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DOI: 10.1055/a-0797-3657
An Overview on Genistein and its Various Formulations
Correspondence
Publikationsverlauf
received 11. Juni 2018
accepted 04. November 2018
Publikationsdatum:
05. Dezember 2018 (online)
- Abstract
- Introduction
- Sources
- Chemistry of Genistein
- Biological Properties of Genistein
- Pharmacokinetics of genistein
- Bioavailability of Genistein
- Bio Safety of Genistein
- Analytical Methods for Determination of Genistein
- An Insight to Formulation Aspects of Genistein
- Conclusions
- References
Abstract
Genistein is the natural isoflavone and a phytoestrogen with a broad range of pharmacological properties, such as tyrosine and topoisomerase inhibition. It also induces apoptosis and cell proliferation inhibition, differentiates cancer cells. Added health benefits include the reduction of osteoporosis by suppressing osteoclasts and lymphocyte functions, decreased the risk of cardiovascular attacks and relieved postmenopausal problems. Genistein traditionally used in Chinese and Ayurvedic medicine and are found to be associated with lower risk of breast, prostate and lung cancer. Numerous factors comprising genetic, epigenetic and transcriptomic alterations are evidenced to be responsible for breast, prostate and lung cancer. In present review, an overview on genistein, the various analytical methods and drug delivery approaches to determine genistein in the formulations are discussed. It may help to develop novel formulations with better solubility and bioavailability of genistein. The tumor cell scan may be targeted to form a stable genistein formulation.
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Introduction
Genistein (4′, 5, 7-trihydroxyisoflavone) [Fig. 1] is an isoflavone. Soybean, a without cholesterol, high protein vegetable, has been accounted for to contain the most genistein. Pint sized quantities of genistein are found in different legumes, for example, chickpeas (garbanzo beans). Soy based edibles contain genistein in variable quantity, for example, soy based newborn child formulas, tofu, soy milk, soy flour, textured soy protein, soy protein isolates, tempeh, and miso. Soy flour contains 53% soy protein. Textured soy protein (TSP) a meat replacement prepared from defatted soy which is found in hamburgers, sausages, hot dogs, meatballs, meat loafs, may contain 50–70% soy protein, depending upon the initial soy material utilized. Soy protein isolates (SPI), used in the preparation of special nutrition foods such as infant formulas, sports drinks, bodybuilding beverages, energy bars, and special diets for the unwell, contain 90% soy protein. Other plant foods that have been shown to contain genistein consist of alfalfa and clover sprouts, barley meal, broccoli, cauliflower and sunflower, caraway, and clover seeds. In 1899 genistein was first time extracted from the dyer's broom, Genista tinctoria thus, the substance name got from the non specific name. Concentration of genistein in bulk part of soy nourishment materials ranges from 0.2 to 1 mg/g, generally as various forms of glycosidic conjugates. Genistein was found in trifolium species as well; however it was isolated from fermentation broth of various kinds of micro-organisms (Streptomyces sp. Pseudomonas sp). [1]
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In this review, various analytical and formulation aspects of genistein have been summarized and analyzed for higher know-how of the problems associated with genistein and processes to overcome the difficulties to broaden a better and stable formulation for nutraceuticals and pharmaceutical applications.
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Sources
The best known sources of genistein are soy-based foods, such as soy cheese or soy drinks (i. e., soy milk and soy-based beverages). The mature soybeans constituted 5.6 to 276 mg/100 g, of genistein and an average content of 81 mg/100 g is often described for comparative purposes [2] . In addition to genistein, soy foods contain another major isoflavone, daidzein, which differs from genistein by the lack of the hydroxyl group at position 5 ([Fig. 1]).
Both isoflavones may exist in their aglycone or glycoside forms. The most common glycoside forms of genistein and daidzein are those of O-β-D-glucoside derivatives at position 7 in both compounds. Because numerous traditional Asian foods are made from soybeans, the average dietary isoflavone intake in Asian countries is in the range of 25–50 mg/day, whereas in Western countries the estimated intake is as low as 2 mg/day [3] [4].
Legumes are considered the second most important source of genistein, at 0.2 to 0.6 mg/100 g, which is present together with the other related isoflavone, daidzein [5]. The genus Lupinus (commonly known as lupin) represents a typical example of the legume that is now widely cultivated for its seeds, which possess a nutritional value similar to soybean. Other important legumes are broad beans and chick peas, which are known to contain significant amounts of genistein, although less than soybeans. The content of genistein in fruit, nuts, and vegetables can vary considerably; the estimated range is from 0.03 to 0.2 mg/100 g [6] . However, in some native cherry cultivars of Hungarian origin, genistein concentrations up to 4.4 mg/100 g have been recorded. An extended list of foods with their genistein content is available online in several databases [2] .
The biotechnological approach used to maximize the isoflavonoid yield by sprouting seeds is the commonest method used to improve the nutritional and medicinal values of certain foods. The metabolic processes of seed germination, which are characterized by degradation of food reserves and anabolic processes devoted to the developing embryo, have been shown to enhance nutritional value primarily by increasing the content of vitamins and plant secondary metabolites, such as isoflavonoids [7]][8] . Accordingly, the increased content of genistein and other isoflavonoid aglycones has been well documented in germinated soybean seeds and related products [9] . During the process of fermentation of soybean products, the content of genistein and related aglycones increases [10] . Through genetic manipulation, it is also possible to obtain genistein from nonlegume plant sources, such as rice. Cloning the enzyme IFS from a genistein-rich soybean cultivar resulted in transgenic rice lines with 30-fold more genistein content [11] . With the medicinal value of genistein and related isoflavonoids now well recognized, soy-based meat substitutes, soy milk, soy cheese, and soy yogurt have recently gained popularity in Europe and the United States.
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Chemistry of Genistein
Chemical nature
Common name: genistein IUPAC name: 5,7-dihydroxy-3-(4-hydroxyphenyl) chromen-4- one Other name: 4,5,7-trihydroxyisoflavone The main dietary source of genistein is the biologically active glucoside genistin. Fermentation or digestion of soybeans or soy products results in the release of the sugar molecule from the isoflavone glycoside, genistin leaving the isoflavone aglycone, genistein [12] .
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Chemical structure
Genistein has a diphenol structure that resembles stereo- chemically human endogenous estrogen (E2) [13] [14]][14.] The similar distance between the OH groups on the opposite sides of genistein and E2 molecules ([Fig. 1]) makes also genistein capable of binding to ER subtypes α and β. Molecular formula: C15H10O5
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Formula
Weight: 270.24
MP: 297–298 oC
Storage temp: 20 oC
Solubility: DMSO soluble
Form: Powder
Color: Off-white
Water solubility: insoluble
Stability: light sensitive
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Active principles
Soy (genistein) is the major source of plant derived phytoestrogen compounds, which has long been used as traditional food [15]. Phytoestrogen are plant-derived secondary metabolites that structurally or functionally mimic mammalian estrogen 17β – estradiol [16] [17] [18] Therefore genistein may be used to overcome breast cancer. There are a number of subtypes of phytoestrogens, including isoflavones, coumestans, lignans, chalcones, flavones, and prenylflavonoids. Isoflavones make up the most common form of phytoestrogens [19] [20] [21] [22]. They have a common diphenolic structure that resembles the structure of the potent synthetic estrogens diethylstilbestrol and hexestrol. Two basic subgroups of isoflavones include aglycones and glycosides. Genistein belongs to the aglycone subgroup of isoflavones.
