Nanoencapsulation of polyphenols for protective effect against colon–rectal cancer

Biotechnology Advances 31 (2013) 514–523

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Biotechnology Advances journal homepage: www.elsevier.com/locate/biotechadv

Research review paper

Nanoencapsulation of polyphenols for protective effect against colon–rectal cancer Isis S. Santos a, Bruno M. Ponte a, Prapaporn Boonme b, Amélia M. Silva c, d, Eliana B. Souto a, e,⁎ a

Faculty of Health Sciences, Fernando Pessoa University (FCS-UFP), Rua Carlos da Maia, 296, P-4200-150 Porto, Portugal Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla 90112, Thailand Department of Biology and Environment, School of Life and Environmental Sciences, (ECVA, UTAD), Vila Real, Portugal d Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Trás-os-Montes and Alto Douro (CITAB-UTAD), Vila Real, Portugal e Institute of Biotechnology and Bioengineering, Centre of Genomics and Biotechnology, University of Trás-os-Montes and Alto Douro (CGB-UTAD/IBB), P-5001-801, Vila Real, Portugal b c

a r t i c l e

i n f o

Available online 23 August 2012 Keywords: Colon cancer Ellagic acid Curcumin Epigallocatechin-3-gallate Gallic acid Nanotechnology

a b s t r a c t The human population at large is exposed to many critical factors (e.g. bad food habits, chemical substances, and stress) leading to the development of serious diseases. Colon or colorectal cancer is one of the most prevalent types of cancer in many countries. Despite being a multi-factorial chronic disease, resulting from the interaction of multiple genetic and environmental factors, the critical factor is mostly a poor diet regimen. Therefore, an accumulation of constant mutations leads to a complex arrangement of events during tumor initiation, development and propagation. It is well known that many plants are rich in polyphenols with anti-oxidant, anti-atherogenic, anti-diabetic, anti-cancer, anti-viral, and anti-inflammatory properties. These compounds are secondary metabolites with the ability to donate electrons to free radicals through different mechanisms. In recent years, a large number of studies have attributed a protective effect to polyphenols and foods containing these compounds (e.g. plants, vegetables, cereals, tea, coffee or chocolate). Polyphenolic compounds have been described to inhibit cancer development and propagation, being used as chemopreventive agents. Some polyphenols reported a preventive action against colon cancer, e.g. curcumin, gallic acid, ellagic acid, and epigallocatechin-3-gallate. The present article focuses on the properties of these molecules as chemopreventive agents and the recent advances on their formulation in nanoparticulate systems for targeted therapy and increased bioavailability. © 2012 Elsevier Inc. All rights reserved.

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . 1.1. Physiopathology of colon and colon–rectal cancer 1.2. Relevance of chemoprevention . . . . . . . . 2. Polyphenols in colon–rectal cancer . . . . . . . . . . 2.1. Curcumin . . . . . . . . . . . . . . . . . . 2.2. Gallic acid and its derivatives . . . . . . . . . 2.2.1. Epigallocatechin-3-gallate . . . . . . 2.2.2. Ellagic acid . . . . . . . . . . . . . 3. Nanoparticulates for targeted colon–rectal therapy . . 3.1. Nanoencapsulation of curcumin . . . . . . . . 3.2. Nanoencapsulation of gallic acid derivatives . . 4. Unresolved questions . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author at: Faculty of Health Sciences, Fernando Pessoa University, Rua Carlos da Maia, 296, Office S.1, P-4200-150 Porto, Portugal. Tel.: +351 22 507 4630x3056; fax: +351 22 550 4637. E-mail address: [email protected] (E.B. Souto). 0734-9750/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.biotechadv.2012.08.005

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1. Introduction Both colon (also known as large bowl) and rectum are parts of the final section of the digestive system. These abdominal organs are subjected to external aggressions constantly making them more susceptible to acute inflammation and chronic diseases. Colon–rectal carcinoma is one of the most common disease problems in many countries, especially in the western civilization (Boghossian and Hawash, 2012). WHO (World Health Organization) studies showed that approximately one million people are diagnosed with colon cancer each year (Sharma et al., 2010). Cancer prevention is one of the most important priorities in public health. During the last two decades, there have been particular efforts to evaluate the chemopreventive role of substances present in natural products (Hostanska et al., 2007). Some epidemiological studies about the relationship between dietary habits and disease risk have demonstrated that diet has a direct impact on public health (Espín et al., 2007). Pharmacological properties are associated to several vegetables, fruits and herbs, which are known to be full of sources of potential molecules for treatment of several malignancies (Espín et al., 2007; Faller and Fialho, 2010; Hervert-Hernández et al., 2011; Hostanska et al., 2007; Landete, 2011; Larrosa et al., 2006). The economic impact that cancer treatment has in public health is well known. As a matter of improving quality of life and to reduce costs, the real importance of prevention is recognized. In this way, there are many incentives leading to the adoption of a healthy diet (Espín et al., 2007; Larrosa et al., 2006). However, the proven benefits of natural anti-oxidants, e.g. polyphenols, which are healthy substances, sometimes have some targeting delivery and bioavailability issues. Therefore, novel formulations based on nanotechnology have been investigated to cope with these problems. In this article, a review about colon-cancer malignancy is provided focusing on some polyphenol properties in cancer chemoprevention and treatment, and the value of nanotechnology as an answer to improve the polyphenol performance in vivo.

