Các D NG Nano Curcumin

Critical Reviews™ in Therapeutic Drug Carrier Systems, 30(4), 331–368 (2013)
Nanocurcumin: A Promising Therapeutic

Advancement over Native Curcumin
Gagan Flora,* Deepesh Gupta, & Archana Tiwari
School of Biotechnology, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, M.P., India
*Address all correspondence to: Gagan Flora; Email: gaganflora@gmail.com
ABSTRACT: Curcumin, a naturally occurring polyphenolic compound, is known to have a

wide range of therapeutic and pharmacological properties. Although it is a considerably prom-
ising compound, its poor water solubility and fast degradation profile make it compromise
over its bioavailability way below the threshold level on administration. Over a period of time,
a lot of emphasis has been given to improve the biodistribution of native curcumin, but it is
only recently that the application of the field of nanotherapeutics has significantly improved its
therapeutic efficacy. This is through the development of nanorange formulations of curcumin,
popularly known as the “nanocurcumin.” These attempts have given a strong platform to reap
all the biological benefits from this phytodrug, which was not significantly plausible earlier.
This review gives an insight into the reasons that make nanocurcumin a more therapeutically
advanced drug than its native counterpart. It also discusses various nanometric formulations of
curcumin that have been reported for its controlled and targeted delivery along with a critical
comparison of its therapeutic efficacy with free curcumin. We also summarize the biological
applications, patented technologies, and current status of the ongoing clinical trials related to
nanocurcumin.
KEY WORDS: curcumin, nanotherapeutics, nanocurcumin, bioavailability
I. INTRODUCTION
Over the years, researchers have given considerable emphasis to improve the safety, af-
fordability, and efficiency regarding the prevention and treatment of chronic diseases.
This has led to a widespread attention into the pharmacopoeia of traditional medicines
as a potent therapeutic choice.
Curcumin is one such naturally occurring low molecular weight polyphenol that
is regarded as the principal active agent of the plant turmeric (Curcuma longa) and is
extracted from its rhizome. It has a long history of being used as a nutritional spice,
coloring agent, and food preservative in India, China, and Southeast Asia. This bioac-
tive agent, apart from its condimental properties, has a surprisingly wide range of phar-
macological activities that includes anticancer, antiviral, antifungal, antioxidant, anti-
angiogenic, and anti-inflammatory properties.1–3
Despite having such promising medicinal attributes, use of curcumin as an effective
therapeutic agent is highly limited. This is on account of its poor pharamacodynamic
action in vivo arising due to poor aqueous dispersion in the environment of neutral or
acidic pH, less absorption in gastrointestinal tract, and rapid metabolism to reduced
0743-4863/13/$35.00 ©2013 Begell House, Inc. www.begellhouse.com 331

332 Flora, Gupta & Tiwari
products (di-, tetra-, hexahydrocurcumin and hexahydrocurcuminol) and their glucuro-

nide or sulfate conjugates along with quick systemic elimination (Fig. 1).4–6 Apart from
this, curcumin, being lipophilic in nature, is highly vulnerable to reticuloendothelial
system (RES) uptake and thus is unable to maintain its therapeutic threshold causing a
low systemic bioavailability.7 In order to sustain the required therapeutic concentration,
a high dose of curcumin coupled with repeated administration is needed. Studies con-
ducted by Wahlstrom et al. showed that administration of curcumin at a dose of 1 g/Kg
in rats resulted in 75% excretion of curcumin through feces while a negligible amount
of curcumin appeared in urine. Blood plasma levels and biliary excretion indicated poor
absorption of curcumin from the gut. Besides this, the quantity of curcumin that reached
tissues outside the gut was found to be pharmacologically insignificant.8 Lao et al. re-
ported the occurrence of traces of curcumin and its metabolites in human plasma and
urine at a dose as high as 12 g per day given orally, which clearly suggested poor absorp-
tion of curcumin.9 Thus, in order to reach the therapeutic threshold, a person needs to
take about 12–20 g of curcumin every day. Else, its concentration would become totally
insignificant in the body after ingestion.10 From the perspective of clinical trials, such a
dose is considered too high and thus not feasible.
Nanotherapeutics is an emerging field of medicine that deals with the formulation of
nanoparticle (NP)–based drugs (nanodrugs) and their controlled delivery for treatment
of a wide variety of diseases. These nanodrugs are highly stable owing to their charac-
teristic surface features and optimum size. Moreover, they also possess large carrying
capacity and can overcome the aforementioned limitations associated with conventional
drugs such as curcumin. Both hydrophilic and hydrophobic drugs can be encapsulated in
nanometric drug carriers that can then be administered through the desired route result-
ing in an improved bioavailability through controlled release of drug from the matrix.11,12
Over a period of time, implementation of nanotherapeutics has suggested numerous
ways to increase the biodistribution of curcumin through the formulation of curcumin-
loaded nanoparticles or “nanocurcumin.” Curcumin has been reported as being encapsu-
FIGURE 1. Chemical structure of curcumin. Curcumin is a member of linear diarylheptanoid

class whose chemical structure is elucidated as 1, 6-heptadiene-3, 5-dione-1, 7-bis-(4-hydroxy-
3-methoxyphenyl)-(1E, 6E). The structure is overall symmetrical having alternatively arranged
single (-C-C-) and double bonds (-C=C-). It is comprised of two phenolic rings (carrying two me-
thoxy and two hydroxyl groups) that are linked via two α,β-unsaturated carbonyl groups. Curcumin
is known to be present in two tautomeric forms: keto and enol. The central part of the enol form
encompasses C=O and C-OH group whereas keto form can have two C=O groups.
Critical Reviews™ in Therapeutic Drug Carrier Systems

