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Fucoidan
Fucoidan
Fucoidan
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Fucoidan is a long-chain sulfated polysaccharide found in various species of brown algae, such as seaweed, and in marine invertebrates.[1] Fucoidan occurs in the cell walls of seaweed serving structural roles.[1]

Commercially available fucoidan is commonly extracted from the seaweed species Fucus vesiculosus (wracks), Cladosiphon okamuranus, Laminaria japonica (kombu, sugar kelp) and Undaria pinnatifida (wakame).[2] Fucoidan extraction methods, purity, global regulatory approvals, and source seaweed species vary among fucoidan products.[1][2] The potential bioactivity of fucoidan extracts is under preliminary research.[1][2][3]

Fucoidan is sold as a dietary supplement, food additive, and as an ingredient in animal feed or cosmetics.[3] Although used in traditional Chinese medicine,[1][2] it has not been approved as a human drug in any country, and no advanced clinical trials have been reported, as of 2019.[3] It is commonly used in Southeast Asian countries[3] and is recognized as a natural health product in Canada,[4] but does not have governmental approval or recognition as a safe ingredient for human use in most western countries.[3]

History

[edit]

Seaweed fossils have been unearthed at Monte Verde in Chile, where archaeological digs have uncovered evidence of their use dating to circa 12,000 BC.[5]

Fucoidan itself was not isolated and described until the early 1900s.[6] In 1913, Swedish Professor Harald Kylin became the first to describe the slimy film found on many seaweeds as 'fucoidin' or 'fucoijin', becoming known as fucoidan based on the international naming convention for sugars.[7]

Research in the early 20th century focused on extracting crude extracts and reconciling some of the conflicting views on fucoidan.[2] Methods of extracts and isolation of fucoidan from brown seaweeds were determined on laboratory scale in 1952.[8]

Laboratory research expanded once fucoidan became commercially available in the 1970s, with studies limited to in vitro and rodent studies.[2] Fucoidan is limited for use as a "complementary" ingredient in supplements, foods, beverages, cosmetics and animal feed because its biological properties and safety have not been adequately demonstrated.[3]

Chemistry

[edit]

Fucoidans are sulfated polysaccharides derived primarily from various species of brown algae.[1][2][3] The main sugar found in the polymer backbone is fucose, giving the name fucoidan.[1] Other sugars are often present alongside fucose, including galactose, xylose, arabinose and rhamnose. The relative content of these sugars in fucoidan varies significantly between species of algae and can also be affected by the extraction method.[1][2] The same holds true for the degree of sulfation and other structural features such as acetylation that are only found in fucoidans from certain species.[1]

The molecular weight of fucoidans is typically high (ca. 50-1000 kDa). Extraction techniques that minimize polymer degradation tend to preserve this feature, while other methods can be used to target more specific molecular weight fractions (e.g. 8 kDa).[citation needed] These low molecular weight fractions are generally low yielding and tend to be used for functional research.[1] Full chemical characterization is complicated by the number of structural features present in fucoidan.[1]

Research

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As of 2019, only laboratory studies, early-stage clinical trials, and case reports have been reported on the potential biological properties of fucoidan.[3]

Safety

[edit]

There is little evidence for the safe use of fucoidan products, as no national regulatory authorities have designated it as safe for human use and no rigorous clinical safety trials have been reported, as of 2019.[3] There is high variation in the quality of products containing fucoidan.[3]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Fucoidan