1.1. Physiopathology of colon and colon–rectal cancer The colon (large intestine or large bowel) is a complex threedimensional structure that can achieve a length of approximately 150 cm (Ellis, 2011; Ponz de Leon and Di Gregorio, 2001; Wilson, 2010). The large bowel is an organ subdivided into the caecum and appendix, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending and sigmoid colon and the rectum and anal canal. This fully vascularized organ is covered by a double layer of external and smooth muscle cells that are adjacent to serosa and subserosal tissues (Ellis, 2011; Ponz de Leon and Di Gregorio, 2001). This organ (as well as the entire gut) has a nervous system of its own, called the enteric nervous system, which is important for controlling movement and secretion. It emphasizes the sacral parasympathetic nerves from mesenteric and pelvic ganglia (Ponz de Leon and Di Gregorio, 2001). The normal colon–rectal mucosa is organized by three leading features namely the epithelium (of the surface and crypts), lamina propria and muscularis mucosae; the latter separates the mucosa from the deeper submucosa (Ponz de Leon and Di Gregorio, 2001; Ponz de Leon and Percesepe, 2000). The regular large bowel

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architecture is based on glands (crypts), which are constituted by columnar and mucinous cells (Ponz de Leon and Percesepe, 2000). A series of genetic mutations, both in germ line and in somatic tissues, are involved in the development of colon–rectal cancer, and it is accepted that the cancer phenotype results from an accumulation of genetic alterations in the cell clone. But there is no mutation pattern to all colon–rectal cancers, and the chronology in which these genetic events occur does not follow a strict order, suggesting more than one pathway leading to the pathology (Draznin and Sun, 2006; El Sebaï et al., 1998; Ponz de Leon and Di Gregorio, 2001; Ponz de Leon and Percesepe, 2000; Sharma et al., 2001). Generally, cancer development can be summarized in three stages: initiation, progression, and promotion (Thangapazham et al., 2006). Overall studies indicate that the pathogenic process producing colon–rectal cancer does not follow a linear path (Araujo et al., 2011; Boghossian and Hawash, 2012; El Sebaï et al., 1998; Ponz de Leon and Di Gregorio, 2001; Ponz de Leon and Percesepe, 2000; Sharma et al., 2001). The development of this kind of malignancy can be the result of a process summarized in Fig. 1 (Ponz de Leon and Percesepe, 2000; Sharma et al., 2001). The initial phases of colon–rectal cancer begin in the normal mucosa, by means of an indiscriminate disorder of cell replication, and with the formation of clusters of enlarged crypts showing biochemical, biomolecular and proliferative anomalies (Boghossian and Hawash, 2012; Ponz de Leon and Di Gregorio, 2001; Ponz de Leon and Percesepe, 2000; Sharma et al., 2001). Without proper treatment, the adenoma will enlarge and develop to a colon–rectal carcinoma that can spread in the body through metastasis (Boghossian and Hawash, 2012; Ponz de Leon and Di Gregorio, 2001; Ponz de Leon and Percesepe, 2000; Sharma et al., 2001). The transition from a benign lesion to a more malignant tumor with metastatic potential has been shown to involve several signaling mechanisms (Boghossian and Hawash, 2012). Most cases of colon–rectal cancer begin with the attendance of common lesions, such as pre-existing adenomatous polyps or adenomas (Cuffy et al., 2006; Foss et al., 2011; Ponz de Leon and Di Gregorio, 2001; Ponz de Leon and Percesepe, 2000; Sharma et al., 2001; Viennot et al., 2009). Adenomas are well demarcated lumps of dysplastic epithelium which can be found in all segments of the large bowel and their frequency increases with age (Draznin and Sun, 2006; Ponz de Leon and Di Gregorio, 2001; Ponz de Leon and Percesepe, 2000). This kind of malignancy initiates on the normal mucosa by cell replication disorder, leading to a formation of abnormal masses of engorged crypts. Most of colon–rectal malignancies develop from demarked masses of epithelial dysplasia, with uncontrolled crypt cell division called adenomatous polyps. Not all polyps undergo malignant changes. An adenoma can only be considered malignant when neoplastic cells pass through the muscularis mucosae and infiltrate the submucosa (Ponz de Leon and Di Gregorio, 2001). In general, this process can result from the combination of age progression, environment, inappropriate diet, chronic inflammation and lack of exercise (Giftson et al., 2010). These conditions have, as consequence, a persistent oxidative stress, which leads to DNA damage, mutations in cancer related genes, a cycle of cell death and regeneration bringing cellular overproduction of reactive oxygen species that ultimately leads to cancer formation (Giftson et al., 2010; Umesalma and Sudhandiran, 2011).

• Aberrant crypt foci Normal

• Small adenoma

Large

Fig. 1. A general view in colon-cancer development. Adapted from Ponz De Leon and Percesepe (2000).

Cancer

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New diagnosis and treatment methods in colon–rectal cancer can reduce the mortality rate. Nevertheless, there still a moderate to high mortality associated to this malignancy, being the third cause of cancer worldwide (Araujo et al., 2011; Sharma et al., 2001; Umesalma and Sudhandiran, 2011), which encourages the adoption of new ways to approach this chronic illness. 1.2. Relevance of chemoprevention Siddiqui and Mukhtar (2010) mentioned that chemoprevention “is a means of cancer management by which the occurrence of the disease can be entirely prevented, slowed, or reversed via administration of one or more naturally occurring and/or synthetic compounds”. Carcinoma cells can generate free radical species or oxygen reactive species (Fang et al., 2009; Kotsinas et al., 2011; Reuter et al., 2010). These oxygen species play a part as crucial molecular mediators in a multiplicity of normal cellular functions, or act as damaging byproducts of the metabolism or come from other exogenous sources, with detrimental effects on normal cell physiology (Kotsinas et al., 2011; Kryston et al., 2011; Sedelnikova et al., 2010). The process that occurs when there is an unbalance between production of oxidants and their elimination by protective mechanisms (anti-oxidants), leading to oxidative stress, which occurs when the organism is submitted to risk factors as the ones mentioned above (Chang et al., 2008; Fang et al., 2009; Reuter et al., 2010). During oxidative stress, the damaging side of reactive oxygen species stands out, which may involve damage of lipids, proteins and DNA, leading to various DNA lesions, that can be the starting point to malignant development (Fang et al., 2009; Kotsinas et al., 2011; Kryston et al., 2011; Reuter et al., 2010; Sedelnikova et al., 2010). Therefore, it can be concluded that one of the major reasons described for the colon– rectal cancer prevalence is the oxidative stress, involved in the initiation and progression of this malignancy (Chang et al., 2008). To prevent colon–rectal cancer, it is important to maintain the balance between anti-oxidants and reactive oxygen species, in order to decrease oxidative stress and the associated disturbances. Therefore, anti-oxidants can act as the efficient chemopreventive compounds for colon–rectal cancer. Although the chemoprevention idea is not a novelty, it still is one of the ways to prevent or slow the development of cancers including colon–rectal cancer. Malignancy chemoprevention comprises the consumption of either natural or synthetic chemicals for the prevention of the initiation, promotion, or progress of cancer (Thangapazham et al., 2006). During the past decades many chemicals were used to prevent a series of diseases that affected the population (Sharma et al., 2001). Some efficient cancer chemopreventive compounds have been already identified (Halliwell, 2008; Sharma et al., 2001). They include the phytochemicals, which are non-nutritive plant constituents that are currently being investigated for chemoprevention in a wide range of diseases for their pleiotropic effects and non-toxicity (Thangapazham et al., 2006). There is rising evidence that a diet rich in fruit and vegetables have a health-protective role, reducing the risk of chronic diseases, because of its high content in valuable phytochemicals, such as polyphenols, tannins and anthocyanins (Faller and Fialho, 2010; Hervert-Hernández et al., 2011; Landete, 2011; Larrosa et al., 2006). Recently, a research article reported that the intake of berries as a source of natural antioxidants may reduce colon cancer risk. In this study the Chilean berries (Myrteola nummularia) revealed to have the higher content of antioxidants (Flis et al., 2012). This study supports the idea that polyphenols act as chemopreventive compounds. 2. Polyphenols in colon–rectal cancer The relationship between diet polyphenols and prevention of malignancies in humans has been an intense field of investigation

