*6.2. Release Mechanism*

Nanodevices (nanocapsules and matrixial nanomaterials) can provide several forms of release for the chemotherapeutic drugs (see Figure 6). Drugs can be desorbed from the matrix or core reservoir (nanocapsules) because of a concentration gradient that can be assisted by swelling or material relaxation, facilitating the release of the bioactive component [109].

**Figure 6.** Drug-releasing mechanism of chemotherapeutic drugs.

The erosion/dissolution implies the loss of the shell or matrix integrity to favor the diffusion of the bioactive component. The erosion/dissolution of the nanodevice can be triggered by pH changes and water content, among others. Usually these systems deliver the bioactive compound quickly once the capsule is in contact with the target environment. Otherwise, the degradation mechanism tends to be a slow as it is mediated by enzymatic reactions [110,111].

An osmotically active drug can be delivered using an osmotic pump, in which the bioactive component is pushed away by a fluid that goes into the capsule via a semipermeable membrane and force the drug to pass throughout an orifice [112].

Along with the nanodevice type, the interaction of the biomaterial/bioactive compound modulates the releasing profile. Bioactive components for CRC treatment are complex; for instance, antioxidants poses aromatic rings with hydroxyl lateral groups, conferring to them a hydrophilic nature [113], and hydroxyl groups can easily generate hydrogen bond interactions with biomaterials. Antioxidants of high molecular weight present an amphiphilic nature, with hydrophilic and lipophilic zones such in the case of vitamin E and carotenoids [114], which can interact with either polar or nonpolar polymers.

Plant extracts contains several bioactive compounds (mixtures of hydrophilic and lipophilic compounds). Nevertheless, most CRC adjuvant extracts are, in general, hydrophilic in nature and water-soluble [90,115–117] and thus can interact with hydrophilic polymers. Likewise, synthetic bioactive compounds have an amphiphilic nature; for instance, 5-FU is a pyrimidine with oxygen and flour lateral groups, conferring it with a hydrophilic nature, but 5-FU can present resonance diminishing its water solubility [118]. According to the above, given the diversity of CRC adjuvants, several polymer-based biomaterials have been used for generating nanodevices for drug delivery systems.

### *6.3. Polymers for Oral Drug Delivery Systems*

Biomaterials have improved the delivery and efficacy of a range of pharmaceutical compounds. In particular, polymer- and lipid-based materials have been designed to release therapeutics for extended periods of time and for targeting specific locations within the body, thereby reducing the toxicity to the

patient whilst keeping the therapeutic effect [110]. Lipid-based drug delivery systems are beyond of the goals of this paper; these formulations types are reviewed in the following references [119–121]. For polymer drug delivery, the oral route has been proven to be most convenient route for chronic drug therapy [119]. For instance, in studies of CRC patients, it has been proven that the oral administration of adjuvant treatments is most suitable for the patient and cost-saving for health systems [122,123]. However, oral administration is challenging for CRC as the drug needs to be protected during passage through the digestive tract before proper delivery. For this application, polymers are advantageous due to their processability at the nanoscale, their wide range of functional groups, and the possibility of generating mixtures, composites, and copolymers, among others [124], favoring the protection of the drug and its delivery profile.

Drug delivery polymers for colorectal cancer can be classified according to polymer nature, into non-charged polymers and charged polymers (anionic, cationic, and zwitterionic), as presented in Figure 7. Non-charged polymers cannot be charged via dissociation; thus, they are strongly stable at any pH value, and they can interact via hydrogen bonding and Van der Waals interactions. Alternatively, charged polymers can generate anionic, cationic, or zwitterionic charges on their surface and can switch from neutral to charged, depending on the hydrogen potential of the surrounding environment. The switching from neutral to charged will influence the chain polymer organization. For instance, Han et al. (2016) found that the carboxylic lateral groups of polyacrylic acid copolymers induces polymer changes in terms of roughness, thickness, and porosity, from pH 5.5 to 9 [125]. Those systems have the advantage of modulating the drug release by pH, as presented in the gastrointestinal fluids. The interaction with these polymers is more likely to be ionic, which is stronger, but requires at least polar or ionic charges in the bioactive compounds.

**Figure 7.** Polymer families for drug delivery systems of antioxidants for CRC.

Mixtures and composites are alternative strategies for creating a synergistic response in the system [126,127]. In the following sections, the strategies for each polymer type in drug delivery systems for CRC are described.

### *6.4. Polymers for Encapsulating Antioxidants for Colorectal Cancer*

Antioxidants for drug delivery have more than 4600 documents indexed in Scopus, with an accelerated growth from 2000 to date. From those, around 44.6% include the word "polymer", which hints at the relevance of creating polymer-based drug delivery systems to protect these compounds. For encapsulating antioxidants, all polymer families have been used for the drug delivery of these compounds.

### 6.4.1. Polysaccharides and Derived Polysaccharides

Polysaccharides are carbohydrate polymers composed of long chains of monosaccharides, such as glucose, fructose, and galactose, among others [128]. Polysaccharides can respond to pH, colon enzyme degradation, or peristaltic movement. For instance, chitosan can response to pH changes, starches can be degraded by amylase enzymes, and ethyl cellulose can be broken by colon waves [129]. Polysaccharides have garnered attention because, like antioxidants, they come from natural sources, allowing the development of bio-based therapies for CRC. Antioxidants have been successfully encapsulated using polysaccharides for nanocapsules such as cellulose, chitosan, and alginate, among others.

