Study on Nano Curcumin Powder Preparation

Curcumin (CUR) is a hydrophobic polyphenolic compound with the chemical formula C21H20O6. It is mainly derived from the rhizomes of the herb turmeric, the rhizomes of calamus, and traditional Chinese medicinal herbs such as Curcuma aromatica. It is mainly composed of three monomers: curcumin, monodemethoxycurcumin, and bisdemethoxycurcumin [1]. The structures of the three monomers are shown in Figure 1. Curcumin is an orange-yellow crystalline powder with a slightly bitter taste. It is a substance that is basically non-toxic to the human body. It is often used as a natural food colouring and flavouring in food. At the same time, curcumin is widely used in the pharmaceutical and functional food industries because of its physiological activities such as antioxidant, anti-aging, anti-cancer, anti-inflammatory, and prevention and treatment of Parkinson's disease.

Due to the low solubility of curcumin in aqueous solution, it can only absorb 1/4 of the total dose, and it will quickly degrade at physiological pH, resulting in low bioavailability and poor pharmacokinetics. Therefore, only a small part of orally ingested curcumin will be digested and absorbed by the body, and it will bind to glucuronide and sulfides in the cells of the gastrointestinal tract, be quickly metabolized and excreted from the body, making it difficult to exert its original physiological effects [2]. However, the physical encapsulation or chemical modification of curcumin into nanocarriers can to some extent solve the problems of poor water solubility, instability and low bioavailability of curcumin. At the same time, it can also play a role in slow and controlled release, reduce the damage and impact of the harsh environment of the gastrointestinal tract on curcumin, and maximize its retention to the absorption site[3]. By introducing the common preparation methods of curcumin nanocarriers and the mechanism of sustained-release carriers, as well as the latest cutting-edge applications, it is hoped that this will provide some practical reference value for the research of curcumin nanomedicines.

1 Preparation of curcumin nanodelivery carriers

Curcumin degrades under processing conditions (light, heat, oxygen and metal ions) and intestinal mucosal conditions (enzymes and pH), has low bioavailability and can interact with other food components. Therefore, delivery vehicles can be prepared using nanotechnology. Curcumin can be nano-encapsulated using different techniques to improve its solubility, stability, and reduce the adverse effects on the sensory properties of the food [1]. Nano-carriers have a very small particle size, carry curcumin for intracellular release, achieve the dual effect of targeting and slow-release, achieve a higher embedding rate and load, and make curcumin have better stability and bioavailability [4].

1.1 Ultrasonic method

The ultrasonic method is one of the most commonly used methods for preparing curcumin nanocarriers. The ultrasonic method involves using substances such as phospholipids and cholesterol in the molten state as the oil phase, and an organic solvent (methanol, dimethyl sulfoxide, etc.) as the water phase. Depending on the type of carrier being prepared, curcumin is dispersed in the water phase or oil phase. Under conditions of magnetic stirring, the water phase is uniformly added to the oil phase to to form an oil-in-water emulsion. After stirring for a specific period of time, ultrasonication was performed, followed by cooling, filtration, and finally, the curcumin nanocarrier was obtained. Cheng Yang et al. [5] used a dissolution-ultrasonication method to prepare curcumin lipid nanocarriers with a small particle size (265.42 nm) and uniformly distributed (PDI 0.30) curcumin lipid nanocarriers with a small particle size (265.42 nm). The results showed that curcumin had an excellent loading effect, with a loading rate of 94.60%, and a rapid release rate of more than 98% at 37 °C and 42 °C.

