A.; Muranishi, S. Degradation of insulin and calcitonin and their protection by various protease inhibitors in rat caecal contents: Implications in peptide delivery to the colon. J. Pharm. Pharmacol. 1997, 49, 164–168. [Google Scholar] [CrossRef] [PubMed]
  97. Clayton, T.A.; Baker, D.; Lindon, J.C.; Everett, J.R.; Nicholson, J.K. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc. Natl. Acad. Sci. USA 2009, 106, 14728–14733. [Google Scholar] [CrossRef][Green Version]
  98. Saitta, K.S.; Zhang, C.; Lee, K.K.; Fujimoto, K.; Redinbo, M.R.; Boelsterli, U.A. Bacterial β-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, ketoprofen or diclofenac: Mode of action and pharmacokinetics. Xenobiotica Fate Foreign Compd. Biol. Syst. 2014, 44, 28–35. [Google Scholar] [CrossRef][Green Version]
  99. Fujiwara, R.; Maruo, Y.; Chen, S.; Tukey, R.H. Role of extrahepatic UDP-glucuronosyltransferase 1A1: Advances in understanding breast milk-induced neonatal hyperbilirubinemia. Toxicol. Appl. Pharmacol. 2015, 289, 124–132. [Google Scholar] [CrossRef][Green Version]
  100. Kim, Y.S.; Unno, T.; Kim, B.Y.; Park, M.S. Sex Differences in Gut Microbiota. World J. Men Health 2020, 38, 48–60. [Google Scholar] [CrossRef]
  101. Gupta, V.K.; Paul, S.; Dutta, C. Geography, Ethnicity or Subsistence-Specific Variations in Human Microbiome Composition and Diversity. Front. Microbiol. 2017, 8, 1162. [Google Scholar] [CrossRef][Green Version]
  102. Dwiyanto, J.; Hussain, M.H.; Reidpath, D.; Ong, K.S.; Qasim, A.; Lee, S.W.H.; Lee, S.M.; Foo, S.C.; Chong, C.W.; Rahman, S. Ethnicity influences the gut microbiota of individuals sharing a geographical location: A cross-sectional study from a middle-income country. Sci. Rep. 2021, 11, 2618. [Google Scholar] [CrossRef]
  103. Stojančević, M.; Bojić, G.; Salami, H.A.; Mikov, M. The Influence of Intestinal Tract and Probiotics on the Fate of Orally Administered Drugs. Curr. Issues Mol. Biol. 2014, 16, 55–68. [Google Scholar]
  104. Matuskova, Z.; Anzenbacherova, E.; Vecera, R.; Tlaskalova-Hogenova, H.; Kolar, M.; Anzenbacher, P. Administration of a probiotic can change drug pharmacokinetics: Effect of E. coli Nissle 1917 on amidarone absorption in rats. PLoS ONE 2014, 9, e87150. [Google Scholar] [CrossRef]
  105. Feng, D.; Zhang, M.; Tian, S.; Wang, J.; Zhu, W. Chitosan-chelated zinc modulates cecal microbiota and attenuates inflammatory response in weaned rats challenged with Escherichia coli. J. Microbiol. 2020, 58, 780–792. [Google Scholar] [CrossRef]
  106. Zheng, J.; Yuan, X.; Cheng, G.; Jiao, S.; Feng, C.; Zhao, X.; Yin, H.; Du, Y.; Liu, H. Chitosan oligosaccharides improve the disturbance in glucose metabolism and reverse the dysbiosis of gut microbiota in diabetic mice. Carbohydr. Polym. 2018, 190, 77–86. [Google Scholar] [CrossRef]
  107. Owu, D.U.; Obembe, A.O.; Nwokocha, C.R.; Edoho, I.E.; Osim, E.E. Gastric ulceration in diabetes mellitus: Protective role of vitamin C. ISRN Gastroenterol. 2012, 2012, 362805. [Google Scholar] [CrossRef][Green Version]
  108. Eliasson, B.; Björnsson, E.; Urbanavicius, V.; Andersson, H.; Fowelin, J.; Attvall, S.; Abrahamsson, H.; Smith, U. Hyperinsulinaemia impairs gastrointestinal motility and slows carbohydrate absorption. Diabetologia 1995, 38, 79–85. [Google Scholar] [CrossRef]
  109. Marathe, C.S.; Rayner, C.K.; Jones, K.L.; Horowitz, M. Relationships between gastric emptying, postprandial glycemia, and incretin hormones. Diabetes Care 2013, 36, 1396–1405. [Google Scholar] [CrossRef][Green Version]
  110. Zhao, M.; Liao, D.; Zhao, J. Diabetes-induced mechanophysiological changes in the small intestine and colon. World J. Diabetes 2017, 8, 249–269. [Google Scholar] [CrossRef]
  111. Redan, B.W.; Buhman, K.K.; Novotny, J.A.; Ferruzzi, M.G. Altered Transport and Metabolism of Phenolic Compounds in Obesity and Diabetes: Implications for Functional Food Development and Assessment. Adv. Nutr. 2016, 7, 1090–1104. [Google Scholar] [CrossRef] [PubMed][Green Version]
