Fucoidan in cancer therapy: from biomedical application to medicinal chemistry approach.

Introduction
Malignant and benign tumors are two distinct kinds of tumors classified within the broader category of tumors. Advancements in molecular oncology elevate comprehension of the processes involved in cancer development [1]. A combination of genetic, environmental, and chemical factors affects the development of tumors. Based on the most recent Global Cancer Map, cancer is expected to become the primary cause of death in 2022, causing 10.2 million fatalities and leading to 19.3 million new cases. There are estimates suggesting that the incidence of cancer will rise by 47% from 2020 to 2040, potentially reaching 28.4 million cases [2]. The prognosis and treatment effectiveness for patients are noticeably influenced by the rate of tumor aggressiveness. Developing drugs and fighting drug resistance is difficult due to cancer’s diversity and complexity. Extended use of chemotherapy medications like cisplatin, doxorubicin, imatinib, gefitinib, and Taxol may lead to resistance to drugs and negative side effects [3, 4]. Hence, conducting research on novel anti-cancer treatments is crucial to reduce side effects or improve the effectiveness of current therapies. Many successful projects in drug development and medicinal chemistry have concentrated on natural compounds uncovered in the ocean [5]. Although significant efforts have been made to treat the cancer and improve the survival and prognosis of patients, there are still challenges in patient treatment. Notably, the tumor cells can develop resistance to traditional therapeutics, such as chemoresistance and radioresistance. Moreover, the new therapeutics, such as immunotherapy, have a number of challenges in cancer treatment, such as immune evasion and side effects. Therefore, the application of biomaterials as safe and biocompatible carriers can further increase the tumor treatment.
Fucoidan (FD), which is a complicated sulfated polysaccharide, can be found in different types of brown seaweed [6–8]. Current research has only described the bioactivities of fucoidans from various brown seaweeds to some extent [9]. Fucoidan’s bioactivity is impacted by aspects such as molecular weight, monosaccharide makeup, and level of sulfation. Furthermore, the composition of Fucoidan obtained from the identical type of species may be influenced by factors like when it is harvested and the methods used for extraction, leading to variations in its content among different species [10]. Growing interest in using brown seaweeds for fucoidan lacks evidence linking productivity, composition, and structure improvements to bioactivity [8, 11]. Even though many types of seaweed have not been thoroughly studied, there are only a limited number of fucoidan extracts on the market, mostly derived from species such as Fucus vesiculosus, Macrocystis pyrifera, and Undaria pinnatifida [8]. Numerous bioactive characteristics of fucoidan have been observed in both laboratory and animal research [12], such as its functions in reducing oxidative stress, clotting, thrombosis, inflammation, viral activity, lipid accumulation, metastasis, diabetes, and cancer [12]. A key discovery from these research studies is that fucoidan has anti-cancer properties, known for its capability to interfere with tumor cell metabolic pathways [13, 14]. Although various kinds of polymers have been applied in the treatment of cancer and the development of delivery systems, the clinical application depends on the biosafety of the nanostructures. Moreover, the developed delivery systems should demonstrate high drug loading and increased specificity towards cancer cells. As a result, application of fucoidan-based delivery systems for improving biocompatibility and delivery potential can further improve the fight against cancer.
This review aims to provide a medicinal chemistry-focused synthesis of current evidence regarding fucoidan in oncology. We analyze structure-activity relationships, including molecular weight, sulfation pattern, monosaccharide composition, and processing, in relation to anticancer mechanisms such as apoptosis, autophagy, epithelial-mesenchymal transition/metastasis, and angiogenesis, with particular attention to the PI3K/Akt, VEGF, and TGF-β pathways. We critically evaluate fucoidan-based biomaterials, including nanoparticles, micelles, and hydrogels, for targeted delivery and photodynamic and chemo-immuno combinations. Additionally, we summarize pharmacokinetics/ADME and route-dependent bioavailability (low molecular weight fucoidan vs. high molecular weight fucoidan) and identify gaps in standardization, safety, and translation to propose design principles and research priorities for the rational development of next-generation fucoidan therapeutics.

Fucoidan: structure and chemistry
Brown algae, like Sargassum and Fucus seaweeds, are a varied group of sea plants mainly located in cold-water areas [14]. Seaweeds have bioactive compounds like fucoidan, proteins, polyphenols, sterols, trace elements, and polysaccharides [15]. Fucoidan is a prominent substance extracted from brown seaweed. Conventional techniques for obtaining fucoidan from seaweeds typically require the use of water, diluted acid, or alkali, leading to laborious processes and significant reagent quantities [16]. The enhancement and innovation of extraction techniques have been driven by technological advancements. For example, activating water molecules within cells with microwaves or ultrasound greatly improves traditional water extraction efficiency and makes cell disruption easier [17]. Another method is enzyme-facilitated extraction, which uses enzymes to break down cell walls and remove their contents, offering precise targeting and efficient catalytic performance [18]. The composition of fucoidan is very complex, consisting of two primary types of connections. The initial kind includes α-l-fucopyranose residues linked by (1→3), while the second kind alternates between α-l-fucopyranose residues linked by (1→3) and (1→4) [19]. Fucoidan is comprised of 34–44% α-l-fucose, as well as other monosaccharides such as galactose, xylose, mannose, and uronic acids, all making up less than 10% of the total polysaccharide content [20]. Sulfate groups are mainly found at the C-4 location, with some presence at the C-3 site as well [21, 22]. Fucoidan is categorized as a natural heteropolysaccharide, much like numerous other varieties in this group [12, 23]. Fucoidan from brown algae is a sulfated carbohydrate similar to heparin [24, 25], with fucose units in unique bonds [15, 26, 27]. Fucoidan’s appeal for various uses lies in its low toxicity in humans and in vivo environments [13, 28]. Fucoidan’s anticancer effects include inhibiting tumor growth, invasion, metastasis, cell cycle progression, angiogenesis, and immune responses [12, 14, 29–32]. Research has investigated how fucoidan inhibits cancer through various molecular pathways in different types of cancer. Review articles have extensively looked at the composition, functions, and roles of fucoidan in healthy and diseased states in laboratory and living organism studies [12, 13, 15, 27]. Variations in fucoidan concentration in studies are attributed to differences in sources and decontamination methods [33]. Alwarsamy and colleagues [34], found that exposing A549 lung cancer cells to 100 µg/mL of fucoidan for 48 h led to a 50% reduction in cell proliferation. Experiments on mice with lung cancer found fucoidan at 10 mg/kg lowered tumor growth by 33% and reduced metastasis by 29%. In contrast, 25 mg/kg had no effect on tumor growth. Overall, fucoidan demonstrated significant anticancer properties at the lower dosage [35]. Research explores diverse fucoidan administration methods: intravenous, subcutaneous, oral, intraperitoneal injections for effectiveness [14, 35–40]. Many research studies have been carried out to investigate the in vivo ADME (absorption, distribution, metabolism, and excretion) characteristics of fucoidan. These vital pharmacokinetic parameters are important for determining the right dosage schedules. Investigations with lab rats have focused on uncovering how fucoidan is absorbed and its bioavailability. In studies with fucoidan from Fucus vesiculosus (737 kDa), scientists found that levels in the blood reached their highest point 4 h post-administration, with any remaining fucoidan collecting in the kidneys. Moreover, research has indicated that rats take in fucoidan from C. okamuranus, leading to its buildup in different organs [41, 42]. Comparative bioavailability studies show that LMWF has higher biological activity compared to moderate molecular weight fucoidan (MMWF) because of its better absorption rate and bioavailability. Furthermore, rats showed great skin penetration when fucoidan (750 kDa) from Fucus vesiculosus was applied topically. The 100 mg/kg body weight topical treatment had a much longer half-life than the same dosage given intravenously. It is interesting that fucoidan can be detected in human serum and urine after being administered topically or orally, indicating uptake through endocytosis [43].
The complex processes needed to cleanse fucoidans, a type of water-soluble polysaccharides, are due to their strong affinity for other hydrophilic components in cell walls, like polyphenols [44, 45]. Priming, gathering, isolating, and refining are the main steps in production. The first step involves taking algae from the bottom of the ocean and then washing, drying, and milling it to enhance surface area and remove contaminants. Due to the diversity of algae, various methods have been developed for their extraction and purification [22]. Methanol and acetone are common organic solvents utilized for extracting hydrophobic elements, such as pigments and lipids, in the extraction procedure. Additionally, heated and pressured acidic or water extractions could be employed depending on the type of algae [46]. Classic methods, like heat extraction, microwave-assisted extraction, and ultrasound-assisted extraction are used to help release polysaccharides without damaging cell walls [44]. Subcritical water extraction and hydrothermal-assisted extraction are two mild techniques designed to enhance fucoidan yields that have been developed [47, 48]. In order to minimize the use of strong chemicals and high temperatures, a new method called enzyme-assisted extraction with cellulase and papain has been developed. Following extraction, fucoidans are isolated from the algal biomass through methods like filtration, dialysis, and centrifugation [49]. Separating low molecular weight fucoidans (LMWFs) from high molecular weight fucoidans is done by using membranes with specific molecular weight cut-off points [50]. Despite their effectiveness, it is still required to further purify the produced fucoidans to create a high-quality polymer suitable for biological uses [51]. Reports indicate the use of non-chromatographic techniques like bleaching and membrane filtering [52], as well as the development of novel separation methods using molecularly imprinted polymers for specific solid-phase extraction [53, 54]. The molecular weights and sulfate patterns of fucoidan extracts may differ greatly depending on various factors such as extraction conditions, the type of algae utilized, and their growth stage [55]. The molecular weight of fucoidans is a crucial factor that affects their biological activity. Notably, the investigation of LMWFs extracts in different biological situations has been prompted by their bioavailability. An investigation conducted by Lin et al. [56] examined how the combination of fucoxanthin and LMWFs (0.8 kDa) affected glucose levels in diabetic mice. The study showed that this mix was more successful in regulating glucose levels compared to using either treatment alone. During a study with patients with metastatic colorectal cancer, LMWFs (0.8 kDa) led to a 24% increase in the disease control rate [57]. Moreover, fucoidan has been separated into different molecular weights, showing that fractions with smaller weights (<30 kDa) have higher cytotoxic effects on cancer cells. Fucoidan fractions with low molecular weights (10–37 kDa) that have been gamma-irradiated showed enhanced antioxidant properties [58]. Notably, it has been reported that high molecular weight fucoidan also has anti-inflammatory and anticancer properties, suggesting that other factors may play a role in influencing its biological effects [59, 60].
Considerable interest has been sparked by the notable enhancement in biological activity of nanoparticles made from fucoidan as opposed to the original fucoidan [61]. These nanoparticles made from fucoidan can respond to changes in pH, making it possible to deliver bioactive compounds to specific disease areas in a targeted manner. A new research study looked into how fucoidan, chitosan, and metallic nanoparticles can be combined for various purposes like drug delivery, contrast enhancement, and tumor targeting [62]. The applications of fucoidan have been broadened in medicinal, environmental, and cosmeceutical fields by combining it with metal-based nano-oxides such as titanium, zinc, and aluminum [63]. Moreover, fucoidan has the ability to efficiently transport anticancer drugs like curcumin and doxorubicin to specific locations for treating cancer [64]. Additionally, studies have demonstrated that the composition and weight of fucoidan can improve the creation of nanoparticles. LMWFs extracted from Fucus evanescens were used to produce nanoparticles with chitosan. These fucoidans contain fucose residues connected through 1→3 and 1→4 bonds, forming a three-dimensional helix structure. The molecular weight and structure of fucoidan play a significant role in the formation of nanoparticles, with its high molecular weight and the existence of 1→3 linked fucose residues being responsible for its aggregation with chitosan (S. cichorioidesi, fucoidan, n.d.) [65].