1.2 Emulsification method

Emulsification is the process of dispersing one liquid in another immiscible (or partially miscible) liquid in the form of very small droplets [6]. Curcumin nanoemulsion can be obtained through the process of emulsification. Emulsification is divided into two types: high-energy emulsification (e.g. high-pressure homogenization, microfluidization, ultrasonic emulsification, etc.) and low-energy emulsification (e.g. spontaneous emulsification, hydrogel method, phase transition temperature method). High-energy emulsification methods use mechanical forces to disrupt two immiscible phases. Emulsifiers reduce the interfacial tension and convert them into stable emulsions of nano-scale droplets. In contrast, low-energy emulsification methods use internal chemical energy to emulsify. Due to changes in temperature or composition, phase transitions or spontaneous emulsification can occur in the system. The curcumin is encapsulated in a nanoemulsion by emulsification. The nanoemulsion can be regarded as small droplets contained in a conventional emulsion. The average particle size is 20–500 nm [7]. It has the advantages of high entrapment rate, large surface area, small volume, and thermodynamic stability. It has better stability for hydrophobic compounds, and the solubility and efficacy of the active substance can be controlled by controlling the droplet size. Its main disadvantage is the relatively high content of surfactants, which has a potentially toxic effect [8].

1.3 Solvent evaporation method

The solvent evaporation method is an important method for preparing nanosphere and nanomicelle. During the solvent evaporation process, the polymer is dissolved in a suitable organic solvent, and the drug is dispersed or dissolved in this polymer solution. The resulting solution or dispersion is emulsified in an aqueous continuous phase to form discrete droplets. In the formation of microspheres, the organic solvent must first diffuse into the aqueous phase, evaporate at the water-air interface, and then, after appropriate filtration and drying, the microspheres can be obtained as hardened and free-flowing microspheres. Cheng et al. [9] prepared curcumin-loaded micelles by the solvent evaporation method, using Pluronic as the carrier material to prepare curcumin@Pluronic drug-loaded micelles. In vitro digestion tests showed that curcumin@pluronic drug-loaded micelles can release up to 80% of the drug in 72 hours, which has a certain sustained-release effect. It can significantly increase the accumulation of curcumin in cells and enhance the in vitro anti-tumor effect of curcumin on prostate cancer PC-3 cells, and also shows a certain in vivo anti-tumor effect.

1.4 Supercritical fluid technology

Supercritical fluid technology is a new type of turmeric nano-carrier preparation technology. Supercritical fluid refers to a special state of a fluid formed when a substance is above its critical temperature and critical pressure. In the industrial application of supercritical fluid technology, supercritical carbon dioxide (SC-CO2) is mostly used.

Ali et al. [11] used SC-CO2 to develop a new manufacturing method for curcumin green nanoparticles. Nanoporous starch aerogels and SC-CO2 technology were used to generate curcumin nanoparticles with low crystallinity. Nanoporous starch aerogels (NSAs; surface area 60 m2/g, pore size 20 nm, density 0.11 g/cm3, porosity 93%) was used as a mould to produce curcumin nanoparticles with the help of supercritical carbon dioxide. The average particle size of the curcumin nanoparticles was 66 nm. Impregnation into the NSA reduced the crystallinity of the curcumin and did not result in any chemical bonding between the curcumin nanoparticles and the NSA matrix. The maximum impregnation capacity was 224.2 mg curcumin/g NSA. Compared with conventional curcumin, curcumin nanoparticles significantly increased the bioavailability of curcumin by 173 times. After curcumin is impregnated into the NSA matrix, the mass concentration of bioavailable curcumin increases from 0.003 mg/mL to 0.125 mg/mL. This not only improves bioavailability, but also reduces crystallinity, which maximizes the use of curcumin and shows that this is a new method for producing food-grade curcumin nanoparticles.

1.5 Electrospinning technology

Electrospinning technology refers to a technology that uses electrostatic forces to transform high-molecular-weight polymers into micro- and nano-scale ultrafine fibers. The basic principle of electrospinning technology is as follows: a high polymer is subjected to a certain pressure and ejected from the needle tip. Through the interaction of strong static electricity in a high-voltage electric field, the droplet extends towards the low-potential end, and is refined into a nanofiber during the extension process. The solvent volatilizes under the action of electrostatic force, air resistance, gravity, Coulomb repulsion, surface tension and viscoelastic force, forming a nano-deposition [12] (as shown in Figure 2).

Chen et al. [13] prepared a new type of curcumin-loaded sandwich nanofibrous membrane (CSNM) using electrospinning technology. This three-layer nanofibrous membrane has good water absorption capacity and water vapor transmission rate, and controls the release of curcumin. In addition, CSNM also shows excellent hemostatic properties, antioxidant activity and antibacterial ability. In vivo studies have shown that the prepared CSNM enhances epidermal regeneration and collagen deposition through its antioxidant effect and significantly reduces the inflammatory response.

