Trends in Food Science & Technology 88 (2019) 445–458

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Trends in Food Science & Technology

journal homepage: www.elsevier.com/locate/tifs

Review

Application of curcumin-loaded nanocarriers for food, drug and cosmetic T

purposes
Zahra Rafieea, Mohammad Nejatianb, Marjan Daeihamedc, Seid Mahdi Jafaria,∗
a
Department of Food Materials and Process Design Engineering, Gorgan University of Agricultural Science and Natural Resources, Gorgan, Iran
b
Department of Food Science and Technology, Tarbiat Modares University, Tehran, Iran
c
Department of Pharmaceutics, School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran

A R T I C LE I N FO A B S T R A C T

Keywords: Background: Curcumin, the major bioactive material of turmeric, has wide functional features such as anti-
Curcumin diabetic, anti-cancer, anti-inflammatory, and antioxidant activities. However, curcumin exhibits some major
Nanocarriers limitations including low water solubility, degradation during processing or within the gastrointestinal tract and
Bioavailability alkaline conditions, leading to decrease of its bioavailability. For these reasons, many studies have tried to
Foods
improve functionality of curcumin and overcome its limitations through delivery systems, especially na-
Pharmaceuticals
noencapsulation.
Cosmetics
Scope and approach: In this review, practical applications of the nanoencapsulated curcumin, prepared by var-
ious techniques in different food, pharmaceutical and cosmetic products have been considered and explained.
The importance of nanoencapsulation in improving functional effects of curcumin in processed foods, such as
coloring, antioxidant and antimicrobial activity has been discussed thoroughly and its potential applications for
medicinal proposes including cancer, cardiovascular and neurodegenerative diseases, viral and bacterial infec-
tions have been reviewed.
Key findings and conclusions: Nano-delivery systems, because of exclusive characteristics of nanoparticles as well
as conventional properties of an encapsulation medium, can provide chemical stability, hydrophilicity, sustained
release and adequate dispersibility of curcumin in final products (food, cosmetics and drug). Consequently, the
pharmacokinetic properties of curcumin including biological half-life and bioavailability (or bioaccessibility)
can be improved resulting in better clinical and functional efficacy in vivo. Although the potentials of curcumin
nanoformulations have been extensively studied in the literature, future studies can better help to find optimum
formulations for clinical and industrial applications of nanoencapsulated curcumin.

1. Introduction
Curcumin is a polyphenol of low molecular weight (368.37 g mol−1)
existing in the Curcuma longa (turmeric) rhizomes (ARAIZA-Calahorra,
Akhtar, & Sarkar, 2018). This perennial herb contains 3–5% of the four
types of curcuminoid derivatives including curcumin, demethox-
ycurcumin, bisdemethoxycurcumin, and cyclocurcumin, so that cur-
cumin is the main (77%) bioactive ingredient (Tayyem, Heath, AL-
Delaimy, & Rock, 2006; Heger, Van Golen, Broekgaarden, & Michel,
2014). Chemically, curcumin belongs to diarylheptanoids and consists
of two aromatic rings bearing two hydroxyl and two methoxyl groups.
The phenolic rings are joined by the aliphatic unsaturated carbon chain
with two carbonyl groups placed at C-3 and C-5 as shown in Fig. 1
(Nelson et al., 2017; Rafiee, Nejatian, Daeihamed, & Jafari, 2018).
Many functional and biological features have been reported for
curcumin. It has been approved by the Scientific Committee for Food of
the European Community and presents the number of E100 in the list of
additives. Curcumin can be used as an antioxidant, flavoring agent
(warm, bitter taste) and natural colorant (a bright yellow color) in
various foods or even culinary applications (Aguilar et al., 2010).
Turmeric and curcumin have been known and widely applied in tra-
ditional medicine for treating various diseases like acne, injuries, am-
bustions, eye infections, skin diseases, stress, and depression (Hatcher,
Planalp, Cho, Torti, & Torti, 2008). Researches in the recent three
decades have shown the remedial effects of this molecule on different
kinds of diseases including cancer, pulmonary and chronic kidney dis-
orders, diseases of the nervous system, metabolic disease, cardiovas-
cular disease and other inflammatory diseases (Aggarwal & Sung, 2009;
Kannappan, Gupta, Kim, Reuter, & Aggarwal, 2011). According to
current scientific evidences, curcumin is severely an anti-inflammation

∗
Corresponding author.
E-mail address: smjafari@gau.ac.ir (S.M. Jafari).

