Unveiling the importance role of lutein-plant-based nanoencapsulation – a future effort to improve their stability and bioaccessibility in combating ocular melanoma

ABSTRACT

Despite its potential benefits, lutein availability can be limited due to inadequate dietary intake of fruits, vegetables, and seaweed. Additionally, lutein faces challenges related to gastrointestinal absorption due to its physicochemical characteristics. To tackle these issues, fortifying staple foods with lutein is proposed, but its low solubility and susceptibility to oxidative degradation present hurdles. Nanoencapsulation technology emerges as a promising solution for improving lutein stability during food processing, storage, and absorption. However, lutein’s stability remains a challenge, with susceptibility to degradation by temperature, UV-light, and oxygen exposure. Food processing involving high temperatures can cause degradation, while specific UV-wavelengths lead to cleavage of lutein molecules. This critical viewpoint carries substantial scientific significance by urging researchers globally to prioritize clinical investigations and the advancement of plant-based lutein nanoencapsulation in basic dietary items. Clinical studies focusing on lutein-plant-based nanoencapsulation approaches are essential to improve its stability and bioaccessibility, ultimately contributing to better vision health.

GRAPHICAL ABSTRACT

KEYWORDS:

• Lutein
• molecular oncology
• natural product
• nanoencapsulation technology
• ocular melanoma
• carotenoids

1. Introduction

Carotenoids are part of the terpenoids pigment family which are abundant in fruits, vegetables, and marine seaweeds, and are linked to several potential health benefits due to their antioxidant and anti-inflammatory properties (Mordi et al., 2020). Lutein (PubChem CID 5,281,243; https://pubchem.ncbi.nlm.nih.gov/compound/5281243) is one of the main carotenoids that can selectively accumulate in the eye, macula, and retina and is believed to have an eye protection effect because of its ability to extinguish reactive oxygen species (ROS) and absorb blue light (Balasubramaniam et al., 2020; Jain & Sirisha, 2020; Roberts & Dennison, 2015). According to a 2019 report from the World Health Organization (WHO), approximately 2.2 billion individuals worldwide are affected by visual impairments, with 1 billion of them not having received any form of treatment (Demmin & Silverstein, 2020; Tedros Adhanom Ghebreyesus, 2019). Following skin melanoma, the second most prevalent form of melanoma is ocular melanoma, which originates from melanocytes found in the conjunctival membrane and uveal tract within the eye (Jovanovic et al., 2013). Epidemiological data indicates that consuming lutein is associated with a reduced risk of age-related macular degeneration and cataracts (Pietro et al., 2016), as well as providing potential benefits in the fight against cancer and tumors (Kavalappa et al., 2021). Lutein is largely contained in carrots, corn, wheat cantaloupe, and orange/yellow paper, in addition to animal sources such as salmon and eggs (Abdel-Aal et al., 2013). Seaweed is another widely available lutein source that has not yet been commonly exploited (Fukushima et al., 2023). However, lutein is exclusively sourced from food, and its availability is often inadequate due to the limited intake of fruits and vegetables. Moreover, the consumption of seaweed is scarce (even though the lutein composition contained is more abundant). In addition to that, the effectiveness of lutein in biological processes relies heavily on how well it gets absorbed in the gastrointestinal system, and this absorption can be hindered by its physicochemical characteristics (Ciccone et al., 2013).

One way to address the challenge of insufficient lutein intake is to create staple foods fortified with lutein, ensuring a regular supply of this compound to the body. In accordance with the WHO guideline 2019, the interventions with fortified food are recommended to prevent the development of ocular diseases, especially for programs engaging large-scale communities (Tedros Adhanom Ghebreyesus, 2019). However, simply adding lutein to food offers minimal nutritional benefits because it has low solubility and is prone to oxidative degradation (Roberts & Dennison, 2015). Nanoencapsulation technology presents an appealing strategy for encapsulating bioactive compounds within a carrier, enhancing stability during food processing, storage, and gastrointestinal absorption (Pateiro et al., 2021; Zaher et al., 2022). Microfluidics has gained popularity in innovative food processing, and the emerging application of microfluidic engineering is nutrient nanoencapsulation (Ravichandran, 2010). This approach may revolutionize how we handle dispersed food systems and enable precise manipulation of structure at the micro level. Due to its hydrophobic nature, lutein needs to be incorporated into mixed micelles for effective gastrointestinal absorption.