1.6 Dialysis method

Dialysis method [14] is to dissolve poorly water-soluble polymers and drugs in an organic solvent that is miscible with water, place the solution in a dialysis bag with a molecular weight cutoff smaller than the drug and polymer but larger than the solvent, immerse the dialysis bag in deionized water or a buffer solution and stir to dialyze. As water penetrates and solvent exudes, the copolymer gradually forms micelles. In order to reduce the adverse reactions of drugs in normal tissues and achieve rapid release in tumor tissues, polymer-drug micelles are usually designed to respond only to specific targets in tumors [15]. Tian et al. [16] obtained CUR-HSC micelles by dialysis and further in vivo simulation experiments and cytotoxicity tests showed that the micelles had the ability to cross the blood-brain barrier and target gliomas. At the same time, they can maintain stability under physiological conditions and exhibit the most effective cell uptake, cytotoxicity and apoptosis effects. In addition, the micelles can remain intact when passing through the blood-brain barrier and accumulate effectively in the brain.

By understanding the preparation methods of the above-mentioned main curcumin nanocarriers, this paper compares their principles and advantages and disadvantages, as shown in Table 1.

2 Mechanism of sustained-release curcumin

The mechanism of carrier loading is mainly through non-covalent forces between the active substance and the carrier material, such as hydrogen bonding, π-π stacking, van der Waals forces, electrostatic effects, etc., and the active substance is loaded and adsorbed by chemical assembly. On the one hand, there are a large number of functional groups on the surface of the nanocarrier, or functional groups are introduced by chemical methods, so that curcumin is covalently coupled to the nanocarrier and combined together. On the other hand, nanocarriers with functional groups such as carboxyl and amine groups increase the solubility of hydrophobic drugs. These high-density functional groups bind the curcumin to the nanocarrier system through electrostatic interactions. In addition, the cavity structure of the nanocarrier has hydrophobic properties, and the hydrophobic nature of the cavity allows more curcumin to be incorporated into the nanocarrier by hydrophobic interaction or hydrogen bonding.

Priyanka et al. [17] connected curcumin to the nanocarrier cellulose nanofibers (CNFs) through hydrogen bonding and π-π stacking. CNFs form interconnected, well-organized porous structures inside, as shown in Figure 3(a), due to the hydrogen bonding between the cellulose. The binding affinity of CNF+CUR is -4.7 kcal/mol, which indicates that curcumin can bind to cellulose through hydrogen bonding and π-π interactions. After CUR encapsulation, a uniform distribution of CUR crystals was observed on the surface of CNF, forming a uniform monolayer on CNF, as shown in Figure 3(b). No crystal aggregates were found on the CNF surface, indicating that CUR is completely integrated into the structure of CNF [14].

The slow-release mechanism of curcumin is mainly achieved through several methods: First, pH-dependent slow-release. When a certain pH is reached, the nanocarrier material begins to break down, and the curcumin encapsulated inside is gradually released, thereby achieving sustained release; second, sustained release can be achieved through enzymatic hydrolysis or thermal decomposition.

Under suitable environmental conditions, the nanocarrier can be gradually broken down by enzymes, exposing the curcumin, or the carrier material can begin to degrade when a specific temperature is reached, both of which can achieve the effect of sustained release; third, the nanodisolution system acts as a carrier to load the active substance. After reaching the corresponding target environment, the carrier material can have different drug release rates due to differences in type or ratio. The release rate of curcumin can be controlled by adjusting the type or ratio of the carrier material. Fourth, sustained release is achieved by cleaving chemical bonds, such as the breaking of hydrogen bonds. The nano-carrier and curcumin conjugate slowly diffuse into the cell or specific environment, and the chemical bonds that bind them together break or dissociate due to non-covalent forces, gradually releasing curcumin in a sustained manner.