Nanocurcumin: A Therapeutic Progress Over Curcumin 333
lated in liposomes,13 biodegradable microspheres,14 chitosan,15 and silk microspheres,16

or complexed with phospholipids.17 Synthesis of curcumin-encapsulated polymeric
NPs by polymerizing N-isopropylacrylamide (NIPAAM) with N-vinyl-2-pyrrolidone
(VP) and poly (ethyleneglycol) monoacryalte (PEG-A) have recently been reported by
Bisht et al.18
This kind of drug delivery system has given very encouraging results thus far. The
nano form of curcumin showed a much higher aqueous dispersion compared to that
of free curcumin, which improved its systemic availability. Nanoencapsulation of cur-
cumin may thus allow improved drug circulation and retention in the body. This not only
reduces the dose but also maintains the threshold level of curcumin thereby transform-
ing its image from a nutritional spice to a clinical medicine.
The review deals with reasons underlying the fact that makes nanocurcumin score
substantially over conventional curcumin in terms of its therapeutic effectiveness. Vari-
ous important formulations that have been reported for the synthesis of nanocurcumin
along with a comparison between the therapeutic profile of curcumin and nanocurcumin
have been incorporated. Biological applications of this novel drug, patented technolo-
gies, and the current status of the ongoing clinical trials are also discussed, suggesting
future directions.
II. PHYSICOCHEMICAL PROPERTIES OF NANOCURCUMIN ENHANCES ITS

BIOAVAILIBILTY IN COMPARISON TO FREE CURCUMIN
Administration of drug into body is done by thoroughly taking into consideration vari-
ous principal factors that include controlling of the rate, time, and location of release of
drug along with its efficacy. All these parameters constitute the pillars of any drug deliv-
ery system and decide the fate and efficiency of any introduced therapeutic substance.
It is observed that conversion of conventional curcumin into the nanometric range sig-
nificantly strengthens its pharmacological effects by providing various features such as
enhanced solubilization, superior biocompatibility, better pharmacokinetic profile, and
controlled drug release.19 These improvements are mainly because of numerous unique
physical and chemical properties that are imparted on conversion of bulk curcumin into
the nano range. These properties include particle size, surface area, hydrophobicity, and
surface charge.20
A. Particle Size
The submicron size of NPs is the single most important physical characteristic that makes
nanocurcumin stand out in terms of its efficacy when compared to free curcumin. This
attribute allows nanocurcumin to reach even those organs where curcumin is virtually
inaccessible. Tsai et al. for the first time conducted a study on rats comparing curcumin
and nanocurcumin in terms of its distribution pattern among different organs after their
intravenous administration. They found that the concentration of curcumin was larger in
liver and kidney than in any other contemporary organ. This was because the systemic
Volume 30, Number 4, 2013

circulation of curcumin in the body is limited since a substantial amount of curcumin

is distributed to the liver and kidney, where it is metabolized and eliminated. However,
on introduction of curcumin NPs, a significant amount of curcumin was found in spleen
and lung. This was credited to the fact that nanoformulation prevented the distribution
of curcumin to major drug metabolizing organs. They also reported that nanocurcumin
significantly increased the curcumin levels in spleen, lung, liver, brain, and kidney com-
pared to free curcumin by increasing half-life and mean residence time.21
Oral uptake of free curcumin compels it to pass through systemic circulation via
portal blood and first-pass metabolism and thus severely hampers its existence. Its nano-
preparation, on the other hand, has been reported to pass systemic circulation with mini-
mizing first-pass metabolism along with escaping endocytosis and phagocytosis, there-
fore improving its bioavailability.21
Nanocurcumin, owing to its size, also adds to its merit the ability of higher intracel-
lular uptake in comparison to conventional curcumin. This property is extremely critical
for targeting the intracellular pathogens in the case of certain infectious diseases. Bisht
et al. reported that polymeric curcumin NPs were robustly taken up by pancreatic cancer
cell lines, which was confirmed by fluorescence microscopy. Furthermore, cell viability
(MTT) assay performed on several pancreatic cell lines demonstrated nanocurcumin’s
comparable efficacy to free curcumin.18 Delivery of curcumin in the nanoscale range
also considerably increases its retention time, circulation time, and mean residence time
in the body.22,23
B. Surface Charge
Surface charge basically represents the electric potential of the NPs, which depends
entirely on its chemical composition. It is observed that NPs with high negative or posi-
tive zeta potential (electrokinetic potential in colloidal systems) are extremely stable in
suspension because these charges avert the aggregation of these particles.24
Curcumin, due to its low solubility in water, aggregates together making it highly
susceptible to opsonization, which involves phagocytosis and eventual clearance of
these aggregates by RES from the body. On the other hand, nanocurcumin due to the
presence of zeta potential disperses entirely in aqueous media forming no aggregates.25
Anitha et al. synthesized curcumin NPs using chitosan and dextran sulphate. The zeta
potential of such particles was found to be reasonably good (–30 mV), which made the
suspension highly stable.26
Formulation of curcumin NPs using inert hydrophilic polymers such as poly(ethylene)
glycol and poly(vinyl)alcohol has also been reported of preventing the aggregation phe-
nomenon on account of its surface charge.27,28
C. Surface Area
Compared to the use of normal curcumin as a drug, its NP formulation has a much larger
surface area. The underlying reason behind this is attributed to its size, which varies

inversely with specific surface area and any reduction in particle size is accompanied by
an increase in surface-to-volume ratio.
The surface area of any nanodrug directly influences its sustained release since it affects
the pharmacokinetics of the drug encapsulated inside the nanocarrier. It was established that
PLGA microspheres exhibit a multiple phase release pattern that constitutes an initial burst
phase followed by a lag phase and a zero-order phase. The initial burst release was accred-
ited to the diffusion of the drug associated with surface and pores. Whereas, the lag phase
and zero-order phase were related to the polymer erosion combined with diffusion.29,30
On similar terms, in vitro release profiles of curcumin from various nanocarriers
such as curcumin-loaded PLGA NPs,21,25,31 curcumin-loaded poly(butyl) cyanoacrylate
NPs,32 curcumin-loaded alginate-chitosan-pluronic composite NPs,15 and curcumin-
loaded dextran sulphate–chitosan NPs26 have suggested a typical biphasic release pat-
tern. Initially, there is a burst release of curcumin for the first 5–12 h. This is followed
by controlled release that can last up to a week.
Temperature and pH also significantly affect the surface area of the nanocarrier
and thus display some control over the pharmacokinetics of loaded curcumin. Lin et
al. studied the in vitro drug release profile of curcumin in curcumin-loaded cationic
liposome-PEG-PEI complex and found that low temperature appreciably hindered the
release of curcumin (10–15% release at 4°C after 120 h), which improved with gradual
increase in temperature (30 and 90% release at 25°C and 37°C, respectively, after 120
h).33 Generally, a faster release of curcumin is observed from its nanocarrier at acidic pH
in comparison to basic pH. But the effect of pH varies with change in the material used
to encapsulate the curcumin.32,34,35
D. Hydrophobicity
The surface charge of the NP alone is not the only factor that has an influence on the re-
lease kinetics of the encapsulated drug. However, it is the collective role of both surface
charge and hydrophobicity of the material that significantly decides its pharmacokinetic
fate. This occurs because hydrophobic drugs such as curcumin have the ability to alter
the degradation kinetics of the polymeric shell of the nanocarrier, which is hydrophilic
in nature. This in turn improves its half-life causing an increment in the biodistribution
of the drug coupled with its efficacy. This approach can also lead to decrement in the
dosage along with reducing the frequency of administration of the drug.36,37
E. Entrapment and Loading Efficiency
The type of carrier system along with the preparation method applied for production of
any nanodrug determines its entrapment efficiency (EE) and loading efficiency (LE).
Entrapment efficiency is the ratio of amount of drug present in the carrier system to the
amount of drug used in the loading process. Whereas drug loading efficiency is the ratio
of drug to the weight of total carrier system.38,39 Both loading and entrapment efficiency
influence the rate and level of drug release from the carrier.