  112. Kobori, T.; Harada, S.; Nakamoto, K.; Tokuyama, S. Functional alterations of intestinal P-glycoprotein under diabetic conditions. Biol. Pharm. Bull. 2013, 36, 1381–1390. [Google Scholar] [CrossRef] [PubMed][Green Version]
  113. Dostalek, M.; Sam, W.J.; Paryani, K.R.; Macwan, J.S.; Gohh, R.Y.; Akhlaghi, F. Diabetes mellitus reduces the clearance of atorvastatin lactone: Results of a population pharmacokinetic analysis in renal transplant recipients and in vitro studies using human liver microsomes. Clin. Pharmacokinet. 2012, 51, 591–606. [Google Scholar] [CrossRef]
  114. Zhelyazkova-Savova, M.; Gancheva, S.; Sirakova, V. Potential statin-drug interactions: Prevalence and clinical significance. SpringerPlus 2014, 3, 168. [Google Scholar] [CrossRef][Green Version]
  115. Mahajan, V.; Hashmi, J.; Singh, R.; Samra, T.; Aneja, S. Comparative evaluation of gastric pH and volume in morbidly obese and lean patients undergoing elective surgery and effect of aspiration prophylaxis. J. Clin. Anesth. 2015, 27, 396–400. [Google Scholar] [CrossRef]
  116. Foucaud-Vignault, M.; Soayfane, Z.; Ménez, C.; Bertrand-Michel, J.; Martin, P.G.; Guillou, H.; Collet, X.; Lespine, A. P-glycoprotein dysfunction contributes to hepatic steatosis and obesity in mice. PLoS ONE 2011, 6, e23614. [Google Scholar] [CrossRef][Green Version]
  117. Rodríguez-Morató, J.; Goday, A.; Langohr, K.; Pujadas, M.; Civit, E.; Pérez-Mañá, C.; Papaseit, E.; Ramon, J.M.; Benaiges, D.; Castañer, O.; et al. Short- and medium-term impact of bariatric surgery on the activities of CYP2D6, CYP3A4, CYP2C9, and CYP1A2 in morbid obesity. Sci. Rep. 2019, 9, 20405. [Google Scholar] [CrossRef]
  118. Sudhakar, S.; Chandran, S.V.; Selvamurugan, N.; Nazeer, R.A. Biodistribution and pharmacokinetics of thiolated chitosan nanoparticles for oral delivery of insulin in vivo. Int. J. Biol. Macromol. 2020, 150, 281–288. [Google Scholar] [CrossRef]
  119. Li, L.; Jiang, G.; Yu, W.; Liu, D.; Chen, H.; Liu, Y.; Tong, Z.; Kong, X.; Yao, J. Preparation of chitosan-based multifunctional nanocarriers overcoming multiple barriers for oral delivery of insulin. Mater. Sci. Eng. C Mater. Biol. Appl. 2017, 70, 278–286. [Google Scholar] [CrossRef]
  120. Lu, P.J.; Hsu, P.I.; Chen, C.H.; Hsiao, M.; Chang, W.C.; Tseng, H.H.; Lin, K.H.; Chuah, S.K.; Chen, H.C. Gastric juice acidity in upper gastrointestinal diseases. World J. Gastroenterol. 2010, 16, 5496–5501. [Google Scholar] [CrossRef]
  121. Ghosh, T.; Lewis, D.I.; Axon, A.T.; Everett, S.M. Review article: Methods of measuring gastric acid secretion. Aliment. Pharmacol. Ther. 2011, 33, 768–781. [Google Scholar] [CrossRef][Green Version]
  122. Chang, F.Y.; Chen, C.Y.; Lu, C.L.; Luo, J.C.; Jiun, K.L.; Lee, S.D.; Wu, C.W. Undisturbed water gastric emptying in patients of stomach cancer. Hepato-Gastroenterology 2004, 51, 1219–1224. [Google Scholar]
  123. Kim, D.H.; Yun, H.Y.; Song, Y.J.; Ryu, D.H.; Han, H.S.; Han, J.H.; Kim, K.B.; Yoon, S.M.; Youn, S.J. Clinical features of gastric emptying after distal gastrectomy. Ann. Surg. Treat. Res. 2017, 93, 310–315. [Google Scholar] [CrossRef][Green Version]
  124. Joshi, G.; Kumar, A.; Sawant, K. Enhanced bioavailability and intestinal uptake of Gemcitabine HCl loaded PLGA nanoparticles after oral delivery. Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci. 2014, 60, 80–89. [Google Scholar] [CrossRef]
  125. Louisa, M.; Soediro, T.M.; Suyatna, F.D. In vitro modulation of P-glycoprotein, MRP-1 and BCRP expression by mangiferin in doxorubicin-treated MCF-7 cells. Asian Pac. J. Cancer Prev. APJCP 2014, 15, 1639–1642. [Google Scholar] [CrossRef][Green Version]
  126. Nanayakkara, A.K.; Follit, C.A.; Chen, G.; Williams, N.S.; Vogel, P.D.; Wise, J.G. Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells. Sci. Rep. 2018, 8, 967. [Google Scholar] [CrossRef][Green Version]
  127. Weiss, R.B. The anthracyclines: Will we ever find a better doxorubicin? Semin. Oncol. 1992, 19, 670–686. [Google Scholar]
  128. Cortés-Funes, H.; Coronado, C. Role of anthracyclines in the era of targeted therapy. Cardiovasc. Toxicol. 2007, 7, 56–60. [Google Scholar] [CrossRef]