3 Curcumin activity and its applications

3.1 Curcumin's anti-cancer properties

Curcumin is considered to be an effective anti-mutagenic and anti-promoter of cancer, and has a significant inhibitory effect on cancer cells. Cancer is caused by mutations in cells attacked by carcinogens. Curcumin can exert an anti-mutagenic effect, block the attack of carcinogens on cells, and prevent cells from becoming cancerous [18]. The anti-cancer mechanism of curcumin mainly involves two pathways: inhibiting the biological effects of TPA and regulating the metabolism of arachidonic acid. Studies have found that curcumin can produce a toxic effect on cancer cells without damaging normal cells. It can also inhibit the activity of various protein kinases associated with tumor growth, induce apoptosis of tumor cells, and prevent cancer cell proliferation [19].

To further explore the anti-cancer effect of curcumin, Fan Ziliang et al. [20] constructed a curcumin nanomicelle using a new undecenoic acid-grafted-ε-polylysine (ε-PLL-UNA) polymer. The drug loading capacity was up to 12.22% ± 2.13%, and the encapsulation rate was as high as 85.12% ± 3.64%. The nanomicelles released 84% of the curcumin over 48 hours, which has a good sustained-release effect. Compared with the curcumin solution, the nanomicelles significantly inhibited the growth of glioma cell spheres.

3.2 Anti-inflammatory activity of curcumin

Inflammation is the body's immediate response to harmful stimuli such as pathogens, chemicals, or physical damage to tissues and cells. Inflammatory cells can repair tissue damage with the help of enzymes and cytokines. Experiments have shown [21] that curcumin can inhibit lipid peroxidation and reduce serine activity, thereby inhibiting the inflammatory response of colon cells. It has also been found to regulate the activity of corticosteroids in the inflammatory response, which is a new target for anti-inflammatory effects [22]. In order to achieve a better therapeutic effect, Shao Junfei et al. [23] developed a curcumin microsphere, which released more than 40% of curcumin within the first 24 hours and a total of 80% within the following 120 hours. This ensures a certain effective blood concentration and achieves a better anti-inflammatory effect. When the microsphere carrier enters the body and is degraded and collapsed, the surface of the microsphere is dissolved by enzymes in the body, and the drug and carrier are dissociated and diffused, so that the drug contained in the microsphere is slowly and controllably released in a quantitative manner, thereby slowing down the release rate of the drug encapsulated in the microsphere, making it a long-acting sustained-release preparation, achieving the purpose of sustained release, and greatly reducing the frequency of administration, as well as reducing the peak and valley phenomenon of the drug [24].

3.3 Curcumin's preventive and therapeutic effects on neurodegenerative diseases

Curcumin is an effective antioxidant that can scavenge free radicals, protect nerves, and regulate various signal pathways. It is involved in regulating the synthesis and expression of transcription factors, biological enzymes, growth factors, and various proteins, thereby blocking the molecular synthesis pathways of related neurodegenerative diseases. Curcumin has metal chelating properties through its two methoxyphenolic groups linked to the β-diketone, which helps to scavenge superoxide and hydroxyl radicals, thereby protecting glutathione and reducing oxidative stress [25].

In a study investigating the effect of curcumin on the learning and memory abilities of rats with Parkinson's disease, Zhu Jiang et al. [26] demonstrated that curcumin intervention can reduce the toxic effects of 6-hydroxy-dopamine on nerve cells in rats, promote the increase of dopamine, dihydroxyphenylacetic acid, and homovanillic acid levels, thereby controlling the progression of Parkinson's disease in rats and significantly improving the learning and memory abilities of Parkinson's disease model rats. Similarly, curcumin also has a significant therapeutic effect on Alzheimer's disease (AD). Curcumin combined with β-amyloid peptide (Aβ) significantly improves its ability to scavenge free radicals and slow down the progression of AD.

3.4 Application of curcumin in the food industry

Curcumin is widely used in the food industry as a food additive, in functional foods and in beverages. As a natural food additive, curcumin has the advantages of being pollution-free, degradable, antibacterial and antioxidant. In the field of food preservation, substances such as microspheres, liposomes, nanoparticles and colloids containing curcumin can extend the shelf life of food through sustained release.