Biomedical application of fucoidan

Fucoidan in wound healing
Chronic wounds represent a significant worldwide health issue. Elevating fucoidan concentration from 0.25% to 1% augmented nanofiber diameter (487.7 ± 125.39 to 627.9 ± 149.78 nm), entrapment efficiency (64.26 ± 2.6% to 94.9 ± 3.1%), and water absorption (436.5 ± 1.2% to 679.7 ± 11.3%). Conversely, in vitro biodegradation diminished as fucoidan increased. Water vapor transfer rates consistently fell within normal parameters throughout all fucoidan levels. Nanofibers including 1% fucoidan within a PVA/DEX matrix demonstrated sustained release, signifying extended fucoidan availability at the wound site. In a rat full-thickness wound model, 1% fucoidan-enriched PVA/DEX nanofibers markedly enhanced mean wound closure (p < 0.0001). Fucoidan-loaded nanofibers have significant potential as future wound dressings, contingent upon more research [66].
A functional hydrosheet dressing including alginate, chitin/chitosan, and fucoidan (ACF-HS) was developed to retain moisture and expedite wound healing. Their effectiveness was evaluated in rats with full-thickness dorsal wounds compromised by mitomycin C. Following a 10-min administration of mitomycin C and comprehensive cleaning, ACF-HS was administered; subsequently, the wounds were excised for histological analysis. In comparison to alginate fiber (Kaltostat®), a hydrogel dressing (DuoACTIVE®), and no therapy, ACF-HS produced significantly enhanced granulation tissue and capillary development on days 7 and 14. In cell culture, ACF-HS–absorbed serum enhanced fibroblast proliferation and served as a chemoattractant for fibroblasts, whereas fibroblast growth factor-2 facilitated endothelial cell proliferation. The findings may not completely apply to standard human healing-impairment models, as mitomycin C causes direct cellular damage, and further assessments of fucoidan biocompatibility are necessary due to possible renal toxicity [67].
Managing wounds infected with methicillin-resistant Staphylococcus aureus (MRSA) continues to pose significant difficulties. Traditional vancomycin treatment frequently results in significant adverse effects and restricted effectiveness due to toxicity and inadequate targeting, highlighting the pressing necessity for novel antimicrobials and precise delivery methods. Anti-infection nanoparticles (LMM NPs) were designed with intrinsic targeting capacity by incorporating low-molecular-weight fucoidan (LMWF) and enveloping the particles with neutrophil membranes for MRSA wound treatment. LMWF has anti-MRSA efficacy equivalent to vancomycin while demonstrating less nephrotoxicity. The neutrophil membrane coating maintains natural membrane constituents, facilitating immune evasion and preferred localization at sites of infection. In an MRSA-infected wound model, LMM NPs exhibited efficient accumulation in infected tissues, revealed excellent biocompatibility and significant antibacterial efficacy, and facilitated rapid healing. These infection-specific, LMWF-loaded nanoparticles signify a promising approach for the targeted treatment of MRSA infections, with significant implications for deep-tissue therapeutic applications [68].
Wound healing continues to be an unresolved challenge in trauma, burns, and diabetes. A smart microneedle patch, filled with nanoparticles and based on pullulan, was developed for stage-responsive drug delivery. Chitosan and fucoidan were utilized to create moxifloxacin-loaded nanoparticles (MOXNPs) with a diameter of 258.0 ± 10.86 nm, a polydispersity index (PDI) of 0.19 ± 0.06, and a zeta potential of 45.1 ± 3.9 mV. MOXNPs, lidocaine (LH), and thrombin (TH) were then integrated into a 30% (w/w) pullulan microneedle array (TH+LH+MOXNPs@MN). The patch comprises homogeneous, cone-shaped microneedles 725 μm in length, exhibits favorable biocompatibility, possesses sufficient mechanical strength for skin penetration, dissolves rapidly in the skin after 55 ± 5 min, facilitates the fast release of TH and LH within 1 h, and ensures continuous release of MOX over 24 h. In a murine skin-wound model, TH+LH+MOXNPs@MN accomplished full closure within 7 days, reinstated collagen deposition, increased cell proliferation and granulation, and decreased pro-inflammatory cytokines. The integrated polysaccharide microneedle system offers swift hemostasis and analgesia while delivering prolonged antibacterial effects, signifying a viable approach for superior wound healing [69].
Bio-multifunctional wound dressings that integrate robust hemostatic properties, antimicrobial and anti-inflammatory effects, improved angiogenesis, and hair follicle regeneration are essential for the healing of full-thickness wounds. Composite sponges were synthesized by combining alginate and chitosan with fucoidan by electrostatic complexation, Ca²⁺ crosslinking, and lyophilization. The resultant alginate/chitosan/fucoidan (ACF) sponges have exceptional elasticity, preserving their form post-bending and compression without failure. The 10% fucoidan formulation (ACF-1) exhibits enhanced hemostatic and antibacterial efficacy, markedly expediting wound closure in a rat full-thickness wound model when compared to alginate/chitosan alone and an ACF sponge containing 30% fucoidan. ACF-1 significantly improves re-epithelialization and dermal collagen deposition, facilitates hair follicle regeneration, boosts vascularization via increased CD31 expression, and diminishes inflammation by reducing TNF-α expression. ACF sponges with optimized fucoidan content have significant promise for full-thickness skin healing [70].
LMWF derived from Undaria pinnatifida, recognized for its anti-inflammatory and antioxidant properties, was assessed for its efficacy in cutaneous wound healing. Five circular dorsal lesions were induced on each rat and treated bi-daily for 7 days with distilled water (DW), Madecasol Care™ (MC), or LMF at concentrations of 200, 100, or 50 mg/mL. In contrast to DW, LMF elicited dose-dependent enhancements in wound contraction, an effect absent with MC. Histological analysis revealed expedited healing under LMF, characterized by increased granulation tissue on day 4, which diminished by day 7, accompanied by a significant decrease in inflammatory cells. LMF improved collagen distribution and angiogenesis in granulation tissue on both day 4 and day 7. Immunoreactive cells for TGF-β1, VEGFR-2, and MMP-9 were increased, indicative of tissue remodeling. Biochemically, LMF decreased lipid peroxidation and enhanced antioxidant activity. LMF promotes cutaneous wound healing via synchronized antioxidant, anti-inflammatory, and growth factor-mediated pathways [71].
Dermal imperfections resulting from inflammation, burns, or infection may necessitate specialized dressings to facilitate healing. Three-dimensional, hydrophilic hydrogels provide a milieu that facilitates cell migration and proliferation, while collagen, a crucial extracellular matrix component, quickly self-assembles into these networks. A hydrogel imitating the extracellular matrix was developed by incorporating glutaraldehyde-derived carbon dots (GACDs) and fucoidan, a sulfated fucose-rich marine polysaccharide, into collagen, resulting in improved mechanical properties, antibacterial efficacy, and immunomodulatory capabilities for multifunctional wound care. The addition of GACD maintained collagen fibril self-assembly while significantly enhancing mechanical strength. The composite hydrogel demonstrated good cytocompatibility and hemocompatibility. The addition of FC markedly reduced TNF-α and IL-1β levels while enhancing TGF-β1, so imparting anti-inflammatory effects, and worked synergistically with carbon dots to enhance antibacterial efficacy. The ECM-like hydrogel facilitated collagen fiber deposition and remodeling in vivo. The platform provides significant anti-inflammatory, antibacterial, and tissue-repair advantages, and its integrated immunomodulation within a collagen scaffold effectively tackles the complex challenges of healing in inflamed or infected wounds—signifying a substantial improvement over single-function dressings with encouraging clinical prospects [72].