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Biological Properties of Genistein
Genistein plays a vital role in a number of biological reactions and pathways. It targets different molecules to exert its effect.
Metabolic pathway and mechanism of action
Genistein acted as an inhibitor of the tyrosine-specific protein kinases of the epidermal growth factor (EGF) receptor and also inhibited the activity of topoisomerases [23]. Genistein potentially inhibits proliferation of various cancer cells and induces cell differentiation and apoptosis. Genistein induced G2/M arrest has been found to be associated with upregulated p21 expression in breast, prostate and lung cancer [24]. Genistein (10–100 µM; 10 min) also reduced glucose uptake in both estrogen receptor-positive MCF-7 and -negative (MDA-MB-231) breast cancer cell lines [25]. Meanwhile, genistein also exhibits antiangiogenic and antioxidant activities that are important for cancer prevention. One of the most important advantages of genistein is its low toxicity in comparison with many current chemotherapeutic drugs.
The isoflavones are also used in prevention of heart diseases [26] [27]. The preventive cardiovascular effects of genistein are indistinct, but may be due to its antioxidant activity, lowering of serum cholesterol, inhibition of tyrosine kinase and/or improvement of vascular reactivity [28] [29.]
Genistein possess significant bone sparing effects among postmenopausal women [27]. In vitro and in vivo studies suggested the beneficial effects on bone mineral density and bone turnover. However, the exact mechanisms are presently mysterious and provisional, but an isoflavone rich diet appears to offer a high potential for the prevention of osteoporosis [30].
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Pharmacokinetics of genistein
Genistein is parent compound, which is metabolized from its plant precursors, biochanin A. In plants, isoflavones are inactive when present in the bound form as glycosides, but when the sugar residue is removed, the compound becomes activated. This plant compound undergoes fermentation by intestinal microflora, with both metabolites and unfermented parent (aglycone) compounds being liable to absorption [31]. The oral administration of genistein results in absorption of this compound with a tmax of 5–6 h and t1/2 of 8h [32] [33] [34]. Only 20–40% of oral genistein is being absorbed from gastrointestinal tract where it goes into enterohepatic cycling. Hence the oral absorption of genistein from GIT is very low leading to low bioavailability [35]. Genistein is rapidly distributed to all tissues and crosses placental barrier and blood brain barrier. The tissue distribution of genistein is highest in the gastro-intestinal tract and liver, consistent with its enterohepatic recycling. In a human study involving radio labelled isoflavones, it was found that the mean volume of distribution normalized to bioavailability (Vd/F), clearance rate, and half-life of [13C] genistein were 258.76 L, 21.85 L/h, and 7.77 h respectively [34].
Dietary isoflavone might be metabolized in the intestine to equol, a metabolite, [7-hydroxy-3-(4′-hydroxyphenyl)-chroman] that has superior estrogenic activity than daidzein, and to other metabolites that are less estrogenic. This metabolite has affinity for both estrogen receptors, ERα and ERβ [36]. The metabolism of genistein closely mimic the metabolism of endogenous estrogens, with phase-II conjugative reactions predominant than phase-I reactions. The major metabolic pathways of genistein are glucuronidation and sulfation with limited CYP reaction [37] UDP glucuronosyl transferase (UGT) and sulfotransferase (SULT) are the key enzymes involved in the phase-II conjugative reactions with isoflavones. Genistein is predominantly conjugated in the intestine with glucuronic acid and to a lesser extent with sulfate. Aglycones might be carried to the target tissues such as breast and prostate by the sulfate and glucuronide conjugates. In target tissues these conjugates could be biologically actived or hydrolysed to generate the aglycon. The aglycone genistein is absorbed from the intestine and conjugated with glucuronic acid during transport across the intestinal epithelial cells. After transport to the liver, the glucuronide may be excreted in the bile, where after it could re-enter the small intestine, allowing genistein to be deconjugated, absorbed, and metabolized for the second time. The usual time ingested aglycones takes to reach peak plasma concentrations is about 4–7 h, where as corresponding β-glycosides takes 8–11 h. [38]
These reactions occur mainly in the intestinal microsomes, concurrent with the absorption. According to previous in vivo/in vitro ADME studies intestinal, biliary and renal excretions are the excretion pathways for genistein metabolites. In urine, genistein is mainly excreted, to a level of approximately 53–76%, as a monoglucuronide and to a much lesser extent as a diglucuronide (12–16%) and as a sulfoglucuronide (2–15%). After oral administration of genistein, only a small fraction of genistein aglycone was excreted through bile and a high level of genistein glucuronides was detected in bile indicating that genistein is mainly excreted in the form of glucuronides. ADME studies revealed that genistein has favourable absorption property in intestine but its poor solubility may prevent absorption without proper formulations [39] [40] [41] [42] [43] .
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Bioavailability of Genistein
Isoflavone bioavailability is a measure of the amount of these compounds that becomes available for tissue distribution where they can exert physiological effects.Various experimental models, including in vivo studies, have shown that genistein from soy extracts, its free form, and its glycoside genistin are readily bioavailable. For example, in freely moving unanesthetized rats with a cannula in the portal vein, genistein was readily bioavailable and was detected in portal vein plasma 15 min after administration with AUC values (0–24 h) of 54 and 24 mmol h/L for genistein and genistin, respectively [38] [44]]. Several studies, however, indicated that the oral bioavailability of genistin is higher than that of genistein [45]. The limitation of genistein bioavailability after oral administration is generally due to its poor water solubility [37] [46]. Genistein also has a bitter taste [47], and formulations to overcome both the limitation of bioavailability and acceptable taste are necessary. Extensive metabolism of genistein in the intestine and post absorption has been documented both in humans and experimental animals. Among the several metabolites identified in the blood and excreta are dihydrogenistein, dihydrodaidzein, 69-hydroxy-O-desmethylangolensin, 4-ethylphenol, glucuronoide and sulfate conjugates of genistein and its metabolites, and 4-hydroxyphenyl-2-propionic aid [37] . The gut microflora is known to cleave the C-ring of the isoflavonoid skeleton to give 4-hydroxyphenyl-2-propionic acid and dihydrogenistein [48].
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Bio Safety of Genistein
There is no clear evidence that the consumption of large amounts of isoflavones in the diet is harmful in humans, although the multiple and complex effects of these compounds suggest that the administration of high doses of isoflavones could induce potentially adverse effects [49]. However, minimal clinical toxicity in healthy postmenopausal women was observed after a single dose that exceeded normal dietary intakes of purified unconjugated isoflavones [50]. The genotoxicity of anticancer agents, such as genistein, may be beneficial because they promote cancer cell death by inducing apoptosis and other cytotoxic processes. However, these agents would also negatively affect normal cells. Genotoxic and potentially adverse effects of genistein (apoptosis, cell growth inhibition, topoisomerase inhibition, and DNA damage) were reported in vitro as well as in experimental animals [51]. However, genistein concentrations used in these studies were much higher than the physiologically relevant doses achievable by dietary or pharmacologic intake of soy foods or supplements.
In vivo studies generally showed negative genotoxicity results [52]. The administration of a purified unconjugated isoflavone mixture (genistein, daidzein, and glycitein) showed minimal toxicity at doses as high as 16 mg genistein/kg body weight [53].
The potential effects of genistein on fertility and fetus development have been largely investigated. Some studies showed that therapeutically relevant doses of genistein have significant negative impacts on ovarian differentiation, estrous cyclicity, and fertility in the rodent model [54] [55].
