Abstract
Microalgae produce a wide array of bioactive compounds with potential applications such as pharmaceuticals and nutraceuticals that are yet to be fully explored. Metabolites from microalgae are known to have various bioactivities including antibacterial, antiviral, anticancer and immunomodulatory activities as well as beneficial effects against metabolic disorders such as obesity, diabetes and hyperlipidaemia. Production of pharmaceuticals and nutraceuticals derived from microalgae is attractive as the photosynthetic organisms can be grown on a large scale under controlled environment. Furthermore, the production platform can be integrated with other applications, especially biofuel production, to improve economic competitiveness based on a biorefinery concept. Microalgae that have been successfully cultured on a large scale for commercial production of pharmaceuticals and nutraceuticals include Spirulina (Arthrospira), Dunaliella, Chlorella and Haematococcus. While various bioactive compounds have been discovered from microalgae, most studies on those compounds are still at the preclinical stage, confined to laboratory experiments. Overall, only very few microalgal products have been successfully brought to the market. This chapter aims to give an overview of the wide range of potential pharmaceuticals and nutraceuticals from microalgae and current status of the production of such compounds as well as to highlight the future directions of research in this field.
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1 Introduction
Microalgae comprise a diverse group of organisms with an estimated number of species of 72,500, but only about 44,000 have been described (de Clerck et al. 2013). This group of organisms consists of the eukaryotic (microalgae) and prokaryotic taxa (cyanobacteria). Apart from the rich biological diversity, microalgae are also known to produce a myriad of metabolites, many of which have potential biomedical applications that have yet to be fully explored (Coates et al. 2013). The breadth of chemical diversity of secondary metabolites from microalgae is related to the vast number of environments they inhabit. While microalgae are mainly found in aquatic environments (49.78% in freshwater and 44.48% in seawater), some species also grow in contaminated and extreme environments including thermal and glacial lakes (Cezare-Gomes et al. 2019). The production of secondary metabolites is related to their possible ecological roles including for defence of the microalgae against predators, protection against infection by various microorganisms and sexual communication (Coates et al. 2013). Interestingly, some of the bioactive compounds that were first isolated from invertebrates were later found to be produced by symbiotic microalgae in those animals. For instance, the anticancer compound dolastatin was originally isolated from the sea hare (Dolabella auricularia) but was later discovered to be synthesized by the cyanobacteria Lyngbya and Symploca (Luesch et al. 2002).
Microalgae are a potential and attractive source of bioactive compounds, as they can be easily cultured, and have short generation times, with doubling time of 3.9–8.1 h for some species (Table 12.1). The doubling time of microalgae can be further shortened by manipulating the culture conditions (de Swaaf et al. 2003; Chen et al. 2013; Table 12.1). Furthermore, microalgae can synthesize structurally complex molecules, which are difficult or impossible to produce by chemical synthesis (Dewi et al. 2018). The possibility of culturing those microalgae also allows an environmentally friendly way to drug discovery, overcoming problems such as overutilization of natural bioresources and use of destructive collection practices (Lauritano et al. 2016). In addition, a “milking” approach can be used where extraction of the high-value products (e.g. use of biocompatible organic solvents and pulsed electric field) does not kill the algae and thus, the process is more environmentally and economically friendly (Vinayak et al. 2015). Large-scale cultivation of microalgae in photobioreactors is possible to produce large volumes of cultures, ranging from 1000 to 6000 L of microalgae such as Chlorella and Spirulina, for the extraction of bioactive compounds (Borowitzka 1999). In addition, microalgae are potential candidates for exploration of new compounds due to their metabolic plasticity, which can be exploited for the production of several compounds with applications in various biotechnology sectors including food, energy, health, environment and biomaterials (Martinez Andrade et al. 2018).
Regulatory bodies such as the US Food and Drug Administration (FDA) set the standards that need to be met before any microalgal product is certified safe for human consumption (Gantar and Svircev 2008). Some of the microalgal products have attained GRAS (generally recognized as safe) status and are marketed as functional food (Gantar and Svircev 2008; Jha et al. 2017a). The most widely sold microalgal products as functional food include Spirulina (Arthrospira) and Chlorella (Andrade 2018). In addition, Haematococcus pluvialis has been approved for human consumption as dietary supplement in several European countries (Lorenz and Cysewski 2000). The food-grade microalgae are a rich source of nutraceuticals such as carotenoids (β-carotene and astaxanthin), C-phycocyanin, long-chain polyunsaturated fatty acids (LC-PUFA), vitamins and polysaccharides (Lorenz and Cysewski 2000; Andrade 2018).
Microalgae produce a wide array of metabolites with diverse bioactivities including anticancer, antibacterial, antiviral and immunomodulatory activities and ameliorating effects against metabolic disorders such as diabetes and hyperlipidaemia (Nagaoka et al. 2005; Renju et al. 2014a; Aboulthana et al. 2018; Dewi et al. 2018). Apart from the limited number of microalgal species that have reached commercial status, the rich microalgal resources with the mentioned bioactivities have not been fully exploited as sources of pharmaceuticals and nutraceuticals (Jha et al. 2017a). There are several reports on large-scale screening of microalgae for bioactive compounds. For instance, in an early study, screening of 1000 cyanobacterial strains from diverse habitats for novel antineoplastic agents identified the families Scytonemataceae and Stigonemataceae as prolific producers of novel cytotoxic compounds (Patterson et al. 1991). Recently, Caires et al. (2018) screened various strains of the benthic filamentous cyanobacteria Neolyngbya for antimicrobial and antioxidant activities. Solvent extracts of the cyanobacteria showed inhibitory activity against the tested bacteria and Candida albicans, and the methanolic extract showed the greatest antioxidant activity. In another study, Lauritano et al. (2016) screened 21 diatoms, seven dinoflagellates, and four flagellate species for antioxidant, anti-inflammatory, anticancer, antidiabetic, antibacterial, and antibiofilm activities.
The aim of this chapter is to give an overview of the wide range of potential pharmaceuticals and nutraceuticals derived from microalgae. The aspect on mass-culture systems, particularly photobioreactors, currently used to produce microalgal biomass for the extraction of pharmaceuticals and nutraceuticals is also discussed. This chapter also aims to highlight the challenges faced in the commercialization of microalgal products as pharmaceuticals and nutraceuticals, and to propose some directions for future research.
2 Bioactivities of Microalgal Compounds and Their Potential Applications as Pharmaceuticals and Nutraceuticals
Microalgal compounds with potential for development into pharmaceuticals and nutraceuticals include astaxanthin, fucoxanthin, C-phycocyanin, sulphated polysaccharides and novel secondary metabolites (Figs. 12.1 and 12.2). In the subsequent sections, the following bioactivities of microalgal compounds will be covered in detail: antibacterial, antiviral, anticancer and immunomodulatory activities, and beneficial effects against metabolic disorders such as obesity, diabetes and hyperlipidaemia. A summary of the microalgal compounds with antibacterial, antiviral and immunomodulatory activities is given in Table 12.2 while those with anticancer activity are listed in Table 12.3.
