**6. Antioxidant Quercetin Polymers**

The polymerization of quercetin is part of a broader effort in recent years to enhance the performance of natural and synthetic antioxidant polymers via covalent insertion of antioxidant species (such as vitamins, curcumin, and quercetin) into polymeric chains [77]. The polymerization products have demonstrated appropriate properties in food packaging (as preserving agents) [78], biomedical and pharmaceutical applications, especially in the production of antioxidant-laden nanoparticles for cancer treatment [77,79,80], or contact lenses and hemodialysis membranes. In both applications, the potency of the antioxidants is contingent on successful polymerization. A distinct advantage of bioconjugates is the exploitation of unique benefits of different bio-conjugates, the slow rates of macromolecular system degradation, and better chemical and cellular stability.

Quercetin is a plant-derived aglycone flavonoid with antioxidant properties that are suitable in the food packaging industry and the production of targeted therapies for cancer, heart, liver, and lung complications [78,80,81]. The primary sources include tea, red wine, and common fruits and vegetables such as onions, berries, apples, red grapes, broccoli, and cherries [80]. The antioxidant properties influence medical and nutritional applications as nutraceutical/nutritional supplement to boost the immune system and elevate protection against cardiovascular and lung conditions, osteoporosis, and tumor growth [80,81]; this is achieved through the neutralization of reactive oxygen species and the mediation of the transduction pathways, enzymatic activity, and function of glutathione. The specific mechanisms for the prevention of liver damage include the inhibition of the cellular activation of various signaling pathways, including NF-κB and MAPK [80]. Moreover, the antioxidant inhibits the release and expression of apoptosis-related proteins triggered by LPS/d-GalN, suppresses oxidation marker-mediated production of LPS/d-GalN. Following the inhibition of the mechanisms listed above, quercetin catalyzes the antioxidant signal transduction pathways (particularly Nrf2/GCL/GSH) and other processes that increase the concentration of glutathione in the cells [79].

The chemical structure and properties of quercetin contribute to its bioavailability and solubility in cellular fluids and moderation of biochemical pathways. However, the commercial exploitation of the antioxidant properties of quercetin depends on the success of the polymerization process, which can be tailored to generate bioactive compounds such as template quercetin (QCT) nanoparticles for free-radical scavenging. The cellular function of the QCT nanoparticles was demonstrated through material characterization using transmission electron microscopy (TEM), dynamic light scattering, H-NMR spectroscopy, Fourier-transform infrared spectroscopy, and UV-Visible spectroscopy [80]. The demonstrated biopharmaceutical application of oxidation-triggered self-polymerization quercetin in the production of targeted therapies by Xu et al. [80] is in line with the findings of Sunoqrot et al. [79]. The latter study documented the successful bio-inspired polymerization of quercetin—a process that resulted in the synthesis of cancer therapies. The nanotechnology-based quercetin–curcumin therapeutics exhibited superior cytotoxic behavior against cancer tumors. However, the superior biological function was dependent on precision in the synthetic process.

In the current case, the quercetin–curcumin-loaded nano-medicine was synthesized in the presence of curcumin and thiol-terminated poly (ethylene glycol) (PEG)-mediated surface functionalization; this was integral in facilitating steric stabilization in a single reaction step. The reactants were exposed to dimethyl sulfoxide [79]—a universal solvent to obtain a homogenous solution. The next polymerization steps entailed the gradual addition of water. The single-step synthesis process preferred by Sunoqrot et al. [79] was confirmed to be efficient by Pouci et al. [77], who noted that the one-step synthesis route was integral to the synthesis of polymer antioxidant conjugates (that are less susceptible to degradation) without emitting toxic byproducts.

Even though Sunoqrot et al. [79] documented successful synthesis and clinical application of quercetin–curcumin-loaded nanoparticles for targeted cancer drug synthesis, the approach does not align with Zhang et al.'s [81] research on the antioxidant properties of quercetin. In contrast to Sunoqrot et al. [79], Zhang et al. [81] advocated the use of quercetin based on its greater reduction potential relative to curcumin. The reduction potential helps to predict the total antioxidant capacity (TAC), which is fourfold higher for quercetin compared to curcumin. The unique chemical and biological properties help explain the cellular action against LPS-induced reactive oxygen species. Considering that experimental data predict clinical applications, further research is necessary to assess the effectiveness of quercetin only and quercetin–curcumin-loaded nanoparticles for targeted cancer tumor treatment. The need to compare antioxidants' potential benefits in combined or individual treatments is consistent with the research of Zhang et al. [81].