Total amount of drug with in the carrier

EE(%)  100
Initial amount of drug taken for loading studies
Total mass of drug with in the carrier

LE(%)  100
Total mass of the carrier system
A survey of literature available on different formulations of nanocurcumin have

shown a highly remarkable range of loading and entrapment efficiency, which are esti-
mated to be 25% wt/wt and 75–99%, respectively, which makes it a highly competitve
drug delivery system.19
III. NOVEL DELIVERY SYSTEMS FOR CURCUMIN: A NANOTHERAPEUTIC AP-

PROACH
Recent advances in nanotechnology have given a very committed platform to improvise

the existing drug delivery systems. Numerous strategies have been devised to formulate
drug-carrying nanoscale particles that enhance the controlled drug delivery regimes.
Very impressive pharmacokinetic data have been observed so far related to drug-loaded
nanometric particles ranging between 10 and 200 nm in diameter in comparison to the
usual small-scale molecular forms of the drug. A manifold improvement has been ob-
served in terms of prolonged systemic circulation, enhanced biodistribution, sustained
drug release profile, and specific targeting.40–42 Various kinds of nanocarrier platforms
such as liposomes, NPs, microspheres, microemulsions, etc., have been reported of en-
capsulating curcumin.
A. Liposomes
Liposomes are spherical vesicles that are prepared through the self-assembly of amphi-
philic phospholipid molecules in an aqueous environment. The phospholipid molecules
arrange in a closed bilayer structure with an aqueous core (Fig. 2). Lipid bilayer and
aqueous core are proficient in encapsulating lipophilic and hydrophilic pharmaceutical
agent, respectively. The properties of liposomes depends on its method of preparation
and the composition of the lipids.43 Liposomes are highly biocompatible structures that
are chemically versatile in nature, and any slight modification in the chemical composi-
tion of lipid bilayer can substantially alter its pharmacokinetic properties, thereby mak-
ing it a suitable choice for drug delivery systems.44,45
Considering these aforementioned properties of liposomes, they have been widely
used in the past few years as a potent vehicle for ameliorating curcumin’s bioavailability
and efficacy. Diverse forms of liposomal curcumin have been prepared with each one
having its own distinct benefits. Liposome-encapsulated curcumin inhibited head and
neck squamous cell carcinoma growth (HNSCC) in vitro and in vivo. Results also sug-
gested that liposomal curcumin is a viable nontoxic therapeutic agent for HNSCC.13 In

FIGURE 2. General representation of the typically used liposome for encapsulation of curcumin in
the hydrophobic region. Liposomes are self-assembling, closed spherical vesicles that consist of
amphiphilic phospholipid bilayers and an inner aqueous core. The lipid bilayer is capable of car-
rying lipophilic curcumin. The phospholipid moieties form a closed bilayer sphere that shields the
hydrophobic groups from the aqueous phase while still keeping contact the with aqueous environ-
ment through its hydrophilic head groups.
another study, different liposomal formulations of curcumin (LCs) demonstrated very

low toxicity to human lymphocytes, splenocytes, and Epstein-Barr virus–transformed
human B cells in vitro. It was also found that LCs had equal or enhanced immunosup-
pression efficacy and enhanced anti-EBV lymphoma cell line efficacy.46 Lu et al. cre-
ated and characterized liposomal curcumin (CUR-L) and folate receptor (FR)–targeted
liposomal curcumin (F-CUR-L) for superior tumor targeting through folate receptors of
tumor cells. F-CUR-L was found to have better solubility, adequate stability, enhanced
cellular proliferation inhibition, higher apoptosis, and antitumor activity than CUR-L.47
Liposome-encapsulated curcumin was also found to be an effective inhibitor of NF-κB
activity along with restraining of the angiogenesis and augmentation of apoptosis in
vitro and in vivo on a xenograft model of disseminated neuroblastoma.48 Kunwar et al.
confirmed that the liposomal vehicle is capable of loading more curcumin into cells.
Lymphoma cells showed preferential uptake of curcumin to lymphocytes.49
Table 1 summarizes the studies31,51-53 that showed comparatively superior therapeu-
tic efficacy of curcumin-loaded liposomal preparations against free curcumin.
B. Nanoparticles
These drug carriers have a size range of about 1–100 nm and are highly preferred by
researchers because of their ability to bring about targeted drug delivery coupled with

TABLE 1. Studies Showing Comparatively Superior Therapeutic Efficacy of Liposomal