Schematic overview of the bioactive compounds from microalgae
Selected bioactive compounds derived from microalgae with potential for the development of pharmaceuticals and nutraceuticals. Example of microalgal producer for each compound is given in parenthesis (Burja et al. 2001; Chen et al. 2003; Mori et al. (2004); Mimouni et al. 2012; Coates et al. 2013; Rodrigues et al. 2015; Assunção et al. 2017; Bertin et al. 2017)
2.1 Antibacterial Activity
There has been a long history in attempts to isolate antibacterial compounds from microalgae since the discovery of chlorellin, which is a mixture of fatty acids, from Chlorella vulgaris and Chlorella pyrenoidosa for its activity against various Gram-positive and Gram-negative bacteria (Pratt et al. 1944). Since then, a variety of antibacterial compounds from microalgae have been characterized, including fatty acids (Desbois et al. 2009), phenolic compounds (Kuntzler et al. 2018), biphenyls (Volk and Furkert 2006), polysaccharides (de Jesus Raposo et al. 2015) and nanoparticles (Patel et al. 2015).
Amongst the fatty acids from microalgae which display antibacterial activity include eicosapentaenoic acid (EPA) and palmitic acid. For instance, Desbois et al. (2009) showed that EPA from Phaeodactylum tricornutum displayed potent antibacterial activity against diverse bacteria including multi-resistant Staphylococcus aureus (MRSA). Recently, Wang et al. (2018a) obtained two active fractions from Phaeodactylum tricornutum, a pure fraction of EPA and another (fraction B) containing new antibacterial substances that displayed antibacterial activities against human pathogenic bacteria. In addition, fatty acid methyl esters (FAME), particularly palmitic acid methyl ester (C16:0), extracted from Scenedesmus intermedius have also been found to display antibacterial activities against both Gram-positive and Gram-negative bacteria (Davoodbasha et al. 2018).
Recently, Senhorinho et al. (2018) screened 40 freshwater green microalgae from water bodies near abandoned mine sites in northern Canada. Of the 40 methanol extracts from the microalgae tested, 37.5% displayed strong inhibitory activity against the human pathogen Staphylococcus aureus, with Minimum Inhibitory Concentrations (MIC) ranging from 16 to >1024 μg/mL. The metabolites identified in the active extracts include amino acids, glycerolipids, sphingolipids, acylcarnitines and biogenic amines. However, there was no significant correlation between the metabolites analysed and antibacterial activity observed.
Nanoparticles (NP) such as silver and gold NP are well known to possess antibacterial activity. There has been increasing interest in using microalgae as bio-factory for the synthesis of such NP (Shankar et al. 2016). The green synthesis approach that uses cell-free extracts from the microalgae is more attractive compared to conventional physical and chemical methods, which are costly and involve the use of hazardous chemicals (Narayanan and Sakthivel 2011). Synthesis of NP may involve extracellular process, where the metal ions are trapped on the cell surface and reduced to elemental metal atoms by specific enzymes. On the other hand, in intracellular synthesis of NP, the ions are transported into the algal cell to form NP in the presence of enzymes.
Da Silva Ferreira et al. (2017) synthesized silver chloride nanoparticles (AgCl-NP) by incubating conditioned medium of Chlorella vulgaris with AgNO3. The AgCl-NP formed was found to have potent antibacterial activity, reducing 98% the growth of Gram-positive Staphylococcus aureus and Gram-negative Klebsiella pneumoniae bacterial pathogens. In another study, Patel et al. (2015) evaluated the ability of 16 strains of cyanobacteria and microalgae to synthesize silver nanoparticles (Ag-NP). The Ag-NP were formed in the presence of the biomass as well as in the cell-free culture medium and might involve extracellular polysaccharide. In the same study, C-phycocyanin from Spirulina and Limnothrix were successfully used for the biosynthesis of Ag-NP. Further, the Ag-NP from all except one strain was found to display antibacterial activity against bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa.
Some cyanotoxins have also been shown to be a promising source of novel antibiotics against multi-resistant bacteria. For instance, microcystin-LR displayed antimicrobial activity against four highly resistant species of Mycobacterium, with MIC ranging from 0.42 to 0.53 μM (Ramos et al. 2015). In addition, phenolic compounds from Spirulina LEB 18 were found to have antibacterial activity against Escherichia coli and Staphylococcus aureus when tested alone or incorporated into nanofibers (Kuntzler et al. 2018). The phenolic compounds in Spirulina contain organic acids such as caffeic, gallic, salicylic and trans-cinnamic acids (de Souza et al. 2015). In another study, simple phenols such as ferulic acid from the chloroform extracts of Dunaliella sp. accounted for the antibacterial activity against Bacillus subtilis ATCC 6633 and E. coli 0157:H7 ATCC 35150 (Kim et al. 2012a). In addition, both purified β-carotene and chlorophyll pigments from the organic solvent extracts of Chlorococcum humicola were shown to display antibacterial activity against Staphylococcus aureus, Vibrio cholerae and Klebsiella pneumoniae (Bhagavathy et al. 2011).
2.2 Antiviral Activity
As viral infection is one of the main threats to human health, there has been great interest in looking for safe, effective and specific antiviral agents. Screening of water, methanolic or ethanolic extracts from microalgae for antiviral activity has been reported by several authors. For instance, in an early study, Lau et al. (1993) reported that only 2% of approximately 900 strains of cyanobacteria were able to inhibit reverse transcriptase activity of the human immunodeficiency virus (HIV) and avian myeloblastosis virus. In another study, Fabregas et al. (1999) screened extracts from ten microalgae for antiviral activity against the viral haemorrhagic septicaemia virus (VHSV) of salmonid fish and the African swine fever virus (ASFV). The study showed that aqueous extracts from Porphyridium cruentum, Chlorella autotrophica and Ellipsoidon sp. displayed significant inhibition of the replication of both viruses, which could be attributed to sulphated polysaccharides. In addition, Abdo et al. (2012) tested methanol and water extracts of five freshwater microalgae against Adenovirus Type 40 and found that only extracts from Spirulina platensis showed significant activity at non-cytotoxic concentrations. In another study, Kok et al. (2011) assessed the inhibitory activities of methanol extracts from Ankistrodesmus convolutus, Synechococcus elongatus and Spirulina platensis against Epstein–Barr virus (EBV) in three Burkitt’s lymphoma (BL) cell lines. The methanol extracts were obtained by homogenizing the dried algal biomass in methanol and after centrifugation, the supernatant was evaporated and the dried extract was reconstituted in the solvent before use for the testing. The study found that the HPLC sub-fraction of the methanol extracts from Synechococcus elongatus (SEF1′) was most effective in reducing cell-free EBV DNA (EC50 = 1.38 μg/mL, therapeutic index >69). In addition, Komatsu et al. (2013) found that acidic polysaccharide fraction from Coccomyxa gleobotrydiformi displayed antiviral activity against influenza A virus through preventing the cell attachment and/or penetration of the virus.
Recently, Afify et al. (2018) found that protein hydrolysates obtained from Scenedesmus obliquus exhibited antiviral activity against Coxsackie B3 virus (CVB3). The inhibitory action of the hydrolysates was at the steps involving attachment, penetration, and adsorption of the viral particles. In addition, the antiviral activity of the hydrolysates was found to be positively correlated with the antioxidant activity of the extracts.