The existing body of research on nutrient nanoencapsulation in conjunction with emulsion-based delivery systems is somewhat limited. Therefore, this critical perspective holds significant scientific importance as it encourages researchers worldwide to focus on clinical research and the development of plant-based lutein nanoencapsulation in staple foods as a means to address nutritional issues related to eye health, particularly in the context of combating ocular melanoma. This initiative aligns with the objectives of the WHO World Report from 2019, which aimed to tackle vision-related challenges and drive action (Demmin & Silverstein, 2020), including through innovative research. We hope that this concise critical perspective will support endeavors aimed at reducing the burden of eye-related conditions and vision impairment, ultimately contributing to the achievement of Sustainable Development Goals (SDGs), with a particular emphasis on SDG 3.8, which focuses on universal health coverage through clinical studies on lutein-plant-based nanoencapsulation conducted by researchers worldwide. In essence, this endeavor recognizes the significance of each individual’s vision in the broader context of global health.

2. Search strategy and selection criteria

References for this review were identified via searches of PubMed for articles published until January 2024, using the search scope of “Articles published in English.” Relevant references cited in those articles were reviewed. The terms were as follows: (eye) OR (vision) AND (nanoencapulation) OR (nanotechnology) (melanoma) OR (cancer) OR (ocular melanoma) OR (oncology) AND (lutein)) OR (carotenoids). Relevant articles were identified by searching the authors’ files in Google Scholar, Scopus, ScienceDirect, and the Springer Online Archives Collection.

3. Results and discussions

3.1. Molecular structure of lutein

As a member of xanthophylls in the carotenoids family, lutein molecular structure is derived from a tetraterpene containing two oxygens in the form of hydroxyl (OH) moieties. The molecule contains 40 carbon with conjugated double bonds and has a close similarity with its xanthophyll counterpart – zeaxanthin (Demmig-Adams et al., 2022). The molecular structure of lutein in 2D and 3D conformations has been presented in Figure 1(a,b). Lutein is biosynthesized by photosynthesis-dependent organisms or genetically modified bacteria, such as Synechocystis sp. (Lehmann et al., 2021), where its pure crystalline isolates tend to have – an orange color appearance. The hydroxyl moieties in the compound could experience esterification, and in the case of marigold-sourced isolate, lutein is commonly found in its esterified form with palmitic acid (Clowutimon et al., 2018). In this esterified form, lutein becomes more susceptible to degradation (Martínez-Delgado et al., 2017). Thus, to obtain the non-esterified or free form of lutein, a reaction with a strong base using aqueous alcohols is required (Clowutimon et al., 2018).

Figure 1. Molecular structure of lutein in 2D (a), and 3D conformations (b). Oxidated derivatives of lutein (c), and SwissADME-generated bioavailability radar (d) (http://www.swissadme.ch/index.php; accessed on 12 March 2023).

3.2. Stability, bioaccessibility, and bioavailability of lutein

Intake of lutein-rich foods (such as paprika, spinach, parsley, lettuce, kale, and peas) has been evidenced to yield ocular health benefits against, but not limited to, age-related macular degeneration (AMD) and cataracts (Buscemi et al., 2018). However, the benefits of lutein from the food source are limited by its bioaccessibility. Upon its entering the gastrointestinal tract, emulsification of lutein into small lipid particles occurs followed by its merging into mixed micelles facilitated by bile salts and biliary phospholipids, where the enterocytes, mediated by scavenger receptor class B type I protein, then plays its role in the micelles absorption (Xavier et al., 2018). The bioaccessibility of lutein has been studied in vitro using gastrointestinal digestion models, where the values ranged from 5% to 100% depending on the types of food or drink (Ochoa Becerra et al., 2020). Fortification of lutein into a fermented milk provides 100% bioaccesibility of lutein (Granado-Lorencio et al., 2010).

The stability of this compound is the limitation of lutein in exerting its health benefits, as the molecule is prone to alteration by the effect of temperature, UV-light exposure, and oxygen exposure. Food processing that requires high temperatures (cooking, drying, frying pasteurization, canning, and so on) could cause the degradation and isomerization in lutein structure (Maiani et al., 2009). Degradation of lutein in wheat grain has been observed to occur at temperatures of as low as 40°C, and it increases significantly after ≥80°C (Ahmad et al., 2013). Exposure to UV-length at certain wavelengths, namely 200–400 nm, 463 nm, and 365 nm has been reported to cause major cleavage of lutein into smaller molecules (Khalil et al., 2012; Kline et al., 2011). Lutein may undergo auto-oxidation owing to the exposure to atmospheric oxygen. Moreover, the oxidation of lutein may also take place during the drying process of the lutein-sourced foods. Hence, it is pretty common for lutein to lose its stability owing to oxidation resulting in the production of apocarotenoids (carotenoids with <40 C atoms) (González et al., 2011), as presented in Figure 1.

