*2.3. Chondroitin Sulfate-Physicochemical Traits and Potential Therapy of IBD*

Chondroitin Sulfate (CS) is a sulfated glycosaminoglycan (GAG) found on cell surfaces and inside the pericellular matrix in the form of proteoglycans from different organisms and is involved with several physiological events [120,121]. CS is a linear polysaccharide formed by the repetition of disaccharide units N-acetyl-D-galactosamine (GalNAc) and D-glucuronic acid (GlcA), which have sulfate groups added by several sulfotransferases in various positions, forming diverse structures with heterogenous characteristics [122,123]. Commercially, the main marine source of CS is shark cartilage but it can also be extracted from octopus, salmon, zebrafish, ray, and squid [96]. CS has biological activity as an immunomodulator, anti-inflammatory, anticancer, antiviral, and anticoagulant [21–26]. It has been highly employed in the treatment of osteoarthritis and tissue engineering, as CS hydrogels proved to accelerate wound healing [21,96] and several studies have investigated its use in the management of IBD.

Similar to chitosan, research has been conducted to employ CS to obtain a controlled release of drugs already in use to treat IBD. Cesar et al. [124] successfully synthesized a polymeric conjugate of 5-ASA and CS capable of improving the biodistribution of the drug and of providing it with a mucoadhesive profile (Figure 7) [124]. The authors suggested that the pharmaceutical could be considered as an alternative therapy for ulcerative colitis [124]. Prednisolone has also been conjugated with CS to improve its delivery to the lower intestines. The result was a nanogel that had its ability to target areas affected by colitis confirmed in vivo [125]. Furthermore, the multi-bioresponsive drug, curcumin, has been used in association with CS. Two studies described the development of curcumin-loaded nanoparticles with their surfaces functionalized with CS. This modification yielded prominently targeted drug delivery to macrophages and was considered a promising therapeutic platform for IBD [65,126]. Additionally, a prospective, observational, follow-up study indicated that IBD patients in remission under CS treatment for osteoarthritis could have a lower incidence of relapses than generally reported in the literature. Although the study had a small sample, it suggested that CS could be applied as a candidate for the treatment of IBD due to its good safety profile and capability of alleviating osteoarthritis-related pain in these patients [127].

**Figure 7.** Mesalamine polymeric conjugate for controlled release. Reprinted from Ref. [124] with permission from Elsevier. Copyright © 2017 Elsevier B.V. License Number: 5022891040345.

#### *2.4. Alginate-Physicochemical Attributes and Therapeutic Option for IBD*

Alginates are a natural biopolymer composed of 1,4-linked (-L-guluronic acid) (G) and (-D-mannuronic acid) (M) residues to form GG, GM, and MM blocks [128]. *Ascophyllum nodosum, Laminaria hyperborea, Saccharina japonica, Macrocystis pyrifera, Laminaria digitata*, and other species of brown seaweeds are the main source extraction with 17 to 45% of the dry weight composed of alginate [129,130]. It is widely available, biocompatible, nontoxic, low cost a has wide application in food processing, biotechnology, and biomedical industry [131,132]. Some studies have pointed out the biological activities of alginates as an antioxidant, anti-inflammatory, immunomodulating, anticoagulant, and anticancer [38–43].

Alginate has non-toxic, non-immunogenic, biocompatible and biodegradable properties [131,133,134], which make it a versatile material for biomedical application as in microspheres, microcapsules, gel beads, hydrogel, film, nanoparticles, pellets, and tablets for drug delivery [133,135]. Several alginate formulations with other marine compounds have been studied in treatments against IBD and some of them were described previously with chitosan. The main applications are in the engineering of drug delivery systems specifically for the colon, which allows its use in the treatment of IBD in a different way than relying solely on pH sensitivity [136]. In this regard, alginate offers a range of microencapsulation through a series of techniques, Samak et al. [137] analyzed alginate microparticles loaded with hydrocortisone hemisuccinate and fabricated via aerosolization and homogenization methods. In vitro experiments were carried out to verify whether the microparticles by each of the techniques were able to suppress the release of the drug in the simulated gastric fluid and promote the release correctly in the simulated intestinal fluid. The results indicated that both methods show potential for producing alginate hydrogel microparticles suitable for colon-specific drug delivery in IBD treatment [137]. A subsequent study confirmed the potential of these techniques for delivering *Nigella sativa* extract using the same in vitro tests [138]. Other studies have investigated alginate formulations to see if they can improve the delivery and effectiveness of drugs used in conventional IBD treatments like corticosteroids) [139,140].

#### **3. Concluding Remarks and Outlook**

Inflammatory bowel disease continues to result in substantial productivity loss and extensive morbidity worldwide. The devastating consequence of inflammatory bowel disease urgently calls for proper treatments, and thus implicate a considerable financial and economic burden to individuals and the entire health care structure, particularly in emerging countries. Marine-derived bioproducts attract incredible interest and appear a revolutionary therapy for IBD due to their health beneficial properties that are ascribed to the presence of characteristic biologically active functional constituents. This review presents some naturally occurring biological entities/compounds derived from different marine species for the efficient management of IBD. Particular focus has been devoted to characteristic attributes, performance evaluation of engineered cues, and point-of-care IBD therapeutics of diverse bioactive compounds from the algal biome. Although the ratio of early surgery is reduced in IBD-associated patient by introducing biological active substances based therapeutic modalities, many challenges remain. Hence, additional research efforts are required to inspect their bioavailability and efficiency in human and animal models. The exploration of marine-derived bioactive compounds will continue to increase in the future depending on new extraction strategies and novel modes of action. Ideally, intensive future research and new research opportunities for marine bioproducts would lead to a more efficacious and safer way for preventing and management of inflammatory bowel disease.

**Author Contributions:** Conceptualization, M.B. and H.M.N.I.; data curation, M.B.; L.V.N.; M.T.S.D.; L.F.R.F. and R.N.S. writing—original draft preparation, M.B.; L.V.N.; M.T.S.D.; L.F.R.F. and R.N.S. writing—review and editing, M.B. and H.M.N.I.; funding acquisition, H.M.N.I. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** Consejo Nacional de Ciencia y Tecnología (CONACYT) is thankfully acknowledged for partially supporting this work under Sistema Nacional de Investigadores (SNI) program awarded to Hafiz M.N. Iqbal (CVU: 735340).

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

