6.4.5. Polyoxazoline

Poly (2-oxazoline) (POZ) is a class of polymers formed by cationic ring-opening that were first identified and synthesized over 50 years ago. These polymers are nonionic, biostable, and water-soluble, and some are polar organic solvents. POZ can be synthesized from readily available non-toxic materials. The interest in using POZ in medical devices and drug delivery is very recent, and their application in multiple platforms is now being recognized by drug delivery scientists [165]. Although there is limited literature about the use of POZ for cancer treatment, some formulations for the treatment of skin cancer are reported. For instance, Simon et al. (2019) developed ointments with quercetin (core) encapsulated in POZ (shell). The POZ produced a stable formulation of spherical nanocapsules of 18 nm in size. Moreover, a good quercetin encapsulation (94% ± 4%) e fficiency was observed with these nanosystems, allowing its homogeneous distribution in the nanocapsule.Therefore, Q-MM can be used as a reservoir of quercetin. Once loaded, quercetin's impact on cancer cell viability was doubled while its antioxidant efficacy was preserved [166]. Accordingly, POZ are an alternative for the encapsulation of antioxidants; hopefully, some new advances in oral drug formulations will be presented in the following years that can be used for CRC.

### 6.4.6. Polypeptides and Polyaminoacids

Polyaminoacids (PAA) and polypeptides (PPD) are polydisperse structures formed by the condensation of amino acid monomers through amide bonds that, contrary to proteins, cannot fold into globular or fibrillar structures [167]. In addition, they can carry versatile reactive functional groups on their side chains (carboxylic acid, hydroxyl, amino, and thiol groups) that allow for a variety of chemical modifications and compatibility with a wide range of bioactive compounds. Some outstanding nanocapsules of polyaminoacids have been developed for cancer treatment. For instance, Choi et al. (2018) encapsulated Celastrol (antioxidant) in PEGylated polyaminoacid-capped mesoporous silica nanoparticles for mitochondria-targeted delivery in solid tumors [107], and Patsula et al. (2019) modified maghemite nanoparticles with poly (l) poly(l-lysine) to protect the iron dioxide core from reaction with the encapsulated antioxidant (epigallocatechin-3-gallate from tea) and to promote the internalization of the nanoparticle of the system into the cancer cell [168].

PPD are special polymers that exhibit antioxidant properties themselves; in Table 3, some recent studies are presented.


**Table 3.** Recent advances in polypeptides (PPD) with antioxidant effects for CRC.

Regarding proteins, there are reports of silk proteins that are able to stabilize polar and non-polar antioxidants, due to the amphiphilic properties of fibroin. For example, Lou et al. (2016) used fibroin to stabilize vitamin C, curcumin, and epigallocatechin gallate. The results indicated that these antioxidants presented improved environmental stabilities of up to 14 days due to the binding of antioxidant molecules to the hydrophobic or the hydrophilic/hydrophilic boundary regions of silk [174]. Despite this work not being directly focused on CRC, it is highly relevant because antioxidants can easily react with air and other environmental conditions, losing their ROS -scavenging properties, prior to be

consumed by the patient; without stabilization, the antioxidant simply will have little or no effect in the patient. Lerdchai et al. (2016) designed a mixture of Thai silk fibroin/gelatin (denaturalized protein) sponges for the dual controlled release of curcumin and docosahexaenoic acid for localized cancer treatment. The sponges were fabricated by freeze-drying and glutaraldehyde cross-linking techniques. The highly cross-linked and slowly degrading silk fibroin/gelatin (50/50) sponge released curcumin and/or DHA at the slowest rate (for 24 days). Sponges were not toxic to L929 mouse fibroblasts, but a ratio of 1:4 (curcumin/docosahexaenoic acid) had the highest inhibitory effect on the growth of cancer cells [175]. Finally, Lozano-Pérez et al. (2017) encapsulated quercetin in silk fibroin nanoparticles (175 nm diameter). The nanoparticles had a negative surface charge that allowed the sustained release of the antioxidant that occurred throughout the experiment in both phosphate buffer saline (pH 7.4) and simulated intestinal fluid (pH 6.8) [176].