Polysaccharides are amongst the compounds that are known to possess antiviral activity and have great potential for pharmaceutical applications (Yu et al. 2018). For instance, a sulphated polysaccharide named calcium spirulan isolated from Spirulina platensis was shown to have potent antiviral activity against both HIV-1 and anti-herpes simplex virus type 1 (HSV-1) (Hayashi et al. 1996). In another study, Rechter et al. (2006) assessed the antiviral activity of intracellular and extracellular fractions containing spirulan-like molecules from Spirulina. The study showed that the spirulan-like fractions displayed strong inhibition against human cytomegalovirus, HSV-1, human herpesvirus type 6 and HIV-1, but only weak or no inhibition against EBV and influenza A virus. While for herpesviruses, the antiviral action of the fractions mainly targeted at viral entry, the action against HIV-1 occurred at a stage later than viral entry.
The sulphated polysaccharide p-KG03 purified from the dinoflagellate Gyrodinium impudium was found to exhibit antiviral activity against influenza type A virus (Kim et al. 2012b). The study further showed that the antiviral activity of the sulphated polysaccharide was associated with its interaction with the viral particles, particularly in the adsorption and internalization steps. In a subsequent study, Yim et al. (2004) showed that p-KG03 also displayed potent antiviral activity (EC50 = 26.9 μg/mL) against encephalomyocarditis virus (EMCV) without any cytotoxic effect. In addition, cell wall sulphated polysaccharide from the red microalga Porphyridium sp. was found to display strong antiviral activity against HSV-1 and 2 and Varicella zoster virus (VZV) (Huleihel et al. 2001). Another sulphated polysaccharide isolated from Navicula directa, named naviculan, was found to have antiviral activities against HSV-1 and 2, and influenza A virus (Lee et al. 2006). In addition, naviculan displayed inhibitory effect against cell–cell fusion between CD4-expressing and HIV gp160-expressing cells.
Amongst the cyanobacterial compounds, cyanovirin-N (CVN) is a potent antiviral agent against HIV that acts by inhibiting the virus cell entry in a highly specific manner (Lotfi et al. 2018). Cyanovirin-N (CVN) is a type of lectins, which are proteins of non-immune origin that are capable of recognizing and binding to glycoconjugate moieties non-covalently (Sharon and Lis 1989) There have been attempts to develop different expression systems for the recombinant production of CVN for use as an effective anti-HIV microbicide. Formulation of the microbicide can be in the form of vagina gels/rings, creams, lubricants or suppositories, delivering the active ingredients slowly during coitus or over extended periods of time.
Cyanovirin-N (CVN) was first isolated from the cultures of Nostoc ellipsosporum (Boyd et al. 1997). The protein was successfully produced recombinantly by expression of a corresponding DNA sequence in E. coli. The antiviral activity of CVN was partly due to its high-affinity interactions with the viral surface envelope glycoprotein gp120. Cyanovirin-N (CVN) has also been found to display antiviral activity against Ebola (Barrientos et al. 2003) and influenza virus (O’Keefe et al. 2003). The potency of CVN against viruses is attributed to the N-linked oligosaccharides with high mannose content that interact with the viral glycoproteins (Barrientos et al. 2006). This shows that the antiviral activity of CVN is not due to its induction of viral particle agglutination, but via inhibition of viral entry.
Other lectins from cyanobacteria which have been shown to exhibit anti-HIV activity include scytovirin (SVN) from Scytonema varium (Bokesch et al. 2003) and agglutinin from Oscillatoria agardhii (OAA) (Sato et al. 2007). O’keefe et al. (2011) have filed a patent on the use scytovirin for treating infections caused by high mannose-enveloped viruses including hepatitis C virus (HCV). Recently, Siqueira et al. (2018) performed a genomic screening of new putative antiviral lectins from the genomic sequences of Amazonian cyanobacteria using a bioinformatics approach. Amongst the seven strains of cyanobacteria screened, 75 unique coding sequences for one or more lectin domains were identified. Using homology modelling and molecular dynamics simulations, the study discovered that Nostoc sp. CACIAM 19 and Tolypothrix sp. CCAM 22 strains presented cyanovirin-N homologues.
2.3 Immunomodulatory Activity
Several bioactive compounds from microalgae have been shown to possess immunomodulatory activity, especially anti-inflammatory effect. For instance, lycopene (cis/all-trans 40:60) from Chlorella marina was found to show significant antioxidant and anti-inflammatory effect in high-cholesterol fed rats (Renju et al. 2014a). Inflammatory biomarkers such as cyclooxygenase, 15-lipoxygenase and myeloperoxidase activity, and C-reactive protein and ceruloplasmin levels in serum were found to decrease significantly in rats fed algal lycopene. In another study, lycopene from Chlorella marina was found to reduce significantly inflammatory marker enzymes such as cyclooxygenase, lipoxygenase and myeloperoxidase in an arthritis rat model, compared to tomato lycopene and the anti-inflammatory drug indomethacin (Renju et al. 2013). There was also a marked reduction in oedema of paw and joint tissues in the rats supplemented with the algal lycopene. The authors further suggest that algal lycopene could be a potential agent for the treatment of anti-inflammatory diseases such as arthritis. In addition, violaxanthin isolated from Chlorella ellipsoidea was found to significantly inhibit nuclear factor-κB (NF-κB) pathways in exerting its anti-inflammatory effect against lipopolysaccharide (LPS)-stimulated RAW 264.7 mouse macrophage cells (Soontornchaiboon et al. 2012).
Another pigment which has been shown to have immunomodulatory effect is C-phycocyanin, which is one of the major pigments in cyanobacteria, especially Spirulina. C-phycocyanin has been shown to display inhibitory activity against allergic responses, such as ear swelling, skin reactions and histamine release from mast cells in a rat model (Remirez et al. 2002). In addition, C-phycocyanin was found to reduce allergic inflammation by suppressing antigen-specific IgE response in a mouse model (Nemoto-Kawamura et al. 2004). In another study, water extract from Botryococcus braunii exerted anti-inflammatory effect by inhibiting the expression of nitric oxide synthase (iNOS) gene and the consequent production of nitric oxide (NO) under oxidative stress in RAW 264.7 murine macrophages (Buono et al. 2012). Recently, Wang et al. (2018b) showed that protein-rich materials after extraction of DHA from bioengineered Schizochytrium sp. ameliorated bowel inflammation in mice. The protein hydrolysate attenuated the induction of pro-inflammatory cytokines and increased the induction of anti-inflammatory cytokines. In addition, the protein hydrolysate promoted the proliferation of colonic crypt stem cells and progenitor cells required for crypt repair. In another study, feeding of Schizochytrium oil rich in DHA has been shown to increase plasma level of the anti-inflammatory cytokine TGF-β1 (Komprda et al. 2016). In another study, supplementation of Spirulina was found to enhance primary immune response in terms of antibody production following tetanus toxoid vaccination in a mouse model (Chu et al. 2013).