https://doi.org/10.1016/j.tifs.2019.04.017
Received 6 December 2018; Received in revised form 19 April 2019; Accepted 19 April 2019
Available online 24 April 2019
0924-2244/ © 2019 Elsevier Ltd. All rights reserved.
Z. Rafiee, et al.
Fig. 1. Chemical structure of curcumin, its loading within nanocarriers (liposome) and application of nanoencapsulated curcumin in different industries.
and wound healing agent and shows antimicrobial effects against yeasts
and molds, as well as various species of Gram-negative and Gram-po-
sitive bacteria (Silva et al., 2018). However, poor water solubility is the
main challenge in industrial applications of curcumin (11 ng/mL
to < 10 μg/mL) (Tomren, Masson, Loftsson, & Tønnesen, 2007; Wang
et al., 2008). Additionally, it may be degraded under processing and
within the gastrointestinal tract (GIT) conditions which consequently
decreases its bioavailability. Curcumin is stable in the systems with
physiological pH values as well as acidic conditions, but under alkaline
conditions, it is easily decomposed (ARAIZA-Calahorra et al., 2018).
Incorporation of curcumin into nanocarriers by different techniques is a
suitable and efficient option for improving its solubility, stability and
functionality (Assadpour, Jafari, & Esfanjani, 2017; Faridi Esfanjani,
Assadpour, & Jafari, 2018). Moreover, the nanocarriers are capable of
releasing curcumin in target sites and therefore have being exploited in
pharmaceutical and food supplements industries.
In a recent article, we reviewed the existing literature on different
techniques of curcumin nanoencapsulation for the food and nu-
traceutical practices (Rafiee et al., 2018). Here, feasible applications of
such curcumin-loaded nanoformulations in food, pharmaceutical and
cosmetic sectors were comprehensively underlined. This would be
useful for readers and researchers to expand their perspective in man-
ufacturing of functional products.
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2. Nanoencapsulated curcumin for the food industry
Fortification of food products with bioactive compounds such as
curcumin has attracted growing consideration due to increment of
awareness and tendency of consumers towards healthy diets
(Assadpour, Maghsoudlou, Jafari, Ghorbani, & Aalami, 2016; Faridi
Esfanjani & Jafari, 2016). Curcumin is not only commonly utilized as a
food colorant, but also it can be utilized within food products as a safe
and natural antimicrobial and antioxidant agent instead of synthetic
ones (Assadpour & Jafari, 2018; Gómez-Estaca, Gavara, & Hernández-
Muñoz, 2015). Previous research works have confirmed notable anti-
oxidant and antimicrobial efficiency of curcumin toward different
strains of bacteria plus some fungal species (Bhawana et al., 2011;
Dovigo et al., 2013; Dubey, Sharma, Narain, Misra, & Pati, 2008; Hu,
Huang, & Chen, 2013; Mun et al., 2013; Sathishkumar et al., 2015).
However, food applications of curcumin have been limited by some
obstacles. Curcumin displays a low water solubility and inadequate
dispersibility in food systems owing to its hydrophobic nature (Huang
et al., 2016; Nguyen et al., 2017). It is also decomposed in contact with
adverse circumstances during storage and food processing, reducing its
efficiency and bioactivity. Moreover, direct usage of curcumin in food
products may cause negative effects on sensorial attributes along with
unpleasant interactions with food components (Fang & Bhandari, 2010;
Mehanny, Hathout, Geneidi, & Mansour, 2016; Paramera, Konteles, &
Z. Rafiee, et al.
Karathanos, 2011). Nanoencapsulation techniques can improve anti-
microbial and antioxidant capacity of phenolic compounds such as
curcumin, because they provide sustained release, good stability, en-
hanced solubility in aqueous mediums for bioactives, therefore leading
to promote their functionality and bioactivity without any considerable
change in quality and sensory properties of fortified food (Abdou,
Galhoum, & Mohamed, 2018; Faridi Esfanjani & Jafari, 2016; Hussain
et al., 2017; Jafari, 2017b).
Several researches have been carried out on nanoencapsulation of
curcumin by various carriers to solve its limitations when directly
added into food systems. As an example, Sadeghi et al. (2014) for-
mulated curcumin-loaded nanoparticles via desolvation method with
the aid of bovine serum albumin (BSA) and different solvents. Based on
their results, acetone gave the highest nanoparticulation efficiency
(99.2%) and nanoparticles with rod and spherical morphology. More-
over, all samples had a PDI lower than 0.2 and encapsulation efficiency
was dependent on concentrations of curcumin and BSA. Glutaraldehyde
as crosslinking agent led to enhancement of storage stability in nano-
particles. Evaluation of release behavior of loaded nanoparticles by
dialysis tubing method revealed high ability of BSA nanoparticles for
the gradual release of curcumin (Sadeghi et al., 2014). another study,
starch nanoparticles were synthetized through nanoprecipitation tech-
nique using different corn starches for encapsulation of curcumin
(Sadeghi, Daniella, Uzun, & Kokini, 2017). Nanoparticles produced by
ethanol and normal corn starch had a particle size below 100 nm and
the highest uniformity. Moreover, curcumin-loaded starch nano-
particles were more stable compared to free one when stored for 10
days at room temperature in PBS (pH = 7). A mixture of BSA and poly-
D-lysine (PDL) with low and high molecular weights were also used to
design soluble coacervate nanoparticles for the loading of curcumin.
According to the results, molecular weight, pH, concentration of salt
and PDL/BSA ratio significantly affected characteristics of coacervate
nanoparticles. Glutaraldehyde could enhance stability of nanoparticles
during three weeks of storage at refrigerated and room temperatures.
BSA in combination with low molecular weight PDL fabricated loaded
nanoparticles with a high stability when stored for three weeks
(Maldonado, Sadeghi, & Kokini, 2017). In a recent work, Sadati
Behbahani, Ghaedi, Abbaspour, Rostamizadeh, and Dashtian (2019)
made nanostructured lipid carriers (NLCs) containing curcumin via
microemulsion–ultrasonication technique by Tween 80 and Pluronic
F167 as surfactant with the aid of stearic acid and caprylic/capric tri-
glycerides as lipid phase. Based on results, all samples had a nanometric
size and were semi-spherical in shape. In addition, NLCs showed out-
standing capability to boost stability of curcumin within simulated
gastric medium up to 2 h (Sadati Behbahani et al., 2019). In the next
section, effects of nanoencapsulation on coloring, antioxidant and an-
timicrobial activities of curcumin have been underlined.
2.1. Coloring activity of nanoencapsulated curcumin
Many studies have investigated nanoencapsulation of curcumin, but
there were only a few ones regarding its usage as a natural colorant,
preservative, and antioxidant within food matrices. For instance,
Gomez-Estaca, Balaguer, Gavara, and Hernandez-Munoz (2012) en-
capsulated curcumin by electrospraying technique and added it into the
semi-skimmed milk. They reported that nanoencapsulation promoted
storage stability and facilitated dispersion of curcumin. Consequently,
nanocurcumin exhibited a higher coloring capacity than commercial
curcumin in semi-skimmed milk (Gomez-Estaca et al., 2012). In another
study, curcumin nanoemulsions were developed by milk proteins (so-
dium caseinate) as emulsifiers and then were used in ice cream for-
mulations (Kumar et al., 2016). Produced curcumin-loaded nanoemul-
sions had good physiochemical characteristics regarding particle size
(333.8 nm), surface charge (−44.1 mV) and encapsulation efficiency
(96.9%). Moreover, nanoencapsulated curcumin exhibited a consider-
able stability under simulated GIT conditions. Both control and samples
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containing nanocurcumin received a similar sensory score. Moreover,
nanocurcumin remained stable against the processing conditions of ice
cream and its encapsulation efficiency was slightly decreased. Hence,
ice cream could be suggested as a suitable delivery system for nano-
curcumin.
In a recent work by Almeida et al. (2018), curcumin as a natural
colorant agent was applied in yogurt samples in diverse forms of water-
dispersible, powder and nanoparticles prepared via solid dispersion.
Curcumin powder displayed the maximum antioxidant, antimicrobial,
cytotoxic and anti-inflammatory effects as compared to other forms of
curcumin which is explainable by considering protective effect of en-
capsulation on curcumin and decease of its availability for a short
period of time. Yogurt samples containing curcumin had acceptable
sensory properties and curcumin made no remarkable effects on their
fatty acids profiles as well as nutritional quality over storage time.
However, yogurt samples treated with modified curcumin were pre-
ferred to those containing free (unencapsulated) curcumin regarding
sensory attributes especially color and dispersibility which are sa-
tisfactory for food applications (Almeida et al., 2018).
2.2. Antioxidant activity of nanoencapsulated curcumin
Curcumin as a phenolic compound presents an outstanding anti-
oxidant activity resulted from hydroxyl group of phenol rings and
protects foods from oxidation. Besides, it plays a protective role in
human body against free radicals (Abdel Fattah, 2016). Curcumin exert
antioxidant activity through multiple ways. It is able to trap various
kinds of free radicals mainly reactive nitrogen and oxygen species.
Curcumin not only improves performance of enzymes with free radicals
scavenging activity like glutathione peroxidase, superoxide dismutase,
and catalase, but also shows inhibitory effects on enzymes which gen-
erate free radicals like xanthine oxidase/hydrogenase and cycloox-
ygenase/lipoxygenase. Also, lipophilic nature of curcumin allows it to
effectively scavenge peroxyl radicals. Thus, this compound can act as a
chain-breaking antioxidant and interrupt propagation chain of oxida-
tion by eliminating peroxyl radicals from system (Hewlings & Kalman,
2017; Marchiani, Rozzo, Fadda, Delogu, & Ruzza, 2014; Menon &
Sudheer, 2007). Nonetheless, antioxidant efficiency of curcumin ex-
periences a considerable loss in food matrices due to its instability,
reaction with food components, poor solubility, and high sensitivity to
alkaline conditions and elevated temperatures. Hence, researchers have
recently made efforts for nanoencapsulation of curcumin to overcome
these drawbacks (Aadinath, Bhushani, & Anandharamakrishnan, 2016;
Chen et al., 2015). Some effects of nanoencapsulation on antioxidant
activity of curcumin have been presented in Table 1.
As an example, ctrospinning method was employed to enclose cur-
cumin with the aid of pullulan and amaranth protein isolate and phy-
siochemical characteristics, release behavior and antioxidant activity of
curcumin-loaded fibers were investigated. Curcumin concentration and
pullulan/amaranth protein isolate ratio showed an obvious impact on
particle size, encapsulation efficiency and morphology of nanofibers.
Curcumin was liberated sustainably under in vitro digestion conditions
as well as in a buffer solution (pH = 7.4). Furthermore, loaded cur-
cumin retained its antioxidant potential after digestion and exhibited a
better free radical scavenging property in ABST assay than its free form.
Encapsulation also protected curcumin from degradation when exposed
to high temperatures (up to 600 °C). Thus, usage of food grade biopo-
lymers for incorporation allows the food industry to take advantages of
bioactive compounds more efficiently (Blanco-Padilla, López-Rubio,
Loarca-PIña, Gómez-Mascaraque, & Mendoza, 2015).
Protein-polysaccharide complex is a suitable choice for enhancing
stability of bioactive compounds (Ghasemi et al., 2017, 2018). In the
study of Yi et al. (2016), α-lactalbumin-dextran conjugates were formed
and confirmed their protective effect on curcumin against harsh en-