Cellulose is the most abundant polymer on earth; it is composed of β1-4 linked d (+) glucose [124,130,131]. Cellulose and its derivatives have been reported as carriers of antioxidants. For instance, Sunnasee et al. (2019) grafted β-cyclodextrins in cellulose nanocrystals, demonstrating that this system is not immunogenic and does not induce oxidative stress in the cell, thus it is safe for intracellular drug delivery [132]. Li et al. (2019) developed a nanoformulation of quercetin and cellulose nanofibers with sustained antioxidant activity. The nanocellulose fibers were an e ffective nanocarrier of the antioxidant with a loading capacity of 78.91% and encapsulation e fficiency of 88.77%; moreover, the quercetin delivery profile was extended to higher times [133]. Ching et al. (2019) encapsulated curcumin in cellulose nanocrystals (via acid hydrolysis), adding surfactants to improve the loading capacity of the release profile of the antioxidant [134]. Ngwabebhoh et al. (2018) developed a Pickering suspension for encapsulating curcumin using cellulose nanocrystrals [106], finding that the capsules were stable for up to 8 days at di fferent pHs [106]. However, the application was directed to antimicrobial properties instead of antioxidants for CRC.

Chitosan is a polysaccharide obtained from chitin deacetylation, composed of β-(1 →4)-linked d-glucosamine (deacetylated unit) and *<sup>N</sup>*-acetyl-d-glucosamine (acetylated unit) [135]. It is a cationic polymer that responds to pH changes and can be converted into hydrogels, making this polymer attractive for the drug delivery of antioxidants. For instance, Kumar et al. (2015) encapsulated naringenin (polyphenol) using chitosan nanocapsules. Their studies proved that encapsulated naringenin has a better anticancer e ffect than free naringenin [136]. Jeong et al. (2016) crosslinked chitosan with resveratrol modified with phospholipids to improve its oral bioavailability and low water solubility. The researchers found an encapsulation e fficiency of up to 85.59%, and an in vitro drug release study suggested a slow and a sustained release governed by di ffusion [137].

Shi et al. (2017) encapsulated β-carotene and anthocyanin in (2,2,6,6-Tetramethylpiperidin-1 -yl)oxyl (TEMPO)oxidized polysaccharides, specifically Konjac Glucomannan, in which some polysaccharides' hydroxyl lateral groups were converted into carbonyl groups, and then the spheres were coated with chitosan. The advantage of the system was its ability to generate oil–water stable systems and to retain the antioxidants at gastric pH values; moreover, the capsules exhibited anticancer effects [138].

Alginates are salts derived from alginic acid, in which the polymer has a carbonyl lateral group liked to a glucose unit, making the polymer negatively charged [139]. Sookkasem et al. (2015) developed novel alginate beads for encapsulating curcumin for colon target therapy; the capsule was able to prevent release in the upper gastrointestinal tract and immediately release the drug upon the arrival of the beads in the colon [139]. However, the approach of Sookkasem et al. was not at the nanoscale; the alginate beads had a diameter in millimeters (macroscale). Similarly, Wang et al. (2019) developed a macroscale capsule but using ZnO instead of Ca2+ as the crosslinking agen<sup>t</sup> to improve the

release profile to a longer time [140]. Approaches at the nanoscale for this polymer have been tested using mixtures and composites, especially with chitosan [141,142], as reported in the following sections.

Maltodextrin ( α 1–4 d (+) glucose) is a low molecular weight polysaccharide that has been broadly used for the encapsulation of food and pharmaceutical ingredients [143]. Ming et al. (2018) encapsulated red ginseng extract, generating a water/oil emulsion, and then coated it with maltodextrin using spray-drying. The researchers found particles ranging from 58 to 400 nm and optimized the conditions to produce them [143]; however, they did not evaluate the release or anticancer e ffects of the produced nanocapsules.

Pan et al. (2018) encapsulated curcumin in soybean polysaccharides (mixture of cellulose, xylogalacturonan, and arabinogalactan, among others), polysaccharides that easily link lipophilic compounds. The capsules were stable at a pH ranging from 2.0 to 7.0 [144]. Li et al. (2017) encapsulated phenolic acid antioxidants to prove the e ffectiveness of producing hollow Arabic gum and short linear glucans from starch templates. Hollow nanocapsules enhanced the antioxidant activity of the phenolic acids and improved the stability of their antioxidant activity in challenging environments with high salt concentrations, and when exposed to UV radiation and high temperatures [145].

Assis et al. (2017) incorporated lycopene nanocapsules in starch films to generate an edible film material, but the application was focused on packaging instead of biomedical e fficacy [146]. Amah et al. (2019) encapsulated catechin in starch-based nanoparticles, providing protection to the catechin against the harsh gastric environment and helping to retain its bioactive properties during an in vitro digestion process [147]. Jana et al. (2017) reviewed di fferent strategies for generating three-stimuli-responsive guar gum composites (pH, time, and enzymes) for colon-specific drug delivery [148]. Finally, Sa ffarzadeh-Matin et al. (2017) prepared an apple pomace polyphenolic extract and encapsulated it in maltodextrin in nanocapsules of 52 nm diameter, optimizing the loading efficiency of the process [149].
