Furthermore, fucoidan from different species is proven effective against different bacterial strains; for instance, fucoidan extracted from
Sargassum polycystum demonstrated significant inhibition of the in vitro bacterial growth of
E. coli,
S. aureus, and
S. mutans, with the highest inhibitory effect observed with
Pseudomonas aeruginosa (21 ± 1.0 mm at the concentration of 50 μg/mL). The in vivo tests performed on
P. aeruginosa-infected zebrafish treated with 15 mg/0.1 kg fucoidan pre- and post-exposure to the pathogen revealed that the fucoidan-pretreated fish showed lower mortality (10%) than fucoidan-post-treated fish (16.6%), while the control group showed total mortality within 20 days
[29][48].
Antifungal activity of fucoidan extracted from
Undaria pinnatifida was investigated by testing fucoidan against three fungal species, namely
Aspergillus flavus,
Aspergillus fumigatus, and
Mucor species, and showed a larger diameter of inhibition zone for
A. fumigatus (11.83 ± 1.0 mm) followed by
A. flavus (8.5 ± 0.87 mm), with
mucor species showing the least response, indicating its resistance to fucoidan treatment
[30][49].
Interestingly, fucoidan as a marine polysaccharide possesses a prebiotic activity on gut microbiota as it can enhance the growth of beneficial gut flora and modulate gut dysbiosis resulting from the transformation of beneficial bacteria into harmful pathogens. Furthermore, fucoidan was reported to modulate cellular immunity, support the intestinal epithelial barrier, and reduce the expression of inflammatory mediators such as TNF-α and IL-6, and it can also directly promote the growth of the beneficial
Lactobacillus species
[31][50].
3.1. Oral Fucoidan Formulations
Although fucoidan has high solubility in water, it has poor gastric solubility and limited absorption from the stomach and upper gastrointestinal tract. In addition, it experiences degradation by normal flora in the lower gastrointestinal tract, producing oligosaccharides and short-chain fatty acids which are rapidly eliminated from the bloodstream by reticuloendothelial clearance. Taking advantage of the poor solubility and low gastric absorption of orally administered fucoidan from the stomach, it can be used as a gastro-protective dietary supplement. Fucoidan can be used orally as a physical barrier and as an anti-inflammatory and oxidative stress suppressor for managing gastric ulcers. In addition to the gastro-protective effect, fucoidan is useful for maintaining the chemical stability of acid-labile drugs in the stomach. In addition, fucoidan can control the release of active pharmaceutical ingredients via pH-sensitive behavior, allowing the release of the drug only in the slightly basic medium of lower GIT
[32][33][34][27,53,54].
The formulation of fucoidan powder in oral tablet dosage form has some challenges based on fucoidan’s physicochemical properties
[24][38]. For example, fucoidan powder is hygroscopic with low flowability due to its irregular particle surfaces and wide size distribution ranging from 10 to 500 μm. The other formulation challenge is the long disintegration time associated with tablets with high dry powder extract content. Therefore, researchers used some tablet excipients such as sodium croscarmellose, crospovidone, lactose monohydrate, and microcrystalline cellulose to improve the disintegration and flowability, engaging the wet granulation technique
[35][55].
3.2. Inhalable Fucoidan Formulations
The pulmonary route of administration has gained much attention as a non-invasive administration route for deep local alveolar delivery of different drugs. Pulmonary drug delivery can also be used for systemic absorption due to the high alveolar absorptive surface area (∼100 m²). This route of administration is characterized by the presence of a thin absorptive layer, rich blood supply, and minimal degradation enzyme activity. Furthermore, pulmonary drug delivery offers the advantages of bypassing proteolytic gastrointestinal degradation and hepatic first-pass metabolism. Therefore, the pulmonary route is more suitable for the systemic delivery of proteins and/or peptides
[36][65].
Natural polysaccharides can act as a carrier for micro/nano aerodynamic particles and aerogels intended for pulmonary delivery
[37][66]. The sulfated fucose polysaccharides can be easily docked in the surface receptors of alveolar macrophages, which host mycobacterium tuberculosis (TB). Researchers investigated the use of spray-dried fucoidan microparticles using fucoidan from
Laminaria japonica as an inhalable formulation containing both isoniazid (INH) and rifabutin (RFB)
[38][60]. This dosage form containing combined therapy for TB improved the patient compliance with treatment due to targeted drug delivery
[38][60]. The aerodynamic properties of this formula were evaluated, and the erratic surface morphology of the microparticles showed favorable flowability and dispersibility, indicated by low tapped density. The aerodynamic diameter of these microparticles was around 2–4 µm, producing favorable deposition into alveoli
[39][59].
3.3. Topical Fucoidan Formulations
The topical drug delivery systems include ointments, creams
[40][69], nanogels and hydrogels
[41][70], wound dressings
[42][71], thin films
[43][72], and smart stimuli-responsive systems
[44][73]. There is a growing tendency by the Food and Drug Administration (FDA) to reformulate different drugs such as anti-inflammatories, analgesics, wound healing enhancers, etc., to be in topical dosage forms. The reason for this is to improve these drugs’ efficacy at the site of action while reducing their possible side effects. The incorporation of active pharmaceutical ingredients (APIs) into a carrier for the topical application provides substantial merits, for instance, enhanced transdermal permeation, protection against first-pass metabolism, ease and convenience of administration, non-invasive drug delivery, and localization of therapeutic effects at the target site of action
[40][41][69,70].