vironmental conditions and oxidation. Moreover, water dispersibility
and antioxidant activity of curcumin promoted upon
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Table 1
Some selected studies on antioxidant activity of nanoencapsulated curcumin.
Nanoencapsulation method/Formulation Assay
Cellulose acetate nanofibers DPPH
Nanoprecipitation method DPPH
Chitosan/poly (lactic acid) nanofibers DPPH
Spray-drying warm aqueous ethanol solution ABTS
with co-dissolved sodium caseinate
Lipid-biopolymer nanoparticles TBARS and radical scavenging
(DPPH, NO, H2O2, reducing power)
activity assays
Amaranth protein isolate/pullulan electrospun ABTS
nanofibers
Starch nanoparticles DPPH and ABTS
Nanocomplexes prepared with both α- DPPH
lactalbumin (ALA) and ALA-dextran
conjugates
Nanoemulsion DPPH, ABTS and TABRS
Nanoemulsion DPPH
Nano spray drying
SLNs ABTS assay and Reducing power
NLCs ABTS
DPPH: 2,2-diphenyl-1-picrylhydrazy; ABTS: 2,2 -azino-bis(3- ethylbenzothiazoline-6- sulfonic acid), SLNs: Solid lipid nanoparticles, NLCs: Nanostructured lipid
carriers, TBARS: Thiobarbituric acid reactive substances.
nanoencapsualtion. Dextran in combination with α-lactalbumin re-
sulted in a higher free radical trapping capacity and stability for cur-
cumin than α-lactalbumin alone (Yi et al., 2016).
In terms of lipid-based nanocarriers, Shah, Zhang, Li, and Li (2016)
fabricated two various types of lipid carriers including oil-in-water (O/
W) Pickering emulsions and nanoemulsions for encapsulation of cur-
cumin using corn oil along with medium chain triglycerides (MCT) as
oil phase. Chitosan-tripolyphosphate nanoparticles were used as aqu-
eous phase in formulation of Pickering emulsions in order to increase
their stability. A mixture of Span 80 and Tween 80 were also applied as
surfactant for preparation of nanoemulsions. A simulated GIT model
composed of different phases (i.e. stomach, intestinal and mouth) was
applied for determination of digestion pattern of samples. Then, impact
of carrier type and their characteristics were assessed on bioaccessi-
bility by measuring release amount of curcumin after digestion into
mixed micelles plus radical trapping activity of curcumin. According to
their results, droplet size and surface charge of all samples evidently
influenced by digestion. For instance, droplet size of Pickering emul-
sions and nanoemulsions formed by corn oil was reached to 86.4 from
18.8 μm and to 1221 from 109 nm after subjecting to the simulated
small intestinal fluids, respectively. Also, ζ-potential of Pickering
emulsions with corn oil changed from 13.17 mV to −2.46, 13.77, and
−27.12 mV in the mouth, stomach and intestine, respectively. On the
other hand, a decline in droplet size caused a significant increase in
bioaccessibility as well as lipid digestion. Bioaccessibility of nanoe-
mulsions formed by MCT and corn oil were 32% and 65%, respectively
while 21% and 53% of bioaccessibility were achieved by Pickering
emulsions containing MCT and corn oil, respectively. Superiority of
nanoemulsions to Pickering emulsions concerning bioaccessibility can
be attributed to their rapid digestion. Moreover, higher bioaccessibility
of curcumin emulsions obtained from corn oil in comparison with MCT-
derived samples was related to higher ability of emulsions containing
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Results Reference
Antioxidant effect of curcumin maintained after the Suwantong, Opanasopit,
electrospinning process Ruktanonchai, and Supaphol
(2007)
Significant increment of antioxidant potency of Yen, Wu, Tzeng, Lin, and Lin
curcumin (2010)
Antioxidant activity retained after high electric field Dhurai et al. (2013)
Nanoencapsulation enhanced antioxidant activity of Pan, Zhong, and Baek (2013)
curcumin due to the improved dispersibility
Improved antioxidant activity of nanocurcumin Pathak, Kanwal, and Agrawal
compared to crystalline curcumin in aqueous media (2015)
- Maintenance of antioxidant potency of Blanco-Padilla et al. (2015)
nanocurcumin after an in vitro digestion process
- Higher antioxidant activity of incorporated
curcumin than free counterpart
Stability of curcumin against UV irradiation Li, Shin, Lee, Chen, and Park
improved and its antioxidant ability retained (2016)
Higher free radical scavenging activity of loaded Yi et al. (2016)
curcumin compared to free one
Lower Lipid oxidation in milk samples fortified with Joung et al. (2016)
nanocurcumin compared to samples containing free
one
Better performance of incorporated curcumin than Shah et al. (2016)
its free counterpart
Redispersibility and antioxidant activity of curcumin Chang, Wang, Hu, and Luo (2017)
significantly improved after drying
Remarkable increase in antioxidant activity of Xue et al. (2018)
curcumin after encapsulation
Better maintenance of antioxidant activity of loaded Sadati et al. (2019)
curcumin during storage than free one
corn oil for trapping large molecules such as curcumin by formation of
several hydrophobic cores than emulsions with MCT. Regarding anti-
oxidant activity, encapsulated curcumin showed a better performance
than its free counterpart, proving the positive impact of emulsion for-
mulations on antioxidant efficiency of curcumin. Oil type and en-
capsulation method influenced antioxidant capacity of all samples.
Radical scavenging activity of nanoemulsions and Pickering emulsions
with corn oil increased from 4.06% in control sample to 37.03% and
49.58%, respectively. Also, MTC as oil phase improved radical
scavenging activity of nanoemulsions and Pickering emulsions from
12.21% to 29.80% and 35.18%, respectively (Shah et al., 2016).
In another work, Joung et al. (2016) prepared curcumin-loaded
nanoemulsions via high pressure homogenization and they were added
into milk for evaluation of the lipid oxidation during storage. Anti-
oxidant activity was determined by various assays including DPPH,
ABTS and TABRS (thiobarbituric acid reactive substances). Nanoe-
mulsions containing curcumin showed a good physical stability during
storage in ambient temperatures. Lipid oxidation was also significantly
lower in milk samples fortified with nanocurcumin compared to sam-
ples containing free one (Joung et al., 2016).
Xue, Wang, Hu, Zhou, and Luo (2018) successfully formulated solid
lipid nanoparticles (SLNs) for loading of curcumin by hot emulsification
approach using stearic acid, pectin and sodium caseinate as solid lipid,
stabilizing additive and emulsifying agent, respectively. Neither toxic
solvents nor synthetic surfactants were used in production of SLNs and
antioxidant potential of loaded curcumin was determined by reducing
power and DPPH assays. Nanoencapsulation boosted antioxidant ac-
tivity of curcumin. On the other hand, curcumin content had a sig-
nificant effect on antioxidant activity and designed food grade SLNs
provided more oxidative stability in higher concentrations of curcumin
(Xue et al., 2018).
Recently, Chang et al. (2019) used egg white protein (EWP) to
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accommodate curcumin. The results confirmed effect of pH and adding
ethanol on structure of protein and characteristics of nanoparticles.
EWP in both forms of solution and nanoparticles showed a higher
ABTS+ scavenging activity as compared to pure curcumin dissolved in
water or ethanol. Free radical scavenging activity diminished during
storage for three days at ambient temperature except for curcumin
dissolved in ethanol. However, encapsulation lowered antioxidant ac-
tivity loss of curcumin over time. Moreover, antioxidant activity of
curcumin was preserved at pH = 3.0 better than pH = 3.8 (Chang
et al., 2019).
2.3. Antimicrobial activity of nanoencapsulated curcumin
Curcumin shows its antimicrobial activity by interaction with pro-
tein FtsZ which has a vital role in cell division of microorganisms. The
oxygen molecules of phenol, two carbonyl groups and methoxyl func-
tional groups linked to phenolic rings of curcumin form hydrogen and
hydrophobic bonds with the catalytic site of this protein which disturbs
GTPase activity of FtsZ, leading to cell death (Kaur, Modi, Panda, &
Roy, 2010; Rai, Singh, Roy, & Panda, 2008). Nevertheless, different
factors such as food components and processing and storage conditions
could negatively influence the antimicrobial potency of curcumin in
food systems. Furthermore, direct usage of curcumin in food systems
may decrease consumer satisfaction. For instance, application of cur-
cumin as a natural preservative in minced meat showed that curcumin
has an strong antimicrobial efficacy against some food pathogens (Es-
cherichia coli O157:H7, Listeria monocytogenes, Salmonella typhimurium,
and staphylococcus aureus) but samples treated with higher concentra-
tions of curcumin were not acceptable in terms of sensory attributes
especially color (Altunatmaz et al., 2016). Nanoencapsulation of phe-
nolic compounds like curcumin in suitable carriers presents great po-
tential to promote antimicrobial properties of phenolic compounds
through overcoming drawbacks associated with their direct applica-
tions such as poor water solubility, low stability and unfavorable in-
teraction with food ingredients (Akhavan, Assadpour, Katouzian, &
Jafari, 2018; Rezaei, Fathi, & Jafari, 2019). Moreover, encapsulated
form of curcumin can effectively interact with microbial cells and fa-
cilitate cell perturbation, increasing inhibitory effect against micro-
organisms (Pagnussatt et al., 2016, Da Silva et al., 2018).
In this regard, Wang et al. (2017a) employed electrospinning
method to enclose curcumin in zein fibers and then evaluated their
antioxidant and antimicrobial capabilities against E.coli and S.aureus.
Encapsulated curcumin had a nanometric size and a high entrapment
efficiency. Concentration of curcumin influenced the particle size,
shape and transition temperature of fibers. Antioxidant capacity of
curcumin was preserved upon encapsulation. Besides, fibers bearing
curcumin showed inhibitory action against bacterial strains tested, but
they were more effective on S.aureus. These authors suggested cur-
cumin-loaded zein fibers as an encouraging alternative to retard mi-
crobial spoilage and prolong shelf life of food products (Wang et al.,
2017a).
Deng, Kang, Liu, Feng, and Zhang (2017) encapsulated curcumin via
electrospinning technique by means of three various surfactants (i.e.
cetyltrimethyl ammonium bromide (CTAB), anionic sodium dodecyl
sulfonate (SDS) and Tween 80) and gelatin as polymer. They revealed
correlation between surfactant type and bioactivity, release pattern and
morphology of nanocurcumin formulations. SDS caused an evident in-
crease in diameter of nanofibers and also had a strong interaction with
gelatin by formation of hydrophobic and ionic bonds which decreased
release rate of curcumin in contrast to other surfactants. CTAB made
nanofibers with a higher antioxidant activity (determined by DPPH and
reducing power assays) than SDS and Tween 80. Moreover, regardless
of surfactant type, nanofibers bearing curcumin were effective on
S.aureus, but only those with CTAB could control growth of E.coli.
Therefore, entrapping bioactive materials in nanofibers by food grade
surfactants can be helpful for developing novel functional foods (Deng
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Trends in Food Science & Technology 88 (2019) 445–458
et al., 2017).
In a recent study, Abdou et al. (2018) prepared nanoemulsions
containing curcumin through the emulsion inversion point technique
with the aid of different oils (cinnamon essential oil, sunflower oil or
garlic essential oil) and Tween 80 as surfactant. In the next step, high
ester pectin solution was mixed with nanoemulsions to prepare dis-
persions for covering chicken fillets before packaging and subsequently
coated samples were analyzed in terms of microbial, chemical, physical
and sensorial characteristics during storage for 12 days at 4 °C. Ac-
cording to their results, size, polydispersity index (PDI) and mor-
phology of nanoemulsion droplets were dependent on oil type. Na-