  129. Thorn, C.F.; Oshiro, C.; Marsh, S.; Hernandez-Boussard, T.; McLeod, H.; Klein, T.E.; Altman, R.B. Doxorubicin pathways: Pharmacodynamics and adverse effects. Pharm. Genom. 2011, 21, 440–446. [Google Scholar] [CrossRef]
  130. Kalaria, D.R.; Sharma, G.; Beniwal, V.; Ravi Kumar, M.N. Design of biodegradable nanoparticles for oral delivery of doxorubicin: In vivo pharmacokinetics and toxicity studies in rats. Pharm. Res. 2009, 26, 492–501. [Google Scholar] [CrossRef]
  131. Feng, C.; Li, J.; Mu, Y.; Kong, M.; Li, Y.; Raja, M.A.; Cheng, X.J.; Liu, Y.; Chen, X.G. Multilayer micro-dispersing system as oral carriers for co-delivery of doxorubicin hydrochloride and P-gp inhibitor. Int. J. Biol. Macromol. 2017, 94, 170–180. [Google Scholar] [CrossRef]
  132. Deng, L.; Dong, H.; Dong, A.; Zhang, J. A strategy for oral chemotherapy via dual pH-sensitive polyelectrolyte complex nanoparticles to achieve gastric survivability, intestinal permeability, hemodynamic stability and intracellular activity. Eur. J. Pharm. Biopharm. Off. J. Arb. Pharm. Verfahr. EV 2015, 97, 107–117. [Google Scholar] [CrossRef]
  133. Feng, C.; Wang, Z.; Jiang, C.; Kong, M.; Zhou, X.; Li, Y.; Cheng, X.; Chen, X. Chitosan/o-carboxymethyl chitosan nanoparticles for efficient and safe oral anticancer drug delivery: In vitro and in vivo evaluation. Int. J. Pharm. 2013, 457, 158–167. [Google Scholar] [CrossRef]
  134. Iannuccelli, V.; Montanari, M.; Bertelli, D.; Pellati, F.; Coppi, G. Microparticulate polyelectrolyte complexes for gentamicin transport across intestinal epithelia. Drug Deliv. 2011, 18, 26–37. [Google Scholar] [CrossRef][Green Version]
  135. Eftaiha, A.F.; Qinna, N.; Rashid, I.S.; Al Remawi, M.M.; Al Shami, M.R.; Arafat, T.A.; Badwan, A.A. Bioadhesive controlled metronidazole release matrix based on chitosan and xanthan gum. Mar. Drugs 2010, 8, 1716–1730. [Google Scholar] [CrossRef][Green Version]
  136. Konturek, P.C.; Brzozowski, T.; Konturek, S.J. Stress and the gut: Pathophysiology, clinical consequences, diagnostic approach and treatment options. J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc. 2011, 62, 591–599. [Google Scholar]
  137. Treenate, P.; Monvisade, P. In vitro drug release profiles of pH-sensitive hydroxyethylacryl chitosan/sodium alginate hydrogels using paracetamol as a soluble model drug. Int. J. Biol. Macromol. 2017, 99, 71–78. [Google Scholar] [CrossRef]
  138. Ofokansi, K.C.; Kenechukwu, F.C. Formulation Development and Evaluation of Drug Release Kinetics from Colon-Targeted Ibuprofen Tablets Based on Eudragit RL 100-Chitosan Interpolyelectrolyte Complexes. ISRN Pharm. 2013, 2013, 838403. [Google Scholar] [CrossRef][Green Version]
  139. Ahmed, T.A.; Aljaeid, B.M. Preparation, characterization, and potential application of chitosan, chitosan derivatives, and chitosan metal nanoparticles in pharmaceutical drug delivery. Drug Des. Dev. Ther. 2016, 10, 483–507. [Google Scholar] [CrossRef][Green Version]
  140. Fabiano, A.; Piras, A.M.; Uccello-Barretta, G.; Balzano, F.; Cesari, A.; Testai, L.; Citi, V.; Zambito, Y. Impact of mucoadhesive polymeric nanoparticulate systems on oral bioavailability of a macromolecular model drug. Eur. J. Pharm. Biopharm. Off. J. Arb. Pharm. Verfahr. EV 2018, 130, 281–289. [Google Scholar] [CrossRef]
  141. Blanquet, S.; Zeijdner, E.; Beyssac, E.; Meunier, J.P.; Denis, S.; Havenaar, R.; Alric, M. A dynamic artificial gastrointestinal system for studying the behavior of orally administered drug dosage forms under various physiological conditions. Pharm. Res. 2004, 21, 585–591. [Google Scholar] [CrossRef]
  142. Bernkop-Schnürch, A.; Kast, C.E.; Guggi, D. Permeation enhancing polymers in oral delivery of hydrophilic macromolecules: Thiomer/GSH systems. J. Control Release Off. J. Control Release Soc. 2003, 93, 95–103. [Google Scholar] [CrossRef]
  143. Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2001, 46, 3–26. [Google Scholar] [CrossRef]
  144. Hu, Q.; Luo, Y. Recent advances of polysaccharide-based nanoparticles for oral insulin delivery. Int. J. Biol. Macromol. 2018, 120, 775–782. [Google Scholar] [CrossRef] [PubMed]
