Polysaccharides are vital macromolecules found extensively in living organisms, playing key roles in various biological processes. They have attracted considerable attention due to their broad spectrum of biological and pharmacological activities, including anti-tumor, immunomodulatory, antimicrobial, antioxidant, anticoagulant, antidiabetic, antiviral, and hypoglycemic effects. This makes them highly promising candidates for biomedical and pharmaceutical applications. Polysaccharides can be sourced from various origins, such as plants, microorganisms, algae, and animals. Their physicochemical properties allow for physical and chemical modifications, leading to enhanced properties and diverse applications in biomedical and pharmaceutical fields. This article delves into the latest applications of polysaccharides and their potential as alternatives to traditional therapies, while also addressing the challenges and limitations associated with their use in pharmaceuticals.
Introduction to Polysaccharides
Polysaccharides are the most abundant naturally occurring macromolecular polymers, derived from renewable sources such as algae, plants, and microorganisms, including fungi and bacteria. Alongside proteins and nucleotides, polysaccharides are essential components of biological systems, involved in cell-cell communication, adhesion, and molecular recognition within the immune system. As a major class of biopolymers (carbohydrates), polysaccharides play critical roles in diverse physiological processes and tumor metastasis. They provide structure, protection, adhesion, and stimuli responsiveness, while also influencing the immune system, blood clotting, fertilization, pathogenesis prevention, and therapeutic efficacy.
Natural polysaccharides can be obtained from various sources, including algae (e.g., alginate), plants (e.g., pectin and gums), microorganisms (e.g., dextran), and animals (e.g., chitosan). They are considered essential functional materials with significant roles in physiological and biological activities, such as antioxidant, antitumor, anti-hyperglycemic, and immune regulation activities. Microbial polysaccharides have been utilized in biotechnology and biomedical sciences for many years. The diverse sources of polysaccharides make them ideal starting materials for chemical modifications, enabling their use in various medical and non-medical fields, including food, energy, wood, paper, textiles, fibers, and oil drilling.
Classification, Chemical Structure, Sources, and Physicochemical Properties
Polysaccharides, the most common form of carbohydrates in nature, are defined by their chemical structure, consisting of monosaccharide units linked by glycosidic bonds. These units can be sugar residues glycosidically linked or covalently bonded to other structures like peptides, amino acids, and lipids. Homopolysaccharides (homoglycans) are composed of identical monosaccharides, while heteropolysaccharides (heteroglycans) contain different monosaccharides.
Glucans are glucose homopolysaccharides, and mannans are mannose homopolysaccharides. Hydrophilic groups such as OH, COOH, and NH2 can form bioadhesive layers with epithelial and mucous membrane tissues. The most common constituent of polysaccharides is d-glucose, but d-fructose, d-galactose, l-galactose, d-mannose, l-arabinose, and d-xylose are also frequently found. Some monosaccharide derivatives in polysaccharides include amino sugars (d-glucosamine and d-galactosamine) and their derivatives (N-acetylneuraminic acid and N-acetylmuramic acid), as well as simple sugar acids (glucuronic and iduronic acids).
Polysaccharides are differentiated by the nature of their monosaccharide components, chain length, and branching. Glycosidic linkages through the anomeric carbon atom between the glycosidic bond donor and acceptor form either linear or branched chains, distinguishing them from proteins and peptides, which have only linear chains. Polysaccharides naturally have storage properties (e.g., starch) or structural properties (e.g., cellulose), providing physical structure and stability. They can also be classified based on their polyelectrolyte properties into positively charged polysaccharides (chitosan) and negatively charged polysaccharides (alginate, heparin, hyaluronic acid, and pectin).
Glycosaminoglycans (GAGs), primary components of the cell surface and cell-extracellular matrix (ECM), have been extensively studied. Heparin, heparan sulfate, hyaluronan, chondroitin sulfate, dermatan sulfate, and keratan sulfate are the most important GAGs polysaccharides in mammalian tissues, with significant biological importance.
Chemical modifications such as sulfation, phosphorylation, and carboxymethylation efficiently modify the biological properties of polysaccharides, making them suitable for drug delivery systems. These modifications can enhance stability, reduce toxicity, and improve biodegradability. Further chemical modifications like grafting, cross-linking, complexation, and covalent coupling add more potential for drug delivery and therapeutic efficacy. Polysaccharides can also replace some excipients or synthetic polymers.