The biomedical applications of quercetin documented by Xu et al. [80] are but a microcosm of the potential industrial applications considering that quercetin is indispensable

in the food production industry, where it is incorporated as an additive in bio-polyether (PEO), bio-polyester (PLA), and commercial starch-based polymer (Mater-Bio) [78]; this depends on the extent of photo-stabilization and artificial photo-stabilization. The oxidationtriggered self-polymerization is depicted in Figure 6. The illustration demonstrates the role of incubation, oxidizing agent, and universal organic solvents in the synthesis of nanoparticles. *Polymers* **2021**, *13*, x FOR PEER REVIEW 20 of 33

**Figure 6.** Synthesis process for template quercetin (QCT) nanoparticles [80] (**a**) Schematic of synthesis and (**b**) Potential chemical pathways of synthesis. **Figure 6.** Synthesis process for template quercetin (QCT) nanoparticles [80] (**a**) Schematic of synthesis and (**b**) Potential chemical pathways of synthesis.

The impact of quercetin additives on the tensile strength, Young's Modulus, and elongation at break of bio-polyether, bio-polyester, and commercial starch-based polymer (Mater-Bio) is depicted in Table 7. The data demonstrate the influence of quercetin on stabilized and un-stabilized systems. The mechanical testing outcomes showed a significant improvement in the elastic modulus, tensile strength, and elongation at break after stabilization with quercetin additives (Q): Cyasorb® and synthetic Light Stabilizers (LS). In particular, a 5 wt% increase in elongation at break and the tensile strength resulted in a 10–20% improvement in the elastic modulus, tensile strength, and elongation at break. However, the microscale changes in the mechanical properties were attributed to different mechanisms. The impact of quercetin additives on the tensile strength, Young's Modulus, and elongation at break of bio-polyether, bio-polyester, and commercial starch-based polymer (Mater-Bio) is depicted in Table 7. The data demonstrate the influence of quercetin on stabilized and un-stabilized systems. The mechanical testing outcomes showed a significant improvement in the elastic modulus, tensile strength, and elongation at break after stabilization with quercetin additives (Q): Cyasorb® and synthetic Light Stabilizers (LS). In particular, a 5 wt% increase in elongation at break and the tensile strength resulted in a 10–20% improvement in the elastic modulus, tensile strength, and elongation at break. However, the microscale changes in the mechanical properties were attributed to different mechanisms.

**Table 7.** Changes in the mechanical properties (elastic modulus, tensile strength, and elongation at break) before and after stabilization with quercetin additives (Q): Cyasorb and synthetic Light Stabilizers (LS) [78]. **Table 7.** Changes in the mechanical properties (elastic modulus, tensile strength, and elongation at break) before and after stabilization with quercetin additives (Q): Cyasorb and synthetic Light Stabilizers (LS) [78].


On the one hand, the changes in the elongation at break of the stabilized bio-polyether, bio-polyester, and commercial starch-based polymer have been linked to the plasticizing effects triggered by the low MW stabilizing molecules such as quercetin [78]. On the other hand, the improvements in the tensile strength and elongation at break have been linked to higher rigidity of the stabilized films in relation to the machine direction [78]. The contrasting changes at the micro scale show that quercetin has unique effects on biofilms for food packaging—a phenomenon that introduces new challenges and benefits in the polymerization of quercetin for industrial applications. On a positive note, the higher orientation of the macromolecules in the presence of the plasticizing agent increases the suitability of quercetin in food packaging. It is deduced that other challenges could be addressed through innovations in polymerization.

The improvements in elastic modulus, tensile strength, and elongation at the break following stabilization with Q and LS by Morici et al. [78] are significant considering that the most common forms of quercetin polymerization are inspired by nature. The polymerization of polyquercetin offers further practical opportunities for developing customized therapeutics that influence glutathione (GSH) and enzymatic activity, moderate the signal transduction pathways, and diminish the availability of reactive oxygen species (ROS).