Curcumin can induce a series of changes in bacteria under certain conditions and concentrations, such as Ca2+ influx and DNA strand breakage. Curcumin affects the structure of the bacterial cell membrane by inducing its production, and exerts an antibacterial effect by destroying the cell membrane [27]. In addition, under light conditions, curcumin can cause an explosion of reactive oxygen species, destroy the adaptive mechanisms of cells and the metabolism of iron, and inhibit the biosynthesis of iron-sulfur clusters, ultimately leading to cell death [28]. Therefore, curcumin has the advantages of antibacterial preservation and oxidation resistance, and has application potential in the food field. Hee et al. [29] prepared a curcumin nanoemulsion (Cur-Nes) that can be added to milk to reduce fat oxidation, which promotes the solubility of curcumin in the oil phase, thereby increasing antioxidant activity and delaying lipid degradation.

4 Conclusion and outlook

Curcumin is a natural polyphenolic compound with multiple active effects that is widely used in food, biomedicine and other fields. However, the poor bioavailability of curcumin in the body has limited its research progress and clinical promotion to some extent. The preparation of curcumin nanocarrier agents has greatly improved the bioavailability of curcumin and increased the effect of curcumin at the cellular level, laying a foundation for further clinical research and the development of functional foods. However, there are still some problems with the preparation of curcumin nanocarriers that need to be urgently solved, such as the gap between practical application technology and research level, low conversion rate, high preparation cost, lack of toxicological verification, mostly remaining in the laboratory stage, and not being applied to industrial production. To solve these problems, on the one hand, it is necessary to reduce production costs, simplify production processes, and improve actual conversion rates; on the other hand, the choice of nanocarrier materials should be more green, non-toxic, environmentally friendly, and available.

Reference:

[1] JAFARI S M, MCCLEMENTS D J. Nanotechnology approaches for increasing nutrient bioavailability[J]. Adv Food Nutr Res, 2017, 81: 1-30.

[2] SHIH F Y, SU I J, CHU L L, et al. Development of pectin- type B gelatin polyelectrolyte complex for curcumin delivery in anticancer therapy[J]. International Journal of Molecular Sciences, 2018, 19(11): 3625.

[3] NUNES S, MADUREIRA A R, CAMPOS D, et al. Solid lipid nanoparticles as oral delivery systems of phenolic compounds: Overcoming pharmacokinetic limitations for nutraceutical applications[J]. Critical Reviews in Food Science and Nutrition, 2017, 57(9): 1863-1873.

[4] Chen S, Sun C, Dai L, et al. Research progress on curcumin delivery vehicles based on biological sources and nanotechnology [J]. Chinese Journal of Food Science, 2019, 19(8): 294-302.

[5] Cheng Yang, Wei Wei, Jin Qingzhe, et al. Study on the encapsulation and release properties of curcumin by preparing lipid nanocarriers with fatty acid glycerol esters [J]. China Oil and Fat, 2020, 45(10): 62-67.

[6] Food Science and Technology Terminology Approval Committee. Food Science and Technology Terminology [M]. Beijing: Science Press, 2020.

[7] ZHANG W, QIN Y, CHANG S, et al. Influence of oil types on the formation and stability of nano-emulsions by D phase emulsification[J].Journal of Dispersion Science and Technology, 2021, 42(8): 1225-1232.

[8] SHARMA A K, GARG T, GOYAL A K, et al. Role of microemuslsions in advanced drug delivery[J]. Artificial Cells, Nanomedicine, and Biotechnology, 2016, 44(4): 1177-1185.

[9] Cheng J, Wang Z, Fu G, et al. Experimental study on the inhibition of curcumin-@pluronic nanomicelles on the growth of prostate cancer PC-3 cells [J]. Shanxi Medical Journal, 2021, 50(11): 1340-1344.

[10] GANGAPURWALA G, VOLLRATH A, DE SAN LUIS A, et al. PLA/PLGA-based drug delivery systems produced with supercritical CO2—A green future for particle formulation? [J]. Pharmaceutics, 2020, 12(11): 1118.

