seem to be focused more on chemical modifications of polysaccharides for designing efficient nanocarriers to be used in clinical trials. Although studies with polysaccharide-based nanosystems show promising proof of concept results, the ultimate performance of these platforms must be established in clinical trials. Besides, bringing the advantages of different polysaccharides together to achieve more efficient and biocompatible hybrid carrier systems has to be considered for successful drug delivery applications.
6.2.2.4 Therapeutics
Several researches report that polysaccharides can be utilized for therapeutic purposes because of their several biological actions such as antioxidant, anticoagulant, antiviral, antidiabetic, antitumor, and immunostimulatory activities [100]. Medicinal polysaccharides also claimed as “biological response modifiers”, are that stimulate the immunological response to infection and disease [158].
The primary effect of polysaccharides was identified as enhancing and/or activating immune response [103]. Lo et al. proposed that arabinose, mannose, xylose, and galactose are the main monosaccharide components contributing to macrophage stimulating activity while being the most common monosaccharide component, glucose showed no clear role in the immunoactivity of polysaccharides [100]. The immunomodulating activity of polysaccharides comprises the activation of macrophages, dendritic cells, tumor-infiltrating lymphocytes, natural killer cells, lymphocyte activated killer cells, and several cytokines such as interferons, tumor necrosis factor, interleukins, and colony-stimulating factors [158]. For instance, glycan has been shown to promote macrophage functions, which include activating the phagocytic ability, enhancing the cytotoxic activity against the tumor cells, enhancing ROS and nitric oxide (NO) production, and promoting the synthesis and secretion of cytokines and chemokines [13]. In another study, in vivo administration of the exocellular polysaccharide of the algae, Porphyridium cruentum to mice has resulted in an increase of the macrophage population as well as in an increase of the acid phosphatase enzyme [159]. Natural polysaccharides from different sources have been found to activate macrophages mainly through the interaction with specific receptors on cells, called pattern recognition receptors (PRRs) including toll-like receptor 4 (TLR4), CD14, dectin-1, and mannose receptor. Receptor activation leads to the production of pro-inflammatory factors through the activation of downstream signaling [100]. In the field of cancer therapy, the potency of bioactive polysaccharides, such as polysaccharides derived from Basidiomycetes class of mushrooms (Krestin from Coriolus versicolor, lentinan from Lentinus edodes, schizophyllan from Schizophyllum commune) and some other botanical herbs (Astragalus membranaceus, Panax ginseng, Angelica sinensis, pectins, and modified citrus pectin), has been reported in preclinical models and claimed to diminish tumor growth and extend the patient’s life by triggering cell cycle arrest, apoptosis and, immune stimulation [158]. On the other hand, activation of immune response by polysaccharides may cause excessive inflammation which leads to sepsis and local or systemic inflammatory disorders. Thus, further studies are needed to investigate whether the pro- and anti-inflammatory factors induced by polysaccharides can ensure the homeostasis.
Heparin is a nontoxic, nonimmunogenic, and noninflammatory sulfated animal polysaccharide [160]. Biological functions of heparin, other than the clinical use as an anticoagulant, have been continuously discovered, such as it was shown that heparin can inhibit the proliferation of vascular smooth muscle cells, suppress delayed hypersensitivity, and stimulate the formation of the new blood vessel. Furthermore, due to its fibrin clot-dissolving and angiogenesis promoting actions, heparin is an effective polysaccharide in the wound healing process [161]. Heparin was suggested to modulate its biological functions through binding with the specific groups of proteins, such as binding with growth factors to enhance their activity [13]. Heparin sulfate is a structurally similar analog of heparin. This linear polysaccharide is found in cell surface or extracellular matrix and governs specific biological activities ranging from acting as a cell surface receptor, proliferation, differentiation, migration, and cancer metastasis to blood coagulation [162]. Even though heparin has been used for treating venous pulmonary embolism, thrombosis, and acute coronary syndrome, it can also activate blood proteins including platelet factor 4 that results in thrombocytopenia. To prevent the risks of potential bleeding and heparin-induced thrombocytopenia, earlier attempts involved depolymerization of heparin to obtain low molecular weight heparin. Today, ultra-low molecular weight heparin (AVE5026) with better pharmacological activities and tolerance in living systems are utilized in clinics [162–164].
In the human body, hyaluronic acid is found in various tissues, such as connective tissues, including eyes, joints, and skin, and fluids. Through binding its receptors, hyaluronic acid displays various biological activities such as modulation of cell functions including migration, adhesion, proliferation, and inflammation. In in vivo, hyaluronic acid has been shown to have chondroprotective effects. Exogenous hyaluronic acid can induce the synthesis of proteoglycan, regulate the functions of immune cells, and reduce the activity of proinflammatory cytokines. Additionally, it has a great water retention ability and thereby play a vital role in regulating tissue hydration and osmotic balance. Because of the high hygroscopicity, hyaluronic acid can significantly regulate the physical properties of the extracellular matrix [13, 165]. Researchers have made great progress in the science of hyaluronic acid-based applications; for example, the use of hyaluronic acid in some eye surgeries, such as the removal of the cataract, corneal transplantation, and repair of a detached retina has been approved by the Food and Drug Administration (FDA) [13]. FDA has also approved the use of hyaluronic acid fillers in the area of cosmetic surgery to reduce the appearance of fine lines and wrinkles, facial folds, and to create structure, framework, and to give volume to the face and lips [166]. However, hyaluronic acid can cause some side effects including delayed hypersensitivity and granulomatous reactions [167]. Therefore, the actions of hyaluronic acid and its derivatives have to be explored mechanistically and more clearly.
Nonetheless, obtaining the functional polysaccharides with high purity and characterizing the structure of them are challenges of naturally occurring polysaccharides to be used in clinics. To overcome the drawbacks including immunogenicity, polysaccharide-based ideal therapeutics with defined bioactivity, biocompatibility, required purity, and appropriate physicochemical properties are needed to be developed.
6.2.3 Cosmetics
The knowledge of skin biology enables the identification of active ingredients which are essential for healthy skin and crucial for the maintenance of its barrier function and integrality. Polysaccharides are known with their protective effects on the skin; therefore, the development of cosmetic formulations with these ingredients can enhance the efficacy of the formulations [168].
In cosmetics, applications of polysaccharides range from peelings with candy sugar crystals up to cleansing products. Polysaccharides used in cosmetics can be categorized as functional and active polysaccharides. Functional polysaccharides can be used in the formulation technology such as gelling agent, film former, thickener, conditioner, suspending agent, and emulsifier while active polysaccharides are used in the cosmetics because of their ability in forming hydrogel structure with moisturizing effect [169]. In the gelling masks, that are spread on the skin in liquid form and then removed after they have solidified into a rubbery substance, the main ingredient is alginic acid. Agar, a mixture of agarose and agaropectin, is used as a consistency and bonding agent. Food-grade carrageenan is an entirely safe and appropriate ingredient for toothpaste, like furcelleran. Chitosan is used for hair conditioning purposes in shampoos and hair gels and used in toothpaste and mouthwashes as a bacteria-inhibiting component. It can also be used in skincare products as a cationic filming agent. Glucan has skin-protecting and tightening features and it is used for the skincare after peeling and laser treatments, after shaving as well as an additive for body lotions. Carboxymethyl cellulose, which is also called sodium cellulose glycolate, is obtained by chemical modification of cellulose. It forms water-soluble sodium salts with thickening properties and the salts can be used in cleansing and washing products as highly effective carriers for dirt particles. Dextrins can retain perfumes and can be used for the slow release
