Novel Fucoidan Pharmaceutical Formulations and Their Potential Application in Oncology—A Review
Abstract
:1. Introduction
2. Materials and Methods
3. Fucoidan Sources and Chemical Structure
4. Fucoidan Biological Activities and Anticancer Mechanisms
4.1. Cell Cycle Arrest and Apoptosis
4.2. Fucoidan Effects on Angiogenesis
4.3. Inhibition of Cell Migration and Metastasis
4.4. Immunomodulatory Anticancer Activity
Fucoidan Source | Dose µg/mL | Cancer Type/ Cell Line | Data Obtained | Reference |
---|---|---|---|---|
Saccharina | 50 | Colon cancer, DLD-1; Brest cancer, T-47D | Cell proliferation inhibition; Inhibition of EGF receptor binding. | [124] |
Sargassum | 200 | Hepatic carcinoma, Huh6, Huh7, SK-Hep1 and HepG2 | Cell proliferation inhibition via TGF-β R1, 2 ↓ Phospho-Smad2/3↓ Smad 4 protein ↓ | [37] |
Sargassum | 100 | Colon cancer, DLD-1 | Cell proliferation inhibition; Inhibition of the formation of cytotoxic colony. | [125] |
F. vesiculosus | 20 | Colon cancer, HT-29 HCT-116 | Induced apoptosis via caspase-8, 9, 7, 3 activation PARP, Bak, Bid, Fas ↑, survivin, XIAP ↓. | [126] |
F. vesiculosus | 1000 | Colon cancer, HT-29 | Cell proliferation inhibition and induced cell apoptosis (↓Ras/Raf/ERK proteins). | [127] |
F. vesiculosus | 300 | Brest cancer, MCF-7 | Induced cell apoptosis via Caspase-8 activation Cytochrome C, Bax ↑ Bcl-2 ↓ Release of APAf-1 ↑. | [32] |
F. vesiculosus | 90–120 | Brest cancer, MDA-MB-231 | Cell proliferation inhibition via expression of phosphorylated Smad2,3 and Smad4 inhibition. | [128] |
F. vesiculosus | 50–400 | Lung cancer, Lewis lung carcinoma cells | Inhibition of metastasis via inhibition of VEGF and MMPs. | [129] |
F. vesiculosus | 400 | Lung cancer, A549 | Cell proliferation inhibition and induced cell apoptosis via Caspase-3 ↑ and PARP cleavage. | [130] |
F. vesiculosus | 1000 | Hepatic carcinoma, Huh-7, SNU-761, SNU-3085 | Cell proliferation inhibition via Caspase-7, -8, -9 ↑. | [131] |
F. vesiculosus | 100–1000 | Hepatic carcinoma, Huh-BAT, Huh-7, SNU-761 | Induced cell apoptosis via Bax, Bid, Fas ↑ Caspase-7, -8, -9 cleavage Phosphorylatedp42/44↑. | [132] |
F. vesiculosus | 150 | Leucemia, HL-60 NB4 THP-1 | Induced cell apoptosis via PARP cleavage Caspase-8, 9, 3 ↑ Mcl-1, Bid ↓. | [133] |
F. vesiculosus | 50–200 | Leucemia, SUDHL-4, OCI-LY8, NU-DUL-1, TMD8, U293, DB | Induced cell apoptosis via PARP cleavage and cleaved caspase-8,9, 3 ↑. | [134] |
F. vesiculosus | 12.5–100 | Leucemia, NB4, HL60 | Cell proliferation inhibition and induced cell apoptosis via Caspase-3, 8, 9, ↑ PARP cleavage and Bax ↑. | [135] |
F. vesiculosus | 20–100 | Leucemia, U937 | Cell proliferation inhibition and induced cell apoptosis via Caspase-3, 8, 9 ↑, PARP cleavage, Bax↑. | [136] |
U. pinnatifida | 200–1000 | Colon cancer, WiDr LoVo Brest cancer, MCF-7 | Cell proliferation inhibition. | [108] |
U. pinnatifida | 10–200 | Lung cancer, A549 | Cell proliferation inhibition and induced cell apoptosis via Bcl 2, p38, Phospho-PI3K/Akt, procaspase- 3↓ Bax, caspase-9, Phospho-ERK1/2 ↑ PARP cleavage. | [137] |
U. pinnatifida | 65.2–1000 | Hepatic carcinoma, SMMC-7721 | Cell proliferation inhibition and induced cell apoptosis via Livin, XIAP mRNA ↓ Caspase-3, -8, -9 ↑ Bax-to-Bcl-2 ratio↑ Cytochrome C ↑. | [138] |
Cladosiphon | 1000 | Brest cancer, MCF-7 | Induced cell apoptosis via PARP cleavage Caspase-7,8,9 ↑ Cytochrome C, Bax, Bid↑. | [139] |
B. bifurcata | 2–9 | Lung cancer, NSCLC-N6 | Cell proliferation inhibition via irreversible growth arrest. | [119] |
5. Fucoidan-Based Pharmaceutical Formulations
5.1. Fucoidan Microparticles
5.2. Fucoidan Nanoparticles
5.3. Fucoidan Liposomes
Active Substance | Dosage Form | Therapeutic Application | Data Obtained | Reference |
---|---|---|---|---|