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Analytical Methods for Determination of Genistein
Because of the increasing popularity of soy foods and the availability of isoflavone supplements, there is an important public health need to accurately quantify the isoflavone content of these soy products. Numerous analytical methods have been developed for identification and quantification purposes.
UV-visible spectroscopy
Isabela da Costa César et al (2008) developed and validated a simple and rapid UV-Visible method to quantify genistein and its glycoside genistin in soy dry extracts, after reaction with AlCl3. The UV-Visible spectrum recorded for a solution of genistein after reaction with AlCl3 showed an intense absorption band with maximum wavelength at 382 nm, which was not found in the UV-Visible spectrum of genistein alone. A similar absorption band was present in the UV-Visible spectrum of a soy dry extract solution, after reaction with AlCl3, attesting the presence of genistein and its glycoside in the analyzed sample [56].
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Mass spectrometry
Chang et al (2000) developed and validated an analytical methodology that was used to determine the pharmacokinetics in blood and distribution of genistein in tissues from rats exposed through continuous dietary intake in a multi generation test [57].
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Liquid chromatography/Tandem mass spectrometry (LC - MS-MS)
An accurate and sensitive analytical method has been developed for the quantification of genistein in dog plasma using high-performance liquid chromatography/tandem mass spectrometry by Duiping et al (2013). The method was successfully applied to a pharmacokinetic comparison of immediate and extended release tablets in beagle dogs after oral administration. Immediate release tablets showed rapid genistein absorption. However, the absorption of genistein was considerably slower and more sustainable for extended release tablets [58].
Holder et al (1999) developed and validated a simple and sensitive analytical method based on LC/ES-MS for the determination of genistein in the blood of rats receiving dietary genistein. The method uses serum/plasma deproteination, liquid-liquid extraction, deuterated genistein and daidzein internal standards, isocratic LC separation, and electrospray mass spectrometric quantification using selected ion monitoring. The sensitivity of LC/ES-MS detection in combination with isotopic labelled internal standards serves to add additional confidence over previous LC/MS methods in the accuracy and precision of determinations by directly providing quality control and assurance information in every sample throughout large sample sets [59].
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Ultra performance liquid chromatography/ Mass spectroscopy (UPLC-MS)
This is a highly sensitive, accurate and robust method used to determine genistein and its 4 metabolites’ concentrations in blood of FVB mice. The method was successfully applied for mouse bioavailability study by using only 20 μl of mouse blood sample, hereby, giving complete pharmacokinetic profile [60] .
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High performance liquid chromatography
A wide variety of analytical techniques have been applied to the quantitation of soy isoflavones in foods and biological fluids. However, methodological improvements for the quantitative analyses of the free plus conjugated forms of isoflavones in human urine and plasma continue to be needed for clinical trials aimed at defining single and multiple-dose safety, pharmacokinetic, and efficacy profiles. Thomas et al (2001) developed validated analytical methods using HPLC with UV detection which enabled the measurement of (1) the free, non-conjugated molecules, (2) the combined ‘‘free plus the sulfate-conjugated molecules’’, or ‘‘free plus sulfate fraction’’, and (3) the total conjugated and free molecules of genistein, daidzein, and glycitein in human plasma and urine. Development of these validated HPLC–UV assay provided novel analytical methods with which the pharmacokinetics and pharmacodynamics of the principle active forms of soy isoflavones can be studied [61].
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An Insight to Formulation Aspects of Genistein
The clinical effectiveness of genistein is hindered by its poor solubility in water, insufficient targeting of cancer cells, rapid in vivo metabolism and excretion, and low serum level after oral administration. One observable strategy to overcome these problems is to design appropriate drug delivery system that may overcome the shortcoming of genistein and greatly improve its performance in anticancer therapy. Recent trends in drug development had led researchers to explore many more potential for developing a robust formulation and thereby enhancing its stability and bioavailability, and minimizing the major drawbacks concerned with the drug.
Formation of solid lipid particulate system
A high potential for drug delivery has been accredited to particulate drug carriers, especially small particles such as micro particles and colloidal system in nanometer range. In particular, solid lipid particulate systems (SLPS) may offer plenty of advantages over conventional dosage forms which include increased solubility of poorly soluble drugs, improve drug stability by protecting them from enzymatic or chemical degradation, and release incorporated drugs at a controlled rate, thereby enhancing drug bioavailability [62] [63]. Furthermore, SLPS can be prepared with physiologically tolerated lipids, which decrease the possibility of undesirable toxicities that can occur with other synthetic materials. They are produced from lipids that are solid at room temperature. The solid lipid is melted and the drug is incorporated into it. The whole system is stabilized by the addition of a suitable surfactant [64]. The matrix of the lipid particle formed is solid which can easily protect the drug molecules against chemical degradation. Particle size is one of the physicochemical properties of SLPS that acts as an essential factor significantly affecting the oral bioavailability of any incorporated drug [62] [65]. The particle size of SLPS determines their surface area and diffusion length for the incorporated drugs to be released from the lipid matrix, which are closely related to the drug dissolution rate from the particles [66] [67]
Utilizing all the advantages of SLPS, Jeong Tae Kimet al. (2017) developed genistein loaded SL Micro and Nanocarrier system by melt dispersion and hot homogenization method techniques respectively. The in vivo pharmacokinetic study of developed SLPs was also carried out in SD rats. Prepared SLPs showed improved oral bioavailability of genistein because they were fabricated to release the incorporated drugs in a controlled manner by varying the composition of the solid matrix, which is a critical determinant of oral bioavailability. As per the authors, particle size of the SLPs is considered one of the most essential properties affecting the oral bioavailability of the incorporated drugs because it largely determines the surface area of the SLPs and diffusion length of the entrapped drugs to be released from the lipid matrix. Therefore, decreasing the particle size of the SLPs increases the drug dissolution rate and enhances the bioavailability. The oral bioavailability of solid lipid microparticles and solid lipid nanoparticles loaded with genistein was enhanced significantly as compared to genistein suspension [68].
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Solid oral dosage form
The oral route of drug administration is the most expedient for patients. Standard compressed, controlled-release and coated tablets are the most common form of solid oral dosages. A wide range and diversity of ingredients are often included in tablet formulations. On routine basis solid oral dosage forms can provide improved administration of important phytochemicals. Few studies related to the development of isoflavone tablets have been conducted. In recent times, the majority of the concerns have been focused on the standardization extract, but little interest has been given to the development of pharmaceutical forms.
Stela R. de Oliveira et al developed tablets of soy isoflavone extracts (genistein & diadzein) using different disintegrating agents, surfactants and diluents by wet granulation or direct compression method and studied the influence of these techniques. Studies showed the formulation designed for direct compression prepared with 50% (w/w) of soy extract resulted in high values for Carr and Hausner indexes, denoting a high cohesiveness of the mixture. Flow rates were found to be inadequate for the necessary tableting technological parameters. Granules prepared by wet granulation exhibited a marked improvement in flow properties and scale of flowability of the soy extract and its formulations was according to USP35 ([Table 1]) [69].