Traditional polysaccharide vaccines may contain contaminants and impurities; therefore, chemically synthetic polysaccharide-based vaccines can overcome these shortcomings.
The stability, hydrophilicity, and biodegradability, along with the diversity of physicochemical properties, provide the basis for the wide range of biological activities exhibited by natural polysaccharides. The biochemical and physical properties of polysaccharides have contributed significantly to their biomedical applications.
Polysaccharide Applications
Vaccine Applications
The immune system is critical in responding to external exposures such as infectious diseases, inflammatory agents, and carcinogens. Given the emerging challenges of cancer and infectious diseases, and the drawbacks of available drugs (resistance, toxicity, and lack of immune responses), pharmaceutical companies are increasingly focused on discovering safe and effective immune-stimulating alternatives. Polysaccharides are considered an excellent choice in this regard. Polysaccharides isolated from traditional Chinese medicine can activate or regulate T lymphocytes and macrophages, enhance interleukin activity, improve antibody levels, and regulate the organism’s immune function. They also enhance immunity through mechanisms such as stimulating macrophages, splenocytes, and thymocytes.
Carbohydrate-based vaccines are intensively studied for their potential as vaccine candidates. Tumor-associated carbohydrate antigens and polysaccharides located on the surface of pathogenic microorganisms can be recognized by the host immune system, opening new avenues in glycobiology and vaccination. Polysaccharides play a vital role in cell-cell recognition and interaction with the immune system, and many vaccine formulations contain polysaccharide-based antigens such as bacterial capsular polysaccharides or tumor-associated carbohydrate antigens. Polysaccharide vaccines have been available for different infectious diseases like Pneumonia and meningitis since the 1980s.
Conventional polysaccharide antigens (mainly high-purified capsular polysaccharides) have disadvantages such as short duration and poor immunogenic response in infants and young children due to the absence of immunological memory and IgM to IgG class switch. To overcome these shortcomings, new polysaccharide vaccines are conjugated to strongly immunogenic protein carriers like diphtheria and tetanus toxins, which induce T cell-dependent responses and enhance immunogenicity through interacting with the immune system.
Biomedical Applications
Polysaccharides have been used in the biomedical fields since the last century due to their biodegradability, biocompatibility, non-immunogenicity, and enhanced solubility and stability. They are considered potential candidates in various biomedical applications. The abundance of polysaccharide sources and their low cost make them ideal for biomedical and biotechnological applications. For instance, algae-derived polysaccharides are used extensively in wound management, regenerative medicine, and controlled drug delivery. The ability of polysaccharide-based biomaterials to form hydrogels is another advantage, with heparin-loaded hydrogels successfully used to deliver bone morphogenetic proteins. Polysaccharides improve the mechanical properties of synthetic polymers, overcoming their poor biological performance.
Drugs, Vaccine Delivery, and Tissue Engineering
Polysaccharides are extensively used as drug carriers, building blocks for drug delivery, bioactive materials, and excipients to enhance drug delivery. They are also gaining attention in tissue engineering, cosmetics, and wound healing. The ability of natural polysaccharides to be shaped and modified for specific goals makes them potential candidates for drug and vaccine delivery. Microorganism-derived polysaccharides like xanthan gum, gellan gum, and scleroglucan have been studied extensively in drug delivery. The absorption of drugs can be increased by loading them into bioadhesive polysaccharide nanoparticle carriers. Other naturally occurring polysaccharides, including pectin, guar gum, amylose, inulin, dextran, chitosan, and chondroitin sulphate, have been investigated for colon-specific drug release and their use as pharmaceutical excipients.
These polysaccharides can deliver drugs to the colon as prodrugs or coating tablets. Chitin and chitosan are low-immunogenic and tissue-compatible polysaccharides effective in wound healing, tissue engineering, bone regeneration, and drug and vaccine delivery. Chitosan is a widely used biopolymer in drug and vaccine delivery systems because it allows for the encapsulation of a wide variety of antigens under mild conditions without organic solvents, avoiding antigen degradation and denaturation.