noemulsions could inhibit growth of bacteria and fungi, extending shelf
life of product. Nanoemulsions obtained from cinnamon essential oil
showed the highest capability to control microbial population
throughout storage period as compared to other oils. At zero time, the
highest rate of reduction in total bacterial count was found in samples
treated with curcumin-cinnamon essential oil nanoemulsion/pectin
coating (CCNC) (80.3%) followed by those with curcumin-garlic oil
nanoemulsion/pectin coating (CGNC) and curcumin-sunflower oil na-
noemulsion/pectin coating (CSNC) which showed 47.4% and 24.7%
reduction, respectively in comparison with control. The same trend was
observed after 12 days of storage and the decline was reached to 97.8%,
93.6% and 40.8% in samples with CCNC, CGNC and CSNC, respec-
tively. Moreover, CCNC, CGNC and CSNC caused 95.1%, 72.9% and
42.6% decrease in psychrophilic bacterial count of fillets compared to
control sample, respectively. Regarding yeast and mold counts, the
lowest growth rates were related to samples treated with CCNC
(0.56 d−1) and CGNC (0.49 d−1), which was attributed to inhibitory
effect of cinnamaldehyde and allicin as main bioactive compounds of
cinnamon essential oil and garlic essential oil against different micro-
organisms. Furthermore, fillets treated with nanoemulsions bearing
cinnamon essential oil or garlic essential oil exhibited a higher water
holding capacity, oxidative stability and texture score as well as less
total volatile nitrogen content than control sample and those coated
with sunflower oil-derived nanoemulsion. Control samples also re-
ceived the least degree of acceptability in sensory features by panelists
(Abdou et al., 2018).
Some researchers have encapsulated turmeric extract in different
nanocarriers and evaluated their antimicrobial activities. For instance,
antioxidant and antimicrobial activities of free and loaded turmeric
methanolic extracts were determined by Abdel Fattah and Tawfik
(2016) and Alnashiand and Abdel Fattah (2016), respectively. They
found that nanoencapsulation improved antioxidant and antimicrobial
activity of turmeric extract against tested microorganisms (L.mono-
cytogenes, E.coli O157:H7, S.aureus, S.typhimurium, B.cereus, Candida
albicans, Geotricum candidum, Fusarium moniliform, Aspergillus flavus,
and Aspergillus. niger) (Abdel Fattah, 2016; Alnashi, 2016). The effect of
nanocurcumin on pathogenic microorganisms has been reviewed in
section 3.4.
3. Nanoencapsulated curcumin for medicinal purposes
Curcumin is historically valuable in medical applications and has
been used as a traditional therapy in various Asian medicines (Sharma,
Gescher, & Steward, 2005). Due to its polyphenolic structure and highly
safe nature, it has been known as a potential therapeutic molecule with
versatile pharmacological activities (Noorafshan & Ashkani-Esfahani,
2013; Yallapu, Nagesh, Jaggi, & Chauhan, 2015). Its therapeutic ap-
plications are highly variant including anti-oxidant, anti-neoplasm,
anti-bacterial, anti-diabetic and anti-inflammatory properties; while it
is proven to have positive effects in the treatment of cardiovascular and
Alzheimer's disease, liver cirrhosis, GIT problems and wound healing
(Gera et al., 2017; Gupta, Patchva, & Aggarwal, 2013; Noorafshan &
Ashkani-Esfahani, 2013; Yallapu et al., 2015).
However, curcumin poses some critical drawbacks which impede its
efficacy as a therapeutic drug molecule. Its highly lipophilic structure
Z. Rafiee, et al.
results in very low aqueous solubility and intrinsic dissolution rate.
Additionally, it shows instability at alkaline pH values and undergoes
rapid metabolism and elimination in vivo. Hence, it has very poor
pharmacokinetic properties including poor absorption and low oral
bioavailability along with low penetration and targeting efficacy (Gera
et al., 2017; Naksuriya, Okonogi, Schiffelers, & Hennink, 2014; Yallapu
et al., 2015). Encapsulation of curcumin in different nanocarriers has
been proposed as an emerging solution for these limitations (Jafari &
Mcclements, 2017). As mentioned in previous sections, nanocarriers
can help to increase the aqueous solubility of curcumin while protecting
it from degrading environment. These formulations can modify the
pharmacokinetic properties of the loaded drug and may increase ther-
apeutic efficiency at the site of action with passive and active targeting
mechanisms, and also higher cellular uptake rates (Gera et al., 2017;
Yallapu et al., 2012, 2013). Different curcumin-loaded nanocarriers
have been designed and studied for various disease conditions and some
formulations have reached the clinical trials (Naksuriya et al., 2014).
Some important and current pharmaceutical applications of these na-
noformulations are summarized in the following sections.
3.1. Nanoencapsulated curcumin against cancer
Curcumin exhibits anti-cancer effects against numerous kinds of
malignancies including head and neck squamous cell carcinoma, mul-
tiple myeloma, and many other malignancies like colorectal, pan-
creatic, breast, prostate, lung, and oral cancer. It can suppress different
cellular processes including cell transformation or proliferation, inva-
sion and metastasis with a combination of complicated mechanisms.
The main anti-cancer mechanisms involve modulation of pro-in-
flammatory cytokines (like tumor necrosis factor [TNF]-α and inter-
leukin IL-6 and [IL]-1β), modulation of numerous apoptotic proteins
including NF–κB, cyclooxygenase (COX)-2, IKKβ, STAT3, and en-
dothelin-1 (Vallianou, Evangelopoulos, Schizas, & Kazazis, 2015;
Yallapu et al., 2012).
Although curcumin is potentially effective against different cancers,
but poor pharmacokinetic properties limit its clinical efficacy.
Utilization of different nanoformulations is a promising approaches in
this regard. A wide range of in vitro and in vivo studies obviously reveal
the therapeutic efficacy of curcumin-loaded nanocarriers including
polymeric nanoparticles, liposomes, SLNs, micelles, etc. in diverse
cancer types (Naksuriya et al., 2014; Yallapu et al., 2012, 2013). The
results of these studies show that nanocarriers can enhance the anti-
cancer efficacy of curcumin by modulation of pharmacokinetic prop-
erties (higher bioavailability and longer biological half-life) and/or
increasing site-specific drug delivery. This can be achieved by pro-
tecting curcumin from degradation, increasing its solubility, controlling
the drug release, promoting membrane transport and/or absorption,
enhancing cellular uptake, and bypassing of cellular efflux pumps
(Naksuriya et al., 2014; Yallapu et al., 2012, 2013).
A vast majority of studies on the literature have been focused on
preparation, characterization and cellular uptake and cytotoxicity of
nanoencapsulated curcumin in different types of cancer cell lines which
have been thoroughly reviewed in previously published review articles
(Gera et al., 2017; Naksuriya et al., 2014; Yallapu et al., 2012, 2013,
2015). In some studies, the pharmacokinetics of formulations have also
been assessed and compared to solutions (Gera et al., 2017; Mohanty,
Das, & Sahoo, 2012; Naksuriya et al., 2014; Yallapu et al., 2012, 2013).
For instance, Khalil et al. (2013) suggested PLGA and PLGA-PEG na-
noparticles as potential nanocarriers for oral delivery of curcumin.
These nanoparticles provided a sustained drug delivery and increased
the bioavailability of curcumin up to 15.6- and 55.4-fold compared to
its suspensions, respectively (Khalil et al., 2013).
Baek and Cho (2017) in a recent study prepared stable N-carbox-
ymethyl chitosan-coated SLNs loaded with curcumin which showed a
higher cellular uptake and cytotoxicity on MCF-7 cells. They also re-
ported a 6.3-fold higher lymphatic uptake and 9.5-fold higher oral
450
Trends in Food Science & Technology 88 (2019) 445–458
bioavailability compared to free curcumin suspensions and suggested
this nanoformulations as effective delivery systems for oral applications
of curcumin (Baek & Cho, 2017).
Some other studies have proven the anti-cancer efficacy of curcumin
nanoformulations in animal models. For example, Gong et al. (2013a)
evaluated curcumin-loaded polymeric micelles for pulmonary carci-
noma. The results showed a sustained in vitro release profile and in-
creased in vitro anti-angiogenesis, cellular uptake and cytotoxicity
compared to free curcumin. The micelles also showed a superior anti-
tumor efficacy in subcutaneous and pulmonary metastatic LL/2 tumor
models compared to free form (Gong et al., 2013a). Lin et al. (2012)
used 270 nm-sized cationic liposome-PEG-PEI complexes for en-
capsulation of curcumin. This nanoformulation caused a 5-fold and 20-
fold increase in cytotoxicity against curcumin-sensitive and curcumin-
resistant cells, respectively. The cytotoxicity was attributed to induced
apoptosis by cell cycle arrest at G2/M phase and rapid accumulation in
the cell. These nanocarriers also inhibited the tumor growth up to
60–90% in mice bearing CT-26 or B16F10 cells (Lin et al., 2012).
Yallapu et al. (2014) evaluated the therapeutic potential of curcumin-
loaded PLGA nanoparticles in prostate cancer. They showed that these
nanoparticles can enter the prostate cancer cells and curcumin is re-
leased in cytosolic compartment. PLGA nanoparticles showed superior
in vivo anti-tumor effects compared to free curcumin in xenograft mice
with additional antineoplastic effects in prostate cancer (Yallapu et al.,
2014).
In a comprehensive study conducted by Zaman et al. (2016), the
efficacy of PLGA-based curcumin nanoparticles in cervical cancer was
assessed in vitro and in vivo. The nanoformulations improved accumu-
lation of curcumin in cervical cancer cells and caused cell arrest in G1-S
transition phase, inducing apoptosis. The designed nanoparticles sig-
nificantly reduced tumor growth in cervical cancer orthotopic xenograft
mouse model while the level of oncogenic HPV E6/E7 and Ki67 pro-
teins were also decreased. Additionally, the formulation decreased the
levels of miRNA-21, in vitro and in vivo, in comparison to free curcumin
while decreasing the levels of IL-6 (Zaman et al., 2016).
The anti-cancer efficacy of milk-derived exosomes containing cur-
cumin was investigated by Aqil, Munagala, Jeyabalan, Agrawal, and
Gupta (2017). The exosomes were taken up by cancer cells via ca-
veolae/clathrin-mediated endocytosis and showed 3–5 times higher
tissue accumulations compared to free curcumin. Also, the curcumin-
loaded exosomes showed a higher anti-proliferative activity against
multiple cancer cell lines including cervical, breast, and lung cancer cell
lines. This formulation showed a significant inhibition of the cervical
CaSki tumor xenograft in nude mice while no systemic toxicity was
observed in the rats (Aqil et al., 2017).
Novel formulations of curcumin-loaded nanoparticles (like
Theracurcumin®, a brand name for curcumin-loaded nanoparticles)
have shown improved pharmacokinetic properties in recent clinical
trials in human volunteers, but still a high-throughput research activity
to develop more efficient curcumin-loaded nanocarriers for cancer
therapy is needed (Naksuriya et al., 2014). Some studies on application
of curcumin nanoformulations in cancer therapy are illustrated in
Table 2.
3.2. Nanoencapsulated curcumin against cardiovascular diseases
Curcumin is also effective in mitigation and treatment of cardio-
vascular diseases and vascular dysfunctions. The cardioprotective me-
chanisms of curcumin are various and mostly related to its anti-in-
flammatory effects. For instance, curcumin can reduce NO oxidation
and shows membrane stabilizing effects in MI, prevents doxorubicin
induced cardiomyopathy, and diabetic complications. Curcumin can
also inhibit p300 and NF-κB which are associated with prevention of
cardiac hypertrophy and cardiac fibrosos, respectively (Wongcharoen &
Phrommintikul, 2009).
Sunagawa et al. (2012) prepared a new curcumin delivery system
Z. Rafiee, et al. Trends in Food Science & Technology 88 (2019) 445–458