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Fucoidan is a complex sulfated rich in L-fucose and sulfate ester groups, primarily extracted from the cell walls of brown seaweeds such as Fucus vesiculosus and Laminaria japonica. First isolated in 1913 by Swedish scientist Harald Kylin from marine algae and initially termed "fucoidin," it was later standardized as "fucoidan" according to International Union of Pure and Applied Chemistry (IUPAC) nomenclature. This heteropolysaccharide often includes additional monosaccharides like , , glucose, and , along with uronic acids and acetyl groups, contributing to its structural variability across species and extraction methods. The structure of fucoidan typically features a backbone of α-(1→3)-linked L- units, with some species exhibiting alternating α-(1→3) and α-(1→4) linkages, and groups attached at positions such as O-2, O-3, or O-4. Molecular weights can range widely, from low-molecular-weight fractions (e.g., 10–300 kDa) to higher ones exceeding 1 million Da, influencing its solubility and bioactivity; for instance, fucoidan from has a molecular weight of approximately 112,800 g/mol and contains about 26.92% and 19.87% . Extraction techniques, including acid, enzymatic, or water-based methods, further affect purity and composition, with yields varying from 2.44% in enzyme-assisted processes from S. japonica. While primarily sourced from in the orders Fucales and Laminariales, trace amounts occur in certain like sea cucumbers and sea urchins. Fucoidan exhibits a broad spectrum of biological activities, attributed to its sulfate content and molecular structure, making it a subject of interest for pharmaceutical and nutraceutical applications. Key properties include anticoagulant effects, where it prolongs activated partial thromboplastin time (APTT) up to 38 units/mg in extracts from Ecklonia kurome, rivaling heparin but with lower bleeding risk. Antiviral activity has been demonstrated against viruses such as herpes simplex (HSV-1 and HSV-2), influenza A, and HIV, with inhibitory concentrations as low as 0.1–0.7 μg/mL in some studies. Antitumor effects involve inducing apoptosis in cancer cells (e.g., hepatocellular carcinoma and breast cancer lines) via pathways like PI3K/AKT/mTOR downregulation and caspase activation, achieving up to 42.93% tumor inhibition in mouse models. Additionally, it displays potent antioxidant capacity, scavenging ABTS radicals at 1.02 mg TE/g and reducing oxidative stress in liver damage models, alongside anti-inflammatory, immunomodulatory, antidiabetic, and wound-healing benefits. Ongoing research explores its potential in functional foods and low-toxicity cancer therapies, though structural heterogeneity poses challenges for standardization.

Occurrence and Extraction

Natural Sources

Fucoidan is primarily found as a sulfated within the cell walls and intercellular matrix of macroalgae belonging to the class Phaeophyceae. These marine organisms synthesize fucoidan as a structural component, contributing to their resilience in intertidal and subtidal environments. Among the key species serving as natural sources, contains fucoidan at levels of approximately 10–18% of dry weight, while yields 0.5–13% of dry weight, varying by tissue type. Other prominent species include Undaria pinnatifida, Ascophyllum nodosum, , and various species such as S. polycystum and S. siliquosum. These are predominantly harvested from coastal regions worldwide, with content varying based on species-specific . The yield and composition of fucoidan in are influenced by environmental factors, including seasonal changes, geographical location, and the maturity stage of the organism. Seasonal variations often result in higher yields during summer months or late sporulation phases, with peaks observed in late summer for species like . Geographical differences, such as those between coastal and deeper-water habitats, affect and levels due to variations in availability and exposure. Additionally, mature or fertile algae exhibit elevated fucoidan content compared to juvenile or sterile stages. Trace amounts of fucoidan-like sulfated polysaccharides occur in minor sources beyond algae, including the jelly coat of sea urchin eggs and certain marine invertebrates such as sea cucumbers. These non-algal sources contribute negligibly to overall fucoidan production compared to brown macroalgae.