Formulation type |
Formulation main Component |
Preparation Method |
Purpose |
Reference |
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Tablets |
Sodium croscarmellose, Crospovidone, Hydroxypropyl methylcellulose, Sodium dodecyl sulfate |
Wet granulation & direct compression |
Immediate release of genistein and diadzein |
[66] |
Solid lipid microparticles (SLM) |
Glyceryl palmitostearate, L-α-Lecithin, Tween 80 |
melt dispersion technique |
Enhancement of bioavailability |
[65] |
Microparticle |
Gelatin A |
Spray drying technique |
Enhanced aqueous solubility and bioavailability |
[43] |
Solid lipid nanoparticles (SLN) |
Glyceryl palmitostearate, L-α-Lecithin, Poloxamer 188 |
hot homogenization method |
Enhancement of bioavailability |
[65] |
Hydrogel Matrix |
κ-Carrageenan |
Matrix retention |
Improve the water solubility of genistein |
[68] |
Micelles |
Pluronic F127 |
Solid dispersion |
Improve oral bioavailability of genistein |
[69] |
Nanoparticles |
Eudragit E, Poloxamer 188 |
Nanoprecipitation |
Improve water solubility & bioavailability of genistein |
[80] |
Nanoparticles |
Poly(ε-caprolactone),D-α tocopheryl polyethylene glycol 1000 succinate |
Modified Nanoprecipitation |
Enhanced permeability and retention effects of genistein NP in tumor cells |
[81] |
Nanostructured lipid carriers |
Glycerol monostearate, Soy lecithin |
high-speed homogenization and ultrasonication probe |
Enhanced oral bioavailability of poorly bioaccessible molecules |
[82] |
Layered Nanoemulsion |
Chia Seed oil, Chitosan, Tween 80 |
Homogenization & ultrasonication |
Targeted delivery along with extended release of genistein |
[83] |
Topical Nanoemulsions |
Medium chain triglycerides and Octyldodecanol |
Spontaneous Emulsification |
Permeation enhancement of genistein through skin. |
[84] |
Liposomes |
Soy phosphatidylcholine, PEG2000-DSPE, cholesterol |
Homogenization & ultrasonication |
Coated liposomes with enhanced permeability & retention |
[85] |
Nanoemulsion based topical hydrogel |
Egg-lecithin, medium chain triglycerides, Octyldodecanol, Carbopol 940® |
Spontaneous Emulsification |
Enhancement of genistein permeation and retention |
[86] |
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Biocompatible super paramagnetic drug delivery system
The practical application of genistein as a low toxicity chemotherapeutic drug is hindered by many of its in vivo properties. To overcome these obstacles, a new multifunctional drug delivery system was developed by Hua-Yan Si et al, based on covalently attaching genistein onto Fe3O4 nanoparticles coated by cross-linked carboxy methylated chitosan (CMCH). Nanoscale materials have been recognized to have great potential in biocompatible drug delivery and target systems due to many inimitable properties, including large surface-to-volume ratios, easy to be taken up by the cells and less sensitive by the immune system in comparison with traditional macro scale materials. Magnetic nanoparticles have shown potential applications in target drug release, magnetic hyperthermia therapy and contrast enhancement in magnetic resonance imaging. The Fe3O4-CMCH-genistein nano-conjugate showed good water solubility and enhanced inhibition effect to the SGC-7901 cancer cells proliferation than the free genistein.Fe3O4-CMCH based nano conjugates proved to be promising multifunctional drug delivery system for chemotherapeutic application that combines drug release and magnetic hyperthermia therapy [70].
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Hydrocolloids
Low oral bioavailability of poorly water-soluble drugs poses an immense challenge during drug development. Various approaches have been developed to improve bioavailability by increasing a drug’s dissolution rate and solubility. Matrix retention is a promising technique to enhance solubility of various less-soluble compounds. In this method, the less-soluble compounds are mixed with a water-soluble carrier through various measures. The commonly used carriers are long-chain polymers, such as carrageenan, polyvinyl pyrrolidone (PVP) and polyethylene glycol (PEG). Hydrocolloids are mostly used to hold water and provide texture for food. They also have the ability to bind guest molecules and by this influence the characteristics of guest molecules. In a broad sense, the term binding includes adsorption and physical entrapment in colloid matrices, as well as inclusion complexation [71].
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Micelles
Polymeric micelles have been utilized as a part of the pharmaceutics field as drug and gene delivery systems. Polymeric micelles can be utilized as effective carriers for compounds having poor solubility, undesired pharmacokinetic qualities and low stability in a physiological situation. The hydrophobic centre of such aggregates acts as a microenvironment for the inclusion of lipophilic compounds, while the hydrophilic part maintains the dispersion stability of the triblock copolymer aggregates.
Suk Hyung Kwon et al. developed Pluronic F127 polymeric micelles using a solid dispersion method with various genistein/triblock copolymer weight ratios. Study demonstrated that genistein-loaded Pluronic F127 polymeric micelles depicted high solubilization capacity and nanoscopic particle size. The in vivo study showed oral bioavailability of genistein loaded in polymeric micelles using rats was greater than genistein powder. Thus, Pluronic F127 polymeric micelles are an efficient delivery system for the oral administration of genistein ([Table 1]) [72].
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Nanoformulation system
The advent of nanotechnology is considered to be the biggest engineering innovation since the industrial revolution [73]. National Nanotechnology Initiative (NNI), has generally defined nanotechnology as the science and technology concerned in the design, synthesis, characterization, and application of materials and devices with at least one of the proportions on the nanoscale (usually in the range of 1–100 nm) [74].The use of nanotechnology to medicine and pharmaceutical formulations, generally referred as nanomedicine, is revolutionizing the medical field through the preface of more proficient therapeutics, medical devices and diagnostics. [75]
Undeniably, nanomedicines could offer ways to circumvent the limitations of phytochemicals and the allied health concerns, such as improving solubility, augmentation of bioavailability, specific targeting of tumour cells or tissues but not the healthy cells, enhanced cellular uptake, reducing doses of phytochemicals and achieving steady-state therapeutic concentration of the phytochemicals over an extended period. Further benefits could also include excellent blood stability, multifunctional design of nanomedicines, limited interaction with synthetic drugs and enhancement in anticancer activities. [76]
Furthermore, MDR is one of the key factors accountable for failure of the phytochemicals therapy in cancer. Using nanocarriers for delivery of phytochemicals is a novel approach to overcome the MDR. Surface modification of nanomedicines can improve phytochemical delivery and overcome drug resistance by changing biophysical interactions between nanomedicines and cancer cell membrane lipids thereby increasing the delivery of phytochemicals to target tissues [77] [78]
Currently improvements in therapeutic efficiency through the use of nanomedicines had received considerable attention due to improved phytochemical delivery to tumours and cancer cells. Phytochemical based nanomedicines various advantages are summarised in [Fig. 2].
![](https://www.thieme-connect.de/media/drugres/201906/thumbnails/10-1055-a-0797-3657-i2018-06-1635-0002.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
Different types of highly proficient nanomedicines have been used to boost the physicochemical properties and effectiveness of phytochemicals against cancer [79] .
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Nanoparticles
Polymeric nanoparticles (Np) represent one of the most innovative non-invasive approaches for the drug delivery system [80] . Nanoparticles are defined as particulate dispersions or solid particles with a size in the range of 10–1000 nm. The drug is dissolved, entrapped, encapsulated or attached to a nanoparticle matrix. The major goals in designing nanoparticles as a delivery system are to control particle size, surface properties and release of pharmacologically active agents in order to achieve the site-specific action of the drug at the therapeutically optimal rate and dose regimen [81.]
Nanoparticles of biodegradable polymers can provide controlled and targeted delivery of the drug with better efficacy and fewer side-effects. Lipophilic drugs, which have some solubility either in the polymer matrix or in the oily core of nanocapsules, are more readily incorporated than hydrophilic compounds, although the latter may be adsorbed onto the particle surface [82] .