Fucoidan in tissue regeneration
Collagen, a unique protein prevalent in mammalian connective tissues, is extensively utilized in biomaterials. Collagen–fucoidan composite films were made and assessed for their tissue-regenerative efficacy. Thermal investigations (TGA, DSC) indicated enhanced thermal stability and an elevated denaturation temperature compared to natural collagen, which is ascribed to intramolecular hydrogen bonding between collagen and fucoidan, corroborated by FTIR. Scanning electron microscopy demonstrated reduced pore diameters compared to the controls. Fucoidan further safeguarded collagen from enzymatic breakdown, hence augmenting structural stability. The films facilitated fibroblast growth and migration in vitro without inducing toxicity. Collagen–fucoidan films serve as an advantageous platform for fibroblast proliferation and have significant potential for tissue-engineering applications [73].
Three-dimensional (3D) composite scaffolds for bone tissue engineering were produced using freeze-drying. Formulations comprised chitosan alone; chitosan–fucoidan; chitosan–nano-hydroxyapatite (nHA); and chitosan–nHA–fucoidan. The physicochemical composition and morphology were analyzed using FT-IR, TGA, XRD, SEM, and optical microscopy. The integration of nHA into the chitosan–fucoidan matrix decreased water absorption and retention. FT-IR analysis showed the presence of phosphate groups in the chitosan–nHA–fucoidan scaffold, which are derived from nHA extracted from salmon bones by alkaline hydrolysis. Microscopy revealed a homogeneous distribution of nHA and fucoidan inside the chitosan matrix, including an interconnected pore size of 10–400 μm, therefore creating a microarchitecture conducive to cellular proliferation and nutrient delivery. In vitro tests utilizing periosteum-derived mesenchymal stem cells demonstrated significant biocompatibility and robust mineralization, especially with the chitosan–nHA–fucoidan scaffold. Chitosan–nHA–fucoidan composites have potential for bone tissue regeneration [74].
A novel electrospun biocomposite integrating polycaprolactone (PCL) with fucoidan—an agent with anticoagulant, antiviral, and immunomodulatory properties—was created. Scaffolds were fabricated using the electrospinning of PCL with 1, 2, 3, or 10 wt% fucoidan. Composites with fucoidan levels ≤ 10 wt% exhibited enhanced tensile modulus and strength relative to pure PCL mats, but hydrophilicity significantly increased at fucoidan concentrations of ≥ 3 wt%. In vitro analysis utilizing MG63 osteoblast-like cells evaluated total protein, alkaline phosphatase activity, and calcium mineralization. SEM pictures revealed a wider cell dispersion and clustering on PCL/fucoidan mats compared to pure PCL, with all assessed cell-related metrics being elevated in the composites. Fucoidan-enhanced PCL biocomposites are very suitable for tissue-engineering applications [75].
Bioceramic–biopolymer composites are pivotal in artificial bone fabrication, with hydroxyapatite (HA) thoroughly investigated for repair and replacement purposes. Hydroxyapatite–fucoidan (HA–fucoidan) nanocomposites were produced using an in situ chemical method and assessed physiologically as alternatives for bone grafts. In comparison to HA alone, the HA–fucoidan nanocomposites elicited a significantly enhanced mineralization response in adipose-derived stem cells, presumably due to the fucoidan component. The expression of osteogenic markers—osteocalcin, osteopontin, collagen, and RUNX-2—was increased on day 7 with HA–fucoidan. In a rabbit model, HA–fucoidan implants demonstrated moderate new bone growth. HA–fucoidan nanocomposites have significant potential for future bone healing and replacement [76].
Bone healing depends on the precise coordination of osteogenesis and angiogenesis, involving interaction between endothelial and bone cells. Fucoidan, a bioactive polysaccharide, facilitates the osteogenic development of human mesenchymal stem cells (MSCs) and therefore enhances angiogenesis, but the mediators remain ambiguous. The connection was clarified by confirming fucoidan’s stimulation of MSC osteogenesis and collecting conditioned medium from fucoidan-treated MSCs (fucoidan-MSC-CM). Fucoidan-MSC-CM induced angiogenic activities in human umbilical vein endothelial cells, including proliferation, tube formation, migration, and sprouting. The expression of VEGF mRNA and the release of its protein significantly increased during fucoidan-induced osteogenesis, but angiogenic activity was reduced by a VEGF/VEGFR binding inhibitor. Fucoidan-MSC-CM also enhanced phosphorylation in the MAPK and PI3K/AKT/eNOS pathways; these effects were significantly inhibited by SB203580 and an AKT1/2 inhibitor. In vivo, fucoidan expedited neovascularization and somewhat promoted bone growth in a rabbit calvarial defect model. The results demonstrate that fucoidan links osteogenesis to angiogenesis through VEGF-dependent signaling involving MAPK and PI3K/AKT/eNOS pathways [77].

Fucoidan in cancer therapy

Fucoidan and apoptosis
Cell removal without inflammation is facilitated by apoptosis, which is identified by the shrinking of the cytoplasm and condensation of chromatin [78, 79]. This process involves two primary routes: the external cytoplasmic pathway triggered by death receptors, and the internal mitochondrial pathway, causing the release of cytochrome C and initiating death signals by changing mitochondrial membrane potential (MMP). Both processes ultimately lead to the degradation of structural and regulatory proteins by executioner caspases [80]. Research on cancer has shown that fucoidan induces apoptosis in hematopoietic, lung, breast, and colon cancer cells in various studies [81–83]. Human colon cancer cells showed activation of caspases 3 and 7 when exposed to a low dose of fucoidan (20 µg/mL) from F. vesiculosus [83], while T-cell leukemia cells required a higher dose (3 mg/mL) for comparable effects [84]. It has been found that Fucoidan can activate important molecules in both the extrinsic pathway (caspase-8) and the intrinsic pathway (caspase-9) [83, 85]. Yamasaki-Miyamoto et al. [82] found that inhibition of caspase 8 hindered fucoidan-triggered cell death in MCF-7 cells. On the other hand, Zhang et al. [81] discovered that fucoidan from Cladosiphon okamuranus caused MCF-7 cell death through a pathway that does not involve caspase. The impact of fucoidan was related to its effect on mitochondrial function, demonstrated by increased levels of cytochrome C and apoptosis-inducing factor (AIF) in the cytoplasm.
Extract from Fucus vesiculosus, fucoidan has been shown to successfully hinder the proliferation of MCF-7 human breast cancer cells through diminishing CDK-4 and cyclin D1 levels. This substance causes cell death by decreasing Bcl-2 and increasing Bax levels, ultimately triggering apoptosis dependent on reactive oxygen species (ROS) through Bid and PARP cleavage. The activation of caspase-7, -8, and -9, and the release of cytochrome C marks the initiation of intrinsic apoptosis in MCF-7 cells [82, 86]. Furthermore, fucoidan usage resulted in decreased invasion and migration, reduced epithelial-to-mesenchymal transition (EMT), enhanced E-cadherin activation, and decreased MMP-9 levels in MCF-7 cells [87]. In trials carried out in live subjects, a notable reduction in metastatic growths in the lungs of 4T1 cells was noted, suggesting the effectiveness of fucoidans from Fucus vesiculosus in inhibiting development in female Balb/c mice implanted with MDA-MB-231 cells. The significant suppression of tumor growth was accomplished by decreasing TGFR-triggered EMT, enhancing epithelial markers and their signaling pathways, and initiating phosphorylation of Smad2/3, Smad4, Snail, Slug, and Twist expression [88]. Fucoidan can regulate both cell cycle advancement and programmed cell death [89]. Park et al. researched the inhibitory effects of fucoidan on the growth of EJ cells derived from bladder cancer patients. Researchers discovered that fucoidan reduces the function of cyclin D1, cyclin E, and cyclin-dependent kinases, leading to the eventual death of EJ bladder cancer cells. Phosphorylation of pRB was blocked in EJ cells pre-treated with fucoidan at a concentration of 150 μg/mL. The phosphorylation of pRB typically results in the disintegration of the pRB-E2F complex, assisting in the progression of the cell cycle. Hence, the reduction in pRB phosphorylation is vital in inhibiting tumors [90]. The research conducted by Wang et al. also investigated cancer metastasis, a complex biological mechanism that allows cancer cells to spread to other faraway areas. The scientists found that using a hot-water method to extract fucoidan from U. pinnatifida stops the spread of liver cancer in mice by inducing apoptosis in Hca-F cells. The results demonstrated that when Hca-F cells were exposed to fucoidan at concentrations between 0.25 and 1.00 mg/mL, there was a significant reduction in the levels of key cell cycle proteins, cyclin D1 and CDK [91]. Alwarsamy and his team conducted an independent study to investigate how fucoidan from T. conoides affects adenocarcinoma epithelial (A-549) cells. Their research discovered that fucoidan is capable of inhibiting the proliferation of A-549 cells and stopping cell cycle advancement in the G0/G1 phase [34]. Treatment with fucoidan has been demonstrated to enhance cancer cell death and hinder cell growth. Fucoidan treatment resulted in decreased levels of glucose-regulated protein 78 (GRP78) and endoplasmic reticulum protein 29 (ERp29) in MDA-MB-231 breast cancer cells and HCT116 colon cancer cells. Even though fucoidan did not affect HCT116 cells, it raised levels of phosphorylated CaMKII, Bax, and caspase-12 in MDA-MB-231 cells through an ER Ca2+-dependent pathway. Furthermore, fucoidan triggered cell death in cancer cells through the activation of p-eIF2α and CHOP, and it also blocked the p-IRE-1 and XBP-1s survival pathway. Additionally, fucoidan’s inhibition of CHOP led to a decrease in DNA damage and cell mortality [92].
Fucoidan’s anticancer promise will hinge on turning its diverse mechanistic signals, caspase-8/-9 activation, ROS-dependent mitochondrial injury, caspase-independent AIF release, ER-stress (p-eIF2α/CHOP) induction, and EMT suppression via TGF-β/Smad into predictable, clinically actionable effects. Priorities include rigorous standardization of source, molecular weight, sulfation pattern, and extraction method to resolve the striking dose disparities noted across cell types, and structure–activity mapping to tune selectivity for tumor over normal tissue. Mechanistic work should define context rules (when MCF-7 cells die via caspases versus AIF; when ER Ca²⁺ pathways dominate) and establish pharmacodynamic biomarkers, caspase-3/7, cytochrome-c, CHOP, E-cadherin, MMP-9, and EMT transcription factors to guide dosing and patient selection. Formulation science (nanocarriers, conjugates, local delivery) and ADME studies are needed to improve bioavailability and tumor uptake, while combination trials should test synergy with chemotherapy, radiotherapy, and immunotherapy (particularly TGF-β blockade or checkpoint inhibitors) to amplify anti-metastatic and anti-EMT effects. In vivo validation must advance beyond single models to patient-derived xenografts and immunocompetent systems that capture stromal and immune crosstalk, alongside toxicity and off-target profiling. Finally, early-phase clinical studies should incorporate harmonized fucoidan specifications, adaptive designs anchored by the above biomarkers, and endpoints sensitive to invasion and metastasis, building a path from heterogeneous preclinical results to reproducible benefit in patients.