Polysaccharide-based nanoparticles are gaining more attention as nanometric carriers for drug delivery. Polycations, prepared by reductive amination between primary amines and periodate oxidized polysaccharides, are considered a new class of non-viral gene delivery systems, and cationic polysaccharides are used as gene transfection vectors. Hydrogels based on cross-linked polysaccharides are used in key applications such as drug delivery systems and tissue engineering, and hyper-branched polymers are excellent carriers for gene delivery nanoparticles.
Antitumor and Immunomodulatory Activities
Tumors are a major health problem and a leading cause of death worldwide. Antitumor activities are found in many plants and marine polysaccharides. A wide variety of natural polysaccharides are effective antitumor agents, such as lentinan and schizophyllan. Polysaccharide-protein conjugates have antitumor activity and can enhance the activity of conventional chemotherapeutical drugs. Polysaccharides have shown immunosuppressive activity against tumor growth. Mushrooms are rich sources of therapeutic agents and have been used for a long time as food and medicinal agents. Natural polysaccharides derived from mushrooms have been extensively studied for their potent antitumor and pharmaceutical activities. Examples include Ganoderma lucidum, which has potent in vitro immune activation and antitumor activity on breast cancer cells, and Lentinus edodes, which exhibits a marked antitumor effect against subcutaneously transplanted sarcoma.
Mushroom-derived polysaccharides produce their antitumor effects through oncogenesis prevention, immune system enhancement, and the induction of apoptosis in tumor cells. Besides antitumor activity, mushroom polysaccharides exhibit a wide range of therapeutic activities and are used in clinical trials to increase the effectiveness of chemotherapeutic agents and minimize their side effects. Algae polysaccharides are also of great importance due to their diversity of pharmacological activities, including antitumor activity. Polysaccharides activate effector cells, such as macrophages, T lymphocytes, B lymphocytes, cytotoxic T lymphocytes, and natural killer cells, to express cytokines, such as TNF-α, IFN-c, and IL-1β, which possess antiproliferative activity and cause apoptosis and differentiation in tumor cells. Nanoparticles covered with saccharides display a higher circulation lifetime in the bloodstream and accumulate significantly in tumor tissues.
Antioxidative Applications
Reactive oxygen species (ROS) can cause damage to the human body, attacking membrane lipids, proteins, and DNA, leading to health disorders such as cancer, diabetes mellitus, neurodegenerative and inflammatory diseases. Antioxidative agents block or reduce the effect of these hazardous agents, improving human health. Given the drawbacks of scientific antioxidants (carcinogenesis and liver damage), alternative natural substitutes are advantageous. Plant-derived polysaccharides are promising candidates because they exhibit strong antioxidant activities, protecting the human body against free radicals and decreasing the complications of many diseases. Due to their biological importance, chemical properties of plant polysaccharides have been extensively investigated for their wide range of applications, such as antitumor, immune-stimulation, and antioxidant activities.
The existence of natural antioxidants capable of scavenging ROS is beneficial, as polysaccharides possess antioxidant activity, protecting against cardio and cerebrovascular diseases caused by free radicals. Many natural polysaccharides, such as Hyriopsis cumingii, have been evaluated for their antioxidative ability against different types of free radicals.
Polysaccharides derived from the traditional Chinese medicinal herb Astragalus showed potent antioxidant and antitumor activity. Sulfated polysaccharides derived from seaweed and red algae also possess anticoagulant/antithrombotic, antiviral, immuno-inflammatory, antilipidemic, and antioxidant activities. Different kinds of polysaccharides have been used for antioxidative purposes, including seaweed polysaccharides (e.g., sulfated polysaccharides), plant polysaccharides (e.g., arabinogalactan, galactomannan, and pectic polysaccharides), and mushroom polysaccharides (e.g., β-glucans and glycoproteins).
Other Applications
Anti-inflammatory Activity
Natural polysaccharides have been widely used in nanomaterials for controlling inflammatory pathologies and have been experimentally tested for their anti-inflammatory activities. The anti-inflammatory effect of polysaccharides could be due to the inhibition of the expression of chemotactic and adherence factors, as well as the activities of key enzymes in the inflammation process. Other polysaccharides inhibit inflammatory-related mediators such as cytokines (IL-1b, IL-6, TNF-a) and NO (nitric oxide), and decrease the infiltration of inflammatory cells. Algae-derived sulfated polysaccharides exhibit their anti-inflammatory effect by interfering with the migration of leukocytes to sites of inflammation.