  145. Bayat, A.; Larijani, B.; Ahmadian, S.; Junginger, H.E.; Rafiee-Tehrani, M. Preparation and characterization of insulin nanoparticles using chitosan and its quaternized derivatives. Nanomed. Nanotechnol. Biol. Med. 2008, 4, 115–120. [Google Scholar] [CrossRef] [PubMed]
  146. Arbit, E. The physiological rationale for oral insulin administration. Diabetes Technol. Ther. 2004, 6, 510–517. [Google Scholar] [CrossRef] [PubMed]
  147. Menzel, C.; Silbernagl, J.; Laffleur, F.; Leichner, C.; Jelkmann, M.; Huck, C.W.; Hussain, S.; Bernkop-Schnürch, A. 2,2′Dithiodinicotinyl ligands: Key to more reactive thiomers. Int. J. Pharm. 2016, 503, 199–206. [Google Scholar] [CrossRef]
  148. Sajjad, M.; Khan, M.I.; Naveed, S.; Ijaz, S.; Qureshi, O.S.; Raza, S.A.; Shahnaz, G.; Sohail, M.F. Folate-Functionalized Thiomeric Nanoparticles for Enhanced Docetaxel Cytotoxicity and Improved Oral Bioavailability. AAPS PharmSciTech 2019, 20, 81. [Google Scholar] [CrossRef]
  149. Samprasit, W.; Opanasopit, P.; Chamsai, B. Mucoadhesive chitosan and thiolated chitosan nanoparticles containing alpha mangostin for possible Colon-targeted delivery. Pharm. Dev. Technol. 2021, 26, 362–372. [Google Scholar] [CrossRef]
  150. Fan, B.; Xing, Y.; Zheng, Y.; Sun, C.; Liang, G. pH-responsive thiolated chitosan nanoparticles for oral low-molecular weight heparin delivery: In vitro and in vivo evaluation. Drug Deliv. 2016, 23, 238–247. [Google Scholar] [CrossRef]
  151. Gradauer, K.; Vonach, C.; Leitinger, G.; Kolb, D.; Fröhlich, E.; Roblegg, E.; Bernkop-Schnürch, A.; Prassl, R. Chemical coupling of thiolated chitosan to preformed liposomes improves mucoadhesive properties. Int. J. Nanomed. 2012, 7, 2523–2534. [Google Scholar] [CrossRef][Green Version]
  152. Dünnhaupt, S.; Barthelmes, J.; Rahmat, D.; Leithner, K.; Thurner, C.C.; Friedl, H.; Bernkop-Schnürch, A. S-protected thiolated chitosan for oral delivery of hydrophilic macromolecules: Evaluation of permeation enhancing and efflux pump inhibitory properties. Mol. Pharm. 2012, 9, 1331–1341. [Google Scholar] [CrossRef]
  153. Dünnhaupt, S.; Barthelmes, J.; Iqbal, J.; Perera, G.; Thurner, C.C.; Friedl, H.; Bernkop-Schnürch, A. In vivo evaluation of an oral drug delivery system for peptides based on S-protected thiolated chitosan. J. Control. Release Off. J. Control Release Soc. 2012, 160, 477–485. [Google Scholar] [CrossRef]
  154. Iqbal, J.; Shahnaz, G.; Perera, G.; Hintzen, F.; Sarti, F.; Bernkop-Schnürch, A. Thiolated chitosan: Development and in vivo evaluation of an oral delivery system for leuprolide. Eur. J. Pharm. Biopharm. Off. J. Arb. Pharm. Verfahr. EV 2012, 80, 95–102. [Google Scholar] [CrossRef]
  155. Dünnhaupt, S.; Barthelmes, J.; Hombach, J.; Sakloetsakun, D.; Arkhipova, V.; Bernkop-Schnürch, A. Distribution of thiolated mucoadhesive nanoparticles on intestinal mucosa. Int. J. Pharm. 2011, 408, 191–199. [Google Scholar] [CrossRef]
  156. Mourya, V.K.; Inamdar, N.N. Trimethyl chitosan and its applications in drug delivery. J. Mater. Sci. Mater. Med. 2009, 20, 1057–1079. [Google Scholar] [CrossRef] [PubMed]
  157. Kulkarni, A.D.; Patel, H.M.; Surana, S.J.; Vanjari, Y.H.; Belgamwar, V.S.; Pardeshi, C.V. N,N,N-Trimethyl chitosan: An advanced polymer with myriad of opportunities in nanomedicine. Carbohydr. Polym. 2017, 157, 875–902. [Google Scholar] [CrossRef]
  158. Sheng, J.; Han, L.; Qin, J.; Ru, G.; Li, R.; Wu, L.; Cui, D.; Yang, P.; He, Y.; Wang, J. N-trimethyl chitosan chloride-coated PLGA nanoparticles overcoming multiple barriers to oral insulin absorption. ACS Appl. Mater. Interfaces 2015, 7, 15430–15441. [Google Scholar] [CrossRef]
  159. Tsai, L.C.; Chen, C.H.; Lin, C.W.; Ho, Y.C.; Mi, F.L. Development of mutlifunctional nanoparticles self-assembled from trimethyl chitosan and fucoidan for enhanced oral delivery of insulin. Int. J. Biol. Macromol. 2019, 126, 141–150. [Google Scholar] [CrossRef]
  160. Ghavimishamekh, A.; Ziamajidi, N.; Dehghan, A.; Goodarzi, M.T.; Abbasalipourkabir, R. Study of Insulin-Loaded Chitosan Nanoparticle Effects on TGF-β1 and Fibronectin Expression in Kidney Tissue of Type 1 Diabetic Rats. Indian J. Clin. Biochem. IJCB 2019, 34, 418–426. [Google Scholar] [CrossRef]