Fucoidan and autophagy
Autophagy is an evolutionarily conserved lysosomal mechanism that preserves cellular homeostasis through the degradation of cytoplasmic constituents. However, in cancer, it exhibits a context-dependent duality: it inhibits tumor initiation by eliminating damaged organelles and proteins, while frequently aiding established tumors by sustaining metabolism, survival, and resistance to therapy. Autophagy, initiated by the ULK1 kinase complex and facilitated by the class III PtdIns3K (BECN1–VPS34) machinery, ATG2–ATG9–WIPI lipid transfer, and LC3/ATG12 conjugation systems, integrates signals from dysregulated pathways prevalent in malignancies, notably PI3K–AKT–MTOR suppression and AMPK activation. Autophagy influences cancer responses to chemotherapy and radiotherapy by regulating glucose, glutamine, and lipid metabolism; DNA damage responses; proliferation; metastasis/EMT; and cell death mechanisms (apoptosis, ferroptosis, necroptosis, immunogenic cell death), frequently contributing to chemoresistance. It also modifies tumor immunity by degrading antigens like MHC-I and modifying dendritic and T-cell functions, hence affecting the tumor microenvironment. In pancreatic cancer, autophagy facilitates growth, glycolysis under hypoxic or starving conditions, EMT, and resistance to gemcitabine, whereas its suppression can increase radiosensitivity; non-coding RNAs and small chemicals (silibinin, ursolic acid, chrysin, huaier) modulate this activity. Considering these conflicting effects, reasonable therapy may necessitate the context-specific use of autophagy inducers or inhibitors, informed by tumor genetics, microenvironmental signals, and autophagy-related biomarkers [93–95].
Fucoidan, a sulfated polysaccharide extracted from brown algae traditionally used in Chinese medicine, shows anticancer properties by stopping the growth of liver cancer cells and lowering PCNA levels. It does not impact factors like bFGF levels or angiogenesis in liver cancer cells or tissues, as well as VEGF, bFGF, IL-8, and heparanase expression [96]. Autophagy in cancerous cells can shield normal cells from the continuous impacts of photodynamic therapy (PDT) by eliminating damaged or unneeded organelles and proteins [97]. Li et al. [98] suggested that autophagy could weaken the effectiveness of in situ vaccinations by inhibiting immunogenic cell death (ICD), leading to decreased antigen exposure and reduced overall immunogenicity. Developed as an in situ vaccination method, CCFG refers to fucoidan-based chlorin e6-chloroquine. The process includes fucoidan-induced macrophage polarization and chloroquine-mediated autophagy suppression, working together to amplify the ICD effect caused by PDT. Research carried out in living organisms has demonstrated that CCFG improves the presentation of antigens when exposed to laser light. This improvement results in a strong on-site vaccination effect and greatly decreases the spread and return of tumors (Fig. 1) [99]. When fucoidan was added to cisplatin, the survival of SCC-25 cells was significantly reduced in comparison to using cisplatin alone. This treatment mix resulted in elevated indicators of apoptosis, such as activated caspase-8, caspase-9, caspase-3, and cleaved poly(ADP-ribose) polymerase (PARP). However, there were no alterations in the rates of autophagy markers like beclin and the autophagy-related 12-autophagy-related 5 conjugate. Fucoidan boosted the cleavage of PARP, activation of caspase-3, and production of cytokeratin-18 fragments in SCC-25 cells by blocking the activation of AKT serine/threonine kinase 1 triggered by cisplatin [100]. Research shows that combining fucoidan with doxorubicin greatly boosts the drug’s capacity to trigger cell death, prevent cell movement, and decrease the growth of drug-resistant lung cancer cells [101]. Fucoidan induces apoptotic and autophagic cell death in AGS gastric adenocarcinoma cells by targeting proteins and caspases [102]. Researchers used various methods to analyze the effects of fucoidan on cervical cancer cells, comparing with suberoylanilide hydroxamic acid as control. The results suggest that exposing HeLa cells to fucoidan causes cytotoxic effects by generating ROS, mitochondrial superoxide (SOO), and decreasing ATP levels. Colorimetric analysis discovered that Fucoidan inhibits HDAC expression in HeLa cells, while also inducing alterations in cell granularity and the appearance of senescence-associated heterochromatin foci. The creation of autophagosomes triggered by fucoidan was detected using monodansylcadaverine, and its involvement in promoting autophagy was validated with flow cytometry using acridine orange staining. Furthermore, changes in the levels of proteins p21, p16, BECN1, and HDAC1 were discovered as indicators of aging, autophagy, and HDAC inhibition through FACS and immunoblotting analysis. Molecular docking analysis confirmed the experimental results by showing how fucoidan interacts with HDAC1 [103]. Fucoidan and HDAC1 [103]. Figure 2 demonstrates the function of fucoidan in the regulation of apoptosis and autophagy. Moreover, Fig. 3 provides a schematic representation of the apoptosis mechanism.
Autophagy is a context-dependent stress-response program with a genuine duality in cancer: on the one hand, basal and inducible autophagy preserve cellular homeostasis by clearing damaged organelles and limiting genomic instability and chronic inflammation, functions that are tumor-suppressive early in oncogenesis, while on the other, once malignancies are established, the same machinery often becomes cytoprotective, enabling tumor cells to withstand hypoxia, nutrient deprivation, oxidative stress, and therapy, thereby fostering dormancy, metastasis, and drug resistance. This paradox hinges on variables such as tumor stage and genotype (TP53, KRAS, PTEN), microenvironmental cues, and crucially, autophagic flux rather than static markers. Consequently, therapeutic modulation must be bidirectional and evidence-driven: inhibition (targeting ULK1, VPS34, ATG4, or blocking lysosomal degradation) can convert protective autophagy into vulnerability to chemo-, radio-, or targeted therapy, whereas induction (via AMPK activation or mTOR suppression) can provoke lethal self-digestion, promote ICD, or restore proteostasis to avert malignant transformation in precancerous settings. Natural products, including fucoidan and fucoidan-based nanostructures, embody this plasticity: depending on molecular weight, sulfation pattern, dose, and delivery format, fucoidan can either trigger cytotoxic autophagy (often through ROS-AMPK-mTOR or ER-stress pathways) or suppress pro-survival autophagy (by impeding Beclin-1 complex formation or lysosomal function), and nanoformulations can be engineered to co-deliver fucoidan with chemotherapeutics or autophagy modulators for spatiotemporally precise effects. Therefore, rational deployment demands careful measurement of flux (LC3-II turnover with and without lysosomal blockade, p62/SQSTM1 degradation, tandem mRFP-GFP-LC3 reporters), integration with apoptosis/ferroptosis readouts, and alignment with stage, genotype, and treatment context.