The bioavailability of lutein is found abundant in the retina, where it can exert its bioactive effects to protect and improve the ocular organ. Other than that, due to its low stability and bioaccessibility, lutein has molecular properties that contribute to its low bioavailability. Based on the bioavailability radar generated by SwissADMET (http://www.swissadme.ch/index.php), lutein has poor bioavailability especially due to its large molecular size and number of rotatable bonds exceeding 9 (Figure 1(c)). Based on the experimental data, lutein is not soluble in water (logP = 7.9) with a polarity of 40.46 Å (Table 1). As the data were derived from in vitro experimental, though it can stimulate the small intestinal digestion, it may fail to make a distinction between bioaccessibility and bioavailability efficiency (Mohammadnezhad et al., 2023; Vlaicu et al., 2023). In human studies, the bioavailability of Lutein (administered as lutein-fortified milk 200 mL/day for 14 days) was found to be as low as 0.56 µmol/L (Granado-Lorencio et al., 2010). Broccoli intake of 200 g/day for 7 days yielded a lutein concentration of 0.30 µM in the plasma and retinal lutein content of 0.91 ± 0.31 ng/g (Granado-Lorencio et al., 2007). Nonetheless, researchers have been developing strategies, including nanoencapsulation, to improve the stability, bioaccessibility, and bioavailability of lutein (Kamil et al., 2016).

Table 1. Molecular properties of lutein based on SwissADME*.

Properties	Values
Molecular weight, g/mol	568.87
Fraction Csp3	0.45
Number of rotatable bonds	10
Number H-bond acceptors	2
Number H-bond donors	2
Molar refractivity	186.76
Polar surface area, Å^2	40.46
Melting point,°C	196
Water insolubility	Insoluble
LogP	7.9

*(http://www.swissadme.ch/index.php; accessed on 12 March 2023).

3.3. General and emerging sources of lutein

Pigmented plant-based foods such as carrots, corn, wheat cantaloupe, and orange/yellow paper, along with animal meats such as salmon and eggs have been suggested as good sources of lutein (Abdel-Aal et al., 2013). Eggs contain lutein and other carotenoids, and their contents can be increased by feeding the laying hens with alfalfa meal (Englmaierová et al., 2019). Today, lutein could be isolated from other alternative sources as presented in Table 2. Marigold flower petals are not traditionally considered the source of nutrients, but recent studies suggest the presence of high lutein in the flower (Dharani et al., 2022; Maheshwari et al., 2023; Shaikh et al., 2023). Lutein content in marigold flowers could reach as high as 35.49% w/w after the supercritical fluid extraction (SCFE) [17]. Endangered Cyclamen sp. flowers have also been investigated for their potential as lutein sources, where the lutein yield reached 44.92—143.91 mg/g dried extract (Cornea-Cipcigan et al., 2022). Extraction techniques contribute to the proportion of lutein contained in the extract. More eco-friendly approaches using magnetic nanoparticles (Savvidou et al., 2022) and non-ecotoxic solvents (such as the combination of choline chloride and glucose) have been employed (Dharani et al., 2022; Savvidou et al., 2022).

Table 2. Updated research on lutein isolation from different plant-based sources and its medicinal benefits in vitro.

Author (Year)	Source	Extraction	Lutein Content	Medicinal Benefits
Shaikh et al. (2023)	Marigold flowers (Tagetes erecta L.) and dried coconut (Cocos nucifera L.)	SCFE using carbon dioxide optimized by using Box-Behnken design (398 bar; 60°C; 149 min)	35.49% w/w	Antioxidant activities (DPPH, ABTS, and FRAP) Anti-inflammatory (protein denaturation)
Sawasdee et al. (2023)	Chlorella sp.	Maceration using ethanol (95%) with a ratio of 1:25 w/v	1.70 mg/g	Induce apoptosis and growth inhibition against various cancer cell lines.
Wang et al. (2023)	Chlorella sp.	Pressurized liquid extraction using DMSO (100%)	3.31 mg/g	Not reported
	Phaeodactylum tricornutum		0.82 mg/g	Not reported
Georgiopoulou et al. (2023)	Chlorella vulgaris	MAE+ethanol (90% v/v) (60°C; 300 watts; 14 min; 22 mLsolv/gbiom)	7.06 mg/g	Antioxidant activity (DPPH)
Maheshwari et al. (2023)	Marigold flowers (Tagetes erecta L.)	Extraction with surfactant-based aqueous two-phase system and optimized by response surface methodology (37.5°C; 0.00375 S/L; 1.5% v/v surfactant)	12.12 mg/g	Antioxidant activity (DPPH)
Koraneeyakijkulchai et al. (2023)	Sweet corn (Zea mays L. ssp. saccharata Sturt)	Freeze-dried and extracted using hexane: acetone: ethanol (2:1:1)	1.43 mg/g	Reduced inflammatory markers via MAPK and NF-κB signaling pathways
Liang et al. (2023)	Haemodorum spicatum bulbs	Freeze-dried and extracted using ethanol	3.23 μg/g	Not reported
Ova et al. (2022)	Chlorella miniata	Soxhlet extraction using ethanol/water with optimized cultivation by RSM (27.5°C; 431 µmol/m^2s light intensity; 3 L/min aeration rate)	42.30 mg/g	Not reported
Cvitković et al. (2022)	Myrtus communis L. leaves	Cryogrinding (6 min) and hydrodistillation (15 min)	0.78 mg/g	Not reported
Dharani et al. (2022)	Targetus erecta L flowers	Extraction using deep eutectic solvents (choline chloride+ glucose)	368.64 mg/g	Not reported
Georgiopoulou et al. (2022)	Chlorella vulgaris	SFE using CO2 (60°C, 250 bar, 40 g/min)	21.14 mg/g	Antioxidant activity (DPPH)
Savvidou et al. (2022)	Haematococcus pluvialis	Selective magnetic separation using magnetic nanoparticles FluidMAG-Amine	0.36 mg/mL	Not reported
Maswanna and Maneeruttanarungroj, (2022)	Tetraspora sp. CU2551	Cultivated in nitrogen-deprived medium and extracted using ethanol	30.57% abundance	Not reported
Ruiz-Domínguez et al. (2022)	Coccomyxa onubensis	SFE using CO2 optimized by RSM (70°C; 40 MPa; 50% v/v ethanol)	15.83 mg/g	Antioxidant activity (ABTS)
Cornea-Cipcigan et al. (2022)	Aerial parts of Cyclamen persicum Mill., C. mirabile Hildebr. C. hederifolium Mill.	Freeze-dried and extracted using methanol: water (80/20)	44.92—143.91 mg/g (C. persicum)	Antioxidant activities (DPPH, ABTS, and FRAP)
Patel et al. (2022)	Chlorella sorokiniana Kh12	Cultivated under mixotrophy (2X-(HT)-9k), ball-milled, and extracted using methanol	13.69 mg/g	Not reported
Englmaierová et al. (2019)	Alfalfa (Medicago sativa L.)	Dehydration	86.30 mg/kg	Not reported