Fucoidan, as a fucose-rich polysaccharide, is known to exert anti-inflammatory, immune-modulatory, and heparin-like anticoagulant action. Furthermore, it has been proven to mediate fast skin regeneration and re-epithelialization by enhancing the migration and build-up of fibroblasts. Fucoidan is used for inhibiting enzymes responsible for the hydrolysis of dermal elastic fibers (elastase, tyrosinase, and collagenase) and the suppression of IgE associated with allergic and inflammatory reactions
[42][43][71,72]. As a result of the relatively high molecular weight, negatively charged sulfate groups, and hydrophilicity, fucoidans generally have a low skin permeation coefficient. It was also found that the anti-inflammatory effect of fucoidan, especially that based on the inhibition of protein denaturation, is dependent on the fucose and sulfate content of the extract obtained from five different brown seaweed species, which are
Saccharina japonica, F. vesiculosus, Fucus distichus, Fucus serratus, and
Ascophyllum nodosum [45][74].
The pharmacokinetic behavior of fucoidan ointment after topical application was studied using carrageenan-induced paw inflammation in a rat model compared to intravenous administration
[44][73]. The tested formulation contained fucoidan, transcutol as a penetration enhancer, and polyethylene glycol (PEG 400) as a surfactant. The plasma levels of topical fucoidan (100 mg/kg) exhibited a longer half-life of 20.75 ± 9.43 h compared to 9.47 ± 2.34 h after IV administration. This prolonged half-life is attributed to the quick drug penetration and retention of the formula in the form of skin and striated muscle reservoirs
[44][73].
The effect of topical application of fucoidan extracted from two different sources (
Undaria pinnatifida extract, containing 85% fucoidan, and a
F. vesiculosus co-extract, containing 60% fucoidan and 30% polyphenol) on the skin was evaluated
[46][75]. Both extracts showed inhibition of enzymes responsible for the hydrolysis of dermal elastic fibers (elastase, tyrosinase, and collagenase). In addition, both extracts increased the expression of the human Sirtuin 1SIRT1 protein, counteracting the effect of UV radiation and oxidative stress. Furthermore, both extracts activated Toll-like receptors 2 and 3 with the expression of antimicrobial peptides and wound healing signals by 387% and 229%, respectively
[46][75].
3.3.1. Fucoidan Creams
Obluchinskaya et al. prepared a fucoidan-based cream with anti-inflammatory action
[47][79]. Formulations contained fucoidan (from
F. vesiculosus with M.W of 735 kDa), olive oil, hydrogenated castor oil, and a surfactant such as poloxamer 407, geleol, gelucire, lanolin, or cremophor
®. The highest fucoidan release in vitro was observed with the formulation containing poloxamer 407 as a surfactant. Moreover, poloxamer 407 increased the colloidal stability and enhanced the rheological properties of the formulation. In the same context, the effect of several penetration enhancers, such as dimethyl sulfoxide DMSO, transcutol P, and polysorbate 80, on fucoidan release was assessed. The use of transcutol P increased the diffusion of fucoidan into the agar plate with superior spreadability of the formulation containing transcutol P over polysorbate 80. On the contrary, the formulation containing DMSO showed the slowest release and the poorest spreadability
[47][79].
3.3.2. Fucoidan Wound Dressing Films
Wound dressing films are a simple, low-cost, and non-invasive choice for the management of wounds and promotion of healing. These films should include some major features such as flexibility, mechanical strength, and a physical barrier. These topical films show the ability to absorb wound exudates and evaporate moisture content. Furthermore, wound dressing films can act as a drug delivery system for antibacterial and tissue regeneration promoter genes
[48][49][50][80,81,82].
3.3.3. Fucoidan Topical Hydrogels
Hydrogels are materials that have the ability to absorb water and swell upon embedding in an aqueous environment. Pharmaceutical hydrogels are composed of physically or chemically cross-linked water-insoluble polymers with hydrophilic functional groups and incorporated high water content of 90%
w/w. Hydrogels provide a variety of physically and biologically interesting characteristics that simulate the physiology of natural tissues. These hydrogels are characterized by softness, flexibility, and a high surface area, along with swelling behavior and high loading capacity of drugs
[3][51][3,84].
Fucoidan is a hydrophilic polysaccharide having some interesting physical characteristics needed for dermal burns and wound treatment. These characteristics are high exudate absorption capacity (high swelling index), mucoadhesion, adequate hygroscopicity, and oxygen permeability. In addition, its pharmacological activity includes heparin-like anti-coagulant, anti-thrombotic, and anti-inflammatory effects
[52][85].