Hypoglycemic and Hypocholesterolemic Activities
Since the 1980s, polysaccharides have been extensively investigated in clinical trials for their hypoglycemic and hypocholesterolemic effects. Ganoderma atrum polysaccharide has potential for the treatment of hyperglycemia, hyperlipidemia, hyperinsulinemia, and insulin resistance, as well as a protective effect on kidney injury in type 2 diabetes. Natural polysaccharides can be used as nanocarriers for proteins, enhancing the stability of loaded proteins and prolonging their therapeutic effect. For example, the bioavailability of orally administered Insulin-loaded dextran-chitosan nanoparticulate polyelectrolyte complex is increased with an extended hypoglycemic effect. Other examples of polysaccharides with hypoglycemic and hypocholesterolemic effects include sulfated polysaccharides extract from Bullacta exarate, chitosan, and Kefiran. Traditional Chinese medicine derived from Tremella fuciformis Mushrooms polysaccharides showed a significant dose-dependent hypoglycemic effect and improved insulin sensitivity by regulating PPAR-γ-mediated lipid metabolism when administered to mice.
Anticoagulant Activity
Anticoagulant activity is among the diverse properties of polysaccharides that have been extensively studied. Unfractionated and low molecular weight heparins are sulfated polysaccharides used as anticoagulant drugs, but they have side effects like bleeding and thrombocytopenia. Polysaccharides, especially sulfated polysaccharides, have many biological activities like anti-tumor, antioxidant, and anticoagulant activities. The high sulfate content is a key factor in the anticoagulant activity of these sulfated polysaccharides. Natural polysaccharides obtained from different marine sources like shellfish (shrimp, crab, squilla, lobster, and crayfish), marine macroalgae (seaweeds), marine fungi, microalgae, and corals, and plant-derived polysaccharides (e.g., pectin) could be considered potential anticoagulant agents.
Antiviral Activity
The antiviral activity of polysaccharides has been recognized since the 1950s. Sulfated polysaccharides from seaweeds have an inhibitory effect against the replication of enveloped viruses, including herpes simplex virus (HSV), human immunodeficiency virus (HIV), human cytomegalovirus, dengue virus, and respiratory syncytial virus. Different microalgae species can produce sulfated exopolysaccharides, which play an important biological role as antiviral agents. Polysaccharides derived from Chinese traditional medicine have also been used for a long time as antiviral agents, strengthening the immune system through activating macrophagocytes to promote their phagocytic ability and induce the secretion of IL-2, IFN-γ, and antibodies. Microalgae polysaccharides also possess antioxidant, antibacterial, and antiviral activities.
Polysaccharides in Coronavirus Disease (COVID-19)
The COVID-19 outbreak has become a major health challenge, necessitating the search for safe and effective therapeutic agents and vaccines. Polysaccharides, with their broad antiviral activity, are promising candidates in COVID-19 prevention and control, both as therapeutic agents and carriers. GAGs, Traditional Chinese Medicine, and marine polysaccharides have shown potent anti-coronavirus activity. Sulfated polysaccharides can interfere with the entry of the virus into the host cell by blocking the positive charge of the pathogen surface receptors. Cationically modified chitosan shows significant inhibition against human coronaviruses HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1, indicating its inhibitory effect against low-pathogenic human coronaviruses. Traditional Chinese herbal medicine contains potential anti-SARS-CoV-2 active compounds, especially Hedysarummultijugummaxim, coptidis rhizoma, and forsythiae fructus.
In vitro experiments show that sulfated polysaccharides bind tightly to the S-protein of SARS-CoV-2, interfering with protein binding to heparan sulfate co-receptors and exhibiting a potent inhibitory effect on viral infection. Polysaccharides from different origins have also shown anti-pulmonary fibrosis activities, making them an alternative agent for preventing or treating pulmonary fibrosis in COVID-19 patients. One of the most common complications of COVID-19 is the susceptibility of infected patients to bacterial secondary infections. Polysaccharides can play a major role in this regard, such as Glycyrrhiza polysaccharide displaying antimicrobial activity, inhibiting the growth of B. cereus, Staphylococcus aureus, E. Aerogens, and Escherichia coli. Purified Chinese yam polysaccharide showed inhibitory activity against E. coli, with a minimum inhibitory concentration (MIC) of 2.5 mg/mL. Recent studies found that Poria cocos polysaccharide could inhibit the growth of S. aureus and E. coli. Asarum polysaccharides in the Lung Cleansing and Detoxifying Decoction play an important role in relieving cough symptoms, which are prevalent in COVID-19 patients.