Fucoidan | Microparticles | Skin burns | Enhanced skin regeneration resulted in an increase in the epithelial thickness in vivo on rabbits. | [155] |
Perfluorooctyl bromide | Microparticles | Thrombosis | High affinity to P-selectin and ability to detect thrombosis in vivo on rats with induced aortic aneurysm. | [156] |
Isoniazid, Rifabutin | Microparticles | Tuberculosis | Effective inhibition of mycobacterial growth. Low toxicity on human alveolar epithelum and monocytic cell line (HTP-1). | [159] |
Doxorubicin | Microparticles | Breast cancer | Significant antiproliferative activity on MCF-7 breast cancer cell line. Low toxicity on mouse myoblasts (concentration 400 µg/mL). | [162] |
N-methyl anthranilic acid | Nanoparticles | Inflammation | Significant reduction in carrageenan-induced inflammation in rats by decreasing the cyclooxygenase-2, (TNF)-α E2, NO, IL-1β, IL-6. | [163] |
Docetaxel | Nanoparticles | Anticancer | High cellular uptake efficiency and subcellular localization. Low cytotoxicity on non-tumor cell lines. | [164] |
Oversulfated fucoidan | Nanoparticles | Anticancer | Inhibition of human umbilical vein endothelial cells HUVECs via competitive binding to bFGF receptors (bFGFRs). | [168] |
Amoxicillin | Nanogels | H. pylori infection | pH-dependent sustained drug release, which can improve the therapy of Helicobacter pylori. | [169] |
Piperlongumine | Nanoparticles | Prostate cancer | Higher cytotoxicity in the PC-3 cells than in the non-cancerous hDFB cells; increased the intracellular ROS levels in the PC-3 cells. | [176] |
Usnic acid | Liposomes | M. tuberculosis | Higher cellular uptake and cellular internalization. | [174] |
6. Fucoidan Nanoparticles for Cancer Therapy
7. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Brown Seaweed | Structure | Reference |
---|---|---|
Fucus evanescens | Main chain of (1→3)-and (1→4)-α-L-Fucp highly substituted by sulfate groups at O2 and/or O3 positions | [6] |
Fucus seratus | Main chain of (1→3)-and (1→4)-α-L-Fucp with short branches of α-L-Fucp-(1→4)-α-L-Fucp and α-L-Fucp-(1→3)-α-L-Fucp in O4 of α-(1→3)-L-Fucp and sulfate groups in O2 and/or O4 positions | [7] |
Chorda filum | Main chain of (1→3)-α-L-Fucp highly ramified at O2 by terminal residues and substituted by sulfate groups at O2 and/or O4 positions. | [7] |
Fucus distichus | [(1→3)-α-L-Fucp-(2,4-di-SO3-)-(1→4)- α-L-Fucp -(2SO3-)-(1→]n | [8] |
Undaria pinnatifida | Backbone structure of (1→3):(1→4)-O-glycosidic bonds | [9] |
Ascophyllum nodosum | [(1→3)-α-L-Fuc-(2SO3-)-(1→4)- α-L-Fuc-(2,3-di-SO3-)-(1→]n | [10] |
Laminaria saccharina | Main chain of (1→3)-α-L-Fucp branched at O2 and O4 of α-L-Fucp by terminal residues and sulfate groups | [11] |
Activity | Dose, µg/mL | Source | Cell Lines | Data Obtained | Reference |
---|---|---|---|---|---|
Antioxidant | 1 | S. japonica | - | DPPH radical and ABTS+ radical scavenging activity | [71] |
Anti- inflammatory | 0.1–100 | S. sagamianum | LPS-induced RAW 264.7 cells | Inhibition of NO, IL-6, IL-1β, TNF-α, iNOS, COX-2, NF-κB p65 | [72] |
Anti- inflammatory | 1–300 | G. pacificum | LPS-induced THP-1 cells | Protected the THP-1 cells against LPS-stimulated cytotoxicity | [73] |
Anti- inflammatory | 3–25 | S. japonica | LPS-induced RAW 264.7 cells | Decreased production of NO and TNF-α, IL-1β and IL-6. | [74] |
Anti- inflammatory | 25–100 | C. minima | LPS-induced RAW 264.7 cells | Inhibition of NO production and expression of PGE2 | [75] |
Antiviral | 10–1000 | L. japonica | Vero E6 cell line from mouse macrophage | Reduced number of infected cells | [76] |
Antiviral | 50–100 | H. elongata | Vero cell line from African green monkey | Inhibition of Herpes simplex virus type 1 intracellular replication | [77] |
Hypoglycemic | 0.5–5 | L. japonica | Cell α-glucosidase | α-glucosidase inhibitory activity | [78] |