Extraction and Purification Methods

Fucoidan extraction typically begins with pretreatment of brown algal biomass, such as drying and grinding, to facilitate solvent access to the cell wall polysaccharides. Traditional methods rely on chemical solvents to solubilize fucoidan while minimizing degradation of its sulfated structure. Hot water extraction, conducted at 70–100°C for 1–4 hours, is a mild approach that yields 5–15% fucoidan depending on the algal species and conditions, though it often co-extracts other polysaccharides like alginates. Acid extraction using dilute acids such as 0.01–2% HCl or H2SO4 at 60–90°C for similar durations achieves higher yields of 10–20%, as demonstrated by a 22.95% yield from Fucus vesiculosus with 0.1 M HCl at 80°C for 2 hours, but risks desulfation at higher acid concentrations. Calcium chloride precipitation (2% CaCl2 at 70–90°C) is commonly integrated to remove alginic acid contaminants, enhancing fucoidan selectivity and yielding up to 15–25% in combined processes. Advanced techniques leverage physical or biological aids to improve efficiency, reduce extraction time, and increase yields while preserving biofunctional groups. Enzymatic employs cellulases, alginate lyases, or carbohydrases at 40–50°C and optimal (4–6) for 1–3 hours, achieving 20–30% yields by selectively degrading cell walls without harsh chemicals, as seen in a 29.35% yield from Sargassum fusiforme polysaccharides. Microwave-assisted extraction (400–600 W for 5–15 minutes) accelerates through effects, delivering 15–25% yields in shorter times compared to conventional heating, with examples from Fucus vesiculosus showing reduced energy use. Ultrasound-assisted extraction (20–40 kHz for 10–30 minutes) induces to disrupt algal matrices, resulting in 20–35% yields and up to 43% higher than dynamic maceration, as reported for Arctic brown algae like Fucus vesiculosus at . Supercritical CO2 extraction under 20–30 MPa and 40–60°C offers solvent-free isolation with 10–20% yields, ideal for heat-sensitive compounds, though it requires specialized equipment. Purification follows crude extraction to isolate fucoidan to >85% purity by removing impurities like proteins, phenolics, and . Initial steps include dialysis using membranes with 3.5–14 molecular weight cut-off to eliminate salts and low-molecular-weight contaminants, often combined with deproteination via Sevag reagent or TCA/acetone. (70–80% v/v, 1:3 ratio) concentrates the polysaccharide fraction, recovering 80–90% of fucoidan while precipitating alginates. Advanced purification employs (e.g., DEAE-Sephacel columns with NaCl gradients) to fractionate based on sulfate content, followed by for molecular weight separation, achieving purities of 90% or higher from Sargassum siliquosum. Yields range from 1–15% overall, influenced by algal species (e.g., 8–12% from species via acid methods), seasonal variations, extraction duration, temperature, and , with advanced methods generally outperforming traditional ones by 20–50%. Challenges include co-extraction of and phenolics, which reduce purity, and structural alterations from excessive heat or acidity, necessitating method optimization for specific sources. Recent innovations up to 2025 emphasize hybrid approaches, such as ultrasound-enzyme combinations, which boost yields to 25–30% while enhancing fucoidan quality and bioactivity, alongside pulsed and ultra-high-pressure extractions for sustainable, high-efficiency isolation from diverse .

Chemical Structure

Composition and Molecular Features

Fucoidan is a sulfated primarily composed of α-L-fucose residues, which constitute 25-93% of the total carbohydrate content, along with groups accounting for 9-40% by weight. These groups are essential for its characteristic properties, while minor sugar components, typically comprising less than 20% of the structure, include , , glucose, , and uronic acids such as . The high fucose and content distinguishes fucoidan from other algal , providing its foundational chemical identity. The molecular backbone of fucoidan generally consists of linear or branched chains of (1→3)-linked α-L-fucopyranose units, frequently interspersed with (1→4) linkages that introduce branching. substitutions occur predominantly at the C-2 and C-4 positions of the residues, though attachments at C-6 or C-3 are also observed, contributing to structural heterogeneity even in purified forms. This arrangement forms a complex, heterogeneous without a strictly repeating unit, reflecting its biosynthesis in . Fucoidans exhibit a broad molecular weight distribution, ranging from 10 to over 1000 , with most native forms averaging 20-200 depending on extraction conditions. Their physicochemical properties are largely dictated by sulfation: they are highly water-soluble and polyanionic, imparting a negative charge that enhances interactions with biological systems, while also conferring high solution suitable for gelling applications. Additionally, fucoidans demonstrate stability up to approximately 200°C, allowing processing under moderate heat without significant degradation. Key analytical techniques for elucidating fucoidan's composition and features include (NMR) spectroscopy, which identifies glycosidic linkages, branching patterns, and sulfate positions through characteristic chemical shifts. High-performance liquid chromatography (HPLC), often coupled with , is routinely used for profiling and quantification of content, ensuring accurate structural characterization. These methods provide essential data for verifying purity and uniformity in research and commercial preparations.