  161. Song, R.F.; Li, X.J.; Cheng, X.L.; Fu, A.R.; Wang, Y.H.; Feng, Y.J.; Xiong, Y. Paclitaxel-loaded trimethyl chitosan-based polymeric nanoparticle for the effective treatment of gastroenteric tumors. Oncol. Rep. 2014, 32, 1481–1488. [Google Scholar] [CrossRef][Green Version]
  162. Huang, A.; Makhlof, A.; Ping, Q.; Tozuka, Y.; Takeuchi, H. N-trimethyl chitosan-modified liposomes as carriers for oral delivery of salmon calcitonin. Drug Deliv. 2011, 18, 562–569. [Google Scholar] [CrossRef]
  163. Li, W.; Zhu, X.; Zhou, X.; Wang, X.; Zhai, W.; Li, B.; Du, J.; Li, G.; Sui, X.; Wu, Y.; et al. An orally available PD-1/PD-L1 blocking peptide OPBP-1-loaded trimethyl chitosan hydrogel for cancer immunotherapy. J. Control Release Off. J. Control Release Soc. 2021, 334, 376–388. [Google Scholar] [CrossRef]
  164. Martins, A.F.; Bueno, P.V.; Almeida, E.A.; Rodrigues, F.H.; Rubira, A.F.; Muniz, E.C. Characterization of N-trimethyl chitosan/alginate complexes and curcumin release. Int. J. Biol. Macromol. 2013, 57, 174–184. [Google Scholar] [CrossRef][Green Version]
  165. Saheb, M.; Fereydouni, N.; Nemati, S.; Barreto, G.E.; Johnston, T.P.; Sahebkar, A. Chitosan-based delivery systems for curcumin: A review of pharmacodynamic and pharmacokinetic aspects. J. Cell. Physiol. 2019, 234, 12325–12340. [Google Scholar] [CrossRef]
  166. Ramalingam, P.; Ko, Y.T. Enhanced oral delivery of curcumin from N-trimethyl chitosan surface-modified solid lipid nanoparticles: Pharmacokinetic and brain distribution evaluations. Pharm. Res. 2015, 32, 389–402. [Google Scholar] [CrossRef]
  167. Kalliola, S.; Repo, E.; Srivastava, V.; Zhao, F.; Heiskanen, J.P.; Sirviö, J.A.; Liimatainen, H.; Sillanpää, M. Carboxymethyl Chitosan and Its Hydrophobically Modified Derivative as pH-Switchable Emulsifiers. Langmuir ACS J. Surf. Colloids 2018, 34, 2800–2806. [Google Scholar] [CrossRef][Green Version]
  168. Wang, J.; Xu, M.; Cheng, X.; Kong, M.; Liu, Y.; Feng, C.; Chen, X. Positive/negative surface charge of chitosan based nanogels and its potential influence on oral insulin delivery. Carbohydr. Polym. 2016, 136, 867–874. [Google Scholar] [CrossRef]
  169. Li, J.; Jiang, C.; Lang, X.; Kong, M.; Cheng, X.; Liu, Y.; Feng, C.; Chen, X. Multilayer sodium alginate beads with porous core containing chitosan based nanoparticles for oral delivery of anticancer drug. Int. J. Biol. Macromol. 2016, 85, 1–8. [Google Scholar] [CrossRef]
  170. Feng, C.; Song, R.; Sun, G.; Kong, M.; Bao, Z.; Li, Y.; Cheng, X.; Cha, D.; Park, H.; Chen, X. Immobilization of coacervate microcapsules in multilayer sodium alginate beads for efficient oral anticancer drug delivery. Biomacromolecules 2014, 15, 985–996. [Google Scholar] [CrossRef]
  171. Cong, Y.; Geng, J.; Wang, H.; Su, J.; Arif, M.; Dong, Q.; Chi, Z.; Liu, C. Ureido-modified carboxymethyl chitosan-graft-stearic acid polymeric nano-micelles as a targeted delivering carrier of clarithromycin for Helicobacter pylori: Preparation and in vitro evaluation. Int. J. Biol. Macromol. 2019, 129, 686–692. [Google Scholar] [CrossRef]
  172. Huang, G.Q.; Zhang, Z.K.; Cheng, L.Y.; Xiao, J.X. Intestine-targeted delivery potency of O-carboxymethyl chitosan-coated layer-by-layer microcapsules: An in vitro and in vivo evaluation. Mater. Sci. Eng. C Mater. Biol. Appl. 2019, 105, 110129. [Google Scholar] [CrossRef]
  173. Le, T.N.; Her, J.; Sim, T.; Jung, C.E.; Kang, J.K.; Oh, K.T. Preparation of Gastro-retentive Tablets Employing Controlled Superporous Networks for Improved Drug Bioavailability. AAPS PharmSciTech 2020, 21, 320. [Google Scholar] [CrossRef]
  174. Park, H.; Park, K.; Kim, D. Preparation and swelling behavior of chitosan-based superporous hydrogels for gastric retention application. J. Biomed. Mater. Res. Part A 2006, 76, 144–150. [Google Scholar] [CrossRef]
  175. Su, F.Y.; Lin, K.J.; Sonaje, K.; Wey, S.P.; Yen, T.C.; Ho, Y.C.; Panda, N.; Chuang, E.Y.; Maiti, B.; Sung, H.W. Protease inhibition and absorption enhancement by functional nanoparticles for effective oral insulin delivery. Biomaterials 2012, 33, 2801–2811. [Google Scholar] [CrossRef]