There has also been interest in screening of microalgae for compounds for skin health, including anti-inflammatory, wound-healing and antioxidative effects (Kim et al. 2018). For instance, Hidalgo-Lucas et al. (2014a) assessed the beneficial effect of a formulation based on Chlorella sorokiniana (ROQUETTE Chlorella sp., RC) on two dermatological disorder models in mice, namely skin inflammation and wound healing. Oral and topical administration of RC at high doses showed significant effects in reducing skin inflammation and had efficient effect on wound-healing process. Similarly, topical and oral administration of formulation based on Schizochytrium (ROQUETTE Schizochytrium sp.) had significant effects on macroscopic score of skin inflammation and efficient effect on healing process, especially at high doses (Hidalgo-Lucas et al. 2014b). In addition, supplementation of Chlorella vulgaris has been able to reduce atopic dermatitis-like symptoms, including dermatitis scores, epidermal thickness and skin hydration, in a mouse model (Kang et al. 2015). In the same study, treatment of Chlorella vulgaris was found to downregulate serum levels of thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC). Also, the treatment downregulated mRNA expression levels of IL-4 and IFN-γ. In another study, sulphated polysaccharide of Porphyridium was found to be an effective anti-inflammatory agent for topical use. Topical application of the polysaccharide on human subjects was found to inhibit the development of erythema induced by a powerful irritant (Matsui et al. 2003).
2.4 Anticancer Activity
Cancer is the second leading cause of death globally, accounting for an estimate of 9.6 million deaths in 2018 (WHO 2018). There has been much interest in exploring for new therapeutic agents for cancer, particularly from natural products, in view of the side effects posed by the current treatment strategies (Pádua et al. 2015) and the development of resistance of tumour cells against currently available drugs (Li et al. 2018). Microalgae are a potential source of anticancer compounds that have yet to be fully explored (Abd El-Hack et al. 2018). Potential anticancer compounds from microalgae include pigments (C-phycocyanin, astaxanthin and fucoxanthin), bioactive peptides, lipid compounds, alkaloids and dinoflagellate toxins (Table 12.3). The anticancer effects of the microalgal compounds are mediated through their action in inducing cytotoxicity, downregulating invasion of tumour cells, and enhancing cancer cell apoptosis.
A wide range of novel metabolites, especially bioactive peptides, from cyanobacteria have been shown to display anticancer activity (Gerwick and Moore 2012). For instance, symplopastin 1, a linear peptide isolated from Symploca hydroides, was found to be a potent microtubule inhibitor that was effective against drug-insensitive mammary tumour and drug-insensitive colon tumour (Luesch et al. 2001). In addition, TZT-1027 (auristatin PE), an analogue of dolastatin (linear peptide), was tested in phase 1 clinical trials due to its good preclinical activity, particularly its antitumour activity against breast carcinoma and lung carcinoma in mice (Kobayashi et al. 1997). In another development, a drug named brentuximab vedotin (Fig. 12.3) developed based on antibody conjugated to dolastatin 10 has been approved by the US FDA for treating Hodgkin’s lymphoma and anaplastic large-cell lymphoma (Gerwick and Moore 2012). Recently, a patent on novel derivatives of dolastatin 10 and auristatins, particularly on their methods of production and use as medicinal products in the treatment of cancer, was filed (Perez et al. 2018).
Brentuximab vedotin, conjugation of antibody with dolastatin 10 (cyanobacterial metabolite), is a drug that has been approved by the US FDA for the treatment of Hodgkin’s lymphoma (Alves et al. 2018)
Cryptophycin-52 (LY355703), an analogue of the cyanobacterial depsipeptide cryptophycin, is another compound that has been brought into phase 1 clinical trial (Sessa et al. 2002). The trial was on patients with advanced solid tumour; however, adverse effects related to neuropathy and myalgia were reported. This was followed by a multi-centre phase 2 clinical trial on patients with non-small-cell-lung cancer (NSCLC) (Edelman et al. 2003). However, the results showed that cryptophycin-52 only has limited activity in NSCLC cells.
Other metabolites from cyanobacteria that have been found to display anticancer activity include apratoxin A, tricophycin A, calothrixin A and hapalindole H (Table 12.3). For instance, apratoxin A, a cyclic depsipeptide isolated from Lyngbya spp. (=Moorea spp.), was found to display potent inhibitory activity against cancer cell growth by inducing apoptosis and cell cycle arrest at G1 phase (Luesch et al. 2006). In addition, apratoxin A was found to show potent antitumour activity against U2OS osteosarcoma cells and this was attributed to its inhibitory action on the cellular secretory pathways (Liu et al. 2009). Recently, Cai et al. (2018) synthesized an analogue of apratoxin, named apratoxin 10 (Apra S10), and demonstrated its potential as an antipancreatic cancer agent using an orthotopic pancreatic patient-derived xenograft mouse model. The compound inhibited growth of pancreatic cancer cells via downregulation of multiple receptor tyrosine kinase and inhibition of growth factor and cytokine secretion.
Trichophycin A, a polycavernoside (polyketide) isolated from Trichodesmium thiebautii, was found to exhibit cytotoxic activity against neuro-2a-neuroblastoma and human colon cancer cell lines (Bertin et al. 2017). In addition, calothrixin A, a phenanthridine alkaloid isolated from Calothrix sp., was found to induce apoptosis in human Jurkat cancer cells and caused G2/M cell cycle arrest (Chen et al. 2003). Recently, Acuna et al. (2018) found that hapalindole H, an alkaloid compound isolated from Fischerella muscicola, displayed selective cytotoxicity against PC-3 prostate cancer cells.
The cyanobacterial pigment C-phycocyanin is another potential compound for the development of anticancer agent (Beata and Katalin 2017). The cell targets of C-phycocyanin include MDR1 gene, cytoskeletal proteins and COX-2 enzymes, making it capable of killing drug-resistant cancer cells (Fernandes et al. 2018). C-phycocyanin has been shown to induce apoptosis and cell cycle arrest as well as suppress cell migration, proliferation and colony formation ability of NSCLC cells by regulating multiple key genes (Hao et al. 2018). In addition, C-phycocyanin was found to show potent anticancer activity against triple-negative MDA-MB-231 breast cancer cells (Ravi et al. 2015). In another study, C-phycocyanin from Spirulina platensis was found to display antiangiogenesis effect on B16-F10 melanoma tumours in a C57BL/6 mouse model (Dibaei et al. 2018). Recently, Liu et al. (2018b) demonstrated that selenium-enriched phycocyanin (Se-PC), when applied via photodynamic therapy approach, was effective in inhibiting tumour development in a mouse liver cancer model.
There have been many studies that evaluated the anticancer activity of algal carotenoids in extract or purified form (Gateau et al. 2017; Cha et al. 2008). For instance, Cha et al. (2008) demonstrated that extracts from Chlorella vulgaris and Chlorella ellipsoidea, containing mainly violaxanthin and lutein, inhibited the growth of HCT116 human colon cells and enhanced apoptosis. In another study, lycopene from Chlorella marina was found to display stronger inhibitory effect against the growth and colony formation of human prostate cancer cells than the carotene from tomatoes (Renju et al. 2014b).