Structural Variations

Fucoidans exhibit significant structural diversity, primarily classified into two main types based on their backbone linkages. Type I fucoidans feature a linear chain of α-1,3-linked L-fucopyranose residues, typically with sulfation at the 2 and 4 positions, as exemplified in species of the genus Fucus such as . Type II fucoidans consist of repeating α-1,3/α-1,4-linked L-fucopyranose disaccharide units, often with branching and sulfation at positions 2, 3, and 4, commonly found in species like Laminaria japonica. Source-specific differences further contribute to this variability. Fucoidans from species generally display higher sulfation degrees, ranging from 30% to 40%, enhancing their polyanionic nature compared to those from Undaria pinnatifida, which have lower sulfation levels of 15% to 25%. In contrast, galactofucoidans from species, such as Sargassum siliquosum, incorporate substantial and exhibit a sugar-to-uronate ratio of approximately 12:1, alongside sulfate contents around 4 mol per disaccharide unit. Several environmental and procedural factors influence these structural features. Seasonally, sulfation and fucose content tend to increase during active growth phases, as observed in Fucus serratus where sulfate levels reach up to 40% in autumn, compared to lower values in spring. Locational variations, including exposure to pollution, can reduce purity and sulfate content; for example, fucoidans from algae show diminished sulfate levels and higher contamination from storage polysaccharides like laminaran due to environmental stressors. Processing methods also induce alterations, such as desulfation under harsh acidic conditions or prolonged extraction times, which degrade sulfate esters and modify the overall composition. Derivatives of fucoidan, particularly oligosaccharides, are generated through controlled to improve specific attributes. These are typically produced via mild acid or enzymatic degradation, yielding fragments with molecular weights of 2-10 that retain core sulfated fucose motifs but exhibit enhanced . Such structural variations directly affect key physicochemical properties. Higher molecular weights, often exceeding 200 in native forms, contribute to greater , while increased sulfate density amplifies the negative charge, thereby improving and electrostatic interactions.

Historical Development

Discovery and Early Research

Fucoidan has roots in traditional Asian , where such as ( species) were utilized for their purported health benefits, including alleviation of , dating back over a in Japanese practices. Early chemical studies prior to the 1950s identified these algal extracts as sulfated , with initial characterizations highlighting their slimy, mucilaginous nature and content derived from species like . The formal discovery of fucoidan occurred in 1913 when Swedish chemist Harald Kylin at isolated a fucose-containing , termed "fucoidin," from of the genus during investigations into biochemistry. Kylin's work, detailed in his seminal paper "Zur Biochemie der Meeresalgen," established fucoidan as a distinct sulfated compound, laying the groundwork for subsequent structural analyses. A key milestone came in 1957 when George F. Springer and colleagues identified fucoidan's properties, demonstrating its ability to inhibit blood coagulation through fractionation of crude extracts from . This finding, published in the Proceedings of the Society for Experimental Biology and Medicine, marked the first recognition of fucoidan's potential in blood coagulation modulation. During the 1970s and 1980s, Japanese researchers advanced structural elucidation of fucoidan, employing methylation analysis to map glycosidic linkages in extracts from brown algae. For instance, studies on Ecklonia kurome revealed a predominant α-(1→3)-linked L-fucose backbone with sulfate groups at the C-4 position, confirming its heterogeneous yet fucose-dominant composition. Concurrent lab tests noted preliminary antiviral effects of fucoidan against various viruses in vitro. Additionally, Baba et al. in 1988 demonstrated that sulfated fucoidans selectively blocked enveloped virus infections, attributing this to interference with viral adsorption.