Jingling Tang et al 2011 developed Eudragit nanoparticulate system to enhance the oral bioavailability of genistein. The genistein nanoparticles were prepared by a nanoprecipitation method. Internal organic phase solutions composed of solvents, making the drug and Eudragit completely soluble, and the external aqueous phase consisted of aqueous solution, along with 1% Poloxamer 188 as surfactant. The surfactant penetrates into the genistein nanoparticles during the nanoprecipitation process to form a stable nanoparticle delivery system. The oral delivery of genistein was found to be enhanced. In vitro release of genistein was found to be prolonged from nanoparticle in comparison with genistein capsule [83].
Nanoparticle (NP)-based anticancer drug delivery systems, especially drug formulations with biodegradable polymeric NPs, have attracted considerable attention for their numerous advantages such as high cellular uptake, enhanced permeability and retention effect, and reduced cancer cell drug resistance.
Zhongyuan Wang et al 2015 developed TPGS-b-PCL nanoparticles to improve the therapeutic effect of genistein in cervical cancer cells. The TPGS-b-PCL nanoparticles were prepared with a modified nanoprecipitation method instead of solvent extraction/evaporation method and characterized. Compared with the NPs prepared by the solvent extraction/evaporation method, the current NPs were much smaller. The novel nanoformulations had higher cellular uptake and could accumulate at the tumor site preferentially due to their enhanced permeability and retention effects. Furthermore, this kind of NPs used as drug carriers have other advantages, such as more reasonable pharmacokinetics and more desirable biodistribution as well as easy industry application. The efficacy of genistein-loaded TPGS-b-PCL NPs on human cervical carcinoma was investigated both in vitro and in vivo, in close comparison with pristine genistein and genistein-loaded PCL NPs. TPGS-b-PCL NPs exhibited a much faster drug release than did PCL NPs. This is probably because of the hydrophilic part of the TPGS, which promotes the uptake and permeation of PBS buffer into the core of NPs to facilitate drug release ([Table 1]) [84].
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Conclusions
This review indicated the recent advances in novel drug delivery systems that may enable researchers to build up successful formulations with improved solubility and bioavailability of genistein. Conversed approaches could be utilized to overcome problems associated with genistein and target the drug to various cancer cells.
#
#
Conflict of Interest
All authors have approved the final manuscript and no potential conflict of interest was reported by the authors.
Acknowledgement
The authors are thankful to Integral University for providing technical support and assigning Communication reference no: IU/R&D/2018-MCN000391, for further communication.
-
References
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- 2 Bhagwat S, Haytowitz DB, Holden JM. USDA database for the isoflavone content of selected foods. Release 2.0. Bethesda (MD): USDA; 2008
- 3 Messina M, Nagata C, Anna HW. Estimated Asian Adult Soy Protein and Isoflavone Intakes. Nutrition and Cancer 2006; 55: 1-12
- 4 Van Erp-Baart MA, Brants HA, Kiely M. et al. Isoflavone intake in four different European countries: The venus approach. Br J Nutr 2003; 89: S25-S30
- 5 Liggins J, Bluck L, Runswick S. et al. Daidzein and genistein contents of vegetables. Br J Nutr 2000; 84: 717-725
- 6 Liggins J, Bluck LJ, Runswick S. et al. Daidzein and genistein content of fruits and nuts. J Nutr Biochem 2000; 11: 326-331
- 7 Ahmad S, Pathak D. Nutritional changes in soybean during germination. J Food SciTechnol 2000; 37: 665-666
- 8 Kim WJ, Lee HY, Won MH. et al. Germination effect of soybean on its contents of isoflavones and oligosaccharides. Food Sci Biotechnol 2005; 14: 498-502
- 9 Quinhone Jr. A, Ida E. Profile of the contents of different forms of soybean isoflavones and the effect of germination time on these compounds and the physical parameters in soybean sprouts. Food Chem 2015; 166: 173-178
- 10 Lee SY, Lee S, Lee S. et al. Primary andsecondary metabolite profiling of doenjang, a fermented soybean pasteduring industrial processing. Food Chem 2014; 165: 157-166
- 11 Sohn SI, Kim YH, Kim SL. et al. Genistein production in rice seed via transformation with soybean IFSgenes. Plant Sci 2014; 217–218: 27-35
- 12 Markovits J, Linassier C, Fosse P. et al. Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II. Cancer Res 1989; 49: 5111-5117
- 13 Cassidy A. Potential tissue selectivity of dietary phytoestrogens and estrogens. Curr Opin Lipidol 1999; 10: 47-52
- 14 Tham DM, Gardner CD, Haskell WL. Clinical review 97: Potential health benefits of dietary phytoestrogens: A review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab 1998; 83: 2223-2235
- 15 Farina HG, Pomies M, Alonso DF. et al. Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer. Oncology Reports 2006; 16: 885-891
- 16 Barnes S, Kim H, Usmar VD. et al. Beyond ERα and ERβ: Estrogen receptor binding is only part of the isoflavone story. The Journal of Nutrition 2000; 130: 656S-657S
- 17 Dixon RA, Ferreira D. Molecules of interest genistein. Phytochemistry 2002; 60: 205-211
- 18 Magee PJ, Rowland IR. Phyto-oestrogens, their mechanism of action: Current evidence for a role in breast and prostate cancer. British Journal of Nutrition 2004; 91: 513-531
- 19 Ososki AL, Kennelly EJ. Phytoestrogens: A Review of the Present State of Research. Phytotherapy Research 2003; 17: 845-869
- 20 Matsuda H, Shimoda H, Morikawa T. et al. Phytoestrogens from the roots of Polygonum cuspidatum (Polygonaceae): Structure-requirement of hydroxyl anthraquinones for estrogenic activity. Bioorg Mol Chem Lett 2001; 11: 1839-1842
- 21 Milligan SR, Kalita JC, Heyerick A. et al. Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer. J Clin Endocrinol Metab 1999; 83: 2249-2252
- 22 Rafi MM, Rosen RT, Vassail A. et al. Modulation of bcl-2 and cytotoxicity by licochalcone-A, a novel estrogenic flavonoid. Anticancer Res 2000; 20: 2653-2658
- 23 Kim H, Peterson TG, Barnes S. Mechanisms of action of the soy isoflavone genistein: Emerging role for its effects via transforming growth factor b signaling pathways. Am J Clin Nutr 1998; 68 suppl 1418S-1425S
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- 28 Fotsis T, Pepper M, Adlercreutz H. et al. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proceedings National Academic Science USA 1993; 90: 2690-2694
- 29 Potter SM. Overview of proposed mechanisms for the hypocholesterolemic effect of soy. Journal of Nutrition 1995; 125: 606S-611S