Astaxanthin and fucoxanthin are amongst the major algal carotenoids that have been widely studied for their anticancer activity. Astaxanthin is a keto-carotenoid produced by Haematococcus pluvialis, especially when it is under unfavourable growth conditions. The carotenoid is accumulated outside the chloroplast and the content can reach up to 4.5% dry weight in Haematococcus pluvialis (Boussiba et al. 1999). The anticancer effect of astaxanthin is suggested to be due to its inflammation and oxidative stress-reducing properties (McCall et al. 2018). In a recent study, McCall et al. (2018) demonstrated that treatment of astaxanthin significantly reduced proliferation rates and migration of breast cancer cells. In another study, Rao et al. (2013) demonstrated that mono- and diester forms of astaxanthin were more potent than the unesterified form of the xanthophyll in reducing UV-DBMA-induced skin cancer in a rat model. In addition, astaxanthin was found to be able to resensitize gemcitabine-resistant human pancreatic cancer cells (GR-HPCC) to gemcitabine (Yan et al. 2017). In addition, Palozza et al. (2009) showed that an astaxanthin-rich lipid CO2 extract from Haematococcus pluvialis inhibited the growth of human colon cancer cell lines. The use of Haematococcus extract instead of purified astaxanthin is attractive, as it reduces the high costs involved in the production, isolation and purification of the carotenoid, which may limit its application in cancer therapy (Palozza et al. 2009).
Fucoxanthin is another algal carotenoid that has been shown to display anticancer activity (Nakazawa et al. 2009; Kim et al. 2010, 2013; Jin et al. 2018; Wang et al. 2018a). While brown seaweeds are the major producers of fucoxanthin, marine microalgae such as Phaeodactylum tricornutum and Isochrysis galbana have also been shown to have the potential for commercial production of the carotenoid (Kim et al. 2012c, d). Fucoxanthin was found to induce reactive oxygen species (ROS) production, promoting apoptosis in HL-60 human leukaemia cells (Kim et al. 2010). In addition, the carotenoid was shown to inhibit growth of other cancerous cells including colon cancer (Caco-2) and prostate cancer (PC-3 and LNCaP) cells by inducing apoptosis (Nakazawa et al. 2009). Recently, Jin et al. (2018) demonstrated that combination of fucoxanthin with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) exerted a strong synergistic effect on apoptosis in human cervical cancer cells by targeting the P13K/Akt/NF-κβ signalling pathway. In another study, Wang et al. (2012b) demonstrated that fucoxanthin could significantly inhibit the growth of sarcoma in xenografted sarcoma 180 (S180) mice. Another in vivo model study showed that the administration of fucoxanthin could significantly inhibit the growth of tumour mass in mice implanted with melanoma B16F10 cells (Kim et al. 2013).
Several toxins produced by dinoflagellates including amphidinolides (APDN), amphidinols (APDL), karlotoxins (KTX), pectenotoxins (PTX) and yessotoxin (YTX) have been shown to display anticancer activity (Leira et al. 2002; Kobayashi and Tsuda 2004; Chae et al. 2005; Waters et al. 2010; Espiritu et al. 2017). For instance, APDN produced by dinoflagellates of the genus Amphidinium displayed strong cytotoxicity against murine lymphoma L1210 and human epidermoid carcinoma KB cell lines (Kobayashi and Tsuda 2004). A study on amphidinol-2 (AM-2) showed that the compound displayed cytotoxicity in HCT-116, HT-29 and MCF-7 cancer cell lines and upregulated the pre-apoptosis markers cfos and cjun in those cell lines (Espiritu et al. 2017). Karlotoxins (KTX), produced by Karlodinium venefictum, are potentially useful for lowering cholesterol or targeting cancer cells high in cholesterol (Waters et al. 2010). Pectenotoxins (PTX) are a group of toxins produced by dinoflagellates of the genus Dinophysis that cause diarrhetic shellfish poisoning (PSP) (Miles et al. 2006). The toxin was found to be highly effective in activating an intrinsic apoptosis pathway in p53-deficient tumour cells (Chae et al. 2005). Yessotoxin (YTX), a polyether toxin produced by Prorocentrum and Gonnyaulax, was found to induce apoptotic changes in BE(2)-M17 neuroblastoma cells (Leira et al. 2002).
Some of the microalgal polysaccharides have also been found to have anticancer activity. For instance, an extracellular polysaccharide (D-galactan sulphate) isolated from the toxic dinoflagellate Gymnodinium sp. A3 (GA3), exhibited cytotoxic effect against a panel of cancer cells (Umemura et al. 2003). The polysaccharide was found to exert its effect by inhibiting DNA topoisomerase I and II. In addition, cell wall sulphated polysaccharide from Porphyridium cruentum was found to exhibit strong antitumour activity against Graffi myeloid tumour in hamsters (Gardeva et al. 2014). The anticancer activity of the sulphated polysaccharide could be associated with its immunostimulating effect as well as with its direct cytotoxic properties.
Several lipid compounds from microalgae have been shown to display anticancer activity. For instance, nonyl 8-acetoxy-6-methyloctanate (NAMC), which is a novel fatty alcohol ester isolated from Phaeodactylum tricornutum, displayed strong suppression on the growth of HL-60 leukaemia cells by upregulating apoptotic pathways (Samarakoon et al. 2014). In addition, curacin A, a lipid compound isolated from Lyngbya masjucula, is another potent agent found to have selective antiproliferative activity against colon, renal and breast cancer cell lines (Gerwick et al. 1994). The compound acts by suppressing the binding of tubulin to colchicine. Another lipid compound, sigmasterol, isolated from Navicula incerta showed potent apoptotic effect against HepG2 liver cancer cells (Kim et al. 2014). Further, polyunsaturated aldehydyes (PUA), an allelopathic agent produced by diatoms, were reported to display cytotoxic effect against A549 lung cancer and COLO 205 colon cancer cell lines (Sansone et al. 2014). In a recent study, supplementation of algal oil rich in omega-3 PUFA was found to significantly suppress pulmonary metastases and outgrowth of melanoma cells in a mouse model (C57BL/6) (Tan et al. 2018).
2.5 Beneficial Effects Against Metabolic Disorders and Other Diseases
Several reports have highlighted the beneficial effects of consuming microalgae as a functional food in ameliorating metabolic diseases such as hyperlipidaemia, diabetes and obesity. For instance, feeding of rats with diets containing dietary fibre from pelleted red microalgal biomass (Porphyridium sp.) or their sulphated polysaccharides was found to significantly lower serum cholesterol levels (Dvir et al. 2000). In addition, the sulphated polysaccharides increased mucosa and muscularis cross-sectional area of the jejunum and caused hypertrophy in the muscularis layer. Similarly, feeding of Spirulina platensis concentrate was found to have hypocholesterolaemic effect in rats and the action was suggested to be due to the action of C-phycocyanin in inhibiting both jejunal cholesterol absorption and ileal bile acid reabsorption (Nagaoka et al. 2005).