Curcumin over Free Curcumin
Composition Outcome of the Study Reference
Liposome-PEG-PEI complex carrying CUR (LPPC) showed 33
CUR, PEI, PEG intensified cytotoxic activity that was found to be 5-fold
higher than free CUR when tested on curcumin-sensitive
cells and 20-fold more active against curcumin-resistant
cells.
CUR, SLP- Bioavailability, pharmacokinetic profile, and absorption rate 50
WHITE, and of oral liposome-encapsulated CUR (LEC) made of com-
SLP-PC70 mercially available lecithins (SLP-WHITE and SLP-PC70)
was assessed. Formulation of SLP-PC70 and CUR was
found to have better dispersability and entrapment efficien-
cy as compared to the groups of free CUR and a mixture
of CUR and SLP-WHITE. Oral LEC gave higher Cmax and
shorter Tmax values. Moreover, a higher value for the area
under the blood concentration-time curve at all time points
was observed. Enhanced gastrointestinal absorption of
LEC and higher plasma antioxidant activity following oral
LEC was observed compared to free CUR.
CUR, DMPC, Treatment of cells with liposomal curcumin for 24–48 h at 51
DPPC, EGG PC, 37ºC resulted in 70–80% inhibition of cellular proliferation of
and Cholesterol prostate cancer cells (LNCaP) without affecting their viability.
On the other hand, free CUR exhibited similar inhibition only
at 10-fold higher doses.
CUR, DMPC, Liposome-encapsulated curcumin (LC) downregulated the 52
and DMPG NF-κB activity, suppressed growth, and induced apoptosis
of human pancreatic cells in vitro. Antitumor and antiangio-
genesis effects of LC were observed in vivo. The activity of
LC was equal to or better than that of free CUR at equimo-
lar concentrations.
The peak serum concentration 1.5 h after the oral admin- 53
CUR, DMPC, istration of crude CUR at a dose of 50 mg/kg was found to
and resveratrol be 50 ng/ml and the level subsequently decreased sharply.
Whereas the mice given curcumin-loaded liposomes (LC)
at the same dose showed serum concentration of CUR at
100 ng/ml after 1.5 h and this level was stable for up to
4.5 h in the range of 80–90 ng/ml. Moreover, CUR level in
whole prostate tissue was approximately 55 ng/ml after 3 h
for LC, which was 2.5 times higher than that of crude CUR.
CUR: Curcumin, PEI: Polyethylenimne, PEG: Polyethylene glycol, DMPC: Dimyristoyl phospha-
tidylcholine, DPPC: Dipalmitoyl phosphatidylcholine, EGG PC: Egg phosphatidylcholine, DMPG:
1,2-dimyristoyl-sn-glycero-3-phosphoglycerol, Cmax: Maximum concentration of curcumin observed
after its administration, Tmax: Time taken by curcumin to reach Cmax.
substantial improvement in solubility and pharmacokinetic profile. Owing to their small

size, NPs can easily pass through the gastrointestinal tract and can circulate in the blood
stream for a longer duration, which enhances their therapeutic strength. They are also
accredited with high versatility, which arises due to their ability of adding a large num-
ber of properties on a single carrier that is virtually out of scope for conventional drug

delivery systems.54 In addition, they have distinct physical and chemical properties that
allow them to carry large doses of chemotherapeutic agents into the targeted cells.55
By the same token, NPs are being extensively used to exploit the high therapeutic
nature of curcumin that is otherwise overshadowed by its hydrophobic nature. Different
types of NPs can be synthesized by altering the carrier materials. In context to curcumin,
polymeric NPs, solid lipid NPs, magnetic NPs, albumin NPs, and polymeric micelles
have been used for its encapsulation and practical assessment of its therapeutic regime.
1. Polymeric Nanoparticles
In contrast to liposomal nanocarriers, which consist of an aqueous core and a lipid bi-
layer, polymeric NPs are comprised of a solid polymer-filled core that provides a better
platform for carrying hydrophobic drugs (Fig. 3). Generally, polymeric NPs are pre-
pared by self-assembly of amphiphillic diblock copolymers. Drug encapsulation into
them is achieved by the gentle mixing of the drug in the copolymeric solution, which
involves the process of self-assembly of copolymers into well-defined NPs. This is fol-
lowed by physical entrapment of the drug molecules in the polymeric matrix.
Numerous types of biodegradable and biocompatible polymers such as poly(D,L-
lactic-co-glycolic acid), poly(ethylene glycol), and poly(butyl)cyanoacrylate have been
widely investigated for synthesizing polymeric NPs to encapsulate curcumin. Recently,
FIGURE 3. General representation of the typically used polymeric nanoparticle for encapsulation
of curcumin. Polymeric nanoparticles are comprised of a solid polymeric core matrix capable of
encapsulating curcumin. It is attributed with having a dimension range between 1 and 1000 nm
with a high surface-to-mass ratio. A modifiable chemical interface can be included in the organic
layer in order to improve the specificity and interaction of the NP with the biological system.

other polymers such as N-isopropylacrylamide (NIPAAM), chitosan, and silk fibroin

have also shown their caliber to encapsulate curcumin with highly promising results.
Delivery of curcumin-loaded alginate chitosan pluronic NPs (ALG-CS NPs) into
HeLa cell lines were studied. Pluronic F127 significantly enhanced the solubility of
curcumin in the ALG-CS NPs. Encapsulation efficiency of curcumin in composite NPs
showed considerable increase over ALG-CS NPs without pluronic. The half-maximal
inhibitory concentrations for free curcumin and encapsulated curcumin were found to
be 13.28 and 14.34 µM, respectively.15 Anitha et al. prepared curcumin-loaded dextran
sulphate chitosan NPs and found that the drug entrapment efficiency was ~74%, and
around 70% of curcumin was released after 120 h. In vitro drug release studies showed
a controlled and pH-dependent curcumin release over a period of one week.26 In another
study, the synthesized curcuminoids-loaded poly(butyl) cyanoacrylate NPs (C-PBCA)
coated with poloxamer 188 illustrated remarkable chemical and physical stability. They
entrapped curcumin effectively, and that too in molecularly dispersed form. The in vitro
release study revealed the controlled drug release profile for a comprehensive period of
time with higher drug release in acidic media.32 Another group formulated and physi-
cochemically characterized stable thermoresponsive nanoconstructs of curcumin using
chitosan-g-(N-isopropylacrylamide) nanocarrier (TRC-NPs). The in vitro drug release
of TRC-NPs was prominent at above the lower critical solution temperature (LCST).
Cytocompatibility of the NPs was proved by MTT assay. The drug-loaded TRC-NPs
showed specific toxicity on cancer cells. Flow cytometric analysis of curcumin-loaded
TRC-NPs showed increased apoptosis on PC3 cells.56
A similar preventive efficacy of silk fibroin (SF)– and silk fibroin-chitosan (SFCS)–
derived curcumin NPs were shown by Gupta et al. Curcumin-polymer conjugates were
tested for efficacy against breast cancer cells. The entrapment and release of curcumin
over eight days was highest for SF-derived NPs as compared to all SFCS blends. The
uptake and efficacy of SF-coated curcumin was significantly higher than SFCS-coated
curcumin in both low and high Her2/neu–expressing breast cancer cells. In conclusion,
SF-derived curcumin NPs showed higher efficacy against breast cancer cells.16 An ex-
cellent in vitro therapeutic efficacy of PBCA nanoparticles coated with chitosan was also
reported against human hepatocellular cancer cell lines. In the same study, hepatocel-
lular carcinoma growth in murine xenograft models and tumor angiogenesis were also
found to be suppressed.57
In a recent study, binding of curcumin on the surface of gold nanoparticles (AuNPs)
was carried out, which considerably increased its antioxidant activity.58 In a similar
work, water-soluble curcumin–conjugated AuNPs were prepared through a one-shot
process, which was later modified by conjugating them to folate–PEG. These modified
AuNPs exhibited better dose dependent toxicity toward different cell lines compared to
free curcumin.59
Kumar et al.60 for the first time provided an approach using curcumin-loaded chi-
tosan NPs for its targeted delivery to deep lung by extratesticular sertoli cells. It was
reported that ~90% of the curcumin load delivered in the injected sertoli cells was dis-
tributed throughout the lungs, including the perialveloar sac area in the lower lungs.60