- 30 Setchell KDR, Lydeking OE. Dietary phytoestrogens and their effect on bone: evidence from in vitro and in vivo, human observational, and dietary intervention studies. American Journal of Clinical Nutrition 2003; 7: 593S-609S
- 31 Sakai T, Kogiso M. Soy isoflavones and immunity. The Journal of Medical Investigation 2008; 55: 167-173
- 32 Setchell KD, Faughnan MS, Avades T. et al. Comparing the pharmacokinetics of daidzein and genistein with the use of 13C-labeled tracers in premenopausal women. Am J Clin Nutr 2003; 77: 411-419
- 33 Setchell KD, Brown NM, Desai P. et al. Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J Nutr 2001; 131: 1362S-1375S
- 34 Chandrasekharan S, Aglin A. Pharmacokinetics of dietary isoflavones. J Steroids Hormon Sci 2013; S12: 2-8
- 35 Yang Z, Kulkarni K, Zhu W. et al. Bioavailability and Pharmacokinetics of Genistein: Mechanistic Studies on its ADME. Anticancer Agents Med Chem 2012; 12: 1264-1280
- 36 Zaheer K, Akhtar MH. An Updated Review of Dietary Isoflavones: Nutrition, Processing, Bioavailability and Impacts on Human Health. Critical Reviews in Food Science and Nutrition 2017; 57: 1280-1293
- 37 de Oliveira MR. Evidence for genistein as a mitochondriotropic molecule. Mitochondrion 2016; 29: 35-44
- 38 Mazumder Md. AR, Hongsprabhas P. Genistein as antioxidant and antibrowning agents in in vivo and in vitro: A review. Biomed Pharmacother 2016; 82: 379-392
- 39 Yang Z, Zhu W, Gao S. et al. Simultaneous determination of genistein and its four phase II metabolites in blood by a sensitive and robust UPLC-MS/MS method: Application to an oral bioavailability study of genistein in mice. J Pharm Biomed Anal 2010; 53: 81-89
- 40 Shelnutt SR, Cimino CO, Wiggins PA. et al. Pharmacokinetics of the glucuronide and sulfate conjugates of genistein and daidzein in men and women after consumption of a soy beverage. Am J Clin Nutr 2002; 76: 588-594
- 41 Doerge DR, Chang HC, Churchwell MI. et al. Analysis of soy isoflavone conjugation in vitro and in human blood using liquid chromatography-mass spectrometry. Drug Metab Dispos 2000; 28: 298-307
- 42 Heinonen SM, Wähälä K, Adlercreutz H. Metabolism of isoflavones in human subjects. Phytochemistry Reviews 2002; 1: 175-182
- 43 Zhang Y, Hendrich S, Murphy PA. Glucuronides are the main isoflavone metabolites in women. J Nutr 2003; 133: 399-404
- 44 Steensma A, Faassen-Peters MA, Noteborn HP. et al. Bioavailability of genistein and its glycoside genistin as measured in the portalvein of freely moving unanesthetized rats. J Agric Food Chem 2006; 54: 8006-8012
- 45 Kwon SH, Kang MJ, Huh JS. et al. Comparison of oral bioavailability of genistein and genistin in rats. Int J Pharm 2007; 337: 148-154
- 46 Motlekar N, Khan MA, Youan BBC. Preparation and characterization of genistein containing poly (ethylene glycol) microparticles. J Appl Polym Sci 2006; 101: 2070-2078
- 47 Huang AS, Hsieh OAL, Chang SS. Characterization of the non-volatile minor constituents responsible for the objectionable taste of defatted soybean flour. J Food Sci 1982; 47: 19-23
- 48 Tamura M, Ohnishi-Kameyama M, Nakagawa H. et al Dihydrogenistein-producing bacterium TM-40 isolated from human feces. Food Sci Technol Res 2007; 13: 129-132
- 49 Sirtori CR. Risks and benefits of soy phytoestrogens in cardiovascular diseases, cancer, climacteric symptoms and osteoporosis. Drug Saf 2001; 24: 665-682
- 50 Bloedon LT, Jeffcoat AR, Lopaczynski W. et al Safety and pharmacokinetics of purified soy isoflavones: single dose administration to postmenopausal women. Am J Clin Nutr 2002; 76: 1126-1137
- 51 Klein CB, King AA. Genistein genotoxicity: Critical considerations of in vitro exposure dose. Toxicol Appl Pharmacol 2007; 224: 1-2211
- 52 Michael McClain R, Wolz E, Davidovich A. et al. Genetic toxicity studies with genistein. Food ChemToxicol 2006; 44: 42-55
- 53 Bloedon LT, Jeffcoat AR, Lopaczynski W. et al. Safety and pharmacokinetics of purified soy isoflavones: Single dose administration to postmenopausal women. Am J Clin Nutr 2002; 76: 1126-1137
- 54 Jefferson WN, Williams CJ. Circulating levels of genistein in the neonate, apart from dose and route, predict future adverse female reproductive outcomes. Reprod Toxicol 2011; 31: 272-279
- 55 Spagnuolo C, Russo GL, Orhan IE. et al. Genistein and cancer: Current status, challenges, and future directions. Advances in nutrition 2015; 6: 408-419
- 56 da Costa César I, Braga FC, Vianna-Soares CD. et al. Quantitation of genistein and genistin in soy dry extracts by UV-Visible spectrophotometric method. Quim. Nova 2008; 31: 1933-1936
- 57 Chang Hebron C, Churchwell MI, Delclos KB. et al. mass spectrometric determination of genistein tissue distribution in diet-exposed sprague-dawley rats. J Nutr 2000; 130: 1963-1970
- 58 Feng D, Qiu F, Tong Z. et al. oral pharmacokinetic comparison of different genistein tablets in beagle dogs. Journal of Chromatographic Science 2013; 51: 335-340
- 59 Holder CL, Churchwell MI, Doerge DR. quantification of soy isoflavones, genistein and daidzein, and conjugates in rat blood using LC/ES-MS. J. Agric. Food Chem 199 47: 3764-3770
- 60 Yang Z, Zhu W, Gao S. et al. Simultaneous determination of genistein and its four phase II metabolites in blood by a sensitive and robust UPLC-MS/MS method: Application to an oral bioavailability study of genistein in mice. J Pharm Biomed Anal 2010; 53: 81-89
- 61 Thomas BF, Zeisel SH, Busby MG. et al. Quantitative analysis of the principle soy isoflavones genistein, daidzein and glycitein, and their primary conjugated metabolites in human plasma and urine using reversed-phase high performance liquid chromatography with ultraviolet detection. Journal of Chromatography B 2001; 760: 191-205
- 62 Luo Y, Chen DW, Ren LX. et al. Solid lipid nanoparticles for enhancing vinpocetine’s oral bioavailability. J. Control. Release 2006; 114: 53-59
- 63 Muller RH, Runge S, Ravell V. et al. Oral bioavailability of cyclosporine: solid lipid nanoparticles (SLN) versus drug nanocrystals. Int J Pharm 2006; 317: 82-89
- 64 Wissing SA, Kayserb O, Muller RH. Solid lipid nanoparticles for parenteral drug delivery. Adv Drug Deliv Rev 2004; 56: 1257-1272
- 65 Desai J, Thakkar H. Effect of particle size on oral bioavailability of darunavir-loaded solid lipid nanoparticles. J Microencapsul 2016; 33: 669-678
- 66 Horter D, Dressman JB. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv Drug Deliv Rev 2001; 46: 75-87
- 67 Muller RH, Mader K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery - A review of the state of the art. Eur J Pharm Biopharm 2000; 50: 161-177
- 68 Kim JT, Barua S, Kim H. et al. Absorption Study of Genistein Using Solid Lipid Microparticles and Nanoparticles: Control of Oral Bioavailability by Particle Sizes. Biomol Ther 2017; 25: 452-459