Fucoidan and metastasis
GIV-A (fucoidan), either by itself or with 5-FU, effectively reduces lung metastases in a mouse model of Lewis lung carcinoma through boosting macrophage activation, complement C3 activation, immune cell response, and changing the hepatic drug-metabolizing system [104]. In HT29 colon cancer cells, fucoidan treatment significantly reduced the expression of cyclin and cyclin-dependent kinase (CDK), as well as inhibited proliferation. Furthermore, the impact of fucoidan on cell migration, apoptosis, and proliferation was enhanced with si-PRNP-induced PrP(c) expression suppression. Administering si-PRNPs containing fucoidan intraperitoneally reduced tumor size and growth in Balb/c nude mice. Angiogenesis was decreased while anticancer activity was enhanced [105]. Fucoidan slowed down the growth of OSCC cells and inhibited their migration and invasion. Bioinformatics analysis indicated that there is a possibility of fucoidan interacting with circFLNA, a circular RNA produced from filamin A (FLNA), a finding that was later validated in OSCC samples and cell lines. In fact, fucoidan raised circFLNA levels in OSCC cell lines. Additionally, both fucoidan and circFLNA have the ability to impact the synthesis of important proteins involved in cell proliferation, apoptosis, migration, and invasion [106]. During a study on microRNA expression, the impact of fucoidan on human HCC cells resulted in a significant increase in miR-29b levels. The increase in miR-29b resulted in a dose-dependent decrease in miR-DNMT3B function. Fucoidan-induced miR-29b inhibits DNMT3B, reducing luciferase activity in DNMT3B 3’-UTR reporter, similar to miR-29b mimic. Consequently, fucoidan intervention caused a rise in the levels of MTSS1 (metastasis suppressor 1) mRNA and protein, which are usually repressed by DNMT3B. Moreover, fucoidan also decreased the expression of the TGF-β receptor and Smad signaling pathway in HCC cells. These collective impacts hindered the invasion of HCC cells by boosting E-cadherin levels, decreasing N-cadherin expression, inhibiting the degradation of extracellular matrix (through upregulation of TIMP-1 and downregulation of MMP2 and MMP9), along with other pathways [107]. Fucoidan extract from Turbinaria conoides displayed potential as an anticancer agent in diverse pancreatic cancer cell lines through inducing cell death, activating caspases, inhibiting the NFκB pathway, and impacting the interaction between p53 and NF-κB [108]. Ups-fucoidan from Undaria pinnatifida sporophylls inhibited Hca-F cell functions by reducing VEGF, c-MET, PI3K/Akt, ERK, NF-κB signaling, and increasing TIMP expression [91]. Studies have demonstrated that fucoidan can decrease colony formation and impede the growth of breast cancer cells, like 4T1 and MDA-MB-231. In Balb/c female mice, fucoidan treatment resulted in a reduction in metastatic lung nodules. The molecular network of TGFβ receptors influences the regulation of EMT in cancer cells. Fucoidan successfully blocked TGFR-induced EMT morphological changes, enhanced epithelial marker expression, decreased mesenchymal marker expression, and lowered levels of transcriptional repressors Snail, Slug, and Twist in 4T1 and MDA-MB-231 cells. This implies that TGFR signaling plays a role in breast cancer cell migration and invasion, and fucoidan inhibits these events during EMT. Fucoidan affected subsequent signaling by decreasing phosphorylation of Smad2/3, expression of Smad4, and levels of TGFRI and TGFRII proteins. Fucoidan inhibited TGFR ubiquitination activity in MDA-MB-231 cells by boosting TGFR degradation and ubiquitination through proteasomes. This research is the initial to show that fucoidan inhibits the growth of breast cancer cells in lab settings and in living organisms by controlling EMT via adjustment of TGFR/Smad-dependent signaling [88]. VMW-FC inhibits colorectal cancer migration and proliferation in a dose and time-dependent manner. It increases apoptotic cells and leads to cell cycle arrest in sub-G1 phase, while also inhibiting xenograft tumor growth in mice without liver or kidney toxicity [109]. Fucoidan shows notable efficacy against prostate cancer cells that are resistant to docetaxel by decreasing NF-κB p50 and Cox2 levels in the signaling pathway that obstructs metastasis and by blocking IL-1R through its connection with P-selectin. Additionally, the simultaneous use of fucoidan and docetaxel had a synergistic impact on the survival of DU/DX50 cells, resulting in a strong anti-cancer effect. This mix shows potential to enhance treatment results and address existing restrictions in therapy [110]. The fucoidan/DOX micelle, which was functionalized with fucoidan, effectively targeted tumors and metastasis by binding to activated platelets, improving anti-tumor effectiveness, and decreasing TGF-β expression to counteract the immunosuppressive microenvironment in a 4T1 spontaneous metastasis model [111]. The administration of Olaparib to TNBC cells resulted in elevated sub-G1 cell mortality and G2/M cell cycle blockage, which were intensified by the presence of Oligo-Fucoidan. Increased amounts of Rad51, PD-L1, as well as EGFR and AMPK activation play a role in both drug resistance and the spread of TNBC. Nevertheless, the joint use of olaparib and Oligo-Fucoidan resulted in a synergistic decrease in Rad51 and PD-L1 levels, as well as a reduction in EGFR and AMPK activity. This mixture also successfully decreased TNBC cell toxicity and stemness, showing greater effectiveness than single treatment in decreasing CD44high/CD24low and EpCAMhigh cell subgroups, and in preventing TNBC stem cell mammosphere creation. Moreover, the combination of Oligo-Fucoidan and olaparib resulted in a reduction of glucose uptake, lactate production, and activity of the IL-6/p-EGFR/PD-L1 pathway related to carcinogenesis. Oligo-Fucoidan decreased olaparib’s adverse effects by lowering the activation of immunosuppressive M2 macrophages and boosting the generation of antitumoral M1 macrophages. The treatment both reduced the invasiveness of M2 macrophages and encouraged their transition to M0 (F4/80high) and M1 (CD80high and CD86high) phenotypes. When treated with olaparib and Oligo-Fucoidan, M0 macrophages were observed to shift towards becoming CD80(+) M1 cells instead of CD163(+) M2 cells. Significantly, giving olaparib with Oligo-Fucoidan through the mouth decreased M2 macrophages and regulatory T cells in tumors and boosted cytotoxic T cells in the lymphatic system, successfully averting TNBC recurrence and spread after surgery in mice [112]. Fucoidan limits gastric cancer cell growth and invasion by decreasing TGF-β1 release and affecting CLEC-2 [113]. Fucoidan extracted from Undaria pinnatifida sporophylls effectively hinders hypoxia’s impact on HIF-1α in Hca-F mouse hepatocarcinoma cells. It diminishes VEGF-C and HGF secretion, cell invasion, and lymphatic metastasis. Fucoidan also inhibits lymphatic vessel growth, reduces HIF-1α nuclear translocation and activity, and decreases levels of various proteins while increasing TIMP-1 levels in laboratory and living organism experiments [114].
EMT is a reversible cell-state program in which carcinoma cells loosen polarity and cell–cell adhesion and acquire motility, survival, and stem-like traits under cues such as TGF-β, Wnt, and Notch, orchestrated by SNAIL, SLUG, TWIST, and ZEB factors and non-coding RNAs. Rather than an all-or-none switch, EMT often yields hybrid epithelial/mesenchymal (E/M) phenotypes that heighten metastatic fitness, therapy resistance, and immune evasion, in tight reciprocity with the tumor microenvironment; these partial EMT states are now documented in patient tumors and circulating tumor cells. Fucoidan, a sulfated polysaccharide from brown seaweeds warrants systematic exploration as an EMT-modulating agent: (i) rigorous structure–function mapping (molecular weight and sulfation pattern) with standardized, GMP-grade preparations; (ii) mechanistic targeting of EMT drivers (promoting TGF-β receptor/Smad axis down-modulation and inhibiting PI3K/Akt, ERK/NF-κB), which preclinical work already implicates; (iii) testing against EMT plasticity and hybrid E/M states using single-cell and spatial readouts; (iv) delivery via fucoidan-decorated nanoplatforms to enhance tumor targeting and combine with chemotherapy, radiotherapy, TGF-β blockade, or immune checkpoint inhibitors; and (v) translational studies that include EMT biomarkers (E-cadherin, vimentin/N-cadherin), circulating hybrid E/M cells, PK/PD, and toxicity endpoints. Early studies and reviews support EMT suppression by fucoidan and point to nano-enabled immunotherapy combinations as especially promising directions.

Fucoidan and angiogenesis
Angiogenesis is the creation of fresh blood vessels. Tumors frequently display unchecked and fast angiogenesis to provide oxygen and nutrients to their quickly multiplying cells [115]. Anti-angiogenic medications offer a fresh approach to treating cancer. Nevertheless, there has been some dispute surrounding the involvement of fucoidan in angiogenesis. While certain research shows that fucoidan can stop the growth of new blood vessels in tumors, other studies propose that it may actually stimulate blood vessel formation. The proangiogenic effects seen were credited to fucoidan’s boost in VEFG expression, according to observers [116]. In contrast, researchers have attributed the anti-angiogenic effects to fucoidan’s capacity to decrease VEFG expression, which is a crucial element in angiogenesis [117]. In 2014, Ustyuzhanina et al. [118] discovered that the impact of fucoidan on angiogenesis is determined by its molecular weight. Fucoidan of greater weight hinders angiogenesis [119], while fucoidan of lesser weight promotes angiogenesis [116]. The rates of sulfation also influence the ability of fucoidan to expand blood vessel growth, as fucoidans with high sulfation show powerful anti-blood vessel growth impacts [120, 121]. In 2015, Chen and coworkers demonstrated that LMWFs inhibited hypoxia-induced HIF-1/VEGF signaling, leading to decreased angiogenesis [122]. These contradictory results emphasize the necessity for more studies to clarify the variables that impact fucoidan’s impact on angiogenesis. Koyanagi and colleagues discovered that fucoidan successfully blocked the activation of vascular endothelial growth factor (VEFG) receptors when VEFG binds to them [120, 123]. Injecting fucoidan at varying dosages in mice showed significant reduction in new blood vessel growth near Sarcoma 180 cells and inhibition of angiogenesis, tumor neovascularization, and tumor growth in mice implanted with VEFG-expressing tumors [124]. Xue and colleagues found that fucoidan significantly decreased VEGF expression within tumors of mice with 4T1 breast cancer cells compared to untreated controls [117]. These promising results indicate that fucoidan may have an important function as an antiangiogenic substance in treating cancer. However, further research is necessary to explore the impact of fucoidan on angiogenesis using different in vivo cancer models.

Fucoidan and PI3K/Akt axis
Many research studies have investigated the possibility of using natural compounds to prevent or treat cancer. Seaweed, eaten as a common food and used in ancient Eastern healing practices for centuries, serves as significant illustrations [125, 126]. Fucoidan from brown sea algae has anticancer, antibacterial, antioxidant, anti-inflammatory, and anticoagulant properties, inducing cell death in human bladder cancer cells. It also reduces levels of certain transcription factors and telomerase activity. Fucoidan, with an average molecular weight of 20,000, contains L-fucose, sulfate ester groups, oligosaccharides, and alginic acid. It obstructs the PI3K/Akt pathway, extending its anti-telomerase and apoptotic influences. Despite raising ROS rates, using N-acetylcysteine reversed fucoidan’s impacts, underscoring the importance of ROS in apoptosis, telomerase inhibition, and the PI3K/Akt pathway [127]. Fucoidan inhibits prostate cancer cell proliferation by impacting the PI3K/Akt pathway. Its increased concentration led to dose-dependent decrease in DU-145 cancer cell viability and chromatin condensation, indicating apoptosis. Fucoidan raised levels of pro-apoptotic markers and reduced anti-apoptotic markers like p-Akt, PI3K, P38, and ERK. In animal trials, fucoidan effectively decreased tumor size and induced apoptosis at certain doses. Furthermore, the impact on protein expression was shown through elevated levels of phosphorylated Akt and ERK [128]. Fucoidan had little effect on healthy ovarian epithelial cells, but it greatly hindered the growth of ovarian cancer (OC) cells. It caused cells to stop dividing at the G0/G1 stage, boosted cell death, and raised levels of proteins that promote cell death. The substance also inhibited the phosphorylation of PI3K and Akt, although IGF-1 could partially reverse these effects [129].
Clarifying fucoidan’s role in tumor angiogenesis and PI3K/Akt signaling will require tightly controlled, mechanism-first studies that standardize molecular weight distribution, sulfation pattern, and extraction chemistry while separating endothelial- versus tumor-intrinsic effects. Because reports alternate between pro- and anti-angiogenic outcomes (VEGF up- vs down-regulation; HIF-1/VEGF inhibition with some low-MW preparations; VEGF-receptor blockade in others), head-to-head factorial designs should systematically vary MW and sulfation and read out convergent endpoints, microvessel density, perfusion imaging, VEGF/VEGFR occupancy, and hypoxia markers across multiple in vivo models, not just single cell lines. In parallel, work on the PI3K/Akt axis should resolve contradictory signaling readouts (decreases in p-Akt/ERK in vitro yet transient increases reported elsewhere) by mapping time- and dose-dependent kinase dynamics, feedback loops, and pathway crosstalk with p38/ERK and IGF-1R, ideally using phospho-proteomics and live-cell reporters. Given ROS’s centrality (and reversal of effects by NAC), trials must pre-specify redox context (dietary antioxidants, tumor oxidative phenotype) and incorporate redox-responsive formulations; telomerase activity and hTERT expression can serve as adjunct pharmacodynamic markers. Drug-delivery science—nanocarriers, depots, or conjugates that enrich high-MW anti-angiogenic fractions or tuned sulfation motifs at the tumor—should be coupled to ADME/toxicity profiling that addresses anticoagulant liabilities and off-target binding. Therapeutically, the most compelling near-term tests are rational combinations: (i) fucoidan fractions with consistent anti-VEGF/VEGFR effects plus anti-VEGF agents or radiotherapy to attack hypoxic niches; (ii) PI3K/Akt-modulating fucoidan with PI3K/AKT/mTOR or IGF-1R inhibitors to deepen pathway suppression; and (iii) schedules that front-load anti-angiogenic, high-MW material to “normalize” vasculature before cytotoxic or immune therapies. Across all studies, a harmonized biomarker panel, VEGF/HIF-1α, p-Akt/p-ERK, telomerase, endothelial markers, and functional imaging should anchor adaptive dosing and patient selection, building a reproducible evidence base that reconciles heterogeneity in preparations with consistent clinical benefit.