  176. Sung, H.W.; Sonaje, K.; Liao, Z.X.; Hsu, L.W.; Chuang, E.Y. pH-responsive nanoparticles shelled with chitosan for oral delivery of insulin: From mechanism to therapeutic applications. Acc. Chem. Res. 2012, 45, 619–629. [Google Scholar] [CrossRef] [PubMed]
  177. Lu, K.Y.; Lin, C.W.; Hsu, C.H.; Ho, Y.C.; Chuang, E.Y.; Sung, H.W.; Mi, F.L. FRET-based dual-emission and pH-responsive nanocarriers for enhanced delivery of protein across intestinal epithelial cell barrier. ACS Appl. Mater. Interfaces 2014, 6, 18275–18289. [Google Scholar] [CrossRef] [PubMed]
  178. Jeong, Y.I.; Jin, S.G.; Kim, I.Y.; Pei, J.; Wen, M.; Jung, T.Y.; Moon, K.S.; Jung, S. Doxorubicin-incorporated nanoparticles composed of poly(ethylene glycol)-grafted carboxymethyl chitosan and antitumor activity against glioma cells in vitro. Colloids Surf. B Biointerfaces 2010, 79, 149–155. [Google Scholar] [CrossRef] [PubMed]
  179. Hauptstein, S.; Bonengel, S.; Griessinger, J.; Bernkop-Schnürch, A. Synthesis and characterization of pH tolerant and mucoadhesive (thiol-polyethylene glycol) chitosan graft polymer for drug delivery. J. Pharm. Sci. 2014, 103, 594–601. [Google Scholar] [CrossRef] [PubMed]
  180. Papadimitriou, S.A.; Achilias, D.S.; Bikiaris, D.N. Chitosan-g-PEG nanoparticles ionically crosslinked with poly(glutamic acid) and tripolyphosphate as protein delivery systems. Int. J. Pharm. 2012, 430, 318–327. [Google Scholar] [CrossRef]
  181. Mo, R.; Jin, X.; Li, N.; Ju, C.; Sun, M.; Zhang, C.; Ping, Q. The mechanism of enhancement on oral absorption of paclitaxel by N-octyl-O-sulfate chitosan micelles. Biomaterials 2011, 32, 4609–4620. [Google Scholar] [CrossRef] [PubMed]
  182. Jain, A.K.; Swarnakar, N.K.; Das, M.; Godugu, C.; Singh, R.P.; Rao, P.R.; Jain, S. Augmented anticancer efficacy of doxorubicin-loaded polymeric nanoparticles after oral administration in a breast cancer induced animal model. Mol. Pharm. 2011, 8, 1140–1151. [Google Scholar] [CrossRef] [PubMed]
  183. Gaucher, G.; Satturwar, P.; Jones, M.C.; Furtos, A.; Leroux, J.C. Polymeric micelles for oral drug delivery. Eur. J. Pharm. Biopharm. Off. J. Arb. Pharm. Verfahr. EV 2010, 76, 147–158. [Google Scholar] [CrossRef] [PubMed]
  184. Nornoo, A.O.; Zheng, H.; Lopes, L.B.; Johnson-Restrepo, B.; Kannan, K.; Reed, R. Oral microemulsions of paclitaxel: In situ and pharmacokinetic studies. Eur. J. Pharm. Biopharm. Off. J. Arb. Pharm. Verfahr. EV 2009, 71, 310–317. [Google Scholar] [CrossRef]
  185. Al-Hilal, T.A.; Alam, F.; Byun, Y. Oral drug delivery systems using chemical conjugates or physical complexes. Adv. Drug Deliv. Rev. 2013, 65, 845–864. [Google Scholar] [CrossRef]
  186. Soares, S.F.; Fernandes, T.; Daniel-da-Silva, A.L.; Trindade, T. The controlled synthesis of complex hollow nanostructures and prospective applications(†). Proc. Math. Phys. Eng. Sci. 2019, 475, 20180677. [Google Scholar] [CrossRef] [PubMed][Green Version]
  187. Sultan, Y.; DeRosa, M.C. Target binding influences permeability in aptamer-polyelectrolyte microcapsules. Small 2011, 7, 1219–1226. [Google Scholar] [CrossRef]
  188. Sultan, Y.; Walsh, R.; Monreal, C.; DeRosa, M.C. Preparation of functional aptamer films using layer-by-layer self-assembly. Biomacromolecules 2009, 10, 1149–1154. [Google Scholar] [CrossRef]
  189. Radwan, S.E.; Sokar, M.S.; Abdelmonsif, D.A.; El-Kamel, A.H. Mucopenetrating nanoparticles for enhancement of oral bioavailability of furosemide: In vitro and in vivo evaluation/sub-acute toxicity study. Int. J. Pharm. 2017, 526, 366–379. [Google Scholar] [CrossRef]
  190. Yang, J.; Chen, J.; Pan, D.; Wan, Y.; Wang, Z. pH-sensitive interpenetrating network hydrogels based on chitosan derivatives and alginate for oral drug delivery. Carbohydr. Polym. 2013, 92, 719–725. [Google Scholar] [CrossRef]
  191. Oshi, M.A.; Lee, J.; Naeem, M.; Hasan, N.; Kim, J.; Kim, H.J.; Lee, E.H.; Jung, Y.; Yoo, J.W. Curcumin Nanocrystal/pH-Responsive Polyelectrolyte Multilayer Core-Shell Nanoparticles for Inflammation-Targeted Alleviation of Ulcerative Colitis. Biomacromolecules 2020, 21, 3571–3581. [Google Scholar] [CrossRef] [PubMed]