ABTS, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid; DMSO, dimethyl sulfoxide; DPPH, 2,2-diphenyl-1-picrylhydrazyl; FRAP, ferric reducing antioxidant power; HPLC, high-performance liquid chromatography; MAE, microwave-assisted extraction; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; RSM, Response Surface Methodology; SCFE, supercritical fluid extraction; SMS, selective magnetic separation.

Moreover, large bodies of evidence have suggested that microalgae could be utilized as the source of carotenoids, including lutein. Chlorella sp. is the commonly reported microalgae used to obtain lutein (Georgiopoulou et al., 2022; Ova et al., 2022; Patel et al., 2022; Wang et al., 2023), while others include Haematococcus pluvialis (Savvidou et al., 2022), Coccomyxa enuresis (Ruiz-Domínguez et al., 2022), and Tetraspora sp (Maswanna & Maneeruttanarungroj, 2022). Diatom Phaeodactylum tricornutum is also among the alternative sources of lutein that have been reported (Wang et al., 2023). Other than optimizing the extraction parameters, a higher yield could be obtained by changing the algal cultivation parameter (Maswanna & Maneeruttanarungroj, 2022; Patel et al., 2022). Which, alga could be cultivated in nitrogen-deprived conditions to optimize the biosynthesis of lutein (Maswanna & Maneeruttanarungroj, 2022). In the pre-treatment stage, the physical force could be applied to create smaller powder particles that could allow higher extraction yield (Marlina et al., 2020). Several examples of this approach are ball-milling (Patel et al., 2022) and cryogrinding (Cvitković et al., 2022).

Lutein or lutein-rich extracts are good antioxidant and anti-inflammatory agents as proven by multiple studies (Belyagoubi et al., 2022; Cornea-Cipcigan et al., 2022; Georgiopoulou et al., 2022, 2023; Liang et al., 2023; Maheshwari et al., 2023; Ruiz-Domínguez et al., 2022; Shaikh et al., 2023). A study even reported the anti-inflammatory activity of lutein in the human retinal pigment epithelial cell line (ARPE-19) that was induced by interleukin (IL)-1β. Chlorella sp. extract with lutein of 1.70 mg/g dried extract was shown to inhibit various cancer cell lines in vitro (Sawasdee et al., 2023). Because this nutrient is highly abundant in plants and microalgae, more studies should be developed to exploit its medicinal benefits.