Fucoidan and VEGF axis
The anti-angiogenic properties of Fucoidan have been proposed, but its specific mechanism and target are still not well understood. This research found that the sulfated fucoidan FP08S2, obtained from Sargassum fusiforme, inhibited tube formation, migration, and invasion in HMEC-1 cells. Experiments conducted both in vitro and in vivo demonstrated that FP08S2 efficiently blocked VEGF-induced angiogenesis, likely by disrupting the interaction between VEGF and VEGFR2. Furthermore, FP08S2 interfered with the VEGFR2/Erk/VEFG signaling pathway in HMEC-1 cells. This compound effectively halted the growth of blood vessels and the intake of A549 cancer cells in mice without immune systems [121]. Administering fucoidan has been proven to stop cachectic weight loss and decrease lung tumor masses in mice with tumor injection by hindering LLC spread and growth in lung tissues. This compound also controls the rates of vascular endothelial growth factor (VEGF), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and matrix metalloproteinases (MMPs) [130]. Fucoidan exhibits chemo-preventive properties in mice with tumors by reducing LLC cell viability, motility, invasion, and MMP activities. Combining fucoidan with sorafenib and Avastin shows promise in hepatocellular carcinoma models, suggesting a potential chemomodulatory role. Additional studies are needed [131].

Fucoidan and TGF-β axis
Fucoidan hinders cell growth, movement, and penetration in stomach cancer, while also lowering TGF-β1 secretion, showing potent anti-cancer advantages. The research discovered that it slows down the development of stomach cancer by enhancing the activation of CLEC-2, a type of receptor. Moreover, the pivotal role of CLEC-2 in the action mechanism of fucoidan is highlighted by the reversal of its inhibitory effects on gastric cancer cells and TGF-β1 production upon its reduction. These studies suggest that fucoidan could be a potential treatment for gastric cancer due to its ability to target key pathways related to cancer development and spread [113].
Future work should translate the VEGF- and TGF-β–axis signals of fucoidan into reproducible therapies by tightly standardizing source, molecular weight, and sulfation (FP08S2 from Sargassum fusiforme) and by proving target engagement with orthogonal assays that directly test VEGF–VEGFR2 binding blockade and downstream VEGFR2/ERK pathway shutdown alongside NF-κB and MMP readouts. In vivo studies ought to move beyond single xenografts to immunocompetent and patient-derived models, simultaneously tracking angiogenesis (microvessel density, perfusion imaging, phospho-ERK), metastasis burden, and cachexia endpoints (body weight, muscle mass) to confirm the reported reductions in VEGF, NF-κB, and MMP activity and the anti-wasting effects. Because CLEC-2 activation appears central to fucoidan’s suppression of TGF-β1 and gastric cancer invasiveness, mechanistic dissection should map CLEC-2 dependency with genetic/antagonist tools and resolve which tumor-microenvironment cells (platelet/immune compartments) mediate benefit, while coupling TGF-β signaling biomarkers (TGF-β1 levels, p-Smad2/3, EMT markers) to response. Rational combinations deserve priority: pairing well-characterized anti-VEGFR2 fractions with bevacizumab or sorafenib in HCC models, and TGF-β–modulating regimens with TGF-β inhibitors or cytotoxics, with schedules that front-load anti-angiogenic activity to “normalize” vasculature before therapy. Formulation and PK work, nanocarriers or conjugates that enrich the most active, safely sulfated fractions at tumor endothelium should proceed in parallel with safety profiling for anticoagulant liabilities, wound-healing interference, and additive bleeding risk with anti-VEGF agents. Finally, early clinical studies should use harmonized chemistry/manufacture controls, pre-specified biomarker panels (circulating VEGF/VEGFR2, NF-κB/MMP activity, TGF-β1, CLEC-2 signaling), and imaging of vascular function, to determine whether fucoidan is best positioned as a chemomodulatory adjuvant or as a primary anti-angiogenic in VEGF- or TGF-β–driven tumors.

Fucoidan-based materials in cancer therapy
A fucoidan-based drug delivery system was created to target P-selectin and minimize the side effects of Doxorubicin. Conjugation of Dox with fucoidan led to the development of fucoidan-doxorubicin nanoparticles (FU-Dox NPs) with controlled size distribution and sustained release profile. After testing on two cell lines—MDA-MB-231 that has high P-selectin levels and MDA-MB-468 that has low P-selectin levels—the FU-Dox NPs showed increased uptake by the cells and toxicity, thanks to their ability to specifically target P-selectin [132]. The development of fucoidan/chitosan nanoparticles (NPs) was described, which involved incorporating gemcitabine into the particles and coupling an ErbB-2 antibody onto their surface (NPs + Gem + Ab). The nanoparticles exhibited a zeta potential value of 21 mV, an average size of approximately 160 nm, and a polydispersity index of 0.18. The surface could only hold up to 10 μg mL⁻¹ of ErbB-2 immobilized. The NPs + Gem + Ab system’s ability to target SKBR3 cells (ErbB-2 positive) more effectively than MDA-MB-231 (ErbB-2 negative) indicates enhanced cellular uptake, in line with ErbB-2 overexpression in specific breast cancer subtypes. To confirm the effectiveness of NPs + Gem + Ab targeting, a co-culture system was set up using human endothelium and SKBR3 cells in vitro. The level of cytotoxicity in endothelial cells stayed consistent at 25% to 30% across all scenarios. The combination of NPs + Gem + Ab was found to be more than 80% toxic to breast cancer cells after 24 h, which was much higher compared to the 15% and 20% toxicity seen with free Gem and NPs + Gem, respectively. In experiments conducted in living organisms, it was found that the newly developed targeting system greatly decreased tumor growth and lung metastasis when compared to untreated controls [133]. Utilizing both fucoidan and lactoferrin for dual targeting, Quinacrine-loaded Undaria pinnatifida fucoidan nanoparticles substantially improved the effectiveness of quinacrine in treating pancreatic cancer by enhancing tumor cell specificity, decreasing tumor size, and boosting survival rates without causing liver damage [134]. Quercetin (QU), which is a polyphenolic compound known for its significant anti-cancer benefits, can be commonly found in various food and medicinal plants [135]. Because of its reduced toxicity and cost, QU shows potential as a viable substitute or addition to man-made anti-cancer medications in cancer therapy [136]. Nevertheless, QU is confronted with the issue of low solubility in water, just like other anticancer drugs, which makes its administration less effective [137]. Different delivery methods have been used to tackle this problem, including integrating QU into carbon-based nanoparticles, polymer micelles, or liposomes [137]. The insufficient therapeutic effectiveness of these nanomedicines is frequently linked to the absence of biological function in the artificial substances, which mainly serve as transporters. The development of QU@FU-TS, which contains QU nanoparticles with anticancer effects, shows promise in cancer chemo-immunotherapy. This nanoparticle was created by self-assembling molecules, using tea saponin (TS) as the eco-friendly linking agent. MD simulations validated QU binding to TS’s hydrophobic tail, with TS’s hydrophilic head interacting with FU to create QU@FU-TS’s outer layer. The main chemical interactions involved hydrogen bonds and π-stacking between QU and TS, while several hydrogen bonds stabilized the connection between the sulfate ester group of FU and the hydroxy group of TS. QU@FU-TS showed higher effectiveness in blocking A549 cell growth than free QU. The anticancer effects included various mechanisms such as triggering oxidative stress, halting cell cycle advancement, and enhancing cell death through apoptosis. In studies conducted inside living organisms, it was also found that QU@FU-TS successfully inhibited the movement and growth of cancer cells (Fig. 4) [138]. In order to develop a more effective treatment for colorectal cancer, researchers coated anticancer polysaccharide Fucoidan with polymeric nanoparticles made from mPEG-PLA-NPs and encapsulated the chemotherapy drug Epirubicin. Analysis of these nanoparticles showed they were stable, round, uniformly dispersed, and had outstanding biocompatibility, controlled release capabilities, and a negative zeta potential. Studies conducted on living BALB/C mice injected with C26 murine cancer cells supported the positive results seen in vitro on the HCT116 cell line in terms of anticancer effectiveness. MTT tests showed that the IC50 values were 3.72 µM for unbound Epi, 33.67 µM for Epi formulations without coating, and 10.19 µM for Epi formulations with coating. Treating mice with tumors using the new NP formulation resulted in increased tumor shrinkage, improved survival rates, and decreased off-target heart toxicity. Tumor size reductions were 37.33% and 61.49% with free FC and Epi, compared to 79.57% with uncoated Epi NPs and 90.34% with coated Epi NPs [139].
Skin cancer is the most common form of cancer. Finding effective chemopreventive agents is a key strategy to prevent their development, often caused by environmental carcinogens like UV rays or chemicals [140, 141]. In chemical skin cancer studies, DMBA is commonly used as a trigger, while further research has linked TPA to tumor promotion [142, 143]. DMBA induces the production of ROS and abnormal activation of the NF-κB signaling pathway and TGF-β, resulting in increased EMT, angiogenesis, and carcinogenesis [144–147]. While studies have demonstrated that anthocyanins have cancer-preventing properties [148–150], their bioavailability is less than 0.1% because they are quickly eliminated from the body and can easily oxidize in water [149, 151]. Their limited absorption and lack of chemical stability pose substantial obstacles to their successful utilization. The combination of fucoidan, an anionic polymer, with anthocyanins resulted in the development of the anthocyanin-fucoidan nanocomplex (AFNC), which improves absorption and chemical stability by utilizing ionic bonding and π–π stacking. Studies conducted in a laboratory setting showed that AFNC had better cell permeability and plasma chemical stability than unbound anthocyanins. Furthermore, it was discovered that AFNC can also block the generation of inflammatory cytokines and the signaling pathway responsible for epithelial-mesenchymal transition (EMT), such as the IκBα/NF-κB pathway. In rats, the bioavailability of AFNC was 3.24 times greater than that of free anthocyanin in the body. In the established DMBA/TPA cancer model, AFNC significantly decreased carcinogenesis (Fig. 5) [152].
The potential of Fucoidan (FCD), a polysaccharide with immunomodulatory properties, in formulating nanoparticles (NPs) with doxorubicin (DOX) for anti-cancer purposes was investigated. A new method for delivering DOX was created by mixing FCD with polyethylenimine (PEI) using electrostatic forces. These NPs based on FCD resulted in noticeably stronger cytotoxic effects, heightened disruption of the cell cycle, and increased apoptosis in tumor cells compared to free DOX. Increased levels of mitochondrial depolarization were recognized as a crucial element fueling this heightened cellular demise. In experiments with tumor-bearing BALB/c mice, the nanoparticles showed almost triple the effectiveness compared to the control treatment. Significantly, this method triggered an immune reaction marked by a steady rise in IL-12 levels in the bloodstream and a transformation of tumor-associated macrophages (TAMs) into an M1-like state. Pharmacokinetic analysis in these models also showed a biphasic pattern in blood DOX levels, with two peaks supporting the concentration of the drug in tumor tissues [153]. Furthermore, chitosan and fucoidan can be utilized to create nanoparticles for the administration of gemcitabine in breast cancer therapy [154]. In a combined biological-thermo-chemo therapy approach, a versatile platform containing fucoidan, doxorubicin, and platinum nanoparticles demonstrated significant efficacy against drug-resistant breast cancer cells. This platform has also enhanced therapeutic outcomes and enabled imaging functionalities [155]. Researchers created novel PLGA nanoparticles (Fn/Tn-PLGA NPs) containing a combination of fucoidan and trabectedin to investigate new treatment approaches for non-small cell lung cancer (NSCLC). The research evaluated levels of protein and messenger RNA expression, utilizing targeted inhibitors and short disruptive RNA transfection for modulating protein activity. The nanoparticles were examined for their cytotoxicity in NSCLC cells, showing they could decrease cell viability, enhance ROS generation, and inhibit cell growth. Research also looked into the fundamental mechanisms of cell death and how they affect cell movement, highlighting the considerable promise of Fn/Tn-PLGA NPs in targeting lung cancer cells [156]. Therefore, materials containing fucoidan have been widely used in the treatment of cancers, primarily through therapeutics delivery [157–162].
Fucoidan-based nanomedicines should move from promising prototypes to clinically robust platforms by standardizing fucoidan’s source, molecular weight, and sulfation while exploiting its intrinsic bioactivity for multi-pronged targeting and therapy: P-selectin–directed FU–Dox systems, ErbB-2–addressed fucoidan/chitosan–gemcitabine constructs, and dual-ligand (e.g., lactoferrin + fucoidan) carriers already show selective uptake and antitumor efficacy, and next iterations can layer “AND-gate” targeting to further restrict off-tumor exposure. Carrier design ought to prioritize fully bioactive assemblies (as with QU@FU-TS and AFNC) that solve solubility and stability bottlenecks for phytochemicals while adding immunomodulation, rather than inert shells that merely transport payloads. Mechanistically, programs should pre-specify biomarkers of target engagement and response, P-selectin occupancy, ErbB-2 binding, mitochondrial depolarization, ROS flux, NF-κB/TGF-β suppression, MMP activity, and macrophage repolarization (M1 shift, IL-12 rise) and pair them with imaging-capable “theranostic” formulations to track tumor delivery, release, and perfusion in real time, capitalizing on the biphasic pharmacokinetics seen with some FCD–DOX nanoparticles to tune dose and schedule. Given encouraging in vivo signals for tumor control, antimetastatic activity, cardioprotection versus free anthracyclines, and skin-cancer chemoprevention, head-to-head studies in orthotopic and immunocompetent models should compare single- versus multi-payload constructs (FU + doxorubicin + platinum, FU + trabectedin) and rational combinations with approved agents (such as sorafenib or bevacizumab in appropriate settings), with endpoints spanning tumor burden, metastasis, cachexia, and immune tone. Safety pharmacology must run in parallel, profiling anticoagulant liabilities, infusion reactions, hepatic and cardiac effects, and potential interference with wound healing, while CMC work delivers GMP-grade, scalable, endotoxin-free fucoidan and tightly controlled nanoparticle size, PDI, and zeta potential. Finally, early clinical studies should be biomarker-stratified (P-selectin-high, ErbB-2–positive, lactoferrin-receptor-rich tumors), incorporate adaptive designs anchored by the above pharmacodynamic readouts, and test whether fucoidan’s role is best as a smart, bioactive matrix for chemo-immunotherapy co-delivery or as a targeted adjuvant that enhances efficacy and reduces toxicity across solid-tumor indications.