  192. Jain, A.; Jain, S.K. Optimization of chitosan nanoparticles for colon tumors using experimental design methodology. Artif. Cells Nanomed. Biotechnol. 2016, 44, 1917–1926. [Google Scholar] [CrossRef][Green Version]
  193. Caddeo, C.; Díez-Sales, O.; Pons, R.; Carbone, C.; Ennas, G.; Puglisi, G.; Fadda, A.M.; Manconi, M. Cross-linked chitosan/liposome hybrid system for the intestinal delivery of quercetin. J. Colloid Interface Sci. 2016, 461, 69–78. [Google Scholar] [CrossRef][Green Version]
  194. Konecsni, K.; Low, N.H.; Nickerson, M.T. Chitosan-tripolyphosphate submicron particles as the carrier of entrapped rutin. Food Chem. 2012, 134, 1775–1779. [Google Scholar] [CrossRef]
  195. Sareen, R.; Jain, N.; Rajkumari, A.; Dhar, K.L. pH triggered delivery of curcumin from Eudragit-coated chitosan microspheres for inflammatory bowel disease: Characterization and pharmacodynamic evaluation. Drug Deliv. 2016, 23, 55–62. [Google Scholar] [CrossRef]
  196. Pandey, S.; Mishra, A.; Raval, P.; Patel, H.; Gupta, A.; Shah, D. Chitosan-pectin polyelectrolyte complex as a carrier for colon targeted drug delivery. J. Young Pharm. JYP 2013, 5, 160–166. [Google Scholar] [CrossRef][Green Version]
  197. Liu, C.; Kou, Y.; Zhang, X.; Dong, W.; Cheng, H.; Mao, S. Enhanced oral insulin delivery via surface hydrophilic modification of chitosan copolymer based self-assembly polyelectrolyte nanocomplex. Int. J. Pharm. 2019, 554, 36–47. [Google Scholar] [CrossRef]
  198. Liu, C.; Kou, Y.; Zhang, X.; Cheng, H.; Chen, X.; Mao, S. Strategies and industrial perspectives to improve oral absorption of biological macromolecules. Expert Opin. Drug Deliv. 2018, 15, 223–233. [Google Scholar] [CrossRef] [PubMed]
  199. Meng, F.; Zhong, Y.; Cheng, R.; Deng, C.; Zhong, Z. pH-sensitive polymeric nanoparticles for tumor-targeting doxorubicin delivery: Concept and recent advances. Nanomedicine 2014, 9, 487–499. [Google Scholar] [CrossRef]
  200. Anwer, M.K.; Iqbal, M.; Muharram, M.M.; Mohammad, M.; Ezzeldin, E.; Aldawsari, M.F.; Alalaiwe, A.; Imam, F. Development of Lipomer Nanoparticles for the Enhancement of Drug Release, Anti-microbial Activity and Bioavailability of Delafloxacin. Pharmaceutics 2020, 12, 252. [Google Scholar] [CrossRef][Green Version]
  201. Khare, T.; Mahalunkar, S.; Shriram, V.; Gosavi, S.; Kumar, V. Embelin-loaded chitosan gold nanoparticles interact synergistically with ciprofloxacin by inhibiting efflux pumps in multidrug-resistant Pseudomonas aeruginosa and Escherichia coli. Environ. Res. 2021, 199, 111321. [Google Scholar] [CrossRef]
  202. Maisetta, G.; Piras, A.M.; Motta, V.; Braccini, S.; Mazzantini, D.; Chiellini, F.; Zambito, Y.; Esin, S.; Batoni, G. Antivirulence Properties of a Low-Molecular-Weight Quaternized Chitosan Derivative against Pseudomonas aeruginosa. Microorganisms 2021, 9, 912. [Google Scholar] [CrossRef]
  203. Traverso, G.; Langer, R. Perspective: Special delivery for the gut. Nature 2015, 519, S19. [Google Scholar] [CrossRef][Green Version]
  204. Pan, J.; Rostamizadeh, K.; Filipczak, N.; Torchilin, V.P. Polymeric Co-Delivery Systems in Cancer Treatment: An Overview on Component Drugs’ Dosage Ratio Effect. Molecules 2019, 24, 1035. [Google Scholar] [CrossRef] [PubMed][Green Version]
  205. Tang, Y.; Liang, J.; Wu, A.; Chen, Y.; Zhao, P.; Lin, T.; Zhang, M.; Xu, Q.; Wang, J.; Huang, Y. Co-Delivery of Trichosanthin and Albendazole by Nano-Self-Assembly for Overcoming Tumor Multidrug-Resistance and Metastasis. ACS Appl. Mater. Interfaces 2017, 9, 26648–26664. [Google Scholar] [CrossRef] [PubMed]
  206. Chen, A.M.; Zhang, M.; Wei, D.; Stueber, D.; Taratula, O.; Minko, T.; He, H. Co-delivery of doxorubicin and Bcl-2 siRNA by mesoporous silica nanoparticles enhances the efficacy of chemotherapy in multidrug-resistant cancer cells. Small 2009, 5, 2673–2677. [Google Scholar] [CrossRef] [PubMed][Green Version]
  207. Jhaveri, J.; Raichura, Z.; Khan, T.; Momin, M.; Omri, A. Chitosan Nanoparticles-Insight into Properties, Functionalization and Applications in Drug Delivery and Theranostics. Molecules 2021, 26, 272. [Google Scholar] [CrossRef]