Commercialization and Key Milestones

The commercialization of fucoidan gained momentum in the following a pivotal announcement at the 55th Annual Meeting of the Japanese Cancer Association in 1996, where researchers presented evidence of fucoidan's ability to induce in cancer cells. This discovery sparked widespread interest in , particularly in and Okinawa, leading to the rapid emergence of fucoidan-based dietary supplements marketed for immune support and health maintenance. Entering the 2000s, advancements in extraction technologies enabled the production of high-purity fucoidan extracts suitable for commercial applications. A notable milestone was the launch of Maritech®, a standardized, organic fucoidan extract derived from Undaria pinnatifida, introduced by Marinova in Australia in 2003 to meet growing demand in nutraceuticals. Concurrently, key patents emerged, such as US Patent 20060210514A1 granted in 2006, which covered methods for isolating and purifying fucoidan from brown seaweeds like Undaria for use in skincare and health products. The 2010s marked significant global expansion, with the fucoidan market growing to exceed $90 million by , driven by applications in supplements and functional foods. A critical regulatory achievement was the European Commission's authorization of fucoidan extracts from Undaria pinnatifida as novel foods in 2017, allowing their incorporation into food products across the under specified conditions. In the , innovation has focused on advanced biomedical uses, including the integration of fucoidan into hydrogels for applications, such as and neural repair, with studies demonstrating enhanced and regenerative properties. In the early , expanded to include fucoidan's potential against , with studies demonstrating inhibition of viral entry. A phase II for fucoidan in combination with for cancer began in 2020. In , Marinova's Maritech fucoidans received organic certification. Patents for oligo-fucoidan derivatives have also advanced, exemplified by US Patent 7749545B2 (issued 2010 but with ongoing relevance) and recent on low-molecular-weight forms for antidiabetic effects through improved glucose control and anti-fibrotic activity in diabetic models. Leading industry players include Marinova in , renowned for its eco-certified extracts, and Kanehide Bio in , a pioneer in mozuku-derived fucoidan production. The sector has increasingly shifted toward sustainable sourcing via , particularly for Undaria pinnatifida, to address wild harvesting limitations and ensure reliability.

Biological Activities and Applications

Medicinal Applications

Fucoidan has garnered attention for its potential in various medicinal applications due to its sulfated structure, which facilitates interactions with biological targets. Its and properties stem from the inhibition of key factors, making it a candidate for supporting cardiovascular health. Fucoidan prolongs activated partial thromboplastin time (APTT), (TT), and (PT), while completely inhibiting the intrinsic factor Xase complex and partially suppressing activity through interactions with cofactor II. These mechanisms position fucoidan as an alternative to traditional anticoagulants like , with applications in preventing and managing conditions such as and . It is commonly available in oral supplements at doses of 100-300 mg/day for cardiovascular support, approved for human consumption up to 250 mg/day by regulatory bodies. In , fucoidan shows promise as an adjunct in cancer by targeting tumor progression pathways. It induces in cancer cells through activation of cascades, involving proteins, PI3K/Akt signaling, and (ROS) generation, while also promoting cell cycle arrest, particularly in the . Additionally, fucoidan inhibits by suppressing (VEGF) expression and (PAI-1), thereby limiting tumor vascularization and . When combined with agents, fucoidan enhances treatment efficacy and reduces side effects such as , improving patient outcomes in various cancers. Fucoidan's anti-inflammatory and antioxidant effects further extend its therapeutic utility to chronic inflammatory conditions. It scavenges ROS, including radicals and , preventing and oxidative damage in tissues. By modulating the pathway and downregulating pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, fucoidan suppresses inflammatory responses in models of and (IBD). In , it aids in modulating proteolysis, while in IBD, it reduces cytokine production to alleviate gut inflammation. Fucoidan also demonstrates potential prebiotic activity by promoting the growth of beneficial gut microbiota, such as Lactobacillus species, and inhibiting pathogenic bacteria through mechanisms like blocking virulence factor interactions and enhancing short-chain fatty acid production. These effects support gut health restoration and may contribute to alleviating dysbiosis in preclinical models. Antiviral and antidiabetic applications highlight fucoidan's broad-spectrum potential. It blocks viral entry and replication by inhibiting attachment to host cells, demonstrating activity against (HSV) and through sulfation-dependent mechanisms. In diabetes management, fucoidan improves insulin sensitivity by alleviating and enhancing glucose metabolism, with effects observed in high-fat diet models at doses around 80-300 mg/kg. Other notable uses include hepatoprotective and roles. Fucoidan protects the liver by suppressing , reducing transaminase leakage, and enhancing responses via sirtuin-1 overexpression, mitigating injury from toxins or metabolic stress. arises from its ability to inhibit ROS, reduce microglial activation, and promote like BDNF, benefiting conditions such as Alzheimer's and . Fucoidan is administered primarily as oral supplements for general use, with intravenous formulations explored in clinical trials for targeted delivery, particularly in and antiviral contexts.