Fucoidan hydrogels in cancer therapy
Hydrogels have recently gained considerable interest because of their remarkable ability to retain water, maintain structural strength, and allow for the passage of substances, all of which aid in enhancing tissue regeneration [163, 164]. In order to overcome the physicochemical constraints of fucoidan-based hydrogels, crosslinking was carried out with hydroxyapatite (HAP) and chitosan gum (CG) [165, 166]. Consisting of fucoidan, alginate, and gellan gum, these hydrogels are made from natural heteropolysaccharides with low toxicity and high biocompatibility [167, 168]. One of the main benefits of these hydrogels is their exceptional biostability, allowing them to retain moisture in injured tissues. Research conducted in the past has evaluated how effective hydrogel nanomaterials based on fucoidan are [169, 170]. All of these substances display beneficial qualities for tissue engineering, such as good physicochemical properties, degradability, lack of toxicity, compatibility with living tissue, and stability [171, 172]. In order to mitigate possible dangers in tissue engineering uses, a novel nanomaterial made from fucoidan and loaded with HAP/CG has been created, showing distinctive characteristics [173]. The characteristics of a hydrogel composite containing nanohydroxyapatite and fucoidan were examined to assess its potential for delivering drugs to cancer cells in the gastrointestinal tract. The tiny nanomaterial was created and identified as small, round nanosheets with outstanding heat resistance. Evaluations of cytotoxicity in vitro, as well as examinations of cell proliferation and migration, showed that the fusion of fucoidan with nanohydroxyapatite and collagen in the nanomaterial is safe, and it enhances cell growth and mobility. Furthermore, experiments conducted in a laboratory setting showed that the modified nanomaterial can prevent ROS and produce singlet oxygen radicals in gastrointestinal cancer cells [174]. Nanoparticles act as obstacles in the body to control how medications are distributed [175]. Nanomaterials’ targeting ability improves with the addition of specific ligands, enabling precise tissue targeting via suitable substituents or groups [176]. Many specific drug delivery uses with hydrogels have been recorded in the field of treating cancer [169, 177, 178]. Recent research has shown that specific monoclonal antibodies have the potential to block the EGFR signaling pathway, allowing for precise drug delivery [179–181]. Utilizing monoclonal antibodies and linked nanomaterials can leverage cell surface biomarkers for accurate targeting of particular cells [182]. Current cancer treatments using nanoparticles mainly target the increased activity of EGFR. Past studies have indicated that hydrogels containing fucoidan and different mixtures of alginates, polyethylene glycol, and gellan gum exhibit strong effectiveness in promoting healing when paired with low-level laser therapy [183] and PDT [169]. Extensive research in the literature has investigated the therapeutic uses of PDT in cancer treatment [184–187]. Hydrogels containing fucoidan and alginate, attached to the epidermal growth factor receptor (EGFR), were created for specific delivery via the EGFR pathway to possibly treat colon cancer. The goal is to develop a hydrogel drug delivery system containing chlorin e6 and EGFR for targeting cancer cells with minimal side effects and toxicity, using PDT. Characterization and in vitro experiments were carried out to assess the effectiveness of the EGFR-hydrogel in colon cancer cells, with protein levels analyzed using Western blotting. The experiments conducted in a controlled environment showed that the hydrogel greatly boosted cell proliferation, movement, and survival in colon cancer. Elevated protein expression levels triggered the EFGR/AKT pathway, resulting in various biological effects in colon cancer cells, including heightened cell proliferation, inhibition of apoptosis, progression of the cell cycle, enhanced cell survival, and increased cell migration. These results indicate that the hydrogel has potential as a focused method for PDT in treating colon cancer (Fig. 6) [188]. The study concentrated on a photodynamic hydrogel for wound healing that includes carboxymethyl cellulose nanofibrils containing fucoidan and alginate. The versatile hydrogel was examined and tested for its healing properties using both laboratory and animal testing techniques. Skin samples were analyzed histologically and immunohistochemically to evaluate the amount of collagen and the presence of fibroblasts. Protein levels were identified through the process of Western blot analysis. The hydrogel greatly increased cell death and survival when exposed to laser light, due to its harmless characteristics and specific groups in a spherical nanostructure. Through the production of singlet oxygen and increased ROS, the hydrogel efficiently attacks and destroys cancer cells. Enhanced production of fibroblast and collagen fiber proteins was associated with quicker healing of wounds [170].
Tumor vaccines designed for therapeutic purposes are receiving considerable recognition in the realm of tumor immunotherapy. These vaccines use tumor antigens to stimulate antigen-presenting cells (APCs), resulting in a series of antigen-specific reactions that aid in the destruction of tumor tissues [189]. Hence, fucoidan has the potential to be used in creating hydrogels for biomedical purposes [190, 191]. Notably, hydrogels have been of importance in the treatment of cancer and drug delivery in the recent years [192, 193] and future studies should specifically focus on the application and development of fucoidan-based hydrogels in drug and gene delivery along with phototherapy-mediated tumor ablation.
Future work on fucoidan hydrogels should turn their versatile chemistry and bioactivity into rigorously controllable, translatable platforms by standardizing fucoidan source/MW/sulfation and optimizing crosslinkers (HAP, chitosan gum, alginate, gellan) to tune injectability, stiffness, degradation, and drug-release kinetics for specific anatomical sites (GI tract, skin, tumor beds). Priority designs include injectable, stimuli-responsive depots that co-deliver cytotoxics (doxorubicin, gemcitabine, epirubicin), photosensitizers (chlorin e6), and immune modulators (chloroquine) while leveraging fucoidan’s intrinsic targeting and immunoregulatory features to generate ROS/singlet-oxygen on demand, repolarize TAMs, and support in situ vaccination; these should be paired with real-time theranostics for depot localization and light-dose mapping. Because EGFR-conjugated systems can inadvertently activate EGFR/AKT and promote proliferation, next-gen constructs must use antagonistic or non-agonizing ligands, avidity-tuned multivalency, and kill-switch architectures (pH/enzymatic linkers that disable targeting outside tumors) with pre-specified safety gates against pro-growth signaling. Mechanistic endpoints should be harmonized, matrix mechanics, release half-lives, singlet-oxygen yield, mitochondrial depolarization, autophagy/ICD markers (LC3B, p62, CRT, HMGB1), macrophage polarization (M1/M2), and epithelial/mesenchymal programs—tested across immunocompetent and orthotopic models and ex vivo human tumor slices. Translational packages must address anticoagulant liabilities, wound-healing interactions, and long-term metabolite safety; incorporate mucus penetration and microbiota stability for GI applications; and deliver GMP-grade, endotoxin-controlled materials with tight control of size/PDI/zeta potential. Finally, early clinical studies should deploy adaptive designs with imaging-anchored PDT parameters, depot pharmacokinetics, and immune readouts, to determine whether fucoidan hydrogels function best as local adjuvants for surgery/radiation, as chemo-photo-immunotherapy depots for unresectable disease, or as chemopreventive dressings in high-risk cutaneous settings.