throughout the past years. One of the reasons for the growing interest in studying these compounds resides on their protector role against colon–rectal cancer (Araujo et al., 2011). Polyphenolic compounds have in their chemical structure at least one aromatic ring with a reactive hydroxyl group, being divided into different classes according to the number of phenolic rings and the structural elements linking this rings, e.g. phenolic acids and flavonoids (Araujo et al., 2011; Verma et al., 2009; Wojdyło et al., 2007). Natural polyphenols comprise of a large group of phytochemicals with more than 8000 identified compounds (Ebrahimi and Schluesener, 2012). They have many useful properties; however, their most important benefit is their anti-oxidant activity. Some in vitro studies reported a potent anti-oxidant activity of polyphenols, having a good scavenging capacity for a wide range of reactive oxygen species (Halliwell, 2008), being pointed out as good chemoprotectors (Fig. 2). The polyphenolic antioxidant capacity of conferring to the cells a reducing environment, inhibiting the free radical activity is the result of an anti-oxidant electron donating characteristic, which allows the oxidation process modulation (Mosca et al., 2002; Neves et al., 2009; Sousa et al., 2007). Therefore, these compounds have the capacity to act in various anti-oxidant mechanisms (Montoro et al., 2005). It can be summarized that polyphenols can exhibit antioxidant effects via different mechanisms, i.e. interaction with the hypoxia-inducible factor 1 (HIF-1) alpha pathway, inducing expression of protective genes against oxidative stress, regulation of reactive oxygen species by interacting with oxidative pathways and scavenging metal ions as pathogenic free radicals (Kelsey et al., 2010). Polyphenols are promising compounds in cancer management because of its capacity to induce apoptosis in cancerous cells by modulating cell signaling cascades (Umesalma and Sudhandiran, 2011). Some examples (Fig. 3) are described below. The dietary intake of these phytopigments was estimated at about 1 g/day in a healthy regime (Landete, 2011). 2.1. Curcumin Curcumin (diferuloylmethane; (1E,6E)-1,7-bis(4-hydroxy-3methoxyphenyl)-1,6-heptadiene-3,5-dione (IUPAC); C21H20O6) is the major component of turmeric. Turmeric (Curcuma longa), which is a widely used spice, especially in Indian cooking, is a rhizomatous plant belonging to the ginger family, and from its yellow pigmented fraction some natural polyphenols occur, denominated curcuminoids, all chemically related to the principal ingredient, curcumin (Das et al., 2010; Goel et al., 2008; Irving et al., 2011; Thangapazham et al., 2006; Wright et al., 2006). Curcumin is a low-molecular weight (368.37 g/mol; (Goel et al., 2008)) compound that is poorly soluble in water and ether but soluble in ethanol, dimethylsulfoxide (DMSO), and acetone, and other organic solvents (Das et al., 2010; Goel et al., 2008; Irving et al., 2011; Wright et al., 2006). This polyphenol has potent antioxidant, anti-inflammatory, chemopreventive, hypocholesterolemic, anti-microbial and anti-neoplastic properties (it has been shown to suppress proliferation in several tumor cells), which can be used alone or in association with conventional treatments that would otherwise be chemo-resistant (colon cancer shows some chemo-resistant characteristics) (Das et al., 2010; Irving et al., 2011; Nayak et al., 2010; Thangapazham et al., 2006; Wright et al., 2006). The conjugated nature of curcumin's chemical structure contributes to its ability to act as an anti-oxidant, an important factor for chemoprevention capacity (Bartik et al., 2010; Thangapazham et al., 2006). There is scientific evidence suggesting that curcumin is of a highly pleotropic structure, that physically interacts with a wide range of molecular targets, e.g., transcription factors, growth factors and their receptors, cytokines, enzymes, and genes regulating cell proliferation (Bartik et al., 2010; Das et al., 2010; Goel et al., 2008). Curcumin's

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Induce endogenous antioxidant enzymes

Dietary polyphenols

Inhibit oxidant enzymes

Biological processes affected

Scavengers of free radicals

Anti-allergy Anti -diabetes Anti -inflammatory Anti -tumour Gastro -intestinal protection Hormone modulation Immune protection Neuroprotection ...