Furthermore, Anitha et al.61 administered curcumin in a carboxymethyl chitosan (CMC)

derivative, N,O-carboxymethyl chitosan (N,O-CMC). Curcumin-loaded N,O-CMC
(CUR-N,O-CMC) NPs displayd a selective toxicity profile toward cancer cells in cyto-
toxicity studies by MTT assay. The cellular uptake of CUR-N,O-CMC NPs was nonspe-
cific, which was confirmed by fluorescence microscopy and was reconfirmed by flow
cytometry.61
Table 2 shows a list of studies18,31,62–65 that showed comparatively superior therapeu-
tic efficacy of curcumin-loaded nanoparticles over free curcumin.
2. Solid Lipid Nanoparticles (SLNs)
These are the submicron colloidal particles made up of natural or synthetic lipid dis-
persed in water or in aqueous surfactant solution (Fig. 4). Lipids used can be highly
purified triglycerides, complex glyceride mixtures, or even waxes.66 Curcumin can be
dissolved or dispersed in the solid core made up of high melting fat matrix and the
hydrophobic end of phospholipid chains. The mean particle diameter of SLNs ranges
from 50 to 1000 nm. SLNs can be administered through various routes such as oral,
parenteral, rectal, ophthalmic, and topical.67 They have numerous advantages such as
low toxicity profile, good biocompatibility, controlled release of the incorporated drug,
long-term stability, and prevention of drug from chemical degradation.68 Various SLN
formulations have been reported for encapsulating curcumin.
In one study, curcumin-loaded SLNs were developed with an aim of enhancing bio-
availability and investigating its therapeutic effects through treatment of biochemical,
behavioral, and histopathological changes induced after oral administration of AlCl3 in
mice. This study for the first time established the curative-therapeutic role (rather than
a mere protective role) of curcumin in Alzheimer’s disease–like symptoms.69 Another
formulation of curcumin-loaded SLNs augmented the therapeutic efficacy of curcumin in
an ovalbumin (OVA)–induced allergic rat model of asthma. Compared to the curcumin-
treated group, administration of curcumin-SLNs into asthmatic rats significantly reduced
the airway hyperresponsiveness and the number of inflammatory cells in lung tissue.70
Table 3 summarizes the studies71–74 that showed comparatively superior therapeutic
efficacy of curcumin-loaded SLNs against free curcumin.
3. Magnetic Nanoparticles (MNPs)
Introduction of MNPs can be regarded as one of the finest examples of the extent of
robust flexibility the field of nanotherapeutics offers. These particles are comprised of a
metal or metallic oxide core encapsulated inside a polymer or inorganic metal coating
that can be functionalized.75 It is this coating that ensures the stability and biocompat-
ibility of the MNP (Fig. 5). This kind of drug delivery involves the use of an external
magnetic field to guide the labeled drug to the target tissue, which assures site-specific
delivery thus improving its efficiency and reducing toxic side effects.76 Curcumin has
been reported as being encapsulated in a few magnetic nanoconstructs.

TABLE 2. Studies Showing Comparatively Superior Therapeutic Efficacy of Curcumin-

Loaded Nanoparticles over Free Curcumin
CUR, The polymeric NPs displayed comparable efficacy to free CUR 18
NIPAAM, VP, against pancreatic cancer cell lines in vitro. Further, studies
and confirmed that nanocurcumin retained the mechanistic specific-
PEG-A ity of free CUR, inhibiting the activation of the seminal transcrip-
tion factor NF-κB, and reducing steady state levels of proinflam-
matory cytokines such as interleukins.
CUR and Encapsulated CUR existed in a highly dispersed state in the 31
PLGA NPs and exhibited good solid-solid compatibility. This nanofor-
mulation demonstrated 2- and 6-fold increases in the cellular
uptake in cisplatin-resistant A2780CP ovarian and metastatic
MDA-MB-231 breast cancer cells, respectively, with improved
anticancer ability compared to free CUR.
CUR, PLGA, PLGA NPs enhanced the bioavailability of CUR by 9-fold on 37
and PVA account of sustained release and longer residence time in vivo
when compared with crude CUR administered with piperine as
an absorption enhancer.
CUR, PLGA, CUR-PLGA NPs formulation showed enhanced cellular uptake 62
and PEG- and increased bioactivity in vitro and superior bioavailability in
5000 vivo over free CUR. In vitro, these NPs exhibited very rapid and
efficient cellular uptake compared to CUR. Encapsulated CUR
was as potent as free CUR in inducing apoptosis of leukemic
cells. In mice, nanocurcumin had better bioavailability along
with a longer half-life than free CUR.
CUR, PBCA, Enhanced accumulation of CUR-loaded PBCA NPs coated with 63
and polysor- polysorbate 80 in brain tissue was observed, which was 2.53
bate 80 times that of the control solution. CUR concentrations in brain
tissues for the control group could not be determined 3 h af-
ter administration. However, at 8 h, the concentration of CUR
in brain tissues for the CUR-loaded PBCA NPs group was still
higher, indicating a superior performance of PBCA NPs over
free CUR.
CUR, PLGA, CUR-loaded PLGA and PLGA-PEG NPs were formulated and 64
and PEG they increased the CUR mean half-life by 4 and 6 h, respective-
ly. Cmax of curcumin increased by 2.9- and 7.4-fold, respectively.
PLGA and PLGA-PEG NPs increased the CUR bioavailability
by 15.6- and 55.4-fold in comparison to free CUR.
Superior anticancer profile of CUR-loaded PLGA NPs was 65
demonstrated by cell proliferation and clonogenic assays. A 2-
CUR and and 6-fold increase in the cellular uptake was reported in cispl-
PLGA atin-resistant ovarian cancer cells and metastatic breast cancer
cells, respectively. Moreover, cystic fibrosis defects in a mice
model were cured by CUR PLGA NPs on account of improved
bioavailability as compared to free CUR
CUR: curcumin, NIPAAM: nisopropylacrylamide, VP: N-vinyl-2 pyrrolidone, HA: hyaluronic
acid, PEG-A: poly(ethyleneglycol)monoacrylate, PLGA: poly (lactide-co-glycolide), PEG:
polyethylene glycol, PVA: polyvinyl alcohol, pBCA: Polybutylcyanoacrylate, ApoE3: apolipopro-
tein E3, Cmax: maximum concentration of curcumin observed after its administration, Tmax: time
taken by curcumin to reach Cmax.