Clinical importance
Fucoidan’s versatility is showcased by its impact on various biological processes and receptor types [194]. Nevertheless, defining a universal mechanism of action remains difficult because of the limited knowledge on the pathways and receptors it affects. The new finding that fucoidan interacts with PTEN has offered fresh perspectives on its impact on cells, possibly leading to further research on this connection. Up to now, there has been no study that specifically investigated the relationship between fucoidan and PTEN, indicating that further research could help clarify the role of PTEN. However, the influence of fucoidan extends beyond just interacting with PTEN, as it affects various pathways and proteins. Even though fucoidan is increasingly acknowledged, the specific ways in which it influences cellular activities remain unclear. Some research indicates that fucoidan has the ability to either stimulate or inhibit the MAPK and PI3K/AKT pathways, depending on the study. Despite these differences, the end outcome has consistently been either apoptosis or a reduction in cell growth, suggesting a more intricate mechanism than previously believed. Fucoidan’s capacity to engage with growth-related receptors is remarkable in cancer treatment, as these receptors are frequently in excess in cancer cells. Developing a thorough map of these receptor interactions could provide more profound understanding of fucoidan’s function. However, its impact on cellular behavior has not been thoroughly investigated. The biological function of fucoidan is closely tied to its structural features, with its function highly dependent on its specific structure. Pinpointing the exact active elements of fucoidan poses a major hurdle, as these elements will determine the optimal formulation of fucoidan for future medical uses. Understanding the structure of fucoidan could lead to enhancing its effectiveness as a treatment option. Nevertheless, the structural diversity of fucoidan makes it challenging to interpret data among various studies or cell lines, hindering the consistency of findings.

Conclusion
The increasing challenges associated with conventional cancer therapies, such as drug resistance, adverse side effects, and the complexity of tumor microenvironments, have driven the need for innovative therapeutic strategies. The exploration of carbohydrate polymers, particularly fucoidan, presents a promising avenue in the pursuit of effective cancer treatment solutions. Fucoidan, a naturally occurring sulfated polysaccharide derived from brown seaweeds, exhibits a diverse array of biological properties that make it an attractive candidate for oncological applications. The review elucidates the multifaceted roles of fucoidan in cancer therapy, emphasizing its capacity to inhibit tumor growth, induce apoptosis, and modulate the tumor microenvironment. These properties are crucial in addressing the limitations of traditional treatments, offering new mechanisms of action that can complement existing therapeutic modalities. The ability of fucoidan to interact with various cellular pathways not only enhances its anticancer potential but also positions it as a vital component in the development of combination therapies. In addition to its direct anticancer effects, fucoidan’s unique chemical structure facilitates the formulation of advanced drug delivery systems, particularly nanoparticles and hydrogels. The integration of fucoidan into nanocarriers represents a significant advancement in targeting and releasing therapeutic agents. The ability to modify the surface characteristics of these carriers enhances their biocompatibility and stability while allowing for precise targeting of tumor sites. This targeted approach minimizes off-target effects, thereby reducing systemic toxicity and enhancing the therapeutic index of chemotherapeutic agents. Moreover, the adaptability of fucoidan-based nanoparticles and hydrogels allows for the incorporation of various therapeutic modalities, including small molecule drugs, RNA interference, and immunotherapeutics. This versatility is instrumental in creating multifunctional systems capable of simultaneous drug delivery and localized treatment, paving the way for improved patient outcomes. The synergistic effects of fucoidan combined with other therapeutic agents not only bolster the efficacy of cancer treatments but also address the challenges of treatment resistance. The future of cancer therapy will likely involve personalized medicine, where treatment regimens are tailored to the individual characteristics of each patient’s tumor. Fucoidan’s ability to enhance drug efficacy while reducing side effects makes it an ideal candidate for incorporation into personalized therapeutic strategies. Further research into the mechanisms underlying fucoidan’s action will provide critical insights into its potential applications and allow for the optimization of formulations to meet specific clinical needs. Despite the promising results observed in preclinical studies, translating fucoidan-based therapies into clinical practice presents several challenges. The variability in the source and structure of fucoidan may affect its pharmacokinetics and pharmacodynamics, necessitating standardized methods for extraction and characterization. Additionally, comprehensive clinical trials are required to establish the safety and efficacy of fucoidan in human subjects. Regulatory considerations will also play a pivotal role in determining the pathways for clinical application. The integration of fucoidan in cancer therapy represents a significant advancement in the field of oncology. Its diverse biological activities and compatibility with nanotechnology open new avenues for developing innovative treatment strategies that improve patient outcomes. As research progresses, the potential of fucoidan to transform cancer treatment paradigms will become increasingly evident. Collaborative efforts between researchers, clinicians, and industry stakeholders will be essential to translate these findings into clinical applications that enhance the quality of life for cancer patients. Ultimately, fucoidan’s unique properties herald a new era in cancer therapy, characterized by improved efficacy, reduced side effects, and a greater focus on patient-centered treatment approaches.
Fucoidan, the sulfated, fucose-rich polysaccharide from brown algae offers a favorable biodegradability profile for biomedical use: its glycosidic backbone can undergo hydrolytic scission and, more efficiently, enzymatic depolymerization by fucoidanases from microbial flora or incorporated enzymes, while in vivo it is cleared primarily through hepatic/splenic uptake with subsequent fragmentation and renal excretion once chains are sufficiently short; degradation and clearance can be tuned by molecular weight, sulfate content, and crosslinking density in hydrogels or polyelectrolyte complexes (with chitosan), enabling predictable scaffold remodeling and drug-release kinetics. “Recyclability” is less relevant post-implantation but matters in manufacturing and device prototyping: fucoidan’s water solubility and reversible ionic/covalent crosslinking allow dissolution, purification, and re-processing into films, fibers, and gels; spent formulations can often be recovered by salt exchange or pH shift, and off-spec batches can be depolymerized into bioactive oligosaccharides for reuse in delivery systems though any recycling loop must re-qualify bioburden, endotoxin, heavy metals, and MW distribution. Toxicologically, fucoidan is generally well tolerated and non-cytotoxic across common cell lines, with low hemolysis and good hemocompatibility when properly purified, but risks center on (i) hemostasis: heparin-like anticoagulant/antithrombotic activity that can potentiate bleeding at higher sulfate densities or doses; (ii) immunomodulation: desired anti-inflammatory or adjuvant effects can tip into complement activation–related reactions in sensitive contexts, especially with nanoparticles; (iii) impurities: seaweed-derived materials may carry protein, polyphenol, or metal contaminants (e.g., arsenic, cadmium, lead) unless GMP-grade purification and tight specifications (endotoxin, ash, metals, residual solvents, sulfate %, polydispersity) are enforced; and (iv) pharmacokinetics: high-MW fractions show limited oral bioavailability and RES accumulation after parenteral dosing, whereas low-MW, narrowly distributed fractions reduce accumulation risk but may alter bioactivity. Overall, with rigorous source control, fractionation, and material characterization, fucoidan’s degradability and reprocessability can be leveraged to create tunable, resorbable biomedical matrices and delivery vehicles while keeping anticoagulant effects, immune interactions, and impurity load within clinically acceptable limits.
Biofabrication of fucoidan for biomedical use spans simple solution processing to advanced additive manufacturing: it can be cast or spin-coated into thin films; freeze-cast/lyophilized or cryogelated into highly porous scaffolds; and electrospun (typically blended with PCL, PLA, gelatin, or collagen) into nanofibrous mats for wound care or tissue interfaces. Hydrogel formation is achieved mainly by polyelectrolyte complexation with cationic partners (chitosan, poly-L-lysine, gelatin) or by covalent chemistries such as EDC/NHS coupling to amines, Schiff-base formation with oxidized polysaccharides, genipin crosslinking after amination, and “clickable” photo-crosslinking when fucoidan is methacrylated (FucMA); multivalent cations can aid network formation, and ionotropic crosslinking is robust when fucoidan is blended with alginate. For drug/gene delivery, fucoidan readily forms PEC nanoparticles, core–shell capsules, and microgels via electrospraying, coacervation, or microfluidic droplet gelation (ionic, enzymatic, or light-triggered), enabling high payload retention of growth factors, peptides, or siRNA. 3D bioprinting uses fucoidan-containing bioinks (often with alginate, GelMA, κ-carrageenan, hyaluronan, or PVA) whose rheology is tuned with glycerol, methylcellulose, or nanoclay and crosslinked post-print by Ca²⁺ (alginate blends), visible/UV light (GelMA/FucMA with LAP/Irgacure), or enzymatically (tyramine-modified systems with HRP/H₂O₂). On devices and implants, fucoidan is deposited as bioactive, hemocompatible coatings by spray-coating or layer-by-layer assembly with polycations to control anticoagulant and anti-inflammatory cues, and surfaces can be further functionalized (via carbodiimide or thiol-ene) to tether peptides or affinity-capture growth factors. Additional formats include aerogels, printable pastes, and composite foams reinforced with nanocellulose or bioactive glass for bone/cartilage, with sterilization handled by aseptic filtration, ethanol, or gamma/EO as material tolerance allows. Collectively, these techniques leverage fucoidan’s sulfated, polyanionic nature to build tunable scaffolds, coatings, and carriers with controllable mechanics, degradation, and bioactivity.