consisting colloidal nanoparticles dissolved in gum ghatti solution. This

Aqil et al. (2017)

Lin et al. (2012)
formulation showed a 27-fold increase in oral bioavailability of cur-

Yallapu et al.

Zaman et al.
Gong et al. cumin and significantly improved perivascular fibrosis in post-MI rats
Reference

(2013a) compared to free curcumin (Sunagawa et al., 2012). Carlson, Cote,

(2014)

(2016)
Alani, and Rao (2014) designed resveratrol and curcumin-loaded
Pluronic-F127 micelles for prevention of doxorubicin-induced cardio-
angiogenesis; anti-tumor efficacy in HUVECs, transgenic zebrafish models, and

proteins in cervical cancer xenograft mouse model; Decreased levels of miRNA-

cancer cells; Superior tumor regression compared to free curcumin in xenograft
against curcumin-resistant cells compared to curcumin; Inhibition of 60–90% of

Improved accumulation in cervical cancer cells and induction of apoptosis via

5-fold higher cytotoxicity on curcumin-sensitive cells and 20-fold more active

free curcumin; Significant inhibition of the cervical CaSki tumor xenograft in

toxicity. The results revealed that this formulation could enhance so-

proliferative activity and 3–5 times higher tissue accumulations compared to

Effective inhibition of proliferation and colony formation ability of prostate

cell arrest in G1-S transition phase; Reduced tumor growth and oncogenic
lubility of these compounds and can mitigate cardiomyopathy by re-

Cellular uptake via caveolae/clathrin-mediated endocytosis; Higher anti

duction of apoptosis and ROS level, while improving doxorubicin
Increased cellular uptake, and cytotoxicity; in vitro and in vivo anti-

efficacy in ovarian cancer cells (Carlson et al., 2014). Soltani,

Bodaghabadi, Mahpour, Ghaemi, and Sadeghizadeh (2016) in-
subcutaneous and pulmonary metastatic LL/2 tumor models

21 and IL-6 in vitro and in vivo, compared to free curcumin.

vestigated the potential of a dendrosomal formulation of curcumin in
tumor growth in mice bearing CT-26 or B16F10 tumors.

prevention of radiation induced atherosclerosis. The formulation sig-

nificantly inhibited the Co60 gamma rays-induced changes in human
umbilical vein endothelial cells by activation of the Nrf-2 pathway

nude mice with no systemic toxicity in the rats.

(Soltani et al., 2016).

3.3. Nanoencapsulated curcumin against neurodegenerative diseases

Curcumin has shown therapeutic potentials in improvement of

neurodegenerative diseases. These effects are related to its anti-oxidant,
anti-inflammatory and anti-protein aggregation activities. The accu-
mulation of toxic β-amyloid peptide (Aβ) in senile plaques is typically
Study outcome

seen in Alzheimer's disease (AD). Curcumin can target the amyloid

pathway and has received great attention in the treatment of AD
mice.

(Darvesh et al., 2012).

Doggui, Sahni, Arseneault, Dao, and Ramassamy (2012) studied
- Cytotoxicity, apoptosis induction, and cellular uptake on LL/

- In vivo studies including systemic toxicity, tumor uptake and

cell cycle analysis in Caski and SiHa cervical cancer cell lines.
- Cellular uptake, cell proliferation, colony forming assay and

effects of curcumin-loaded PLGA nanoparticles on human neuro-

- In vivo suppression of tumor growth in mice bearing tumors

- Cell proliferation assay in lung (H1299 and A549), cervical

- In vitro antiangiogenic activity in primary human umbilical

- Cell proliferation, clonogenic, and Western blot analyses in

- In vivo anti-tumor efficacy in subcutaneous and pulmonary

xenograft mouse model, In vivo assessment of miRNA-21in

- Cytotoxic activity on 10 different curcumin-sensitive and

human prostate cancer cell lines (DU-145 and PC-3 cells)

(HeLa) and breast cancer (MDA-MB-231 and T47D) cells

blastoma SK-N-SH cells. The nanoparticles were able to protect cells

- Tumor growth in NOD SCID gamma (NSG) orthotopic

against H2O2 and prevented H2O2-induced ROS formation and glu-

tumor targeting capability in C4-2 xenograft mice.

tathione consumption (Doggui et al., 2012). Cheng et al. (2013) de-

- In vivo drug extravasation and anti-angiogenesis

- Tissue distribution in the lung, liver, and brain

signed polyethyleneglycol-polylactide (PEG-PLA) di-block polymeric

micelles to increase bioavailability of curcumin and enhance its pene-
tration into the Blood Brain Barrier (BBB). After oral administration in
- Cellular uptake studies in H1299 cells

Tg2576 AD model mice, a significant improvement was seen over

- In vivo Tumor Xenograft Studies
vein endothelial cells (HUVECs)

metastatic LL/2 tumor models.

curcumin resistant cancer cells

control in working and cue memory. The nanoparticles significantly

increased curcumin plasma concentrations and bioavailability with a 6-
Examples of comprehensive studies on curcumin nanoformulations for treatment of cancer.

fold higher AUC in brain (Cheng et al., 2013). Mourtas et al. (2011)
proposed a new formulation of curcumin-loaded nanoliposomes which
had the proper planar structure required for interaction with Aβ and
they reported a high affinity of these nanoparticles for Aβ1-42 fibrils
mice tissues.