  208. Jo, S.D.; Ku, S.H.; Won, Y.Y.; Kim, S.H.; Kwon, I.C. Targeted Nanotheranostics for Future Personalized Medicine: Recent Progress in Cancer Therapy. Theranostics 2016, 6, 1362–1377. [Google Scholar] [CrossRef]
  209. Hong, S.C.; Yoo, S.Y.; Kim, H.; Lee, J. Chitosan-Based Multifunctional Platforms for Local Delivery of Therapeutics. Mar. Drugs 2017, 15, 60. [Google Scholar] [CrossRef][Green Version]
  210. Liu, Y.; Kong, M.; Cheng, X.J.; Wang, Q.Q.; Jiang, L.M.; Chen, X.G. Self-assembled nanoparticles based on amphiphilic chitosan derivative and hyaluronic acid for gene delivery. Carbohydr. Polym. 2013, 94, 309–316. [Google Scholar] [CrossRef]
  211. Tan, C.S.S.; Lee, S.W.H. Warfarin and food, herbal or dietary supplement interactions: A systematic review. Br. J. Clin. Pharmacol. 2021, 87, 352–374. [Google Scholar] [CrossRef] [PubMed]
Figure 1. The schematic illustration of the GI physiological barriers affecting drug absorption. When one orally takes the drug-loaded chitosan nanomaterials (e.g., chitosan-based nanoparticles with chemical modification, conjugated chitosan, and chitosan-based polyelectrolyte complex), they encounter GI physiological challenges, including a variable pH along the GI tract, GI motility and gastric emptying, intestinal transit, digestive enzymes, transporter protein expression, gut microbiota, and disease conditions. The GI physiological challenge can be influenced by aging, gender, and ethnicity. Created with
Figure 1. The schematic illustration of the GI physiological barriers affecting drug absorption. When one orally takes the drug-loaded chitosan nanomaterials (e.g., chitosan-based nanoparticles with chemical modification, conjugated chitosan, and chitosan-based polyelectrolyte complex), they encounter GI physiological challenges, including a variable pH along the GI tract, GI motility and gastric emptying, intestinal transit, digestive enzymes, transporter protein expression, gut microbiota, and disease conditions. The GI physiological challenge can be influenced by aging, gender, and ethnicity. Created with
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Figure 2. The mechanistic insights of the enhancement of drug absorption by drug-loaded chitosan nanomaterials in the intestine. The ideal properties of these nanomaterials include (i) protection against GI luminal degradation, (ii) mucoadhesion, (iii) permeation enhancement, (iv) controlled drug release, and (v) inhibition of P-gp, MRP-2, or BCRP. Abbreviation: P-gp, P-glycoprotein; MRP-2, multidrug resistance protein-2; BCRP, breast cancer resistance protein. Created with
Figure 2. The mechanistic insights of the enhancement of drug absorption by drug-loaded chitosan nanomaterials in the intestine. The ideal properties of these nanomaterials include (i) protection against GI luminal degradation, (ii) mucoadhesion, (iii) permeation enhancement, (iv) controlled drug release, and (v) inhibition of P-gp, MRP-2, or BCRP. Abbreviation: P-gp, P-glycoprotein; MRP-2, multidrug resistance protein-2; BCRP, breast cancer resistance protein. Created with
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Pathomthongtaweechai, N.; Muanprasat, C. Potential Applications of Chitosan-Based Nanomaterials to Surpass the Gastrointestinal Physiological Obstacles and Enhance the Intestinal Drug Absorption. Pharmaceutics 2021, 13, 887.

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Pathomthongtaweechai N, Muanprasat C. Potential Applications of Chitosan-Based Nanomaterials to Surpass the Gastrointestinal Physiological Obstacles and Enhance the Intestinal Drug Absorption. Pharmaceutics. 2021; 13(6):887.

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Pathomthongtaweechai, Nutthapoom, and Chatchai Muanprasat. 2021. "Potential Applications of Chitosan-Based Nanomaterials to Surpass the Gastrointestinal Physiological Obstacles and Enhance the Intestinal Drug Absorption" Pharmaceutics 13, no. 6: 887.

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