3.4. Lutein in the cancer and tumor research (in Vivo/in vitro)

Antitumor activities of lutein were witnessed in 2003 by Chew and colleagues who used mouse models injected with mammary tumor cells (B. P. Chew et al., 2003). They found that lutein induces selective apoptosis toward tumor cell and inhibit its angiogenesis (Figure 2) (B. P. Chew et al., 2003). Similar to the research performed by other research groups, the viabilities of in vitro cancer cells were found reduced in the lutein-treated sample (Gansukh et al., 2019; Liu et al., 2016; Luan et al., 2021; Omar et al., 2021; Rafi et al., 2015; Ruiling, 2019; Yamagata et al., 2017). Lutein-induced apoptosis is mostly evidenced by the upregulation of Bax and downregulation of B-cell lymphoma 2 (Bcl-2) along with the downregulation of Bcl-2/Bax ratio (Figure 2) (B. P. Chew et al., 2003; Eom et al., 2023; Gansukh et al., 2019; Sawasdee et al., 2023; Yamagata et al., 2017). Downregulation of Bcl-2 is an important step in the initiation of the caspase signaling cascade during apoptosis as the protein is responsible for the formation of apoptosome (Figure 2) (Ola et al., 2011). Caspase-3, as the dominant executioner dominant caspase in cell apoptosis (Brentnall et al., 2013), has been found positively affected by the introduction of lutein (Eom et al., 2023; Gansukh et al., 2019; Kavalappa et al., 2021; Yamagata et al., 2017). Nonetheless, the precursor of this caspase, procaspase-3, has been reported to be overexpressed in various malignancies and contributes positively to the oncogenic transformation as its low-level activity induces subapoptosis instead of apoptosis (Boudreau et al., 2019). In this light, lutein has been found as a promising activator of procaspase-3, −8, and −9 and a promoter of caspase enzymatic activities (Sawasdee et al., 2023). Furthermore, the presence of lutein impacts positively to the activation of pro-apoptotic nuclear transcription factor p53 (Figure 2) (B. P. Chew et al., 2003; Luan et al., 2021).

Figure 2. Anticancer mechanism of lutein.

Lutein is also known to induce apoptosis against cancer and tumor cells via oxidative pathways. Photo-oxidized form of lutein could reduce endogenous antioxidants, namely glutathione and malondialdehyde (MDA), that increase the oxidative stress that could inhibit the growth of HeLa cells (Lakshminarayana et al., 2010). A study found that exposure of lutein to human buccal mucosa squamous carcinoma BICR10 cells could increase the expression of oxidative stress-responsive kinase-1 (OXSR1) which is a member of serine or threonine protein kinase family (Enășescu et al., 2021). Clear evidence of oxidative stress-related apoptosis by lutein in a recent study using gastric cancer AGS cells (Eom et al., 2023). The level of reactive oxygen species (ROS) was found to increase concomitant to the activation of NADPH oxidase resulting in apoptosis (based on bax, bcl-2, caspase-3, and cell viability profiles) (Eom et al., 2023). The foregoing apoptosis could be reversed by the introduction of N-acetylcysteine acting as an antioxidant with NADPH oxidase inhibition as its mechanism of action (Eom et al., 2023). The formation of ROS as a means of lutein-induced apoptosis has also been witnessed in another study using HeLa cell lines (Gansukh et al., 2019). Nonetheless, ROS is beneficial in cancer cells during a hypoxic state that stabilizes hypoxia-inducible factor-1α (HIF-1α) further implicating the malignancy (Chandel et al., 2000). Treatment using lutein in this state could attenuate the ROS and consequently downregulate the HIF-1α (Y. Li et al., 2018).

Additionally, studies have suggested that lutein may impair the growth of cancer and tumor cells through other pathways. Upregulations of nuclear factor erythroid 2-related factor-2 (Nrf-2) and heme oxygenase-1 (HO-1) have been witnessed in lutein-treated HT29 cells, in which these findings are associated with the antiproliferative activity of lutein (Liu et al., 2016). A study using multiple cancer cell lines revealed that lutein reduces phosphorylated forms of protein kinase B (AKT) and the mammalian target of rapamycin (mTOR), thereby inhibiting the AKT/mTOR survival signaling (Sawasdee et al., 2023). Lutein also disrupts cancer growth by altering the expressions of cancer stem cell-related markers namely SOX-2, NANOG, CD44, CD133, SLCA11, and ABCB1 (Yamagata et al., 2017). Lutein could affect the expression of long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs) that are associated with tumor progression (Y. Zhang et al., 2021). As a combinatorial therapy with doxorubicin, lutein may increase its efficacy whilst reducing its adverse inflammatory effects (Luan et al., 2021). Findings of lutein as anticancer and antitumor agents as reported by multiple in vitro/in vivo studies have been summarized in Table 3.

Table 3. Recent studies (in vivo/in vitro) of lutein as an anticancer or antitumor.