Cosmetic and Industrial Applications

Fucoidan serves as a moisturizing agent in cosmetic formulations due to its water-binding capacity and ability to form hydrogels that enhance skin hydration. It is incorporated into creams and serums, often derived from species extracts, at concentrations typically ranging from 0.1% to 1% to provide these benefits without irritation. In anti-aging products, fucoidan contributes through mechanisms such as stimulation and UV protection, helping to mitigate effects by scavenging . Its properties make it suitable for skincare targeting conditions like and , soothing irritated in topical applications. Recent trends in 2025 include nano-encapsulated forms of fucoidan to improve penetration and efficacy in serums and moisturizers. In the food industry, fucoidan functions as a GRAS-approved functional ingredient in dietary supplements, valued for its antioxidant properties that extend shelf life in beverages. It also acts as a thickener in gels and emulsions, enhancing texture in processed foods due to its rheological characteristics. Beyond cosmetics and food, fucoidan finds use in industrial applications such as tissue engineering, where it forms hydrogels serving as scaffolds at concentrations of 1-5% to support cell growth and biocompatibility. In wastewater treatment, its sulfate groups enable metal chelation, effectively binding heavy metals like lead and cadmium for removal from contaminated water.

Research and Therapeutic Potential

Preclinical Investigations

Preclinical investigations into fucoidan have extensively explored its mechanisms and efficacy through cell culture assays and animal models, highlighting its potential as a multifunctional therapeutic agent. In antitumor studies, fucoidan has demonstrated robust induction of in various lines, particularly and colon cancer cells. For example, treatment of human colon cancer HT-29 cells with fucoidan suppressed proliferation and triggered via inhibition of the Akt signaling pathway, achieving half-maximal inhibitory concentrations (IC50) in the range of 50-200 μg/mL. Similarly, in oral HSC-3 cells, fucoidan promoted caspase-dependent and autophagic at comparable concentrations, underscoring its role in disrupting survival pathways. These effects are mediated by upregulation of pro-apoptotic proteins such as Bax and downregulation of anti-apoptotic , as observed in multiple models. In vivo antitumor efficacy has been validated in xenograft mouse models, where fucoidan administration consistently reduced tumor burden. In Lewis lung carcinoma (LLC1) xenografts in mice, intraperitoneal fucoidan treatment inhibited tumorigenesis and decreased tumor volume by 40-60% compared to controls, primarily through (TLR4)-dependent generation and immune modulation. Analogous results were reported in 4T1 xenografts in mice, where fucoidan curtailed tumor growth by 50% and limited by suppressing and invasion. These findings indicate fucoidan's capacity to enhance and inhibit in solid tumors, though outcomes vary with dosage and administration route. Antiviral preclinical assays reveal fucoidan's interference with enveloped virus lifecycle stages, notably against and (HSV). In Madin-Darby canine kidney (MDCK) cells infected with , fucoidan inhibited replication with EC50 values of 10-50 μg/mL by blocking viral attachment and fusion to host membranes via electrostatic interactions with viral glycoproteins. For HSV-1 and HSV-2, similar concentrations prevented viral entry in Vero cells, competing for positively charged sites on viral envelopes and reducing plaque formation by up to 90%. These mechanisms highlight fucoidan's broad-spectrum potential without direct to host cells. Fucoidan's antioxidant capabilities have been quantified in radical scavenging assays and oxidative stress models. The DPPH assay showed fucoidan scavenging up to 80% of free radicals at 1 mg/mL, with activity proportional to its sulfate content and molecular weight. In carbon tetrachloride-induced liver injury models, oral fucoidan administration (100-200 mg/kg) significantly lowered levels and restored and activities, mitigating hepatic oxidative damage. These effects position fucoidan as a protector against in tissue-specific contexts. Anti-inflammatory investigations demonstrate fucoidan's suppression of key inflammatory pathways in cellular and animal systems. In (LPS)-stimulated RAW 264.7 macrophages, fucoidan dose-dependently reduced TNF-α production by 50-70% at 50-100 μg/mL, alongside inhibition of activation and release. In carrageenan-induced paw models in mice, fucoidan (20-50 mg/kg) alleviated arthritis-like , decreasing paw swelling by approximately 50% and lowering TNF-α and IL-6 levels through modulation of MAPK signaling. Such outcomes suggest therapeutic relevance for inflammatory disorders. Advances from 2020 to 2025 have emphasized nano-fucoidan formulations to overcome limitations and enable targeted delivery. Fucoidan-coated nanoparticles facilitated miRNA delivery to pancreatic ductal cells , enhancing while exploiting P-selectin overexpression for tumor specificity. In diabetic streptozotocin-induced models, nano-fucoidan (50 mg/kg) reduced fasting blood glucose by 20-30% and improved via modulation and reduced hepatic . These innovations amplify fucoidan's antidiabetic potential in preclinical settings. Despite these benefits, preclinical data indicate limitations, including species-specific variations in activity due to differences in fucoidan structure across brown algae sources, which can influence sulfate content, molecular weight, and bioactivity potency.