Polysaccharides: Future Prospects, Limitations, and Challenges
Polysaccharides are the most abundant natural biopolymers, and recently they have gained more attention as applicable substances in different biomedical areas. Many properties contribute to their excellent reputation: they are economically cheaper, can be chemically modified to suit specific purposes, and, unlike synthetic biopolymers (which have drawbacks such as toxicity and long-time synthetic approaches), polysaccharides are comparably safe. Another advantage is their resemblance to biological macromolecules like the natural extracellular matrix (ECM), increasing the potential for using them in cell therapy approaches. Over the past few years, there has been increasing interest in the application of polysaccharide materials in the field of tissue engineering.
Mushrooms have been used for a long time, and recently they have gained more importance in cancer therapy. Polysaccharides derived from mushrooms, such as chizophyllan, lentinan, grifolan, polysaccharide-peptide complex (PSP), and polysaccharide-protein complex (PSK), can induce the immune response and produce the antitumor effect, making them promising candidates against tumors in the future. The safety of polysaccharides is a crucial factor, and a strong advantage that will make the use of their increase in the future. Many other organic synthesis and chemical modifications caused severe environmental pollution, which could be improved by substitution to natural polysaccharides.
From a drug delivery perspective, polysaccharides have been increasingly used in many different forms to control the delivery of drugs due to their biocompatibility and biodegradability properties. The diversity of functional groups located on polysaccharide structures, such as hydroxyl, amino, and carboxylic acid groups, could be further modified to serve as a specific biological tool in different fields like vaccine adjuvants, drug carriers, tissue engineering scaffolds, and many other pharmacological activities. Natural polysaccharides such as glycogen, cellulose, and starch were engineered onto biologically superior molecules by numerous methods, such as chemical modification, co-polymer grafting, and atom transfer radical polymerization (ATRP), to promote its candidature in biopharmaceutics. Conjugation between hydrophilic groups of polysaccharides with hydrophobic groups of drugs can form prodrugs with amphiphilic properties, which can be self-assembled to form nanostructures with improved water solubility.
On the other hand, since polysaccharides are usually derived from natural sources, there are some limitations and challenges in pharmaceutical and biological fields, such as batch-to-batch variations, microbial contamination, reduced viscosity during the storage, thickening, and uncontrolled rate of hydration. These drawbacks could be minimized by modifications such as grafting, cross-linking, and blending with other natural/synthetic/semi-synthetic polymers. The high variability of polysaccharides in nature adds a new difficult task in extraction and purification. Over and above, polysaccharides naturally found in complex with other compounds like proteins and lipids, and their isolation requires efficient and precise methods to avoid co-extraction and contamination with other compounds. Finally, the determination and fully understand of the structural activity relationship of polysaccharides shall provide new opportunities in pharmaceutical and biological applications.
Conclusion
Polysaccharides are the most available natural biopolymers with diverse physical and chemical properties that render them promising candidates in many biomedical areas. Polysaccharides have several advantages over other synthetic polymers: they are safe, economical, stable, hydrophilic, biocompatible, biodegradable, and prone to chemical modifications and tailoring for specific purposes in a wide variety of applications, such as the preparation of pharmaceutical materials, drug release agents, and plasma substitutes. Polysaccharides can be applied biologically in many different therapeutic fields like immunoregulatory, anti-tumor, anti-virus, anti-inflammatory, antioxidation, and hypoglycemic activity.
Over the past decades, polysaccharides have attracted extensive attention and can be considered as one of the most potent alternatives to conventional therapy. Even though carbohydrate-based pharmaceuticals are proved effective in different areas, they are not gaining as much interest as proteins or nucleic acid-based drugs. At the end of this review, we recommend further studies and investigation because many discoveries still lie ahead and many biological activities of a variety of polysaccharides are still not fully understood. Extensive investigation and elucidation of the structural activity relationship of polysaccharides are crucial to give more insight into the exact mechanisms of their biological activities and fully explore their future applications.