Modulate several signal pathways Fig. 2. Involvement of dietary polyphenols on cellular mechanisms and the ultimate biological effect. Adapted from Han et al. (2007).

capacity to inhibit the transcription factor nuclear factor kappa B (NF-kappaB) and consequent inhibition of pro-inflammatory pathways makes this compound valuable in all three stages of carcinogenesis (Heber, 2008; Thangapazham et al., 2006). Curcumin has been used in several clinical trials, for many types of diseases, such as colorectal cancer (36–3600 mg/day × 120 days), irritable bowel syndrome and others (as reviewed by Goel et al., 2008). However, the poor bioavailability and chemical instability of curcumin are considered as problems in cancer therapy (Donsì et al., 2011; Nair et al., 2010; Nayak et al., 2010). 2.2. Gallic acid and its derivatives Gallic acid (3,4,5-trihydroxybenzoic acid (IUPAC); C6H2(OH)3COOH) is a natural phenol, prevalent in several plants and fruits, such as tea leaves, oak bark, pineapples, bananas, lemons, apple peels and grapes (Giftson Senapathy et al., 2011; Giftson et al., 2010). Gallic acid is also a low molecular weight compound (170.12 g/mol) and is water soluble. Several biological properties have been attributed to gallic acid,

e.g., anti-inflammatory, anti-mutagenic, and antioxidant (Giftson et al., 2010). It was proven that gallic acid tends to have a significant chemoprotective effect on 1,2-dimethylhydrazine (DMH) induced colon carcinogenesis (Giftson Senapathy et al., 2011; Giftson et al., 2010). DMH is an indirect colon-specific carcinogen, metabolized in the liver that can induce the development of methyl adducts with DNA bases, point mutations, micronuclei and sister chromatid exchanges (Giftson Senapathy et al., 2011; Giftson et al., 2010; Umesalma and Sudhandiran, 2011). The adduct construction leads to genetic mutations and altered normal gene transcription, which restricts normal cell growth, besides inducing oxidative stress (Giftson Senapathy et al., 2011; Giftson et al., 2010). DMH promotes apoptotic processes in the large bowel, besides enhancing cellular propagation of colonic epithelial cells, normal in human colon cancer (Giftson et al., 2010). In this way, colon specific carcinogen DMH compromises normal cell development that leads to cancer formation (Giftson Senapathy et al., 2011; Giftson et al., 2010; Umesalma and Sudhandiran, 2011).

Fig. 3. Chemical structures of curcumin (A), gallic acid (B), epigallocatechin-3-gallate (C) and ellagic acid (D).

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However, DMH, per se, is not chemically active, but is stimulated by phase-I and phase-II xenobiotic-metabolizing enzymes to exhibit mutagenic and carcinogenic effects. It was found, in DMH induced rats, a notorious potential activity of gallic acid to modulate both phase-I and phase-II xenobiotic-metabolizing enzymes that has reduced colon damage caused by DMH carcinogen. Hence, gallic acid has a major impact on colon cancer chemoprevention (Giftson Senapathy et al., 2011). Besides gallic acid itself, its derivatives, i.e. epigallocatechin3-gallate and ellagic acid, have been also investigated for colon cancer protection and/or treatment. 2.2.1. Epigallocatechin-3-gallate Epigallocatechin-3-gallate ([(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3, 4-dihydro-2H-chromen-3-yl] 3,4,5-trihydroxybenzoate (IUPAC); C22H18O11) is one of the major green tea polyphenolic constituents, having a molecular weight of 458.37 g/mol (Berger et al., 2001; Dube et al., 2011; Ohishi et al., 2002; Umeda et al., 2008). Green tea is obtained from the tea leaves [Camellia sinesis (Theacacea)] which are processed in a way to prevent the oxidation of the green leaf polyphenols (black tea and oolong tea, obtained from the same tea leaves, present the majority or a great portion of the polyphenols oxidized, respectively), thus green tea has the higher content in antioxidants, being the epigallocatechin-3-gallate the principal cathechin, contributing to about 1/3 of the total antioxidant capacity (Thangapazham et al., 2007). Apart from a great antioxidant activity, tea extracts have been reported to have other biological activities. There are some studies demonstrating that this molecule leads to growth inhibitory responses to cancer cells, without jeopardizing normal cells. This capacity to obstruct cancer cell growth, induce DNA damage as well as apoptosis of cancer cells leads to a possible chemotherapeutic action for colon cancer treatment (Araujo et al., 2011; Berger et al., 2001; Umeda et al., 2008). In this way, other scientific studies demonstrated that epigallocatechin-3-gallate, in combination with other cancer preventive agents, could reduce the adverse effects of those cancer preventive agents (Berger et al., 2001). The chemopreventive effects of epigallocatechin-3-gallate are strongly supported by results from epidemiological, cell culture, animal and trial studies, which demonstrated a great anti-cancer potential associated with safety, low cost and bioavailability (Berger et al., 2001; Singh et al., 2011). Some in vitro cell culture studies showed that epigallocatechin-3-gallate, besides being a good anti-oxidant compound, could suppress an inflammatory process, the causes of transformation, hyperproliferation, and initiation of carcinogenesis (Singh et al., 2011). An in vitro cell culture study showed that epigallocatechin-3-gallate inhibits cell growth (cell cycle arrest, at G0/G1 phase) and induces apoptosis in cancerous cells, by shifting the expression of cell cycle regulatory proteins, triggering killer caspases (essential for the cellular apoptosis process), and suppressing NF-kappaB activation. Epigallocatechin-3-gallate regulates and promotes IL-23 DNA repair and stimulates cytotoxic T cell activities in a tumor microenvironment. This compound also blocks carcinogenesis by modulating the signal transduction pathways involved in cancer development (Singh et al., 2011). These anti-proliferative and proapoptotic effects of epigallocatechin3-gallate have been shown to be selective for cancer cells, as normal cells were not affected by its treatment (Berger et al., 2001; Singh et al., 2011). Epigallocatechin-3-gallate, in cancer cells, leads to the inhibition of the activity of specific tyrosine kinase receptors and related downstream pathways of signal transduction (Singh et al., 2011). The DNA topoisomerases (topo) I and II are essential enzymes involved in multiple transactions related to DNA that include DNA replication, transcription, chromosome condensation, and probably DNA recombination. The relevance of topo-mediated DNA cleavage has been demonstrated in tumor cell death, being recognized as a