There have also been animal model studies which showed that consumption of microalgae (whole biomass or extract) could have antidiabetic effect. For instance, algal extract prepared from Nannochloropsis oculata was found to lower glucose and C-reactive protein levels and restore insulin to normal level in streptozotocin-induced diabetic rats (Aboulthana et al. 2018). A study on diabetic rats showed that oral supplementation of Spirulina platensis could lead to an increase in trace minerals and antioxidant enzymes and lowering of plasma concentrations of glucose and inflammatory markers such as TNF-α and IL-6 (Nasirian et al. 2018). Another study showed that supplementation of omega-3 fatty acids extracted from microalgae could prevent the appearance of health complications caused by inflammatory states in diabetic rats (Gutierrez-Pliego et al. 2018). Recently, Zhang et al. (2018) demonstrated that administration of fucoxanthin significantly improved glucose/lipid metabolism and insulin resistance and prevented pancreatic histological changes in a diabetic mouse model. In addition, administration of astaxanthin has been shown to prevent the progression of diabetic nephropathy induced by oxidative stress in a mouse model (Naito et al. 2004).
Another metabolic disorder that is of great concern is obesity, as it has become a global threat to public health and imposes a huge expenditure on healthcare costs (Chu and Phang 2016). Amongst the algal compounds, fucoxanthin is one of the most well studied in terms of antiobesity effect (Gammone and D’Orazio 2015). Feeding of fucoxanthin was found to reduce the levels of inflammatory markers such as interleukin-18 (IL-18), TNF-α, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in an obese mouse model (Tan and Hou 2014). In addition, a combination of fucoxanthin and conjugated linoleic acid was found to reduce serum levels of triacylglycerols, glucose and leptin in diet-induced obese rats (Hu et al. 2012). Fucoxanthin also affects hepatic lipid contents by regulating metabolic enzyme activities and stimulating fatty acid oxidation activity (Woo et al. 2010). In addition, fucoxanthin exerts its antiobesity effect by inducing uncoupling protein 1 (UCP-1) expression in white adipose tissue (WAT), which enhances energy dissipation through fatty acid oxidation and heat production (Maeda 2015).
Long-chain omega-3 PUFA such as EPA and docosahexaenoic acid (DHA) has long been recognized to provide significant health benefits, particularly in reducing cardiac diseases such as arrythmia, stroke and hypertension (Romieu et al. 2005; von Schacky 2008; Ulmann et al. 2017). Dietary DHA has also been shown to be important for proper development of the brain and eye (Ward and Singh 2005). While fish oil is the major dietary source of EPA and DHA, it is not suitable for vegetarians and the odour makes it unattractive. Furthermore, there is concern over the decreasing global stocks of fish as sustainable sources of EPA and DHA for human nutrition (Ulmann et al. 2017). There are a variety of alternative sources of EPA and DHA including microalgae that are being explored for commercial production (Adarme-Vega et al. 2012). Amongst the microalgae, species of Thraustochytrium, Schizochytrium and Crypthecodinium are rich in DHA, while those of Phaeodactylum and Monodus are good sources of EPA (Ward and Singh 2005). In addition, the diatom Odontella aurita is another source of EPA, which has been commercialized as a dietary supplement (Mimouni et al. 2012). Algal DHA from Crypthecodinium cohnii produced by Martek Inc. has received approval for inclusion in infant formulae in the US (Ward and Singh 2005).
2.6 Other Bioactivities
Microalgae are known to produce a variety of compounds with antioxidative activity, particularly carotenoids such as astaxanthin, β-carotene and lutein (Chu 2011; Gateau et al. 2017). Such carotenoids are not only consumed as dietary supplement but also as natural food additives, which are better accepted by consumers than synthetic ones (Gateau et al. 2017). Amongst the carotenoids, astaxanthin is a very powerful antioxidant, as its activity is ten times more than other carotenoids such as zeaxanthin, lutein, canthaxanthin and β-carotene, and 100 times higher than α-tocopherol (Higuera-Ciapara et al. 2006). The protective effects of astaxanthin against diseases such as cancer, inflammatory diseases, diabetes and cardiovascular disease involve antioxidative mechanisms that prevent oxidative damage to cells (Ambati et al. 2014).
Among the carotenoids, consumption of lutein and zeaxanthin has been shown to be beneficial in reducing the development and progression of age-related macular degeneration (AMD) (Carpentier et al. 2009). Lutein and zeaxanthin are the two major macular pigments in the retina, which function as blue light filters and antioxidants. Increasing age has been proven to be a risk factor for the development and progression of AMD (Carpentier et al. 2009). Lutein is currently produced from marigold oleoresin, but several microalgae have been shown to contain higher amounts of the pigment than most marigold cultivars (Fernandez-Sevilla et al. 2010). The potential microalgal producers of lutein include Muriellopsis sp. (Del Campo et al. 2001), Scenedesmus almeriensis (Sánchez et al. 2008) and Chlorella protothecoides (Shi and Chen 2002).
In another development, there have been several reports on the beneficial effects of microalgae consumption in enhancing cognitive activity and ameliorating memory loss. For instance, in a recent study, Choi et al. (2018a) showed that extract from Spirulina maxima fermented with Lactobacillus planterium HY-08 could ameliorate scopolamide-induced memory impairment in mice. The efficacy of the fermented extract was suggested to be due to the synergistic effects of β-carotene and other bioactive substances, particularly in increasing extracellular signal-regulated kinases (ERK)-signalling and inducing expression of p-cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF). In another study, feeding of Chlorella-supplemented diet was found to reduce oxidative stress and prevent the decline in memory loss in a transgenic mouse model of age-dependent dementia (Nakashima et al. 2009). The studies by both Choi et al. (2018a) and Nakashima et al. (2009) showed the beneficial effects of Chlorella and Spirulina as functional food in enhancing cognitive activities. In both studies, algal extract or whole algal meal was tested rather than pure compounds.
3 Mass Culture of Microalgae for the Production of Pharmaceuticals and Nutraceuticals
Scaling up of microalgal cultures is an important aspect that needs to be considered in commercial production of pharmaceuticals and nutraceuticals from microalgae, as critically reviewed by Borowitzka and Vonshak (2017). It has been estimated that to produce 1 tonne/year of protein, about 18,300 L of culture are required, while production of β-carotene requires about 182,600 L of culture and fucoxanthin would require about 548,000 L. Most commercial production of microalgae is operated using outdoor open ponds due to its lower costs rather than closed systems, although the processing conditions are far from being optimal (Guedes et al. 2011). However, open pond systems have numerous issues including the difficulty in controlling temperature, light distribution and CO2 concentration, possibility of microbial contamination, and low biomass productivity (Guedes et al. 2011; Borowitzka and Vonshak 2017). Of great concern is microbial contamination, as it may compromise the quality of the final products. Thus, the production of high-value pharmaceuticals and nutraceuticals needs to be operated using photobioreactors (PBR). Closed systems using PBR allow the culture to be well controlled with the benefits of low contamination risk, high biomass productivity and high CO2 fixation efficiency (Wang et al. 2012a).