Immuno- modulatory | 5–125 | S. fusiforme | B lymphocytes | Promote LPS-induced spleen lymphocyte proliferation | [79] |
Anticancer | 25–100 | S. coreanum | HL-60, CT-26, B-16 and HeLa cell model | Cell apoptosis and activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase | [80] |
Anticancer | 120 | F. vesiculosus | HeLa G-63, Hep G2 and Chang liver cells model | Inhibition of cell proliferation | [81] |
Anticancer | 10–500 | U. pinnatifida | Sarcomas and carcinosarcoma cell lines | Induced apoptosis | [82] |
Anticancer | 0.05–100 | B. fuscopurpurea | Ovarian cancer cells | Inhibition of A2780, COC1, SKOV3, HO-8910 and OVCAR3 ovarian cancer cells proliferation | [83] |
Effect | Dose | Source | Tested Model | Reported Results | Reference |
---|---|---|---|---|---|
Anticancer | 5 g/kg p.o. | C. okamuranus | Mice with induced colon cancer | Significantly suppressed tumor growth | [84] |
Anticancer | 5 mg/kg i.p. | F. vesicolosus | Mice with induced breast cancer | Inhibition of angiogenesis and induction of apoptosis | [85] |
Anticancer | 200 mg/kg i.p. | - | Mice with induced hepatocellular carcinoma | Inhibition of cancer cells proliferation | [86] |
Anticancer | 0.25 mg/day i.v. | F. vesicolosus | Mice with induced breast cancer | Cancer metastasis prevention | [87] |
Anticancer | 75 mg/kg p.o. | S. plagiophyllum | Mice with induced hepatocellular carcinoma | Inhibition of carcinogen metabolism | [88] |
Anticancer | 100 mg/kg p.o. | C. okamuranus | Mice with induced sarcoma | Tumor growth reduction by NO produced by macrophages | [89] |
Immuno- modulatory | 10 mg/kg i.v. | - | Rabbits with induced bacterial meningitis | Decreased influx of leukocytes into the cerebrospinal fluid | [90] |
Immuno- modulatory | 50 mg/kg i.v. | - | Mice with L-selectin deficient | Mobilization of hematopoietic progenitor stem cells | [91] |
Immuno- modulatory | 25 mg/kg i.v. | F. vesiculosus | Rats with induced myocarditis | Inhibition of extravasation of macrophages and CD4+ T cells | [92] |
Immuno- modulatory | 200 mg/kg p.o. | - | Mice with induced leishmania infection | Th1 switch in Leishmania infection | [93] |
Immuno- modulatory | 20 mg/kg i.p. | F. vesiculosus | Mice | Increased levels of TNF-α and IL-6 in spleens and blood serum | [94] |
Immuno- modulatory | 20 mg/kg p.o. | U. pinnatifida | Mice with induced herpes simplex | Increased activity of NK cells | [95] |
Immuno- modulatory | 50 mg/kg i.p. | M. pyrifera | Mice | Increased maturation and activation of NK cells | [96] |
Immuno- modulatory | 500 mg/kg p.o. | U. pinnatifida | UVB-irradiated mouse skin | Lowered IFN-γ levels after irradiation; reduced skin edema | [97] |
Anti- inflammantory | 25 mg/kg i.v. | F. vesiculosus | Mice with induced pancreatitis | Decreased levels of IL-1β, TNF-α and myeloperoxidase | [98] |
Anti- inflammantory | 10–400 mg/kg p.o./i.p. | F. vesiculosus | Mice with induced acute colitis | Decreased levels of IL-1α, IL-1β and IL-10 | [99] |
Anti- inflammantory | 50–100 mg/kg p.o. | L. japonica | Mice with induced liver damage | Reduced levels of TNF-α, IL-1β and IL-6 | [100] |
Anti- inflammantory | 100 mg/kg p.o. | L. japonica | Mice with induced diabetes melitus | Reduced blood glucose level and serum levels of IL-1β, IL-6, TNF-α | [101] |
Anti- inflammantory | 50–200 mg/kg p.o. | L. japonica | Mice with induced myocarditis | Decreased levels of TNF- α and IL-6; increased levels of IL-10 | [102] |
Anti- inflammantory | 50–200 mg/kg p.o. | S. muticum | Mice with induced rheumatoid arthritis | Decreased levels of TNF-α, IFN-γ and IL-6 | [103] |
Anti- inflammantory | - | C. okamuranus | Mice with induced chronic colitis | Decreased levels of IL-6 and increased levels of IL-10 | [75] |