FIGURE 4. General illustration of the typically used solid lipid nanoparticle for encapsulation of
curcumin. SLNs are spherical nanometric particles having a size range of 50 to 1000 nm. They
are comprisd of a matrix made up of solid physiological lipids dispersed in an aqueous surfactant
solution. It is this matrix that constitutes the core of the SLN and incorporates curcumin in highly
dispersed form.
In an attempt to formulate curcumin-loaded magnetic NPs, encapsulation of cur-

cumin in supermagnetic magnetic porous silica was done, which ensured a targeted and
sustained release mechanism under physiological pH with high magnetic mobility.76 An-
other group explored the efficacy of curcumin conjugated with poly(ethylene glycol)-
assisted magnetic iron oxide NPs. The system represented an architecturally appealing,
magnetically responsive bioconjugated system possessing synergistic participation of
the partners, with prospective applications in the medical domain.77
4. Albumin Nanoparticles
Human serum albumin (HSA) is regarded as the most abundant and highly versatile
plasma protein that carries out various important biological activities of the body.78 It
acts as a natural carrier of numerous hydrophobic molecules such as fatty acids, hor-
mones, and fat-soluble vitamins. Recently, a good deal of focus has been given to ex-
plore the possibility of exploiting albumin in improving the pharmacokinetic profile of
hydrophobic drugs mainly because of its nontoxic and non-immunogenic nature.79


Loaded Solid Lipid Nanoparticles over Free Curcumin
CUR, Polysorbate 80, In vivo pharmacokinetic investigations performed after 71
soy lecithin, and water oral administration of CUR-loaded SLN (C-SLNs) and
free CUR in rat plasma revealed significant improve-
ment in bioavailability done by C-SLNs (39 times at 50
mg/kg; 155 times at 1 mg/kg; 59 and 32 times at 12.5
and 25 mg/kg, respectively) with respect to free CUR.
CUR, transferrin, The cytotoxicity and cellular uptake of transferrin- 72
HSPC, DSPE, chol, conjugated CUR SLN (Tf-C-SLN) was found to be
triolein, and poloxamer increased considerably as compared to CUR solu-
188 bilized surfactant solution (CSSS) and CUR-loaded
SLN (C-SLN). Flow cytometric studies revealed the
enhanced anticancer activity of Tf-C-SLN compared
to CSSS and C-SLN. Apoptosis was the mechanism
underlying the cytotoxicity.
Curcuminoids, polox- In vitro release studies showed a prolonged release of 73
amer 188, AOT, stearic curcuminoids from the SLNs (up to 12 h). This study
acid, and GMS also showed that the stability of curcuminoids-loaded
SLNs was significantly improved as compared to free
curcuminoids in the cream formulation.
CUR, Lauroglycol FCC, A novel liquid SEDDS consisting of Lauroglycol FCC, 74
Labrasol and Transcutol Labrasol and Transcutol HP as an oil phase, a sur-
HP and Aerosil 200 factant and a cosurfactant, respectively, was formu-
lated and further developed into a solid SEDDS by a
spray-drying technique using Aerosil 200 as the solid
carrier. This solid SEDDS gave a faster in vitro dis-
solution rate than the crude powder. It also allowed a
significant improvement in CUR bioavailability in rats
after oral administration compared to a crude powder
suspension formulation.
CUR: curcumin, HSPC: hydrogenated soya phosphatidylcholine, DSPE: distearoyl phos-
phatidyl ethanolamine, chol: cholesterol, AOT: dioctyl sodium sulfosuccinate, GMS: glyceryl
monostearate, SEDDS: self-emulsifying drug delivery system
Kim et al. described the preparation of curcumin-loaded HSA NPs (CCM-HSA-NPs)

along with carrying out its physicochemical and pharmaceutical characterizations. The
CCM-HSA-NPs showed greater water solubility, which was 300-fold that of curcumin.
In vivo study revealed preferential uptake of CCM-HSA-NPs by tumors leading to its
high concentration. The antitumor activity of CCM-HSA-NPs was also evaluated over
tumor growths and body changes in nude mice for a period of 18 days. It was found
that CCM-HSA-NPs administered at a dose of 10 mg/kg intravenously for 10 days sup-
pressed the tumor growth (HCT 116 or MiaPaCa2) by 52 or 64% at day 10, and by 47
or 58% at day 18, respectively. On the other hand, only 18 or 26% at day 10, and 18 or
25% at day 18 for free CUR was observed, respectively.80

FIGURE 5. General representation of the typically used magnetic nanoparticle for encapsulation
of curcumin. MNPs range from 1 to 100 nm in size and are comprised of a solid magnetic core that
is generally made of iron oxide encapsulated inside a polymeric shell or inorganic metal coating.
The metallic core is bound to curcumin and is responsible for its delivery. An MNP is concentrated
in the targeted area of the body by means of a magnetic field that ensures its site-specific delivery.
C. Polymeric Micelles
These kinds of NPs are composed of polymeric chains that are formed by the spontane-
ous self-assembly of the polymeric segments in liquid arising as a result of hydrophobic
or ion pair interactions between them. Its structure encompasses a hydrophobic core and
an outer hydrophilic shell. It is the core that carries therapeutic drugs such as curcumin,
while the shell is responsible for its interaction with the solvent (Fig. 6).81,82 Polymeric
micelles carrying drugs have high water solubility, high drug loading capacity, and lon-
ger circulation in blood.83
Curcumin-loaded pluronic/polycaprolactone micelless were created that exhibited
better loading efficiency and sustained release, and displayed superior performance
through in vitro cytotoxicity and cellular uptake in Caco2 cells compared to its native
free curcumin.84 Ma et al.85 prepared injectable CUR-loaded polymer micelle by means
of poly-(ethylene oxide)-b-poly(e-caprolactone) (PEO-PCL). PEO-PCL micelle-encap-
sulated curcumin retained its cytotoxicity in B16-F10 mouse melanoma cell line, SP-53,
Mino, and JeKo-1 human mantle cell lymphoma cell lines. Even after 96 h, the level of
drug release or micellar internalization provided enough drug concentration within the
cell for a similar effect to that of free curcumin.85
efficacy of curcumin-loaded polymeric micelles against free curcumin.

