6.4.8. Poly(vinylpyrrolidones)

Polyvinylpyrrolidone (PVP), commonly called polyvidone or povidone, is a water-soluble polymer made from the monomer *N*-vinylpyrrolidone by free-radical polymerization in the presence of AIBN as an initiator [182]. Dry PVP is a hygroscopic powder and readily absorbs up to 40% of water by its weight [182]. Nanofibers, particles, and films have been loaded with antioxidant extracts for drug delivery systems.

Sriyanti et al. (2017) and Andjani et al. (2017) developed electrospun nanofiber mats of polyvinyl(pyrrolidone) (PVP) with *Garcinia mangostana extract* (GME). The researchers found strong interactions of the PVP with the extract, which was molecularly dispersed in the electrospun PVP nanofiber matrix. The composite nanofiber mats exhibited very high antioxidant activities despite having been exposed to a high voltage during electrospinning [183,184]. A similar strategy was adopted by Andjani et al. (2017) and Zahra et al. (2019) using rotatory force spinning for encapsulating GME and Garlic (*Allium sativum*) extract; however, the obtained fibers were at the microscale [185,186].

Kamaruddin et al. (2018) developed sub-micron particles by the electrospraying of PVP and green tea extract. The researchers optimized the processes for obtaining the particles and saw the potential for drug delivery systems [186]. However, the particles were not tested for drug delivery applications

for colorectal cancer. Similarly, Guamán-Balcázar et al. (2019) generated sub-micron particles of PVP with mango leaf extract, finding a relationship between the mango leaf extract/PVP ratio, temperature, and pressure of the supercritical antisolvent extraction process with the particle size (some of the particles were at the nanoscale). The in vitro desorption test showed a release profile of the extract components lasting up to 8 h under simulated intestinal fluids at pH 6.8 [187].

Contardi et al. (2019) produced a new material of PVP plasticized with p-coumaric acid for the encapsulation of bioactive compounds of interest in the pharmaceutical industry. An initial model of the encapsulation of carminic acid was evaluated, finding that by varying the ratio of PVP to p-coumaric acid, the release profile can be adjusted from minutes to hours; for instance, a ratio of 2:1 (PVP/p-coumaric acid) has a release profile lasting up to 70 h to obtain 100% release [188].

### 6.4.9. Composites, Copolymers, and Mixtures

Composites and polymer mixtures take advantage of the synergystic e ffects of two polymers. For instance, one polymer may be highly compatible with the bioactive compound but not pH sensitive, thus the combination with another shell polymer will tailor the release profile. Some recent advances are presented below.

Thanyacharoen et al. (2018) developed a composite material of polyvinyl alcohol with chitosan to deliver gallic acid (antioxidant). The results seem promising as the gallic acid was released for periods longer than 16 h and its antioxidant properties were conserved [189].

Al-Ogaidi (2018) mixed two polysaccharides, alginate, and chitosan, to load vitamin C into nanoparticles of 25–30 nm in size. Moreover, Al-Ogaidi evaluated the e ffect of the pH on the overall size of the system, finding higher release at a pH of 6. Furthermore, it was found that entrapping vitamin C within the nanoparticle enhanced its anticancer activity [142]. Similar studies were carried out by Aluani et al. (2017) using quercetin instead of vitamin C [190]. Rahaiee et al. (2017) developed alginate–chitosan nanoparticles to stabilize crocin, an antioxidant with anticancer e ffects; crocin is highly sensitive to pH, heat, and oxidative stress, making its e ffectiveness reduced. The alginate–chitosan nanoparticles showed a controlled release profile in simulated gastrointestinal fluids and e ffectively protected crocin from the environment prior to being released [191].

Huang et al. (2016) improved the water dispersibility of curcumin, using core-shell nanoparticles of zein (core) and alginate–pectin (shell). The researcher found that curcumin-loaded core-shell nanoparticles were shown to have superior antioxidant and radical scavenging activities compared to curcumin solubilized in ethanol [192]. Likewise, Wei et al. (2019) developed zein–propylene glycol alginate–rhamnolipid composite nanoparticles to overcome the limitations of resveratrol such as water insolubility and chemical instability; the nanoparticles controlled the release for up to2h[193].