Anti- inflammantory | 12.5–50 μg/mL | C. minima | Zebrafish embryos | Decreased production of NO, ROS, COX-2, iNOS | [104] |
Anti- inflammantory | 300 mg/mL p.o. | U. pinnatifida | Mice with induced rheumatoid arthritis | Reduced cartilage and bone destruction and inflammation | [105] |
Anti- inflammantory | 2.5–300 mg/kg p.o. | T. ornata | Rats with induced arthritis | Decreased levels of TNF-α, IL-6 and PGE2 | [106] |
Anti- inflammantory | 50 mg/kg p.o. | T. ornata | Mice with paw edema | Reduced the expression of genes of COX-2, IL-1β, the NF-κB signaling pathway | [107] |
Source, Mw | Copolymer | Drug | Preparation Method | Administration Route | Reference |
---|---|---|---|---|---|
F. vesiculosus, 200–400 kDa | Gold nanoparticles | Doxorubicin | Electrostatic complexation | Ocular | [148] |
L. japonica, 80 kDa | Protamine | Doxorubicin | Self-assembly | Intravenous | [178] |
F. vesiculosus, 200–400 kDa | Polyethyleneimine | Doxorubicin | Coacervation | Intravenous | [179] |
F. vesiculosus, 200–400 kDa | Polyallylamine HCl | Copper sulfide | Layer-by-layer | Intratumoral | [180] |
F. vesiculosus, 200–400 kDa | Polyallylamine HCl | Methotrexate | Self-assembly | NA * | [149] |
F. vesiculosus, 200–400 kDa | Chitosan/Chondroitin | Fucoidan | Coacervation | Oral | [181] |
F. vesiculosus, 50–190 kDa | Chitosan | Methotrexate | Self-assembly | Topical | [182] |
F. vesiculosus, 50–190 kDa | Chitosan | Curcumin | Self-assembly | Oral | [183] |
Fucoidan Source | Cancer Type | Dose Applied | Study Type | Number of Patients | Clinical Results | Reference |
---|---|---|---|---|---|---|
LMW fucoidan from S. hemiphyllum | Metastatic colorectal cancer | 4 g/day | Randomized, double-blind, controlled trial | 54 | Improved disease control | [192] |
LMW fucoidan from C. okamuranus | Advanced metastatic cancer | 400 mL/day | Open-label clinical study | 20 | Improved therapy | [67] |
LMW fucoidan from C. okamuranus | NK cells from patients in remission | 1.5 g twice a day | Randomized double-blind placebo-controlled study | 39 | Enhanced NK cell activity | [193] |
HMW fucoidan from C. okamuranus | Colorectal cancer | 150 mL/day | A randomized trial | 20 | Decreased general fatigue | [194] |
Fucoidan (without clarification). | Rectal cancer | N/A | A double-blind randomized placebo-controlled study | 100 | N/A | [195] |
Fucoidan as a dietary supplement | Squamous cell carcinoma | 4.4 g/day | A randomized double-blind study | 119 | Study not completed. | [196] |
Fucoidan as a dietary supplement | Hepatocellular carcinoma | 4.4 g/day | A randomized double-blind study | 100 | Study not completed. | [197] |
LMW fucoidan as a dietary supplement | Lung cancer | 4.4 g twice a day | A double-blind randomized controlled trial | N/A | Withdrawn. | [198] |
LMW fucoidan from Undaria pinnatifida | Brest cancer | 500 mg twice a day | Open label non-crossover study | 20 | Co-administration with letrozole, tamoxifen. | [199] |
LMW fucoidan from Nemacystis decipiens | Prostate, liver, breast, pancreatic cancer | 60–300 mL/day | Case report | 10 | Decreased tumor markers | [42] |
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Zahariev, N.; Katsarov, P.; Lukova, P.; Pilicheva, B. Novel Fucoidan Pharmaceutical Formulations and Their Potential Application in Oncology—A Review. Polymers 2023, 15, 3242. https://doi.org/10.3390/polym15153242
Zahariev N, Katsarov P, Lukova P, Pilicheva B. Novel Fucoidan Pharmaceutical Formulations and Their Potential Application in Oncology—A Review. Polymers. 2023; 15(15):3242. https://doi.org/10.3390/polym15153242
Chicago/Turabian StyleZahariev, Nikolay, Plamen Katsarov, Paolina Lukova, and Bissera Pilicheva. 2023. "Novel Fucoidan Pharmaceutical Formulations and Their Potential Application in Oncology—A Review" Polymers 15, no. 15: 3242. https://doi.org/10.3390/polym15153242