[11] ALI UBEYITOGULLARI, OZAN N CIFTCI. A novel and green nanoparticle formation approach to forming low-crystallinity curcumin nanoparticles to improve curcumin’s bioaccessibility[J]. Sci Rep, 2019, 9(1): 19112.

[12] Deng L, Zhang H. Application of electrospinning technology in the food industry. Food Science, 2020, 41(13): 283-290.

[13] CHEN K, PAN H, JI D, et al. Curcumin-loaded sandwich- like nanofibrous membrane prepared by electrospinning technology as wound dressing for accelerate wound healing[J]. Mater Sci Eng C Mater Biol Appl, 2021: 112245-112245.

[14] Wu L. Study on curcumin mPEG_(114)-PCL_(36) block copolymer micelles [D]. Guangzhou: Southern Medical University, 2013.

[15] CHEN W, ZHONG P, MENG F, et al. Redox and pH- responsive degradable micelles for dually activated intracellular anticancer drug release[J]. Journal of Controlled Release, 2013, 169(3): 171-179.

[16] TIAN C, ASGHAR S, HU Z, et al. Understanding the cellular uptake and biodistribution of a dual-targeting carrier based on redox-sensitive hyaluronic acid-ss-curcumin micelles for treating brain glioma[J]. International Journal of Biological Macromolecules, 2019, 136: 143-153.

[17] PRIYANKA K, WASEEM R, ABHA M. Lemongrass derived cellulose nanofibers for controlled release of curcumin and its mechanism of action[J]. Industrial Crops and Products, 2021, 173: 1-9.

[18] Xue Yan, Xia Tian, Zhao Jianbin. Research progress on the anti-cancer mechanism of curcumin [J]. Chinese Herbal Medicine, 2000(2): 1-4.

[19] KARTHIKA C, HARI B, MANO V, et al. Curcumin as a great contributor for the treatment and mitigation of colorectal cancer[J]. Experimental Gerontology, 2021, 152: 111438.

[20] Fan Ziliang, Jin Binghui, Xu Xiangfang, et al. Preparation and in vitro antitumor evaluation of curcumin-loaded nanomicelles [J]. Journal of Wenzhou Medical University, 2017, 47(9): 625-630, 636.

[21] ANTO RJ, MUKHOPADHYAY A, DENNING K, et al. Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: Its suppression by ectopic expression of Bcl-2 and Bcl-xl[J]. Carcinogenesis, 2002, 23(1): 143-150.

[22] Sun Jingru, Feng Yuchao. Research progress on the biological functions of curcumin [J]. Agro-Products Processing, 2020(16): 67-71, 4.

[23] Shao Junfei, Jiang Zhifeng, Sun Jun, et al. Preparation, characterization and properties of curcumin-loaded nanospheres [J]. Jiangsu Medicine, 2010, 36(20): 2435-7.

[24] Liu Binli, Rong Kun, Li Muzi, et al. Research progress on the application of sustained-release and controlled-release systems in intra-articular injections [J]. World Traditional Chinese Medicine, 2014, 9(5): 669-671, 675.

[25] MANDAL M,JAISWAL P, MISHRA A. Role of curcumin and its nanoformulations in neurotherapeutics: A comprehensive review[J]. Journal of Biochemical and Molecular Toxicology, 2020, 34(6): e22478.

[26] Zhu Jiang, Guo Sen, Zhang Shuo, et al. Effects and mechanism of curcumin on learning and memory in Parkinson's disease rats [J]. Chinese Journal of Gerontology, 2021, 41(22):5049-53.

[27] Huang Hahe, Huang Chongxing, Zhang Linyun, et al. Research progress on the application of curcumin in food preservation [J]. Food Industry Science and Technology, 2020, 41(7): 320-4, 31.

[28] SHLAR I, DROBY S, RODOV V. Modes of antibacterial action of curcumin under dark and light conditions: A toxicoproteomics approach[J]. Journal of Proteomics, 2017, 160: 8-20.

[29] HEE J J, MI J C, JUN T K, et al. Development of food- grade curcumin nanoemulsion and its potential application to food beverage system: Antioxidant property and in vitro digestion[J]. Journal of Food Science, 2016, 81(3): N745- N753.