Many different types of PBR have been developed since the first flat panel PBR described by Burlew (1953). There are a variety of reactor designs including vertical column, tubular and flat panel PBR. Some examples of PBR used for the culturing of microalgae to produce pharmaceuticals and nutraceuticals are given in Table 12.4. Tubular PBR, which consist of an array of transparent tubes built in straight, bent or spiral patterns are amongst the most popular configuration (Wang et al. 2011). Using a Computational Fluid Dynamics (CFD) simulation approach, Guler et al. (2019) compared the performance of three types of PBR, namely flat plate, airlift and stirred tank for biomass and fucoxanthin production from Phaeodactylum tricornutum. The authors found that the highest biomass and fucoxanthin production was from the cultures grown in the flat-plate PBR.
There are also instances where both open and closed systems are integrated for commercial production of high-value chemicals from microalgae. For instance, an outdoor culture system consisting of both PBR and open pond was successfully developed to generate dense biomass of Haematococcus pluvialis for the extraction of astaxanthin (Olaizola 2000). In this system, the microalga was first grown in an outdoor PBR (25,000 L) before being transferred daily to an open pond system, where astaxanthin accumulation was induced. In a recent study, a hybrid system consisting of open pond and PBR, with culture medium circulating between both, was used to grow the oleaginous microalga Scenedesmus dimorphus under indoor and outdoor conditions (Liu et al. 2018a). The algal biomass productivity of the hybrid system increased 46.3–74.3% compared with the open pond and was 12.5% higher than that of PBR. Recently, Wang et al. (2018a) set up a pilot plant of 20 specially designed polyethylene phytobags (volume 150 L each) for the culturing of Phaeodactylum tricornutum to produce EPA. The EPA was shown to have potent antibacterial activity and have potential use as a feed supplement. In a recent development, Dunaliella salina was successfully grown on seawater desalination concentrate in floating PBR anchored on the ocean field of Lingshui Bay in China for the production of β-carotene (Zhu et al. 2018). The floating PBR system is an innovative design as the ocean provides a natural habitat with large cultivable area for microalgae and it facilitates temperature control due to the high specific heat capacity of seawater (Kim et al. 2016). In addition, the energy from waves can be used to mix the culture.
There have been reports on the successful cultivation of microalgae for products such as carotenoids and DHA under heterotrophic condition. For instance, Chlorella protothecoides grown heterotrophically on glucose and urea in fermenters scaled up to 30 L produced high biomass concentration (45.8 g/L) and attained high lutein productivity (49.18 mg/L/day) (Shi and Chen 2002). Similarly, Crypthecodinium cohnii grown on acetic acid (feeding rate of 50% w/w) on a fed-batch mode under heterotrophic condition afforded final concentrations of 109 g/L dry biomass, 61 g/L lipids and 19 g/L DHA (de Swaaf et al. 2003). The use of fermentation strategy under heterotrophic mode is an attractive strategy to reduce costs in producing high-density algal biomass without the need of light. However, not all microalgae or microalgal products can be produced this way (Borowitzka 1999).
Dinoflagellate toxins have great potential in pharmaceutical applications, as discussed in the previous sections. However, only few of those compounds have led to commercial products. The main challenge faced is to generate sufficient biomass for the extraction of the bioactive compounds (Camacho et al. 2007). While producing large quantities of other microalgae such as Chlorella, Spirulina, Dunaliella salina and Haematococcus pluvialis has proved to be successful (Borowitzka 1999; Ben-Amotz 2004; Belay 2013), culturing of dinoflagellates poses new challenges. The growth rates of dinoflagellates are lower than typical microalgae and the biomass attained are usually low. As the toxin concentrations are very low, extremely large volumes of cultures are required for the extraction process (Camacho et al. 2007).
The design of PBR for the culturing of dinoflagellates needs to consider the extreme sensitivity of such microalgae to shear stress and hydrodynamic forces (Cao et al. 2015; Gallardo-Rodriguez et al. 2016). The levels of shear stress that dinoflagellates can withstand are two orders of magnitude lower than most animal and plant cells (Chisti 1999; Juhl et al. 2000). In one study, García Camacho et al. (2007) showed that the tolerance of Protoceratium reticulatum, a producer of yessotoxin, to shear stress was very low compared to other dinoflagellates and animal cells. The dinoflagellate cells were damaged to varying degrees under low shear stress of >0.12 to 0.20 mN/m2. Turbulence due to agitation, shaking, aeration and stirring has been reported to inhibit the growth of dinoflagellate cultures (Pollingher and Zemel 1981; Berdalet 1992; Juhl et al. 2001).
Despite the challenges, there have been several successful ventures in mass culturing of dinoflagellates to produce bioactive compounds. For instance, a pilot-scale bioprocess was developed for the production of karlotoxin-enriched extracts of Karlodinium veneficum using a bubble column and a flat-panel PBR (80–281 L) under outdoor conditions (Lopez-Rosales et al. 2018). The bubble column PBR proved to be a better culture system than the flat panel PBR based on the maximum cell productivity attained (58 × 103 cells/mL/day). In another pilot-scale study, Molina-Miras et al. (2018) developed a LED-illuminated bubble column PBR (80 L) to culture Amphidinium carterae for the production of amphidinols (APDN). As APDN were excreted by cells into the medium, a dry APDN-enriched extract (49 mg/L) was recovered from the supernatant.
Integration of bioprocessing of the algal biomass for bioactive compound production with other applications such as biofuel production, CO2 fixation and bioremediation based on a biorefinery concept is an attractive approach to improve economic competitiveness (Giraldo-Calderón et al. 2018; Costa et al. 2019). Figure 12.4 illustrates how the various applications of microalgae can be integrated using a biorefinery approach. An example of how this concept is applied is the culturing of Haematococcus pluvialis in bubble column reactors to remove flue gas, attaining high biomass and astaxanthin productivity (Choi et al. 2018b). In another set-up, Spirulina platensis grown in a flat-plate PBR was used to produce C-phycocyanin and simultaneously mitigate CO2 emissions during its growth (Chen et al. 2013).
Integration of bioactive compound production with other applications of microalgae, including biofuel production, based on a biorefinery concept
Another example of biorefinery process, focusing on the downstream processing aspect, was reported for the production of fucoxanthin by Isochrysis galbana (Gilbert-López et al. 2015). A green chemistry approach was used to extract a variety of products from the microalgal biomass. The process involved first the extraction of fucoxanthin using supercritical CO2, followed by recovering other fractions with high antioxidant activity and, eventually, carbohydrates and proteins from the residual biomass. In another biorefinery process, lipids and carotenoids were extracted from Nannochloropsis sp. using supercritical CO2 and the residual biomass was subjected to dark fermentation for production of biohydrogen (Nobre et al. 2013). Details of various aspects of biorefinery for Nannochloropsis in relation to induction, harvesting and extraction of EPA-oil and other products such as high-value proteins were recently reviewed by Chua and Schenk (2017).