potentially effective molecular target for some antitumor drugs, some are already in use but causing severe side effects. Topoisomerase I and II (that cause transient break in one or in the two DNA strands, respectively) activities are both higher in colon cancer than in normal colonic cells. It was demonstrated that epigallocatechin3-gallate inhibits topoisomerase I but not topoisomerase II, bringing out the chemotherapeutic capacity of this molecule against colon cancer (Berger et al., 2001). 2.2.2. Ellagic acid Ellagic acid (2,3,7,8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5, 10-dione (IUPAC); C14H6O8), has a molecular weight of 302.20 g/mol. This dimeric derivative of gallic acid rarely occurs free in diet crops (Landete, 2011; Larrosa et al., 2006), but usually occurs in food products conjugated with glycoside moiety (e.g., glucose, xilose) or forms part of ellagitannins (polymeric molecules) (Heber, 2008; Landete, 2011; Larrosa et al., 2006; Sharma et al., 2010). These compounds usually occur in fruits (e.g., pomegranates, persimmon, raspberries, black raspberries, strawberries, peach, plumes), nuts (e.g. walnuts, almonds), vegetables and wine (Heber, 2008; Landete, 2011; Larrosa et al., 2006, 2010; Malik et al., 2011; Rosillo et al., 2011; Sharma et al., 2010; Vattem and Shetty, 2003). However, ellagitannins are not absorbed by the human gut but can be hydrolyzed to ellagic acid by colonic gastrointestinal flora (Larrosa et al., 2006). Ellagic acid has a significant attractiveness in food supplements because of its potentially beneficial effects against a wide range of diseases (Malik et al., 2011). The anticancer effect of ellagic acid has been extensively studied in a number of cancer cells, where it exhibited anti-proliferative activity, with the ability to cause cell cycle arrest and to induce apoptosis in many human cancer cell lines (Larrosa et al., 2006). The anticancer effects of ellagic acid have been demonstrated in several types of cancers including skin, esophageal, and colon cancers (Malik et al., 2011). Caco-2 cells are a widely accepted in vitro model for colon cancer. It has been reported that ellagic acid has an anti-proliferative effect and induces apoptosis via a mitochondrial pathway in Caco-2 cells, without interfering with the normal colon cells (Larrosa et al., 2006). Moreover, a study exploring the activity of ellagic acid demonstrated that ellagic acid could induce apoptosis in DMH-induced colon carcinoma and participate in a wide range of DNA maintenance reactions that prevents genomic instability (Umesalma and Sudhandiran, 2011). Besides, anti-oxidant and anti-cancer activities, as previously described, ellagic acid also has anti-inflammatory, anti-bacterial, anti-angiogenesis, anti-atherosclerosis, anti-hyperglycemic, antihypertensive and cardioprotective effects (Landete, 2011; Larrosa et al., 2010; Malik et al., 2011; Rosillo et al., 2011). 3. Nanoparticulates for targeted colon–rectal therapy Nanotechnology aims for the production of particles in nanoscale (10 to 1000 nm) and large surface-to-volume ratios (Rao and Geckeler, 2011; Sanna and Sechi, 2012; Siddiqui et al., 2012). Since cancer development happens in the nanoscale, nanotechnology has been really respected as a prospective form of cancer prevention, diagnosis and treatment, being mentioned as “cancer nanotechnology”. This technology offers many potential benefits in cancer research ranging from, but not limited to, passive and active targeting, increasing solubility and/or bioavailability of bioactive compounds (Siddiqui et al., 2012), of natural or synthetic origin. Cancer nanotechnology products are considered to have great potential with unique therapeutic properties since they can infiltrate tumors deeply with a high level of specificity. It can be mentioned that nanoparticles can be the answer to cancer therapy problems due to their particular size and characteristics (Siddiqui et al., 2012). The National Cancer Institute considers nanotechnology as an emerging field that offers a means to revolutionize modern medicine in the areas of

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cancer prevention, diagnosis and treatment (Nair et al., 2010; Siddiqui et al., 2012). Most polyphenols show low in vivo bioavailability, limiting their application in cancer prevention and treatment. Through nanoencapsulation, the targeting of some substances is possible as well as potentiating their effect. There are some successful cases of using nanoparticles containing nutraceuticals, such as, green tea polyphenols and curcumin, which can confirm the usefulness of “nanochemoprevention” and “nanochemotherapy” (Fang and Bhandari, 2010; Hu et al., 2012; Nair et al., 2010; Sanna et al., 2011; Siddiqui et al., 2012). The application of nanotechnology can be practical as a strategy to improve the action of polyphenolic compounds, resulting in an emerging treatment modality in serious diseases like cancer. Recently, nanoparticle therapeutics for targeting of the inflamed intestinal mucosa and for prostate cancer treatment have been reviewed (Collnot et al., 2012; Sanna and Sechi, 2012). The potential value of natural products, as a source of bioactive compounds is well known, being very useful for medical applications because of their ability to reduce/suppress cancer risk and development (Nair et al., 2010; Sanna and Sechi, 2012). However, the low solubility of the phytochemicals affects their absorption by the gastrointestinal system. Another major obstacle in biological activity of dietary structures is their bioavailability and metabolism. Some natural molecules suffer many changes during metabolism, e.g. ellagic acid (Larrosa et al., 2006). The nanoencapsulation is an important issue to enhance bioavailability of polyphenols (Nair et al., 2010). Nanotechnology is an important means to achieve many goals, i.e. improving the delivery of poorly water-soluble drugs, site-directed delivery of drugs towards specific biological and molecular targets, innovative diagnostic tool development, and combination of therapeutic agents with diagnostic probes (Sanna and Sechi, 2012). A remarkable progress in nanoparticle-based therapeutics occurred in the last decade (Sanna and Sechi, 2012). The 2006 European Technological Observatory survey demonstrated that at least 150 pharmaceutical companies were developing nanoscale therapeutics (Nair et al., 2010). Besides their toxicity in cancer cells, several chemotherapeutics show the tendency to harm normal cells after administration, leading to severe side effects. Thus, it is important to improve drug targeting for the specific location of action, supporting the distribution of the required drug amount into the target site, decreasing adverse side effects caused by normal cell damage of uncontrolled drug circulation in the bloodstream (Nair et al., 2010). According to the description of the National Nanotechnology Initiative and some literatures, nanostructures should be only 1 to 100 nm in at least one dimension (Nair et al., 2010; Sanna and Sechi, 2012). For clinical applications, nanoparticles should range from 5 to 200 nm to avoid the risk of embolism (Sanna and Sechi, 2012). The nano size requirement can be achieved through several rational designs, including top-down and bottom-up approaches (Nair et al., 2010). Nanoparticles are developed with the aim of modifying the pharmacokinetics of modern drugs by improving their efficiency, stability, and solubility, reducing their toxicity, besides the target-site specificity (Nair et al., 2010). In addition, a remarkable progression has been made by producing nanoparticle based therapeutic products to improve pharmacokinetics and bioavailability properties from polyphenols (Sanna and Sechi, 2012). Parameters such as size, surface characteristic and shape are the main physicochemical properties to address when developing these strategies in drug delivery (Sanna and Sechi, 2012). Dimensions are fundamental for the delivery of long-circulating nanoparticles on the foundation of physiological parameters such as hepatic filtration, tissue extravasation, tissue diffusion, and kidney excretion (Nair et al., 2010). The nanoencapsulation of phytochemicals with the ability to interfere with one or more of the carcinogenesis process phases has