3.4. Injectable Fucoidan Formulations
Injectable hydrogels should have the ability to undergo a phase transition in response to temperature changes, particularly from ambient temperature to physiological temperature. These systems permit in situ hydrogel injection in a convenient minimally invasive solution form with subsequent solidification inside the body. Hydrogel formation occurs immediately after temperature change without the need for chemical initiators
[20][31]. As previously mentioned, fucoidan cannot form an injectable thermo-responsive gel matrix unless mixed with another thermo-responsive polymer, i.e., chitosan, hyaluronic acid (HA), gelatin, xyloglucan, etc.
[53][89].
3.5. Advanced Fucoidan Formulations
Advanced fucoidan formulations include liposomes, nanoparticles, fucospheres, and scaffolds, as illustrated in
Figure 34.
Figure 34.
Advanced fucoidan formulation approaches.
3.5.1. Liposomes
Liposomes have several beneficial properties, especially in cancer treatment, when compared to other nanosystems. These properties include improving drug solubility, stability, and delivery to specific target sites
[54][92].
Fucoidan extracted from
F. vesiculosus was encapsulated into a nano-sized liposomal carrier composed of lecithin (phosphatidylcholine) and tested for anticancer and immunomodulatory effects. The results of this study showed increased anticancer activity as well as a reduction in the levels of interleukin-6 and tumor necrosis factor-α compared to fucoidan nanoparticles
[55][93].
3.5.2. Nanoparticles
Nanotechnology-based drug carriers are highly prominent in the area of targeted drug delivery for the treatment of various diseases
[56][57][58][59][96,97,98,99]. Targeted delivery of chemotherapeutics is greatly beneficial because these drugs suffer from low aqueous solubility, rapid clearance, and high toxicity. All these delivery limitations can be overcome by the use of biocompatible and biodegradable polymeric nanocarriers
[60][61][62][100,101,102].
Recently, fucoidan has played a key role in nanotechnology-based medicine for different biomedical applications. Fucoidan in nanomedicine can be used as a nanocarrier for many drugs or it can be combined with different cationic polymers to encapsulate different cargos, besides being used as an effective therapeutic agent on its own
[10][63][10,103].
Fucoidan is a promising carrier for nanoparticle formulation. The formulation of fucoidan nanoparticles by the self-assembly technique enables fucoidan particles to arrange themselves into a capsule structure that is ready for drug entrapment. The ionotropic cross-linking of fucoidan with polymers having opposite net charge (e.g., chitosan, Polyallyamine hydrochloride, Polyethyleneimine, Hexadecylamine, isobutyl cyanoacrylate) is a common technique for the preparation of drug-loaded nanoparticles
[17][25].
3.5.3. Fucospheres
A conventional way of processing fucoidan and chitosan polymers for the construction of microsphere-based drug delivery systems is by cross-linking fucoidan and chitosan to form “fucospheres”
[64][65][108,109]. The drug loading and encapsulation efficiency inside fucospheres are mainly affected by the concentrations and molecular weights of fucoidan and chitosan, as well as drug properties
[66][110].
Sezer et al. prepared bovine serum albumin (BSA)-loaded fucospheres composed of cross-linked chitosan and fucoidan with particle sizes ranging from 0.61 to 1.28 µm and smooth, poreless, spherical morphology
[67][111]. The particle size depended on the concentration of fucoidan, chitosan, and BSA. The encapsulation efficiency of BSA varied between 51.8% and 89.5%. Increasin
3.5.4. Scaffolds for Tissue Engineering
Fucoidan as a biomacromolecule can be used as a building block to produce self-assembling biomaterials, which can resemble the natural extracellular matrix necessary for cell culture and tissue engineering. Protein–polysaccharide hybrid hydrogels arranged via co-assembly or conjugation between peptides and polysaccharides provide a promising approach to tissue engineering
[68][114]. This hybrid hydrogel can overcome the formerly reported problems such as lack of mechanical strength and low biological functionality associated with applying self-assembling polymers and synthetic peptides separately
[68][114].
A thermodynamically driven hydrogel based on co-assembly between fucoidan and self-assembled peptide (SAP) was applied as a scaffold for skeletal muscle progenitor cells
[69][115]. The myoblasts cultured on fucoidan scaffolds were smaller in size and had less multinucleated synthetia, with limited spreading and no observed toxicity. The scaffold matrix showed a 10-fold increase in stiffness compared to polysaccharide-free scaffolds
[69][115].
4. Fucoidan Pharmacokinetics
Pharmacokinetics (PK) generally describes the pathway of the drug into the body and how the body reacts to it in four main processes: absorption, distribution, metabolism, and elimination (ADME system). Comprehending the pharmacokinetic behavior of fucoidan is crucial for determining dosage recommendations and the most suitable dosage form for each condition to achieve effective therapeutic outcomes.
The pharmacokinetic behavior of fucoidan from variable species was evaluated using experimental animals such as mice, rats, and rabbits after oral, topical, and parenteral administration. Recently, a group of researchers investigated the pharmacokinetic parameters of fucoidan extracted from
Laminaria japonica after an intravenous injection of (50 mg/kg) in rabbits. The PK results showed a maximum plasma concentration (C
max) of 110.53 µg/mL after a maximum time (T
max) of 5 min
[70][71][117,118].