The use of wastewater as a low-cost substrate for the culturing of microalgae can be an important component of the biorefinery approach. For instance, Olguin (2012) highlighted the potential of growing Spirulina in seawater supplemented with anaerobically digested piggery waste for waste treatment and production of biogas, biodiesel and high-value chemicals such as C-phycocyanin using the biorefinery approach. However, strict regulatory requirements need to be complied with in ensuring that products derived from microalgae in wastewater are free from potential impurities if they are to be marketed as pharmaceuticals or nutraceuticals (Borowitzka and Vonshak 2017). Efficient extraction technologies (e.g. supercritical fluid extraction and enzyme-assisted extraction) are crucial in order to attain high yields and to obtain products of high purity (Sosa-Hernandez et al. 2018).
4 Future Directions of Research
The pharmaceutical and nutraceutical industries based on microalgae are still confined to a few well-established products such as astaxanthin and C-phycocyanin. Also, commercial production of microalgae as functional food is based on only a few species, notably Spirulina platensis, Haematococcus pluvialis, Chlorella spp. and Dunaliella salina. As highlighted in this chapter, there is a diverse range of potential bioactive compounds that have been discovered from microalgae. However, there are many hurdles that need to be overcome before such compounds can be further developed for the pharmaceutical and nutraceutical industries.
Despite the many reported studies on bioactive compounds from microalgae, most have been exploratory, focusing mainly on mechanistic aspects confining to laboratory investigations. Most studies on the bioactivities of microalgal compounds are still at the pre-clinical stage based on cell lines or animal models. Very few clinical trials have been conducted to validate the efficacy of such compounds in human subjects. Dolastatin 10 (Vaishampayan et al. 2000) and cryptophycin 52 (Edelman et al. 2003) are amongst the microalgal compounds that have been brought to clinical trials to evaluate their anticancer activity. There have been more clinical trials on astaxanthin compared to other microalgal compounds. The clinical trials on astaxanthin have been conducted on human subjects to assess its hypolipidaemic, hypotensive and antioxidant effects (Ambati et al. 2014). Despite the potential anticancer activity of astaxanthin, as highlighted in this chapter, there have been not been any clinical trials of astaxanthin conducted on cancer patients. So far, there has been only one drug developed from microalgal compound, brentuximab vedotin (dolastatin conjugated with antibody), which has been approved as a cancer therapeutic agent (Gerwick and Moore 2012). More clinical trials on microalgal compounds are urgently required before new therapeutic agents can be brought to the market.
Scaling up of microalgal cultures to ensure sufficient supply of biomass for the extraction of bioactive compounds is a crucial part in the development of the pharmaceutical and nutraceutical industries based on microalgae (Borowitzka and Vonshak 2017). Although many microalgae have been identified as a source of bioactive compounds, very few have been evaluated beyond laboratory culture conditions. The potential species should be assessed for their performance when grown on a large scale under outdoor conditions. An example of such large-scale study using 10 pilot-scale trials involving high-rate algae ponds (HRAP) and PBR (flat-panel and tubular forms) was reported by Wolf et al. (2016). The aim was to assess the interaction between solar energy input, ambient temperature and system surface area-to-volume ratio in influencing yield and areal and volumetric productivities of Chlorella sorokiniana and Chlorella sp. cultured in those systems. Moving forward, new tools such as artificial intelligence (AI), particularly neural learning and statistical and evolutionary learning-based techniques, should be applied in optimizing productivity and costs in mass culture of microalgae (Jha et al. 2017b). The AI tools that can be applied involve statistical models such as Bayesian and naïve Bayes, clustering, hidden Markov and nearest-neighbour models.
The use of molecular approaches, particularly “omics’” tools, to enhance production of the desired microalgal metabolites is another area that has seen much advances in recent years (Guarnieri and Pienkos 2015). Microalgae are now regarded as highly attractive candidates for development as microbial factories. More studies are needed to unravel the biosynthetic pathways for the high-value metabolites in microalgae. Metabolomics approach will be useful for a comprehensive analysis of the secondary metabolites and elucidation of the pathways involved in the synthesis of the novel compounds in microalgae (Prakash et al. 2018). Metabolic and genetic engineering can then be applied to manipulate production of the microalgal metabolites. For instance, modification of the carotenoid biosynthesis pathway by genetic engineering has resulted in an increase of 67% astaxanthin production in the transformed strains of Haematococcus pluvialis compared to the wild-type (Galarza et al. 2018). Genome mining is another approach that is worth further exploring in attempts to discover novel metabolites in microalgae for the development of new drugs. Using this approach, instead of whole-genome sequencing, it allows rapid identification of gene clusters that code for specific compounds (Shih et al. 2013). The chemical structure of the compound can then be predicted based on the sequence information using in silico modelling.
Improving the delivery and bioavailability of bioactive compounds from microalgae is another area that warrants further investigations. This area is particularly relevant to microalgal products such as astaxanthin, which is already in the market, and potential new drugs intended for commercialization. For instance, the low bioavailability of astaxanthin may result in low assimilation into the body system, reducing its effectiveness as a supplement (Anarjan et al. 2013). There have been some recent studies that aimed to develop astaxanthin formulations in encapsulated forms to enhance its bioavailability (Khalid and Barrow 2018; Niizawa et al. 2018). In another line of development, nanoformulations using a wide variety of nanoparticles and their polymerized forms is an emerging approach in the development of new cancer drugs (Bajpai et al. 2018). For instance, a carbon-based nano-delivery system for anticancer drugs, in combination with genetically bioengineered biosilica from Thalassiosira pseudonana, was developed to kill targeted cancer cells without any adverse effect on normal and healthy cells (Delalat et al. 2015).
5 Concluding Remarks
There are indeed a diverse range of bioactive compounds from microalgae that have great potential to be developed for pharmaceuticals and nutraceutical applications. The bioactivities of microalgal metabolites that have attracted much interest include anticancer, antibacterial, antiviral and immunomodulatory activities, and their beneficial effects in ameliorating metabolic disorders such as diabetes, obesity and hyperlipidaemia. However, there are only a few pharmaceuticals and nutraceuticals derived from microalgae that have been successfully brought to commercialization. Amongst the well-known commercial microalgal products include astaxanthin, fucoxanthin, C-phycocyanin, β-carotene and PUFA. Clinical trials to evaluate the efficacy and safety of other bioactive compounds from microalgae are urgently needed before the compounds can be considered for the development of new drugs. Also, the feasibility of mass culturing of the selected microalgae under outdoor conditions needs to be critically evaluated. Production of bioactive compounds integrated with other applications such as biofuel production and CO2 biofixation based on a biorefinery concept is an attractive strategy to enhance economic feasibility.
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Acknowledgements
The first author would like to acknowledge the funding and support from the International Medical University for algal biotechnology research. Phang S.M. would like to acknowledge the following grants: UM Algae (GA003-2012); MOHE-HiCoE Grant Phase 2 (2019-2021); UM Grand Challenge-SBS No.GC002B-15SBS.
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Chu, WL., Phang, SM. (2019). Bioactive Compounds from Microalgae and Their Potential Applications as Pharmaceuticals and Nutraceuticals. In: Hallmann, A., Rampelotto, P. (eds) Grand Challenges in Algae Biotechnology. Grand Challenges in Biology and Biotechnology. Springer, Cham. https://doi.org/10.1007/978-3-030-25233-5_12
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