FIGURE 6. General representation of the typically used polymeric micelles for encapsulation of
curcumin. Polymeric micelles are made up of an amphiphilic block or graft copolymers that pro-
vide it with a core-shell structure with a size range of 10 to 200 nm. The core forms the hydro-
phobic domain and is responsible for encapsulation of curcumin, while the shell constitutes the
hydrophilic domain.
D. Microemulsions and Nanoemulsions
Microemulsions and nanoemulsion are attributed with having a number of properties

that make them a competent choice for their use as a vehicle for targeted drug delivery.
These are essentially made up of two different immiscible liquid phases (generally oil
and water) that are stabilized with the aid of a surfactant that may be in conjunction
with an additional cosurfactant.90 They are usually isotropically clear dispersions with
a size range of 5–100 nm (Fig. 7). They are acknowledged with possessing high ther-
modynamic stability and high solubilization characteristics, with improved drug release
kinetics.38 Attempts have been made to improve the therapeutic aspects of curcumin by
encapsulating it in various microemulsion carriers.
Wang et al.91 used a mouse ear inflammation model to demonstrate the enhanced
anti-inflammation activity of curcumin encapsulated in O/W emulsions prepared from
triacylglycerols (MCT) as oil and Tween 20 as emulsifier. The mean droplet size of the
emulsion ranged from 618.6 to 79.5 nm. There was a 43% and 85% inhibition effect
on 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced edema of mouse ear for 618.6
and 79.5 nm 1% curcumin O/W emulsions, respectively. Negligible effect was found
for 1% curcumin in 10% Tween 20 water solution.91 In another finding, exposure to cur-
cumin-containing microemulsions had cytotoxic effects, but the addition of ultrasound


Loaded Polymeric Micelles over Free Curcumin
CUR and MPEG- The CUR/MPEG-PCL micelle rendered CUR completely 86
PCL dispersible in water and slowly released CUR in nine days
(only 54.6% release of CUR was observed from the mi-
celle). Cur/MPEG-PCL micelles inhibited the growth of
C-26 colon carcinoma more effectively than free CUR
through inhibiting angiogenesis and directly killing cancer
cells. Encapsulation of CUR in MPEG-PCL micelles also
improved the pharmacokinetics of CUR (t1/2, AUC(0–∞) and
Cmax for the CUR/MPEG-PCL micelle were 1.74, 6.02, and
1.41 times that for the free CUR, respectively).
CUR, A 1000- to 2000-fold increment in the aqueous solubility 87
Zein F-6000, Me- and around 6-fold enhancement in stability of PEG-zein
thoxy PEG succin- formed stable micelles was noted. Micellar CUR showed
imidyl a sustained drug release for 24 h coupled with significantly
succinate higher cell uptake than free CUR in drug-resistant NCI/
ADR-RES cancer cells in vitro. Moreover, a noteworthy,
3-fold reduction in IC50 value of CUR was evidenced by mi-
cellar formulations of CUR.
CUR, PLGA, and Biodistribution studies in mice showed that the PLGA-PEG- 88
PEG PLGA micelle formulation promoted enrichment of CUR in
lung, brain, and kidney and decreased drug uptake by the
liver and spleen. In brain, 4 h after the administration, drug
concentrations for micelles reached a peak value of 161.9
ng/g, which was 6.28-fold that of CUR solution (25.8 ng/g). In
addition, plasma AUC(0–∞), t1/2α, t1/2β, and MRT of CUR micelles
were increased by 1.31-, 2.48-, 4.54-, and 2.67-fold compared
to the CUR solution, respectively.
CUR, Pluronic P123, The in vitro cytotoxicity assay showed that CUR-loaded 89
and Pluronic F68 mixed micelles (Cur-PF) composed of Pluronic P123 (P123)
and Pluronic F68 had higher cytotoxic effects on MCF-7
and MCF-7/ADR cells. The concentration of curcumin in
CUR-PF micellar solution was about 3.02 mg/mL, which
significantly increased the solubility of CUR compared to
the free drug (11 ng/mL). Compared to free CUR, higher
growth inhibition of CUR-PF in the sensitive and multidrug-
resistant cells were observed.
MPEG-PCL: monomethoxy poly(ethylene glycol)-poly(ε-caprolactone), PLGA: poly- (D,L-
lactide- co-glycolide), PEG: poly-(ethylene glycol), Cmax: maximum concentration of curcumin
observed after its administration, Tmax: time taken by curcumin to reach Cmax¸ AUC (area under
curve of the drug concentration time profile): extent of bioavailability, t1/2: terminal half-life of
curcumin, IC50: half-maximal inhibitory concentration of curcumin.
waves strongly enhanced those effects, especially on oral squamous cell carcinoma cell
line OSCC-25. It was suggested that the effect of sound on the release of curcumin may
help to maintain its effective concentration for chemotherapy, especially for the more
aggressive cell lines.92 An improvement in the skin permeation ability of curcumin was
seen through its delivery in the form of an oil-in-water microemulsion assembled using
lecithin and Tween 80 as surfactants and ethyloleate as the oil phase.93

FIGURE 7. General representation of the typically used microemulsion for encapsulation of cur-
cumin. Microemulsions are isotropically clear and thermodynamically stable mixtures of two im-
miscible liquids such as oil and water having a size range of approximately 10 to 100 nm. These
mixtures are stabilized using surfactants and cosurfactants. They are biphasic, having a hydro-
phobic phase that carries curcumin together with a hydrophilic phase.