Author, Year [Ref]	Model	Findings
Yamagata et al. (2017)	A549 human lung adenocarcinoma cells	Apoptosis via Bcl-2/Bax and caspase-3 Altering the expressions of cancer stem cells biomarkers (SOX2, NANOG, CD33. CD133, SLCA11, ABCB1)
Y. Li et al. (2018)	MCF7 MDAMB157 human breast cancer cell lines	Promoting cell cancer apoptosis. Suppressing HES1, HIF-1α, NOTCH signaling, and ROS.
Omar et al. (2021)	Human liver HepG2, breast MCF-7, lung A549, prostate PC3, and colon HCT116 cancer cell lines	IC50 = 3.10±0.47 μg/mL (MCF-7) and 6.11±0.84 μg/mL (HepG2) Non-active against A549, PC3, and HCT116 cells. Non-toxic towards HFB4 cells.
Y. Zhang et al. (2021)	MCF7 cells	Downregulating CASC9 expression and upregulating miR5903p
Luan et al. (2021)	Sarcoma 180 (S180) cell	Reducing cell proliferation and suppressing PCNA Promoting apoptosis-relevant gene p53. Inhibiting NF-κB.
Kavalappa et al. (2021)	MCF-7 and MDA-MB-231 cells	Downregulation of SOD-2, HO-1, and Nrf2. Downregulation of PKB, phosphorylated ERK1/2, NF-κB. Elevation of caspase-3 activity with downregulation of Bcl-2 and poly-ADP ribose polymerase.
Enășescu et al. (2021)	Human cells BICR10 of buccal mucosa squamous carcinoma	Increasing OXSR1 and reducing MMP-9
Ruiling (2019)	Gastric cancer stem cells from human gastric cancer cell line SGC-7901	IC50 = 91.58 mmol/L Reduced proliferation and increasing apoptosis Increase PI3K and Akt mRNA Downregulation of p-PI3K and p-Akt protein
Eom et al. (2023)	Gastric cancer AGS cells	Apoptosis via NADPH oxidase-induced ROS (Bcl-2/Bax, caspase-3, DNA fragmentation, cell viability). Activating NF-κB.
Gansukh et al. (2019)	Human cervical carcinoma (HeLa) cell lines	84.85% cell growth inhibition after 48 h Elevation of ROS and caspase-3 activation Downregulation of Bcl-2 expression and upregulation of Bax expression Inducing nuclei DNA damage
S. Zhang et al. (2022)	A549 lung cancer cells	Inducing DNA damage Activating the ATR/Chk1/p53 signaling pathway
	Mice injected with A549 cells	Longer mice survival with impeded tumor growth
Sawasdee et al. (2023)	Lung cancer A549, cervical cancer Hela, breast cancer MCF7, hepatocellular carcinoma Huh7, and cholangiocarcinoma CCA; KKU213A.	Induce apoptosis by lowering procaspase-3, −8, and −9 and increasing caspase enzymatic activity Reduce Bcl-2, phosphorylated-AKT, and phosphorylated-mTOR proteins
Liu et al. (2016)	Human colon cancer HT29 cells	Inhibiting cell proliferation (78.09% after 72 h) Upregulation of mRNA and protein expression levels of Nrf-2 and HO-1
Lakshminarayana et al. (2010)	human cervical carcinoma cell lines (HeLa)	Photo-oxidized lutein has higher efficacy against HeLa cell growth and in reducing glutathione and MDA.
Rafi et al. (2015)	Prostate cancer (PC-3) cells	Reducing cancer cell growth, especially in combination with chemotherapeutic agents. Altering genes related to cell growth and apoptosis.
B. P. Chew et al. (2003)	Mouse with inoculated mammary tumor cells	Inducing cancer cell apoptosis (Bcl-2/Bax and p53). Reducing lymphocyte apoptosis.

ATR, ataxia-telangiectasia and rad3-related; Chk1, checkpoint kinase 1; MMP-9, matrix metalloproteinase-9; OXSR-1, oxidative stress responsive kinase-1; PKB, phosphorylated protein kinase B; ERK1/2, extracellular-regulated kinase ½; HO-1, heme oxygenase-1; MDA, malondialdehyde; NF-κB, nuclear factor-kB; Nrf2, nuclear factor erythroid 2-related factor-2; PCNA, proliferating cell nuclear antigen; SOD-2, superoxide dismutase-2.

3.5. Evidence from clinical studies

In clinical studies, researchers have explored multiple clinical benefits of lutein. In a systematic review, diatery lutein was found to increase cognitive function among healthy adults (Nouchi et al., 2020) but a more recent meta-analysis conclude that the improvement was not significant (J. Li & Abdel‐Aal, 2021). In a small-scale randomized controlled trial, supplementation of dietary lutein was proven to increase eye health among healthy subjects based on macular pigment optical density, contrast sensitivity, as well as glare sensitivity (Machida et al., 2020). Food enrichment with lutein, in a long-term intervention, was found to be significant in increasing macular pigment optical density (Schnebelen-Berthier et al., 2021), as well as preventing age-related macular degeneration (E. Y. Chew et al., 2022). As previously discussed, lutein has potent activity against cancer and tumor cells. Therefore, its potential as a preventive and therapeutic agent against cancer and tumors is worth receiving a spotlight.