(Mourtas et al., 2011). In another study conducted by this group in

Model used

2 cells

2014, anti-Transferrin-conjugated PEGylated nanoliposomes were de-

signed and characterized. They reported that both ligand-targeted li-
posomes and simple liposomes showed a high affinity for the Aβ de-
posits on samples obtained from patients with AD and could retard Aβ1-
Monomethyl poly (ethylene glycol)-poly

42 peptide aggregation in Thioflavin assay. However, active-targeting

(ε-caprolactone) (MPEG-PCL) micelles

Cationic liposome-PEG-PEI complexes

with anti-Transferrin significantly improved the uptake in BBB cellular

model (Mourtas, Lazar, Markoutsa, Duyckaerts, & Antimisiaris, 2014).
Another attempt for active targeting of curcumin-loaded nanolipo-
somes to BBB was conducted by Mathew et al. (2012). They suggested
Milk-derived exosomes

PLGA nanoparticles to increase the solubility of curcumin, and deco-

PLGA nanoparticles

PLGA nanoparticles

rated the surface of nanoparticles with Tet-1 peptide to enhance BBB

Characteristics

uptake. The designed nanoparticles showed a high in vitro cellular up-

take into GI-1 glioma cells and were able to destroy amyloid aggregates,
and exhibited anti-oxidant properties showing no toxicity (Mathew
et al., 2012). Sandhir et al. (2014) proposed curcumin-loaded SLNs for
Huntington's disease. The cell culture and in vivo studies showed that
Polymeric nanoparticles

Polymeric nanoparticles

SLNs can cause a significant improvement in neuromotor coordination

Type of nanocarrier

Polymeric micelles

of Huntington's disease-induced rats. Hence, they suggested these cur-

cumin-loaded nanoparticles as a promising formulation to ameliorate
mitochondrial dysfunctions in Huntington's disease (Sandhir et al.,
Exosomes
Liposome

2014).
Table 2

451
 Z. Rafiee, et al.

Table 3
Studies considering the antimicrobial properties of curcumin-loaded nanocarriers.
Type of nanocarrier Characteristics Study design Study outcome Reference

Curcumin nanoparticles
Curcumin nanoparticles
Curcumin nanoparticles
Curcumin-loaded chitosan
nanoparticles
Curcumin-loaded polymeric
Prepared by a wet-milling technique
Prepared by supercritical CO2
Prepared by precipitation of curcumin from
organic solution in boiling water
Prepared by polymerization of chitosan in the
presence of PEG 400 and hydrolyzed
Tetramethyl orthosilicate (TMOS- HCl)
Prepared from chitosan or PLGA
MIC was examined against Staphylococcus aureus, Bacillus subtilis, The activity of nanoformulations was more pronounced against Bhawana et al.
E.coli, Pseudomonas aeruginosa, Penicillium notatum and Aspergillus Gram-positive than Gram-negative bacteria; Better anti-bacterial (2011)
niger activity than anti-fungal activity.
The anti-bacterial activity (MIC) was examined against gram The MIC of nanoparticles was %50 lower than free curcumin Xie et al. (2015)
positive (S. aureus) and gram negative (E. coli) bacteria solution.
Anti-bacterial activity against E. coli, S. aureus, and Pseudomonas The nanoparticles exhibited in vitro anti-bacterial activity against Pandit et al.
aeruginosa using Kierby–Bauer disc diffusion method all tested bacteria. (2015)
Colony forming unit (CFU) quantification was performed on CFU quantification showed that curc-np exerted a 97.0% reduction Krausz et al.
MRSA and P. aeruginosa isolates to determine antimicrobial of MRSA growth (Fig. 2C) and 59.2% reduction of P. aeruginosa (2015)
activity/Antimicrobial activity was also evaluated in vivo by growth/Curc-np reduce bacterial burden in MRSA-infected burn
homogenizing infected burn wounds and quantifying CFUs wounds.
present in tissue on day 3 and 7
Rats were inoculated with Giardia lamblia cysts then treated with The parasite was successfully eradicated from stool and intestine. Said et al. (2012)

452
nanoparticles
Nanostructured lipid carriers
Liposome
Chitosan nanoparticles
Curcumin nanoparticles
Curcumin nanoparticles
Prepared by nanoemulsion technique employing
high-speed homogenizer and ultrasonic probe
PEGylated liposomes containing Artemisinin,
alone or in combination with curcumin
Curcumin was bound to the surface of chitosan
nanoparticles
Produced by high-frequency ultrasonication
Prepared by a solvent and antisolvent
precipitation technique
curcumin formulations and the number of Giardia cysts in stools
and trophozoites in intestinal sections were detected.
In vivo antimalarial activity was assessed in malaria induced
Albino mice after injection of formulation for 3 consecutive days.
Artemisinin-based liposomal formulations was tested in
Plasmodium berghei NK-65 infected mice
In vitro and in vivo stability was assessed in mouse plasma, oral
bioavailability and pharmacokinetic properties were evaluated in
mice and in vivo antimalarial activity was tested on Plasmodium
yoelii infected mice.
Antimicrobial activity of nanocurcumin, microcurcumin and
macro-turmeric were evaluated aginst E.coli, Salmonella
enteritidis, Streptococcus mutans and S. aures
Using nanocurumin along with silver nanoparticles as an anti-
biofilm agent against Pseudomonas aeruginosa and S. aureus
2-fold increase in anti-malaria activity of nanoparticles was seen Nayak et al.
compared to curcumin in in vivo model. (2010)
Artemisinin and curcumin-loaded PEGylated liposomes showed an Isacchi et al.
immediate antimalarial effect. (2012)
Reduced curcumin degradation in mouse plasma in vitro, increased Akhtar et al.
oral bioavailability and survival of mice infected with a lethal (2012)
strain of Plasmodium yoelii (N-67).
Fivefold increase in antimicrobial activity by nanoencapsultion of Gopal, Muthu, and
curcumin; Higher solubility, penetration and antimicrobial activity Chun (2016)
of nanocurcumin compared to macro-turmeric and
microcurcumin; The most susceptible bacteria: E.coli and S.
enteritids
Inhibition of biofilm formation with the combination of silver and Loo et al. (2015)
curcumin nanoparticles
Significant effect of nanocurcumin content on anti-biofilm activity
Trends in Food Science & Technology 88 (2019) 445–458
Z. Rafiee, et al.
3.4. Anti-pathogenic effects of nanoencapsulated curcumin
Curcumin has been known as a traditional anti-microbial agent and
a variety of studies have proved its efficacy against numerous Gram-
negative and Gram-positive bacteria. However, efforts have been made
to increase its anti-microbial efficacy by incorporating into different
nanoparticles. A general review in this regard has been published by
(Silva et al., 2018). Table 3 summarized some of the recent studies on
anti-microbial effects of nanoencapsulated curcumin.
Bhawana et al. (2011) prepared curcumin nanoparticles with a wet-
milling technique. The solubility of curcumin was increased in this
nanoformulation. The minimum inhibitory concentration (MIC) of
curcumin was examined against Aspergillus niger, Bacillus subtilis, E.coli,
S.aureus, Pseudomonas aeruginosa, and Penicillium notatum. The results
demonstrated that this nanoformulation of curcumin was more active
against Gram-positive than Gram-negative bacteria. Furthermore, it
exhibited better anti-bacterial activity than anti-fungal activity. The
transmission electron microscopy (TEM) analysis revealed that these
particles can cause cell death by entering the bacterial cell through
complete breaking of the cell wall (Bhawana et al., 2011). Xie et al.
(2015) prepared curcumin nanoparticles via supercritical CO2. They
reported a higher solubility and increased anti-bacterial, antioxidant
and anti-cancer efficacy for this curcumin-loaded nanoparticles. The
results also revealed a better anti-microbial efficacy of nanoparticles
and the MIC of nanoparticles was 50% lower than free curcumin so-
lution (Xie et al., 2015). In another study conducted by Pandit,
Gaikwad, Agarkar, Gade, and Rai (2015), curcumin nanoparticles were
prepared by precipitation of the bioactive from organic solution in
boiling water and their anti-bacterial activity against some pathogenic
bacteria was evaluated. They reported that curcumin nanoformulations
exhibit in vitro anti-bacterial activity against E.coli, S.aureus, and
P.aeruginosa (Pandit et al., 2015). Krausz et al. (2015) synthesized
curcumin-loaded chitosan nanoparticles and reported in vitro growth
inhibition of methicillin-resistant S.aureus (MRSA) and P.aeruginosa in a
dose-dependent manner. The synthesized nanoparticles could inhibit
planktonic growth of both microorganisms and induced cellular da-
mage of MRSA. The nanoparticles could also decrease bacterial burden
of full-thickness burns in vivo (Krausz et al., 2015).
Some studies have shown anti-parasite activity of curcumin nano-
formulations. Said, Elsamad, and Gohar (2012) reported the positive
role of curcumin-loaded nanoparticles (including chitosan and PLGA
polymeric nanoparticles) in treatment of the intestinal giardiasis, and
regarded it as a curable and safe treatment (Said et al., 2012). Nayak,
Tiyaboonchai, Patankar, Madhusudhan, and Souto (2010) showed a 2-
fold increase in anti-malaria activity of lipid-based curcuminoid nano-
particles over free curcumin after parenteral administration in an in vivo
model (Nayak et al., 2010). Furthermore, Isacchi et al. (2012) designed
PEGylated liposomes containing Artemisinin and curcumin, which
provided a highly significant therapeutic benefit in vivo in mice infected
with Plasmodium berghei NK-65 (Isacchi et al., 2012). Chitosan-bound
curcumin nanoformulations were also evaluated for their anti-malaria
effects by Akhtar, Rizvi, and Kar (2012). The designed nanoparticles
showed an increased stability in mouse plasma in vitro and better up-
take by mouse RBC compared to free curcumin. Curcumin-loaded
chitosan nanoparticles improved the oral bioavailability of curcumin
and increased the survival of mice infected with a lethal strain of
Plasmodium yoelii (N-67) (Akhtar et al., 2012).
In a recent work, Karimi, Ghanbarzadeh, Hamishehkar, Mehramuz,
and Kafil (2018) incorporated turmeric extract into NLCs by high shear
homogenization. Nanoparticles (112.4 nm) presented a sustained re-
lease pattern as well as a high physical stability. A significant increase
was observed in antioxidant and antimicrobial activity of curcumin
against Gram-negative bacteria (E.coli, Acinetobacter juni and P.aerugi-
nosa) after nanoencapsulation (Karimi et al., 2018).
453
Trends in Food Science & Technology 88 (2019) 445–458
3.5. Anti-viral effects of nanoencapsulated curcumin
It has been thoroughly reported that curcumin poses inhibitory ef-
fects against viruses interfering some critical steps of virus replication
cycle. Curcumin has been studied as an anti-viral agent against nu-
merous viruses like Herpes simplex virus (HSV), Human
Immunodeficiency Virus (HIV), Hepatitis viruses, influenza type A
virus, and Ebola virus. This natural compound can directly interfere
with the viral replication machinery or suppress the essential cellular
signaling pathways in viral replication cycle such as inflammation, and
apoptosis and including PI3K/Akt, NF-κB s (Mathew & Hsu, 2018).
In a study conducted by Gandapu, Chaitanya, Kishore, Reddy, and
Kondapi (2011), the potentials of curcumin-loaded apotransferrin na-
noparticles for inhibition of HIV-1 replication was studied in vitro.
Nanoparticles showed a sustained delivery of curcumin and decreased
curcumin cytotoxicity up to 50% compared with free curcumin. The
nanoformulation of curcumin showed about 3-fold higher anti-HIV
activity compared to its free form and inhibited the HIV-1 induced
expression of IL-1β,Topo II α, and COX-2 and completely blocked the
synthesis of viral cDNA (Gandapu et al., 2011). Yang, Li, and Huang
(2016) introduced curcumin modified silver nanoparticles for sy-
nergistic anti-viral effects of curcumin and AgNPs in respiratory syn-
cytial virus (RSV) infection. These nanoparticles showed a high in-
hibitory effect against RSV infection in tissue culture infectious dose
assay and 2-fold lower viral titers were resulted. The nanoformulations
could inactivate the RSV and prevent the host cells from infecting (Yang
et al., 2016).
3.6. Wound healing activities of nanoencapsulated curcumin
Curcumin has shown notable wound healing properties. It can
promote the wound healing process through different mechanisms in-
cluding involvement in the tissue remodeling process, granulation or
tissue formation, and collagen deposition. It can also interfere with
epithelial regeneration and promote fibroblast proliferation and vas-
cular density (Akbik, Ghadiri, Chrzanowski, & Rohanizadeh, 2014).
A nanoformulation of curcumin was developed by Li et al. (2012)
with methoxy poly (ethylene glycol)-b-poly(ɛ-caprolactone) copolymer
(MPEG-PCL) and then it was incorporated into the N,O-carboxymethyl
chitosan/oxidized alginate hydrogel. This nanoformulation showed an
improved stability and slow release. In vivo wound healing experiments
revealed improved re-epithelialization of epidermis and collagen de-
position in the injured tissue (Li et al., 2012). Gong et al. (2013b)
prepared curcumin-loaded polymeric micelles in a thermosensitive
hydrogel formulation for wound healing. This formulation exhibited
proper tissue-adhesion and provided extended release of curcumin. The
in vivo wound healing effects of formulation was examined on linear
incision and full-thickness excision wound models. The results in-
dicated that curcumin-loaded polymeric micelles could enhance cuta-
neous wound repair and caused higher collagen content, better gran-
ulation and wound maturity, a highly significant decrease in superoxide
dismutase, and slight increase in catalase (Gong et al., 2013b).
Krausz et al. (2015) prepared curcumin polymeric nanoparticles
from chitosan and PEG 400 as an anti-microbial and wound healing
agent. This formulation accelerated the wound healing process in a
murine burn model and could enhance collagen deposition, formation
of granulation tissue, and neoangiogenesis (Krausz et al., 2015).
As mentioned above, curcumin nanoformulations are extensively
under study and some formulations have reached the clinical trial.
Table 4 summarizes some clinical trials conducted on curcumin nano-
formulations.
4. Application of nanoencapsulated curcumin in the cosmetic
industry
Curcumin has been considered in cosmetic applications due to its
 Table 4
Clinical trials conducted on curcumin nanoformulations.
Formulation type Study title Disease/condition Aims ClinicalTrials.gov
Z. Rafiee, et al.