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been approved as an auspicious methodology for cancer controlling (Hu et al., 2012). In tumor targeting, it is essential that nanoparticles resist to hydrostatic and biophysical/biochemical obstacles, overcome cellular treatment resilience, struggle against biotransformation processes, and resist unexpected degradation or abrupt clearance (Nair et al., 2010). Nanoparticle surface properties are important for their interface with the location, i.e. particles with a negative or positive superficial charge show increased reticulo-endothelial clearance. For that reason, dropping nonspecific interfaces and monitoring surface charge by steric stabilization prevents some nanoparticle losses in undesirable locations (Nair et al., 2010). Nanoparticles have a large surfaceto-volume ratio that is capable of changes by rational design (Nair et al., 2010; Sanna and Sechi, 2012). The surface properties of nanoparticles will regulate their solubility, stability, and clearance characteristics (Nair et al., 2010), but the molecular approach of designing drug delivery systems must cover other parameters, such as stability, administration, absorption, metabolism, and bioavailability at target location (Liechty and Peppas, 2012). Nanoparticles are available in inorganic and organic materials, including liposomes, micelles, quantum dots, polymeric nanoparticles, gold nanoparticles and magnetic nanoparticles (Breunig et al., 2008; Mudshinge et al., 2011). The major problem is however, that they are recognized as foreign bodies in vivo, and so, being easily opsonized and removed from the circulation before reaching their target (Breunig et al., 2008). To overcome this problem, passive or active targeting strategies can be used to prolong drug residence time in blood (Breunig et al., 2008; Nair et al., 2010). Examples include those produced from lipids. Incorporation of some drugs in lipid nanoparticles is a smart approach to overcome bioavailability (Lim et al., 2004). Due to their biodegradability, biocompatibility, and targetability, the lipid based nanoparticles have been used for several administration routes, e.g. oral, transdermal, ocular, and intravenous (Arias et al., 2011). Lipid based colloids (Fig. 4) can be based on vesicular systems or on solid nanoparticles. Vesicular systems include nanoemulsions and liposomes. Nanoemulsions can be characterized as fine dispersions of liquid droplets (50–200 nm), usually oil-in-water (o/w), where the poorly soluble drugs are found absorbed in the oil core or adsorbed on the o/w interface (Donsì et al., 2011; Fasolo et al., 2007; Wang et al., 2008). These droplets are produced using appropriate emulsifiers at the o/w interface, by means of ultra-energy emulsification methods (e.g. high shear blending, high pressure homogenization and ultrasonic homogenization), as well as low-energy emulsification methods (e.g. phase inversion temperature method). Nanoemulsions are effective in several cases. For example, they can improve the dispersability of the poorly soluble drugs in aqueous phase, protect the bioactive compounds from interaction with diet compounds, reduce the impact on the organoleptic properties on food, and enhance absorption as well as bioavailability via the passive transport across the cell membrane due to their nanosize droplets (Donsì et al., 2011; Wang et al., 2008). Liposomes are vesicles composed of at least one phospholipid bilayer, spontaneously produced by dispersion of phospholipids into aqueous media (Arias et al., 2011). The liposomes in the nanometer range are called nanoliposomes (Mudshinge et al., 2011). These particles are prepared using amphiphilic lipids, e.g. cholesterol, glycolipids, membrane proteins or polymers. Their membrane bilayer stability, encapsulation efficiency and retention capacity of loaded drug depends on the qualitative composition of the membranes (Arias et al., 2011; Mudshinge et al., 2011). This distinctive structure (lipid membrane surrounding an aqueous cavity) allows them to load both hydrophobic and hydrophilic molecules (Mudshinge et al., 2011). The solid nanoparticles can be classified as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC). SLN can be characterized as aqueous dispersions of solid lipid matrices stabilized by surfactants,

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Lipid based colloids Solid nanoparticles

Vesicular systems • Nanoemulsions(liquid droplets 50-200 nm)

• Solid-lipid nanoparticles(SLN)

Improve dispersability of poor water soluble drugs.

Load hydrophobic, hydrophilic, and ionic compounds(e.g., peptides)

• Liposomes (unilamelar or multilamelar;

• Nanostructured lipid carriers (NLC) Load hydrophobic compounds

Load hydrophobic and hydrophilic compounds Fig. 4. Lipid based colloids.