In human subjects, a study suggests that the risk of colorectal cancer could be avoided by consuming lutein, where the mechanism is thought to be interplayed with DICER1 rs3742330 polymorphism (Kim et al., 2019). Since lutein is among the only two dietary carotenoids (the other one being zeaxanthin) that could be accumulated in the retina, it is thought to be a valuable bioactive compound to treat ocular melanoma (Buscemi et al., 2018). Unfortunately, there is still little evidence on the role of lutein as a therapeutic or preventive agent against ocular melanoma. Zeaxanthin, an isomer of lutein, has been found active against uveal melanoma C918 cells by showing inhibitory activities against the productions of matrix metalloproteinase (MMP)-2 and NF-κB (Bi et al., 2016). The evidence from an in vivo study also suggests zeaxanthin’s preventive effect against uveal melanoma cell growth (Xu et al., 2015). A randomized controlled trial (n = 42) revealed that supplementation of lutein, zeaxanthin, and meso-zeaxanthin could improve the macular pigment optical density (MPOD) in patients with glaucoma (Loughman et al., 2021). However, the evidence is considered insufficient as the sample size was too small for statistical interpretation and the duration was too short for visual field assessment (Loughman et al., 2021). Moreover, the benefit of lutein supplementation against ocular melanoma might be limited by its bioaccessibility and bioavailability. Future research should employ strategies that could overcome the foregoing limitations, which is through nanoencapsulation. Lutein in the form of nanoparticles has been shown with higher efficacy against buccal mucosa squamous BICR10 carcinoma cells as compared to its normal-sized form (Enășescu et al., 2021).

Finally, it is critical to create more efforts in improving clinical studies that focus on the stability and bioaccessibility of lutein for health vision via lutein-plant-based nanoencapsulation approaches, especially to combating ocular melanoma.

3.6. Potential of nanoencapsulation technologies for lutein delivery

Being acknowledged as a modern food technology, nano encapsulation has in fact been reported to improve the stability and bioavailability of various bioactive compounds including fruit extracts, ferulic acid, epigallocatechin-3-gallate, quercetin, curcumin, and other phenolic compounds (Tahir et al., 2021). In a recent study, essential oils extracted from Origanum glandulosum Desf. was evidenced to have increased cytotoxicity against Hep-G2 cells in its nanocapsules form, though its DPPH antioxidant activity was reduced (Ali et al., 2020). In a more comprehensive study, the encapsulation approach through complexation with pea protein nanofibrils resulted in higher chemical stability and water stability (Yi et al., 2022). More importantly, its anticancer activity against Caco-2 cells was improved significantly (Yi et al., 2022).

In terms of carotenoids, encapsulation has been used to increase the efficacy of lycopene where it has been proven in vitro against breast cancer cells (Vasconcelos et al., 2020). Interestingly, the lipid-based nanoencapsulated lycopene did not exhibit hemolytic activity against erythrocytes (Vasconcelos et al., 2020). Lutein was reported to have exceptional increases in bioaccessibility along with hepatic and ocular accumulations in rat model after encapsulated in a mixed nanoemulsion of oleic and linoleic acid (Toragall et al., 2021). Nano-scale delivery system of lutein, which was derived from combination of liposomes and chitosan, was able to increase the endogenous antioxidant activity in the liver of mice (G. Zhang et al., 2023). A study reported that a nanoencapsulated lutein has a cytotoxicity against Caco-2 cells which was negatively correlated with the lutein solubility (Luo et al., 2024). The role of balancing the solubility and permeability of lutein via nanoencapsulation in optimizing its anticancer activity has been reported in a study using Caco-2 cells in vitro (Luo et al., 2024). Strategies in encapsulating lutein can be performed through various nano-scale systems including that employing nanoemulsions, polymeric nanoparticles, polymer-lipid nanoparticles, or limposomes, where more details on these strategies have been discussed previously (Algan et al., 2022; Y. Li et al., 2024; Vieira & Conte-Junior, 2022). Taken altogether, nanoencapsulation could increase the bioaccessibility, bioavailability, and bioaccumulation of lutein but its efficacy is varied, hence requiring further studies.

4. Conclusions

Lutein, a member of the carotenoid family, has gained attention for its potential health benefits, particularly in the context of eye health and its role in combating ocular melanoma. Lutein, which can be found in various fruits, vegetables, and marine seaweeds, is known for its antioxidant and anti-inflammatory properties. It selectively accumulates in the eye, particularly in the macula and retina, offering potential protection against oxidative damage and blue light exposure. Research and epidemiological data have suggested that lutein intake may lower the risk of age-related macular degeneration, cataracts, and potentially even certain cancers and tumors. However, lutein is primarily sourced from food, and its availability can be limited due to dietary choices. Additionally, its effectiveness in biological processes depends on efficient gastrointestinal absorption (Graphical Abstract), which can be hindered by its physicochemical properties.