Identifier

Surface-controlled water soluble Phase I study of surface-controlled water soluble curcumin Advanced cancer Evaluation of the highest tolerable dose and safety of formulation NCT01201694
curcumin (THERACURMIN CR-011L)
Liposomal curcumin Safety, tolerability and pharmacokinetics of liposomal curcumin Drug safety Evaluation of the safety, tolerability and pharmacokinetics of NCT01403545
in healthy volunteers - a phase I dose escalation study increasing doses of intravenous liposomal curcumin in healthy
subjects
A phase IB dose escalation study on the safety, tolerability and Patients with advanced cancer Determination of the safety profile and maximum tolerated dose NCT02138955
activity of liposomal curcumin in patients with locally advanced who have failed standard of (MTD) of increasing doses of intravenous liposomal curcumin in
or metastatic cancer care therapy cancer patients
Nanocurcumin capsules (containing Effects of oral nanocurcumin on expression levels of micrornas Ankylosing spondylitis Number of subjects with a reduction in signs and symptoms of NCT03140657
curcumin nanoparticles, and treg cells and th17 cells development factors in ankylosing Ankylosing spondylitis 4 month after treatment
Exirnanosina) spondylitis patients
Nanomicelle curcumin The effects of nanomicelles curcumin on glycemic control, serum Metabolic syndrome Evaluation of blood pressure and some serum biomarkers related NCT03534024
lipid profile, blood pressure and anthropometric measurements to metabolic syndrome including blood glucose level and serum
in patients with metabolic syndrome lipid profile (HDL, LDL, Cholesterol and TG)
Effects of nanocurcumin on serum oxidative stress, Metabolic syndrome Evaluation of some serum biomarkers like total antioxidant NCT03514667
inflammation, adiponectin and NF-kB in blood mononuclear capacity (TAC), serum malondialdehyde (MDA), and serum C-
cells in metabolic syndrome patients (nuclear factor-κB) reactive protein (CRP)
Curcumin conjugated with plant Phase I clinical trial investigating the ability of plant exosomes Colon cancer Comparison of the effect and the concentration of curcumin in NCT01294072
exosomes to deliver curcumin to normal and malignant colon tissue normal and cancerous tissue after administration of the curcumin
formulations; Safety, immune responses and histochemical
staining are also evaluated as secondary outcomes

454
Table 5
Studies considering cosmetic applications of curcumin nanoformulations.
Type of nanocarrier Characteristics Study design Study outcome Reference