Arunkumar created nanocapsules of 100 nm using poly (lactic-co-glycolic acid)-polyethylene glycol to improve the solubility and stability of lutein (an antioxidant with poor solubility). The capsules showed higher stability and improved the bioability of the lutein, enhancing the antiproliferative e ffect of the antioxidant, evidenced by the lower lethal concentration (LC50) of 10.9 μM for the nanocapsules and 25 μM for free lutein [194].

Jaiswal et al. (2019) synthesized methyl methacrylate (MMA)-modified chitosan (CS) by a green method via a Michael addition reaction between CS and MMA in ethanol. The nanoparticles of approximately 100 nm had, in an in vitro drug release study, a maximal curcumin entrapment e fficiency up to 68% with a high release at a pH of 5.0 and a lower one at physiological pH [195]. Positive charges on chitosan will generate maximum delivery at acid pH (stomach) rather than neutral (colon). Consequently, this strategy is not recommended for CRC treatment, since curcumin would be delivered before arriving at the desired area.

Eatemadi et al. (2016) developed a nanoparticle of PCL-PEG-PCL to encapsulate chrysin (antioxidant). The researcher investigated the e ffect of chrysin-loaded PCL-PEG-PCL on the T47D breast cancer cell line. The cell viability assay showed that chrysin has a time-dependent cytotoxic effect on the T47D cell line. Furthermore, the conducted studies showed that encapsulated chrysin has

a higher antitumor e ffect on the gene expression of FTO, BRCA1, and hTERT than free chrysin [196]. This study was not focused on CRC, but these systems can be easily extrapolated to gastrointestinal drug delivery.

Wu et al. (2016) evaluated the structural, mechanical, antioxidant, and cytocompatibility properties of membranes prepared from PHA and arrowroot (*Maranta arundinacea*) starch powder (ASP). Furthermore, the researchers grafted acrylic acid to PHA (PHA-g-AA). The PHA-g-AA/ASP membranes had better mechanical properties than the PHA/ASP membrane. This e ffect was attributed to greater compatibility between the grafted PHA and ASP. The water-resistance of the PHA-g-AA/ASP membranes was greater than that of the PHA/ASP membranes, and a cytocompatibility evaluation with human foreskin fibroblasts indicated that both materials were nontoxic. Moreover, ASP enhanced the polyphenol content and antioxidant properties when they were encapsulated [197].

### *6.5. Polymers for Encapsulating Synthetics and Hybrid Adjuvants for CRC*

Synthetics and hybrid adjuvants are based on 5-FU. As explained previously, 5-FU is the gold standard for cancer and CRC adjuvant treatment. However, along with the growing interest in natural antioxidants, new hybrid compounds derived from 5-FU conjugated with natural or synthetic molecules have been developed; for example curcumin, has been conjugated with 5-FU to act synergistically by enhancing cellular uptake and accumulation, by inducing the destabilization of the cytoskeleton and loss of mitochondrial membrane potential, initiating early and late apoptosis in cancer cells [198]. Furthermore, synthetic drugs can be mixed with other natural or synthetic compounds to potentiate them or reduce the side e ffects. An example of this strategy is the mixing of 5-FU with resveratrol to reduce the toxicity of 5-FU against healthy cells [199]. Examples of other hybrids and mixtures were reviewed by Carrillo et al. (2015); the paper can be consulted in the following reference: [200].

The first attempts at looking at polymer encapsulation techniques for 5-FU and its derivatives are limited, mainly due to 5-FU being first patented in 1957 and then the research into encapsulating the molecule being governed by pharmaceutical companies. However, today, most of the patents have expired, making these compounds attractive for developing drug delivery systems. According to Scopus, there are more than 2800 documents related to 5-FU drug delivery systems. In 2018, more than 180 papers were published, and among them, 114 include the word "polymer". In the Table 4, some representative work from 2015 to 2019 is presented.


**Table 4.** Recent advances in using 5-fluorouracil (5-FU) and its derivatives in polymer encapsulation strategies for CRC.


### **Table 4.** *Cont.*

According to the above table, recent advances in synthetic adjuvants have been focused on improving the bioavailability of 5-FU. For example, for a pH-sensitive polymer that will deliver the 5-FU in the colonic area, the modification of the polymer surface with folic acid makes it selective for receptors that are more active in cancer cells, for targeted therapy. Moreover, the blending of polymers and bioactive compounds is a new approach to reducing the toxic side effects of 5-FU and enhancing its therapeutic effects.