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- 71 Chen F, Peng J, Lei D. et al. Optimization of genistein solubilization by κ-carrageenan hydrogel using response surface methodology. Food Science and Human Wellness 2013; 2: 124-131
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- 77 Patel NR, Pattni BS, Abouzeid AH. et al. Nanopreparations to overcome multidrug resistance in cancer. Adv Drug Deliv Rev 2013; 65: 1748-1762
- 78 Peetla C, Vijayaraghavalu S, Labhasetwar V. Biophysics of cell membrane lipids in cancer drug resistance: implications for drug transport and drug delivery with nanoparticles. Adv Drug Deliv Rev 2013; 65: 1686-1698
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Correspondence
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References
- 1 Ganai AA, Farooqi H. Bioactivity of genistein: A review of in vitro and in vivo studies. Biomedicine & Pharmacotherapy 2015; 76: 30-38
- 2 Bhagwat S, Haytowitz DB, Holden JM. USDA database for the isoflavone content of selected foods. Release 2.0. Bethesda (MD): USDA; 2008
- 3 Messina M, Nagata C, Anna HW. Estimated Asian Adult Soy Protein and Isoflavone Intakes. Nutrition and Cancer 2006; 55: 1-12
- 4 Van Erp-Baart MA, Brants HA, Kiely M. et al. Isoflavone intake in four different European countries: The venus approach. Br J Nutr 2003; 89: S25-S30
- 5 Liggins J, Bluck L, Runswick S. et al. Daidzein and genistein contents of vegetables. Br J Nutr 2000; 84: 717-725
- 6 Liggins J, Bluck LJ, Runswick S. et al. Daidzein and genistein content of fruits and nuts. J Nutr Biochem 2000; 11: 326-331
- 7 Ahmad S, Pathak D. Nutritional changes in soybean during germination. J Food SciTechnol 2000; 37: 665-666
- 8 Kim WJ, Lee HY, Won MH. et al. Germination effect of soybean on its contents of isoflavones and oligosaccharides. Food Sci Biotechnol 2005; 14: 498-502
- 9 Quinhone Jr. A, Ida E. Profile of the contents of different forms of soybean isoflavones and the effect of germination time on these compounds and the physical parameters in soybean sprouts. Food Chem 2015; 166: 173-178
- 10 Lee SY, Lee S, Lee S. et al. Primary andsecondary metabolite profiling of doenjang, a fermented soybean pasteduring industrial processing. Food Chem 2014; 165: 157-166
- 11 Sohn SI, Kim YH, Kim SL. et al. Genistein production in rice seed via transformation with soybean IFSgenes. Plant Sci 2014; 217–218: 27-35
- 12 Markovits J, Linassier C, Fosse P. et al. Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II. Cancer Res 1989; 49: 5111-5117
- 13 Cassidy A. Potential tissue selectivity of dietary phytoestrogens and estrogens. Curr Opin Lipidol 1999; 10: 47-52
- 14 Tham DM, Gardner CD, Haskell WL. Clinical review 97: Potential health benefits of dietary phytoestrogens: A review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab 1998; 83: 2223-2235
- 15 Farina HG, Pomies M, Alonso DF. et al. Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer. Oncology Reports 2006; 16: 885-891
- 16 Barnes S, Kim H, Usmar VD. et al. Beyond ERα and ERβ: Estrogen receptor binding is only part of the isoflavone story. The Journal of Nutrition 2000; 130: 656S-657S
- 17 Dixon RA, Ferreira D. Molecules of interest genistein. Phytochemistry 2002; 60: 205-211
- 18 Magee PJ, Rowland IR. Phyto-oestrogens, their mechanism of action: Current evidence for a role in breast and prostate cancer. British Journal of Nutrition 2004; 91: 513-531
- 19 Ososki AL, Kennelly EJ. Phytoestrogens: A Review of the Present State of Research. Phytotherapy Research 2003; 17: 845-869
- 20 Matsuda H, Shimoda H, Morikawa T. et al. Phytoestrogens from the roots of Polygonum cuspidatum (Polygonaceae): Structure-requirement of hydroxyl anthraquinones for estrogenic activity. Bioorg Mol Chem Lett 2001; 11: 1839-1842
- 21 Milligan SR, Kalita JC, Heyerick A. et al. Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer. J Clin Endocrinol Metab 1999; 83: 2249-2252
- 22 Rafi MM, Rosen RT, Vassail A. et al. Modulation of bcl-2 and cytotoxicity by licochalcone-A, a novel estrogenic flavonoid. Anticancer Res 2000; 20: 2653-2658
- 23 Kim H, Peterson TG, Barnes S. Mechanisms of action of the soy isoflavone genistein: Emerging role for its effects via transforming growth factor b signaling pathways. Am J Clin Nutr 1998; 68 suppl 1418S-1425S
- 24 Chan KK, Siu MK, Jiang YX. et al. Estrogen receptor modulators genistein, daidzein and ERB-041 inhibit cell migration, invasion, proliferation and sphere formation via modulation of FAK and PI3K/AKT signaling in ovarian cancer. Cancer cell international 2018; 18: 65
- 25 Keating E, Martel F. Antimetabolic effects of polyphenols in breast cancer cells: Focus on glucose uptake and metabolism. Frontiers in nutrition 2018; 5: 25
- 26 Food Standards Agency 2003; Phytoestrogens and Health, Committee on Toxicology of Chemicals in Food, Consumer Products and the Environment https://cot.food.gov.uk/sites/default/files/cot/phytoreport0503.pdf
- 27 Kurzer MS. Phytoestrogen supplement use by women. The Journal of Nutrition 2003; 133: 1983S-1986S
- 28 Fotsis T, Pepper M, Adlercreutz H. et al. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proceedings National Academic Science USA 1993; 90: 2690-2694
- 29 Potter SM. Overview of proposed mechanisms for the hypocholesterolemic effect of soy. Journal of Nutrition 1995; 125: 606S-611S
- 30 Setchell KDR, Lydeking OE. Dietary phytoestrogens and their effect on bone: evidence from in vitro and in vivo, human observational, and dietary intervention studies. American Journal of Clinical Nutrition 2003; 7: 593S-609S
- 31 Sakai T, Kogiso M. Soy isoflavones and immunity. The Journal of Medical Investigation 2008; 55: 167-173
- 32 Setchell KD, Faughnan MS, Avades T. et al. Comparing the pharmacokinetics of daidzein and genistein with the use of 13C-labeled tracers in premenopausal women. Am J Clin Nutr 2003; 77: 411-419
- 33 Setchell KD, Brown NM, Desai P. et al. Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J Nutr 2001; 131: 1362S-1375S
- 34 Chandrasekharan S, Aglin A. Pharmacokinetics of dietary isoflavones. J Steroids Hormon Sci 2013; S12: 2-8
- 35 Yang Z, Kulkarni K, Zhu W. et al. Bioavailability and Pharmacokinetics of Genistein: Mechanistic Studies on its ADME. Anticancer Agents Med Chem 2012; 12: 1264-1280
- 36 Zaheer K, Akhtar MH. An Updated Review of Dietary Isoflavones: Nutrition, Processing, Bioavailability and Impacts on Human Health. Critical Reviews in Food Science and Nutrition 2017; 57: 1280-1293
- 37 de Oliveira MR. Evidence for genistein as a mitochondriotropic molecule. Mitochondrion 2016; 29: 35-44
- 38 Mazumder Md. AR, Hongsprabhas P. Genistein as antioxidant and antibrowning agents in in vivo and in vitro: A review. Biomed Pharmacother 2016; 82: 379-392