Lipid-core nanocapsules Curcumin and resveratrol encapsulating LNCs were
(LNC) prepared by precipitation of preformed polymer method
using PCL, grape seed oil, sorbitan monoestearate
Lipid vehicles Curcumin was incorporated into lipid vehicle consisting
of lauric acid, isopropanol, and surfactants (Tween 80 and
F127) in order to inhibit the growth of propionibacterium
acnes as an anti-bacterial and anti-infammatory agent.
Vesicular carriers Curcumin-loaded liposomes, ethosomes, and
transfersomes were prepared as cream.
Cyclodextrin-based Cyclodextrin/curcumin complex
nanoformulations
Liposomes Anionic liposomes of curcumin/anionic, cationic and
amphoteric liposomes of carboxyfluoresceine
In vitro antioxidant activity and photostability study was
conducted.
Propionibacterium acnes growth inhibition of the
formulation was evaluated in vitro. The mechanism of
curcumin accumulation in porcine skin was evaluated
using neonate pig skin.
Effects of vesicular carriers on ultraviolet radiation-
damaged skin were assessed through examination of the
skin hydration level and sebum content.
Cyclodextrin/curcumin complex or curcumin solution
were placed on top of excised porcine skin and left on for
5 min then the samples were frozen in liquid nitrogen and
10-μm-thick slices were prepared and viewed with
fluorescence microscopy.
Liposomes containing carboxyfluoresceine or curcumin as
hydrophilic and lipophilic model drugs were applied on
pig ear skin and the depth of penetration was measured by
laser scanning microscopy in histological sections.
In vitro antioxidant activity of polyphenols against OH Coradini et al.
radicals was enhanced by nanoencapsulation, and a better (2014)
effect was observed after their co-nanoencapsulation.
Curcumin-loaded lipid vesicles could efficiently accumulate Liu and Huang
in the neonate pig skin and inhibit propionibacterium acnes (2013)
Curcumin-loaded vesicles showed good skin penetration and Kaur and Saraf
photoprotective effects with the following order: curcumin- (2011)
loaded transfersomal creams > ethosomal
creams > liposomal creams > curcumin creams > empty
transfersome cream > empty ethosome cream > empty
liposome cream > base cream
Solubilized curcumin in an aqueous cyclodextrin vehicle Konradsdottir et al.
(HPγCD) was delivered deep into the skin hair follicles. The (2009)
HPγCD complex appears to selectively target the hair
follicles.
Liposomal formulations penetrated considerably deeper into Jung et al. (2006)
the hair follicles and showed approximately 48% of relative
penetration depth at day 3 after application.
Trends in Food Science & Technology 88 (2019) 445–458
Z. Rafiee, et al.
antioxidant and anti-inflammatory effects on the skin. It poses anti-
aging, anti-wrinkle, sunscreen and skin regenerative activities and can
lead to a better skin appearance. Curcumin can be used as a coloring
agent in nail-care and lip-care products. Nanoencapsulation of cur-
cumin can enhance its efficacy, providing better skin penetration and
retention (Ganesan & Choi, 2016). There are few studies considering
the cosmetic applications of curcumin-loaded nanocarriers which are
discussed in the following section and have been summarized in
Table 5.
Coencapsulation of resveratrol and curcuminin in nanocapsules
with lipid core have showed enhanced delivery of these agents and
increased antioxidant activities; it is suggested that this formulation can
delay aging effects on the skin (Coradini et al., 2014; Friedrich et al.,
2015). Liu and Huang (2013) suggested curcumin-loaded lipid vehicles
for the treatment of acne vulgaris as an anti-bacterial and anti-in-
flammatory agent. They examined skin accumulation and propioni-
bacterium acnes growth inhibition of the formulation in vitro. The results
revealed that curcumin-loaded lipid vesicles could considerably accu-
mulate in the neonate pig skin and inhibit propionibacterium acnes (Liu
& Huang, 2013). Kaur and Saraf (2011) examined the photoprotective
effects of vesicular systems of curcumin including liposomes, etho-
somes, and transfersomes on ultraviolet radiation-damaged skin. The
skin hydration level and sebum content was assessed and the following
order was seen for all cream formulations:
curcumin-loaded transfersomal > curcumin-loaded ethosomal >
curcumin-loaded liposomal > curcumin-loaded > empty transfer-
some > empty ethosome > empty liposome > base cream
They concluded that curcumin-loaded vesicles could have a better
skin penetration and show good photoprotective effects (Kaur & Saraf,
2011).
Some studies have shown that curcumin-loaded nanocarriers can
effectively penetrate into the hair follicles and can be used for delivery
of curcumin deep into and through the hair follicles. For example,
Konradsdottir, Ogmundsdottir, Sigurdsson, and Loftsson (2009) re-
ported deep penetration of cyclodextrin-based curcumin nanoformula-
tions in porcine hair follicle (Konradsdottir et al., 2009). Jung et al.
(2006) used curcumin-loaded liposomes as a follicular delivery system
in pig ear skin. The liposomal formulations penetrated deeply into the
hair follicles and reached a penetration depth of approximately 48% of
the hair follicle length (Jung et al., 2006).
5. In vitro versus in vivo tests for curcumin-loaded nanocarriers
A wide variety of in vitro and in vivo studies can be conducted to
evaluate the safety and efficacy of curcumin nanoformulations ac-
cording to their potential application. In vivo studies can better predict
the efficacy and/or safety of nanoformulations inside the body, while,
in vitro studies are conducted in a highly controlled condition which
allows better understanding of details and mechanisms. Release profiles
are generally defined in a simulated medium that the formulation is
intended to be used. The medium is usually a buffered solution with
pH = 7.4, simulating release in body fluids, or it can be selected as a
specific medium according to the rout of administration. Lin et al.
(2012) proposed cationic liposome-PEG-PEI complex for encapsulation
of curcumin as an anti-tumor agent. The release profile was conducted
in phosphate buffered saline at 37 °C and showed a sustained release of
90% of curcumin in about 120 h which can result in controlled release
of drug in tumor area (Lin et al., 2012). Liu, Jing, Han, Zhang, and Tian
(2019) examined curcumin-loaded zein nanoparticles for oral delivery
of curcumin. Curcumin release in simulated gastric and intestinal fluids
(SGF and SIF) was evaluated and compared to its free form in ethanol.
They reported controlled release of curcumin from nanoparticles sug-
gesting the formulation as a proper oral delivery carrier for curcumin
(Liu et al., 2019).
Cell culture studies are another category of in vitro studies used for
evaluation of curcumin nanoformulations. These studies are conducted
455
Trends in Food Science & Technology 88 (2019) 445–458
to assess the efficacy and/or safety of formulations inside the living
cells in in vitro conditions. Furthermore, cell culture studies can be
utilized to understand the related mechanisms of action and also to
estimate cell permeability and absorption of formulations as well. As
curcumin has significant anti-tumor efficacy, cell culture experiments
are extensively employed to evaluate the anti-tumor activity and its
related mechanism of action via cellular uptake, cell proliferation,
colony forming assay or cell cycle analysis in different cell lines
(Naksuriya et al., 2014). Yallupa et al. (2010) evaluated the transport
and retention efficiency of curcumin-loaded PLGA nanoparticles in
A2780CP and MDA-MB-231 cancer cell lines. They also used cell cy-
totoxicity studies to evaluate the anti-tumor activity and assessed the
expression of apoptosis associated proteins in both cell lines using im-
munoblot assay. The results showed 2 and 6-fold increase in curcumin
uptake into the metastatic cell lines, compared to free curcumin. De-
tailed experiments showed that the nanoparticles can inhibit the pro-
lifereation and colony formation of cancer cells by enhanced apoptosis
(Yallapu, Gupta, Jaggi, & Chauhan, 2010). However, during in vitro
studies cells are exposed to high static concentrations of curcumin for a
long time and interpretation of the results to the dynamic in vivo con-
centrations may be difficult.
On the other hand, in vivo pharmacokinetic profile of curcumin-
encapsulated nanoformulations can significantly influence the efficacy
of formulations. Tumor Xenograft animal models are generally used to
examine the anti-tumor activity of nanoformulations. Zaman et al.
(2016) studied cellular uptake, cell proliferation, colony forming assay
and cell cycle inhibition of PLGA nanoparticles in cervical cancer cell
lines. They reported up to about 2-fold more accumulation of curcumin
in cervical cancer cells compared to the free form. Curcumin-loaded
nanoparticles could also reduce cell viability and clonogenicity and
induce apoptosis in vitro with superior effects to free curcumin. The
nanoparticles reduced the tumor burden in vivo better than free cur-
cumin and could suppress the expression of HPV oncogenic proteins
and cell proliferation marker in mice. Curcumin-loaded nanoparticles
showed a superior in vitro and in vivo anti-tumor efficacy compared to
free drug (Zaman et al., 2016).
In vitro antibacterial and antifungal activity tests are also used to
evaluate the efficacy of curcumin nanoformulations against proposed
microorganisms including G+ or G-bacteria. Different in vitro methods
are available to assess susceptibility of bacteria to formulations.
Quantitative dilution methods have been widely used to evaluate the
antimicrobial efficacy of curcumin-loaded nanoformulations compared
to the free form (Silva et al., 2018). Krausz et al. (2015) evaluated the
growth inhibitory effects of curcumin nanoparticles on methicillin-re-
sistant S. aureus (MRSA) and P. aeruginosa in vitro. Both free and nano-
encapsulated curcumin showed in vitro antibacterial effects but the re-
sults did not show a significant difference between curcumin in MRSA
isolates, while a significant difference was seen for P. aeruginosa iso-
lates. The in vivo efficacy of formulation was also tested in MRSA-in-
oculated murine wound model. Curcumin nanoformulations sig-
nificantly reduced bacterial counts on days 3 and 7 compared to control
and also free curcumin. The same results were seen considering wound
healing efficacy of formulations (Krausz et al., 2015). Comparison of
the in vitro and in vivo results shows that the results may be correlated or
different depending on study conditions; both type of studies are ne-
cessary and will help us to make better conclusions.
6. Conclusion
Curcumin is a natural compound with polyphenolic nature. This
bioactive ingredient has been proved to have a wide range of functional
and biological activities. In addition to uses as food additives such as
colorant and antioxidant, it is used in remedies purposes.
Nanoencapsulation techniques have been commonly applied to en-
hance the functional properties of curcumin. In according to mentioned
content in different sections of this review, nanoformulations of
Z. Rafiee, et al.
curcumin are potentially useful in the near future for the different bio-
products but there is a need for further studies, especially on cosme-
ceutical and food fields, to give the researchers and industries a broad
range of deeper information. Moreover, creating more economical
scalable methods to nanoencapsulate curcumin is an industrial ne-
cessity for reducing production costs providing better competition with
synthetic additives and drugs. Additionally, there is still a pressing need
to investigate toxicological safety of the curcumin application as a na-
nomedicine for the prevention and treatment of various diseases or/and
as a nanoadditive in the food products. Clinical case-by-case trials can
be suitable to assure general consumption of these novel bio-sub-
stances.
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