or dry powders acquired by spray drying or lyophilization (Arias et al., 2011). Its mean diameter range is between 50 and 1000 nm (Mudshinge et al., 2011). These formulations are composed by a solid lipid (at both room and physiological temperatures), emulsifiers and an aqueous solvent (Arias et al., 2011; Mudshinge et al., 2011; Singhal et al., 2011). On a microscopic way, the organization of these systems is almost perfect, close to a “brick wall”, where the lipids are packed. This system is produced by melting the solid lipid to be dispersed into nanosized lipid droplets in an aqueous medium, being submitted to several production procedures already proposed for this kind of formulation, e.g. high pressure homogenization, emulsification-solvent diffusion method, ultrasonication technique and microemulsion technique (Arias et al., 2011; Mudshinge et al., 2011). SLN are characterized for their physical stability, protection against labile drug degradation, low toxicity, controlled drug release, and ease of formation. They can be applied in lipophilic, hydrophilic, and ionic molecules, proteins, and peptides (Arias et al., 2011). SLN also show other exceptional properties, e.g. small size, large surface area, high drug loading, interaction between phases and interphases, and are attractive for their potential to improve performance of pharmaceuticals, nutraceuticals and other substances. Advantages of SLN are the use of physiological lipids in their composition, the avoidance of organic solvents in the production process (which would be potentially toxic), a wide application spectrum for different administration routes and drugs, besides being more stable and easy to produce in large scale when compared to liposomes (Mudshinge et al., 2011). NLC are nanocarriers produced from a combination of solid and liquid lipids where the nanoparticles are solid at room temperature. The production of these systems is based on solidified emulsion (dispersed phase) technology, which is submitted to a hot high-pressure homogenization technique with homogenization temperatures of 80 °C or higher (Mudshinge et al., 2011; Obeidat et al., 2010). The NLC can be administered via oral, ocular, pulmonary and intravenously (Obeidat et al., 2010). NLC are characterized by a highly unordered lipid structure providing the drug accommodation (Mudshinge et al., 2011). In general, lipid nanoparticles can be surface modified to be site-specific and interact to the specific target. In some cases, to enhance the circulation half-life time, the surface of the nanoparticle needs to be highly hydrophilic (Breunig et al., 2008; Lemarchand et al., 2004; Nair et al., 2010). Polyethylene glycol (PEG) is one of the most used polymers to enhance the nanoparticle circulation half-life in the blood stream, avoiding mononuclear phagocyte system sequestration (Almeida and Souto, 2007; Breunig et al., 2008; Lemarchand et al., 2004; Nair et al., 2010). Even though these particles may be compatible to tumor targeting, the chemical link between the drug and

the target site is often a problem because of the lack of reactive groups at the surface of PEG based nanoparticles. Polysaccharide coating is being considered as an accepted answer to this problem (Lemarchand et al., 2004). Polysaccharides are an important class of physiological molecules, having a well-known list of biocompatibilities and biodegradabilities, the elementary features required for polymers as biomaterials, besides having quite a few properties not found in other natural polymers (e.g. antitumor, anti-bacterial or antiviral capacity) (Lemarchand et al., 2004). Their characteristics (i.e., outstanding biocompatibility and simplicity in preparation) led to an extensive study of nanoparticles containing hydrophobically modified polysaccharides as drug carriers (Park et al., 2008). Many polysaccharides are widely used in preparation of dosage forms such as alginates and chitosan. Alginates are valuable polymers for pharmaceutical formulations, being also extensively used in the food industry (Liew et al., 2006). They occur in nature as non-toxic polysaccharides with two monomers, the beta-D mannuronic acid and the alpha-1-glucoronic acid (Fangueiro et al., 2012; Liew et al., 2006; Ludwig, 2005). Alginates can be used for sustained therapeutic action in the gastrointestinal tract due to their interaction ability with the mucus related to the improvement of adhesiveness (Fangueiro et al., 2012; Liew et al., 2006). Another interesting polysaccharide is chitosan. Chitosan is a deacetylated derivative of chitin and is a nontoxic and biodegradable mucoadhesive polymer, (Mazzarino et al., 2012; Park et al., 2008; Qi et al., 2007). This cationic polysaccharide has various biological activities, e.g. antitumor activity, immune-enhancing effect, antimicrobial and antifungal properties (Qi et al., 2007), besides being a good candidate for gene delivery for its positive charge that enables the formation of polyelectrolyte complexes with DNA (Park et al., 2008). The small size of chitosan nanoparticles may exhibit biological effects, having a higher antitumor activity due to its membrane disrupting and apoptosis-inducing activities for cancer cells (Qi et al., 2007). 3.1. Nanoencapsulation of curcumin In order to enhance the targeting delivery and bioavailability of polyphenols, practical chemoprevention agents, remarkable formulation development can be made by preparation of nanotechnology products. The nanoencapsulation of curcumin in a biodegradable polymeric methoxyPEG-palmitate amphiphilic conjugate turned this polyphenol readily soluble in an aqueous system, with good stability over a wide pH range (Sahu et al., 2008). Curcumin loaded in cross-linked based N-isopropylacrylamide, N-vinyl-2-pyrrolidinone, and PEG acrylate nanoparticles showed more cytotoxicity in pancreatic cancer cell lines, besides a bioavailability 9 folds higher than the bulk substance. The authors demonstrated that curcumin