To address the challenge of insufficient lutein intake, the development of staple foods fortified with lutein has been proposed, to ensure a consistent supply of this compound to individuals. However, simply adding lutein to food may not provide significant nutritional benefits due to its poor solubility and vulnerability to oxidative degradation. Nanoencapsulation technology emerges as a promising strategy to enhance the stability, bioavailability, and bioaccessibility of lutein in food products. Furthermore, microfluidic engineering is gaining traction as an innovative approach to nutrient nanoencapsulation, offering the potential for precise control of micro-level structures in dispersed food systems. This critical perspective underscores the importance of clinical research and the development of plant-based lutein nanoencapsulation in staple foods to address nutritional challenges related to eye health, including the prevention and treatment of ocular melanoma. This aligns with the objectives of the WHO World Report from 2019, which emphasized the importance of research and innovation in tackling vision-related issues. The hope is that this endeavor will contribute to reducing the burden of eye-related conditions and vision impairment, ultimately supporting the achievement of Sustainable Development Goal 3.8, which focuses on universal health coverage through clinical studies on lutein-plant-based nanoencapsulation conducted by researchers worldwide.

Furthermore, this text provides insight into the molecular structure of lutein, its sources, stability, and bioavailability. It highlights the potential benefits of lutein as an antioxidant and anti-inflammatory agent, as well as its role in inducing apoptosis in cancer and tumor cells through various pathways. While there is promising evidence of lutein’s therapeutic potential, especially in preventing and treating certain cancers and ocular health issues, further research is needed to address issues related to its stability and bioavailability. In summary, lutein shows great promise as a bioactive compound with a wide range of potential health benefits, and efforts to improve its delivery and efficacy through nanoencapsulation are essential for future research and clinical applications. Lutein intake is recommended to maintain eye health with possibility of preventing ocular melanoma. The absence of clinical studies on nanoecapsulated lutein for ocular melanoma management present the opportunity for further research in this topic.

Author contributions

Conceptualization, Fahrul Nurkolis, Muhammad Iqhrammullah, Hardinsyah Hardinsyah and Nurpudji Astuti Taslim; Data curation, Fahrul Nurkolis, Rony Abdi Syahputra and Andi Yasmin Syauki; Formal analysis, Fahrul Nurkolis, Muhammad Iqhrammullah, Rudy Kurniawan, Dionysius Subali, Happy Kurnia Permatasari and Andi Yasmin Syauki; Investigation, Rudy Kurniawan and Dionysius Subali; Methodology, Fahrul Nurkolis and Muhammad Iqhrammullah; Software, Reggie Surya and Vika Anggari; Supervision, Dian Aruni Kumalawati, Happy Kurnia Permatasari, Raymon R. Tjandrawinata, Nelly Mayulu, Hardinsyah Hardinsyah, Nurpudji Astuti Taslim and Bonglee Kim; Validation, Happy Kurnia Permatasari, Raymon R. Tjandrawinata, Nelly Mayulu, Hardinsyah Hardinsyah, Nurpudji Astuti Taslim and Bonglee Kim; Visualization, Fahrul Nurkolis, Muhammad Iqhrammullah, Faqrizal Ria Qhabibi and Vika Anggari; Writing – original draft, Fahrul Nurkolis, Muhammad Iqhrammullah, Rudy Kurniawan, Hardinsyah Hardinsyah and Nurpudji Astuti Taslim; Writing – review & editing, Fahrul Nurkolis, Muhammad Iqhrammullah, Rony Abdi Syahputra, Dionysius Subali, Reggie Surya, Dian Aruni Kumalawati, Faqrizal Ria Qhabibi, Raymon R. Tjandrawinata and Bonglee Kim. More specific, Dr. Happy Kurnia Permatasari is an expertise in Molecular and Biochemistry of Cancer and is responsible for writing section of cancer mechanism.; Prof. Dr. Bonglee Kim has a strong background in Anticancer of Herbal Medicine and is responsible for writing and revising section 5 and edited main article.; Prof. Dr. Hardinsyah Hardinsyah., Prof. Dr. Nurpudji Astuti Taslim., Dr. Nelly Mayulu, and Dr. Andi Yasmin Syauki has a strong background in Nutrition and Functional Food from Natural Product and is responsible for writing and revising Lutein. All authors have read and agreed to the published version of the manuscript.

Acknowledgment

We offer a great thank you to the Chairman of the Indonesian Association of Clinical Nutrition Physicians, Professor Nurpudji Astuti Taslim, MD., MPH., PhD., Sp.GK(K), and the President of the Federation of Asian Nutrition Societies (FANS), Professor Hardinsyah, Ph.D., for reviewing and providing suggestions, as well as input on the draft of this opinion article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

There is no data related to this review article. The data were only sourced from the literature listed in this article (Data included in article/supp. material/referenced in article).

Additional information

Funding

This research received no external funding. However, the APC was funded by Happy Kurnia Permatasari (Faculty of Medicine, University of Brawijaya, Indonesia).