Clinical Trials and Human Studies

Clinical trials investigating fucoidan in humans have primarily focused on its potential as an adjunct therapy for cancer treatment, radiation protection, and other conditions, with most studies being small-scale phase II trials or pilot studies up to 2025. These trials generally assess fucoidan's role in alleviating treatment-related side effects rather than as a primary anticancer agent, building on preclinical evidence of its anti-inflammatory and immunomodulatory properties. Safety has been consistently reported as favorable at doses below 1 g/day across multiple studies, though large-scale phase III trials remain scarce. In cancer-related applications, a phase II randomized double-blind trial (NCT04597476, recruiting as of 2025) is evaluating 300 mg/day of fucoidan in patients with head and neck undergoing treatment to assess effects on , including . Similarly, an ongoing trial (NCT06855524, recruiting as of 2025) in gastrointestinal and gynecological cancer patients receiving is testing fucoidan for preventing chemotherapy-related compared to . A double-blind randomized -controlled study published in 2023 on low-molecular-weight fucoidan as an adjunct to concurrent chemoradiotherapy (CCRT) for locally advanced rectal cancer showed improved treatment tolerance, with significantly lower rates of rash (0% vs. 9.3%) and (75% vs. 95.3%) in the fucoidan group, alongside better physical well-being scores. A randomized controlled trial published in September 2025 evaluated low-molecular-weight fucoidan as an adjunct to transarterial chemoembolization (TACE) for unresectable , reporting improved tumor control and preserved liver function with a favorable safety profile. For , an ongoing as of 2025 (NCT05616507) is examining oligo-fucoidan for protecting function post-radiotherapy in cancer patients, aiming to reduce radiation-induced through its effects. In other areas, small randomized trials have explored fucoidan for , reporting approximately 30% pain reduction after 12 weeks of supplementation in mild-to-moderate cases, though results vary by dose and extraction method. Limited human studies on viral infections suggest benefits, such as shorter duration of flu-like symptoms in supplemented individuals, potentially due to antiviral mechanisms observed in earlier lab data. Available systematic reviews up to 2022 indicate a favorable safety profile in human studies at doses under 1 g/day, with no serious adverse events reported, but limited evidence for efficacy as a standalone , primarily supporting its use as a supportive . The (NCI) lists oligo-fucoidan as an investigational agent for anticancer applications, with no regulatory approvals for therapeutic use. Key gaps include the absence of large phase III trials to establish long-term efficacy and optimal dosing in diverse populations.