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nanoparticles were more active than free curcumin in inhibiting some inflammatory mediators, i.e. TNFa-induced NF-kappaB activation and suppressing NF-kappaB regulated proteins involved in cell proliferation, invasion and angiogenesis (Nair et al., 2010). A study developed by Donsì et al. (2011) showed that curcumin could be encapsulated in solid fat nanoemulsions, promoting its solubility in aqueous systems (important to improve bioavailability) and avoiding the drug recrystallization during storage. Curcumin-loaded in human serum albumin nanoparticles for intravenous administration, using albumin bound technology, could provide higher water solubility and better in vivo antitumor activity than free curcumin (Kim et al., 2011). Curcumin-loaded chitosan particles were developed to improve a mucoadhesive property on gastrointestinal tract mucosa, leading to enhancement of active absorption (Mazzarino et al., 2012). Curcuminoids, the active substances in turmeric, were also encapsulated via nanotechnology formulation (nanoemulsion technique). Lipid nanoparticles, with sizes ranging between 100 and 250 nm, containing curcuminoids could exhibit controlled delivery of the active substances for longer periods and increased the absorption by the gastrointestinal tract (Nayak et al., 2010). 3.2. Nanoencapsulation of gallic acid derivatives It was reported that nanoparticles containing epigallocatechin-3gallate have shown a promising anti-oxidant activity when compared to the non-loaded drug (Nair et al., 2010). Encapsulation of epigallocatechin-3-gallate in chitosan-tripolyphosphate nanoparticles was evaluated as a useful approach for enhancing oral delivery and reaching beneficial therapeutic effects of epigallocatechin-3-gallate such as anti-oxidant, neuro-protective and anti-cancer activities (Dube et al., 2011). Additionally, epigallocatechin-3-gallate nanoparticles (encapsulated in polylactic acid–polyethylene glycol) were able to improve efficacy of the chemoprevention capacity in prostate cancer cells (Sanna et al., 2011). Some polysaccharide nanoparticles, charged with epigallocathecin3-gallate, besides retaining biological activity, could reduce cell viability and inducing apoptosis in prostate cancer cells, even with reduced concentration (Sanna and Sechi, 2012). Siddiqui et al. (2010) developed some studies to explore the nanochemoprevention value of epigallocatechin-3-gallate encapsulated in polylactic acid and polyethylene glycol nanoparticles used in preclinical settings in mice. In comparison to non-encapsulated epigallocatechin-3-gallate, it was noticed that the nanosystem was over 10-fold keener in keeping the polyphenol biological effectiveness (in cell growth inhibition, proapoptotic, and angiogenic inhibitory effects) with longer half-life and presented a 10-fold dose advantage, in inhibiting tumor cell growth. It was also reported that epigallocatechin-3-gallate in the form of nanoparticles composed of caseinophosphopeptides and chitosan provided higher bioavailability than that in the form of bulk substance (Hu et al., 2012). Besides nanoencapsulation of epigallocatechin-3-gallate in the form of pure active substances as previously described, nanoencapsulation of this chemopreventive agent in the form of green tea extract is also determined. Although there are many kinds of tea, such as green tea, black tea, and oolong tea, the green tea extract has been well investigated for its cancer chemopreventive effects, performed by its abundant catechins, e.g. (−)-epigallocatechin-3-gallate, (−)-epigallocatechin, (−)-epicatechin-3-gallate and (−)-epicatechin (Chen and Dou, 2008; Yang et al., 1998). Chitosan nanoparticles prepared by ionic gelation method using carboxymethyl chitosan and chitosan hydrochloride as carriers of tea polyphenols extracted from green tea were found to have significant antitumor activity against HepG2 cells (cell line derived from a hepatocellular carcinoma). The results of this study indicated that tea polyphenols could be released from chitosan nanoparticles and then interfere with the HepG2 cell apoptosis cascades (Liang et al., 2011). Those obtained nanocarriers should be applicable for colon–

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rectal cancer prevention since green tea polyphenols have been proven to have an activity against the human colon cancer cell line HT-29 (Yang et al., 1998). 4. Unresolved questions Data on applications of nanotechnology in prevention against colon–rectal cancer are still not complete. Generally, the benefits of nanotechnology products containing chemopreventive agents were proven by in vitro studies using several cell lines. Although some investigations were preformed in vivo, the animals used could not totally mimic the real internal environment of a healthy or diseased patient. However, there is an increase in the tendency of using nanoencapsulation for natural anti-oxidants aiming to decrease the risk of colon–rectal cancer. 5. Conclusions Polyphenols are well known to have chemoprotective effects. This type of prevention can be very beneficial to human health due to prevention of cancer initiation and development. For their positive characteristics, polyphenols can be a major support to reach this goal. However, these substances have bioavailability problems limiting their full capacity in the cell environment. The nanochemoprevention, i.e. associating nanotechnology to chemoprevention, could be very useful to improve polyphenol performance in the human body, enabling them to reach the target site more easily. In this way, nanotechnology can enhance the outcome of chemoprevention aiming to overcome colon cancer. Acknowledgements The authors wish to acknowledge Fundação para a Ciência e Tecnologia do Ministério da Ciência e Tecnologia, under the reference ERA—Eula/002/2009. AMS was supported by the European Union Funds (FEDER/COMPETE) and by national funds (FCT—Portuguese Foundation for Science and Technology) under the project FCOMP-01-0124-FEDER-022696 and by a research project grant (PEst-C/AGR/UI4033/2011). References Almeida AJ, Souto E. Solid lipid nanoparticles as a drug delivery system for peptides and proteins. Adv Drug Deliv Rev 2007;59:478–90. Araujo JR, Goncalves P, Martel F. Chemopreventive effect of dietary polyphenols in colorectal cancer cell lines. Nutr Res 2011;31:77–87. Arias JL, Clares B, Morales ME, Gallardo V, Ruiz MA. Lipid-based drug delivery systems for cancer treatment. Curr Drug Targets 2011;8:1151–65. Bartik L, Whitfield GK, Kaczmarska M, Lowmiller CL, Moffet EW, Furmick JK, et al. Curcumin: a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention. J Nutr Biochem 2010;21:1153–61. Berger SJ, Gupta S, Belfi CA, Gosky DM, Mukhtar H. Green tea constituent (−)-epigallocatechin-3-gallate inhibits topoisomerase I activity in human colon carcinoma cells. Biochem Biophys Res Commun 2001;288:101–5. Boghossian S, Hawash A. Chemoprevention in colorectal cancer—where we stand and what we have learned from twenty year's experience. Surgeon 2012;10:43–52. Breunig M, Bauer S, Goepferich A. Polymers and nanoparticles: intelligent tools for intracellular targeting? Eur J Pharm Biopharm 2008;68:112–28. Chang D, Wang FAN, Zhao Y-S, Pan H-Z. Evaluation of oxidative stress in colorectal cancer patients. Biomed Environ Sci 2008;21:286–9. Chen D, Dou QP. Tea polyphenols and their roles in cancer prevention and chemotherapy . Int J Mol Sci 2008;9:1196–206. Collnot EM, Ali H, Lehr CM. Nano- and microparticulate drug carriers for targeting of the inflamed intestinal mucosa. J Control Release 2012. http://dx.doi.org/ 10.1016/j.jconrel.2012.01.028. Cuffy M, Abir F, Longo WE. Management of less common tumors of the colon, rectum, and anus. Clin Colorectal Cancer 2006;5:327–37. Das RK, Kasoju N, Bora U. Encapsulation of curcumin in alginate–chitosan–pluronic composite nanoparticles for delivery to cancer cells. Nanomedicine 2010;6: 153–60. Donsì F, Sessa M, Mediouni H, Mgaidi A, Ferrari G. Encapsulation of bioactive compounds in nanoemulsion‐based delivery systems. Procedia Food Sci 2011;1: 1666–71.

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