- 39 Yang Z, Zhu W, Gao S. et al. Simultaneous determination of genistein and its four phase II metabolites in blood by a sensitive and robust UPLC-MS/MS method: Application to an oral bioavailability study of genistein in mice. J Pharm Biomed Anal 2010; 53: 81-89
- 40 Shelnutt SR, Cimino CO, Wiggins PA. et al. Pharmacokinetics of the glucuronide and sulfate conjugates of genistein and daidzein in men and women after consumption of a soy beverage. Am J Clin Nutr 2002; 76: 588-594
- 41 Doerge DR, Chang HC, Churchwell MI. et al. Analysis of soy isoflavone conjugation in vitro and in human blood using liquid chromatography-mass spectrometry. Drug Metab Dispos 2000; 28: 298-307
- 42 Heinonen SM, Wähälä K, Adlercreutz H. Metabolism of isoflavones in human subjects. Phytochemistry Reviews 2002; 1: 175-182
- 43 Zhang Y, Hendrich S, Murphy PA. Glucuronides are the main isoflavone metabolites in women. J Nutr 2003; 133: 399-404
- 44 Steensma A, Faassen-Peters MA, Noteborn HP. et al. Bioavailability of genistein and its glycoside genistin as measured in the portalvein of freely moving unanesthetized rats. J Agric Food Chem 2006; 54: 8006-8012
- 45 Kwon SH, Kang MJ, Huh JS. et al. Comparison of oral bioavailability of genistein and genistin in rats. Int J Pharm 2007; 337: 148-154
- 46 Motlekar N, Khan MA, Youan BBC. Preparation and characterization of genistein containing poly (ethylene glycol) microparticles. J Appl Polym Sci 2006; 101: 2070-2078
- 47 Huang AS, Hsieh OAL, Chang SS. Characterization of the non-volatile minor constituents responsible for the objectionable taste of defatted soybean flour. J Food Sci 1982; 47: 19-23
- 48 Tamura M, Ohnishi-Kameyama M, Nakagawa H. et al Dihydrogenistein-producing bacterium TM-40 isolated from human feces. Food Sci Technol Res 2007; 13: 129-132
- 49 Sirtori CR. Risks and benefits of soy phytoestrogens in cardiovascular diseases, cancer, climacteric symptoms and osteoporosis. Drug Saf 2001; 24: 665-682
- 50 Bloedon LT, Jeffcoat AR, Lopaczynski W. et al Safety and pharmacokinetics of purified soy isoflavones: single dose administration to postmenopausal women. Am J Clin Nutr 2002; 76: 1126-1137
- 51 Klein CB, King AA. Genistein genotoxicity: Critical considerations of in vitro exposure dose. Toxicol Appl Pharmacol 2007; 224: 1-2211
- 52 Michael McClain R, Wolz E, Davidovich A. et al. Genetic toxicity studies with genistein. Food ChemToxicol 2006; 44: 42-55
- 53 Bloedon LT, Jeffcoat AR, Lopaczynski W. et al. Safety and pharmacokinetics of purified soy isoflavones: Single dose administration to postmenopausal women. Am J Clin Nutr 2002; 76: 1126-1137
- 54 Jefferson WN, Williams CJ. Circulating levels of genistein in the neonate, apart from dose and route, predict future adverse female reproductive outcomes. Reprod Toxicol 2011; 31: 272-279
- 55 Spagnuolo C, Russo GL, Orhan IE. et al. Genistein and cancer: Current status, challenges, and future directions. Advances in nutrition 2015; 6: 408-419
- 56 da Costa César I, Braga FC, Vianna-Soares CD. et al. Quantitation of genistein and genistin in soy dry extracts by UV-Visible spectrophotometric method. Quim. Nova 2008; 31: 1933-1936
- 57 Chang Hebron C, Churchwell MI, Delclos KB. et al. mass spectrometric determination of genistein tissue distribution in diet-exposed sprague-dawley rats. J Nutr 2000; 130: 1963-1970
- 58 Feng D, Qiu F, Tong Z. et al. oral pharmacokinetic comparison of different genistein tablets in beagle dogs. Journal of Chromatographic Science 2013; 51: 335-340
- 59 Holder CL, Churchwell MI, Doerge DR. quantification of soy isoflavones, genistein and daidzein, and conjugates in rat blood using LC/ES-MS. J. Agric. Food Chem 199 47: 3764-3770
- 60 Yang Z, Zhu W, Gao S. et al. Simultaneous determination of genistein and its four phase II metabolites in blood by a sensitive and robust UPLC-MS/MS method: Application to an oral bioavailability study of genistein in mice. J Pharm Biomed Anal 2010; 53: 81-89
- 61 Thomas BF, Zeisel SH, Busby MG. et al. Quantitative analysis of the principle soy isoflavones genistein, daidzein and glycitein, and their primary conjugated metabolites in human plasma and urine using reversed-phase high performance liquid chromatography with ultraviolet detection. Journal of Chromatography B 2001; 760: 191-205
- 62 Luo Y, Chen DW, Ren LX. et al. Solid lipid nanoparticles for enhancing vinpocetine’s oral bioavailability. J. Control. Release 2006; 114: 53-59
- 63 Muller RH, Runge S, Ravell V. et al. Oral bioavailability of cyclosporine: solid lipid nanoparticles (SLN) versus drug nanocrystals. Int J Pharm 2006; 317: 82-89
- 64 Wissing SA, Kayserb O, Muller RH. Solid lipid nanoparticles for parenteral drug delivery. Adv Drug Deliv Rev 2004; 56: 1257-1272
- 65 Desai J, Thakkar H. Effect of particle size on oral bioavailability of darunavir-loaded solid lipid nanoparticles. J Microencapsul 2016; 33: 669-678
- 66 Horter D, Dressman JB. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv Drug Deliv Rev 2001; 46: 75-87
- 67 Muller RH, Mader K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery - A review of the state of the art. Eur J Pharm Biopharm 2000; 50: 161-177
- 68 Kim JT, Barua S, Kim H. et al. Absorption Study of Genistein Using Solid Lipid Microparticles and Nanoparticles: Control of Oral Bioavailability by Particle Sizes. Biomol Ther 2017; 25: 452-459
- 69 de Oliveira SR, Taveira SF, Marreto RN. et al. Preparation and characterization of solid oral dosage forms containing soy isoflavones. Brazilian Journal of Pharmacognosy 2013; 23: 175-181
- 70 Si H-Y, Li D-P, Wang T-M. et al. Improving the Anti-Tumor Effect of Genistein with a Biocompatible Superparamagnetic Drug Delivery System. Journal of Nanoscience and Nanotechnology 2010; 10: 1-7
- 71 Chen F, Peng J, Lei D. et al. Optimization of genistein solubilization by κ-carrageenan hydrogel using response surface methodology. Food Science and Human Wellness 2013; 2: 124-131
- 72 Kwon SH, Kim SY, Ha KW. et al. Pharmaceutical Evaluation of Genistein-loaded Pluronic Micelles for Oral Delivery. Arch Pharm Res 2007; 30: 1138-1143
- 73 Sahu AN. Nanotechnology in Herbal Medicines & Cosmetics. Int J Res Ayurveda Pharm 2013; 4: 472-474
- 74 NNI. 2005;National nanotechnology initiative: research and development leading to a revolution in technology and industry, office of sciences and technology policy, Washington, DC, USA http://www.nano.gov/nanotech-101/what
- 75 Ahmad J, Akhter S, Rizwanullah M. et al. Nanotechnology based inhalation treatments for lung cancer: state of the art. Nanotechnology Sci Appl 2015; 8: 55-66
- 76 Bhadoriya SS, Mangal A, Madoriya N. et al. Bioavailability and bioactivity enhancement of herbal drugs by nanotechnology: A review. J Curr Pharm Res 2011; 8: 1-7
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