Regulatory Status and Safety

Approvals and Regulatory Listings

In the United States, the Food and Drug Administration (FDA) has granted Generally Recognized as Safe (GRAS) status to specific fucoidan extracts. GRN 565, notified in 2015, covers high-purity fucoidan from Undaria pinnatifida for use as an ingredient in foods such as baked goods, soups, and seasonings at levels up to 30 mg per serving, with no questions raised by the FDA regarding its safety under intended conditions. Similarly, GRN 661, notified in 2017, affirms GRAS status for fucoidan concentrate from Fucus vesiculosus, permitting its incorporation into similar food categories at comparable levels, again with FDA concurrence on safety. These notifications, submitted by Marinova Pty Ltd for their Maritech® extracts, support use in food supplements at daily intakes up to 385 mg, based on toxicological data and historical consumption patterns. In the , fucoidan extracts from Undaria pinnatifida received authorization under Regulation (EU) 2017/2470, allowing their use in foods and food supplements following safety assessments by the . This status, effective from 2018 but building on earlier evaluations, specifies labeling as "fucoidan extract from Undaria pinnatifida" and limits intake to ensure safety margins. In , the (TGA) lists fucoidan-containing supplements in the Australian Register of Therapeutic Goods (ARTG), such as product ID 482172 for ImmFucoidan, enabling their marketing as complementary medicines after compliance with quality and efficacy standards. In , fucoidan from (Okinawa mozuku) is used in functional foods, with traditional consumption supporting general claims, though specific approvals under the Foods for Specified Health Uses (FOSHU) framework are limited. The (NCI) classifies fucoidan, particularly oligo-fucoidan variants, as an investigational agent for , noting its potential in preclinical models for induction and tumor inhibition without therapeutic approval for clinical use. It is referenced in NCI's Physician Data Query (PDQ) summaries on complementary and , highlighting ongoing studies in supportive cancer care but emphasizing the lack of established efficacy or standardization. No approvals for fucoidan as a exist globally, limiting it to supplement and food applications. Internationally, variations persist: in , select imported fucoidan products have obtained "" health food registration from the , permitting sales with approved health claims after rigorous safety reviews. However, restrictions apply to high-iodine algae-derived products, including some fucoidan sources, due to risks of disruption; European and Australian regulations cap iodine at 150–500 μg per daily serving to mitigate excess intake.

Safety Profile and Quality Control

Fucoidan exhibits a favorable general safety profile, with low observed in animal models. In rats, the oral LD50 is greater than 2 g/kg body weight, indicating minimal risk of acute poisoning. Extracts recognized as (GRAS) by the FDA are considered for consumption at doses ranging from 100 to 500 mg per day, based on comprehensive toxicological evaluations. At higher doses, such as exceeding 4 g daily, mild gastrointestinal upset may occur, though short-term studies in healthy volunteers reported no significant abnormalities in abdominal or fecal conditions after 2 weeks of excessive intake. Potential risks associated with fucoidan primarily stem from its properties and environmental contaminants in algal sources. Due to its ability to inhibit factors and potentially enhance the effects of agents, fucoidan should be avoided or used cautiously by individuals on blood thinners like or to prevent additive bleeding risks. Additionally, used for fucoidan extraction can accumulate such as , , and lead, as well as excess iodine, with concentrations in unprocessed sometimes reaching up to 10 times regulatory limits in polluted waters, necessitating careful sourcing to mitigate exposure. Toxicity studies further support fucoidan's safety, showing no genotoxic potential. The conducted on fucoidan from Undaria pinnatifida demonstrated negative results for mutagenicity across multiple bacterial strains, up to concentrations of 5,000 μg/mL. A 2025 review of , including fucoidan variants, affirmed no major risks at typical supplement doses (under 1,000 mg/day), as these selectively target the intrinsic pathway without broadly disrupting . Quality control measures are essential to ensure fucoidan products meet standards, focusing on purity and contaminant limits. Commercial extracts are typically standardized to contain greater than 85% fucoidan by weight, verified through sulfate content assays that quantify the characteristic sulfation pattern. Heavy metal testing employs (ICP-MS) to confirm levels below 10 ppm for and other toxins, aligning with pharmacopeial guidelines for algal-derived supplements. Certain vulnerable populations require special precautions with fucoidan use. It is contraindicated during due to insufficient safety data and potential fetal risks from anticoagulant effects or iodine excess, and in individuals with bleeding disorders to avoid exacerbation of hemorrhage. Interactions with have been noted, potentially increasing international normalized ratio (INR) by additive action, warranting INR monitoring if co-administration occurs. Recent 2025 insights from preclinical and observational data reinforce long-term tolerability. Studies up to 12 weeks at 300 mg/day in patients showed no adverse effects, while a 2025 review highlighted the absence of in extended exposures, supporting for up to one year in healthy adults at doses around 1,000 mg/day without or hematological changes. As of 2025, no major new regulatory changes have been reported, though ongoing reviews by bodies like EFSA continue for algal-derived .

References

  1. https://pmc.ncbi.nlm.nih.gov/articles/PMC6245444/
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