efficacy of curcumin-loaded micro- and nanoemulsions against free curcumin.
E. Solid Dispersion (SD)
Solid dispersion is essentially a molecular dispersion of two different compounds; usu-

ally a hydrophobic drug such as curcumin entrapped in an inert hydrophilic carrier or
matrix in a solid state.99 On exposure to aqueous media, solid dispersion dissolves fa-
cilitating the release of the drug in the form of fine colloidal particles. This kind of
formulation reduces the particle size to nano range with improved wettability leading to
an enhancement in pharmacokinetic profile and biodistribution of the drug. Solid dis-
persions can be prepared by any of the methods such as solvent-based, fusion-melt, and
hybrid fusion-solvent methods.100
Paradkar et al. formulated a preparation of curcumin–PVP K30 (PVP) solid dis-
persions by a spray drying method to improve dissolution of curcumin in acidic me-
dium. Physical characterization studies revealed that in comparison to corresponding
physical mixtures, the modifications in solid state during the formation of disper-
sion justified the formation of the high-energy amorphous phase. Dissolution studies
of curcumin and its physical mixtures showed negligible release even after 90 min.


Loaded Micro- and Nanoemulsions over Free Curcumin
Composition Outcome of the Study References
CUR, Capryol 90, The optimal formulation of microemulsion, which con- 94
Cremophor RH40, sisted of Capryol 90 (oil), Cremophor RH40 (surfac-
and Transcutol P tant), and Transcutol P aqueous solution (cosurfactant),
enhanced the solubility of CUR up to 32.5 mg/mL. The
relative bioavailability of CUR in microemulsions was
22.6-fold higher than that in suspension.
CUR, propylene gly- The prepared SMEDDS when diluted with water formed 95
col, ethyl oleate, and a nanoemulsion of CUR that had markedly enhanced
Cremorphor solubility (21 mg/g of CUR in SMEDDS) in conjunction
with better dissolution in vitro (more than 95% of CUR
in SMEDDS dissolved in pH 1.2 or 6.8 buffer solutions
in 20 min, while less than 2% of crude CUR within 60
min did the same). After 24 h the absorption of CUR
in SMEDDS by the intestine of rats was found to be
93.8%, which was distinctly higher than CUR suspen-
sion by 3.86 times.
CUR, Cremophor EL: The release of about 80% of CUR from CUR-SMEDDS 96
Labrasol (1:1), and in liquid and SMEDDS pellet forms was observed that
mixtures of oil: Labra- was 16-fold greater in comparison to the unformulated
fac PG and Capryol CUR. Pharmacokinetic studies in rats revealed that
90 (1:1). both liquid and pellet SMEDDS showed 14- and 10-fold
greater absorption, respectively, of CUR compared to
the same oral dose of the CUR aqueous suspension.
CUR, ethanol, Cre- A drastic improvement in the relative oral bioavailability 97
mophor, and isopropyl of SMEDDS by 1213% compared with CUR suspension
myristate, was observed.
CUR, Gelucire 44/14, SNEDDS curcumin formulation significantly improved 98
Labrasol, Vitamin E functional and behavioural alterations by causing re-
107 TPGS, PEG 400, duction in motor nerve conduction velocity (MNCV) and
citric acid anhydrous, nerve blood flow (NBF). Biochemical parameters such
and HPMC E5 as depletion of antioxidant enzymes and enhanced lipid
peroxidation was successfully annulled by SMEDDS
in comparison to native curcumin. Deficits related to
inflammatory proteins (NF-κB, IKK-β, COX-2, iNOS,
TNF-α and IL-6) were also effectively improved by
SMEDDS better than free curcumin.
SMEDDS: self-microemulsifying drug delivery systems, SNEDDS: self-nanoemulsifying drug
delivery system, TPGS: tocopheryl polyethylene glycol succinate, PEG: poly-(ethylene glycol),
HPMC: hydroxypropyl methyl cellulose
Whereas, solid dispersion showed complete dissolution within 30 min.101 In another

effort, a curcumin nanosuspension (CUR-NS) was prepared that enhanced the solubil-
ity of curcumin by 600-fold with respect to its crude counterpart. CUR-NS showed
amplified cytotoxicity in HeLa and MCF-7 cells compared with the curcumin suspen-
sion.102
Table 6 summarizes the studies103–105 that showed comparatively superior therapeu-
tic efficacy of a curcumin-loaded solid dispersion against free curcumin.

F. Nanospheres and Microcapsules
Since the past decade, significant advancement has been done in the ways drugs are be-
ing administered. The improvements have considerably made organ-targeted delivery
highly feasible in combination with sustained drug release kinetics. Nanospheres and
microcapsules form an integral part of this league that have been prepared exclusively
with the aim of controlled drug delivery for an extended period of time.106 Although the
terms nanosphere and microcapsule are used synonymously, they have a minute differ-
ence. Nanospheres are strictly solid matrix particles in which the principal ingredient
(drug) is blended, whereas a microcapsule is comprised of an inner core and an outer
polymeric shell. The inner core, just like a nanosphere, is the carrier of drug (Fig. 8).107,108
Curcumin was successfully accumulated in hollow microcapsules with polyelectro-
lyte multilayer shells. Cytotoxicity studies conducted on L929 cell lines to evaluate the
TABLE 6. Studies Showing Comparatively Superior Therapeutic Efficacy of Curcumin

Solid Dispersions over Free Curcumin
CUR, Polystyrene Nanocrystal SD (CSD-Cur), amorphous SD (ASD-Cur), and 103
beads, HPMC-AS, nanoemulsion (NE-Cur) were prepared. Both SDs (20 mg
Dioxane, PEG400, CUR/kg) were 3- to 5-fold higher in Cmax and AUC values
PG, Tween 80 of plasma CUR levels than CUR (100 mg/ kg). Whereas,
similar Tmax and half-lives were observed for CUR and SDs.
Dissolution study results showed that both SDs gave a pro-
longed release of CUR, as compared with NE-Cur and free
CUR. A 12- (ASD-Cur), 16- (CSD-Cur), and 9-fold (NE-Cur)
increase in oral bioavailability was reported when compared
with CUR alone.
CUR and Solutol Pharmacokinetic study of the SD formulation in rat showed 104
HS15 that bioavailability, solubility and dissolution of the drug was
significantly improved as compared to pure CUR. The in
vivo performance of 1:5 SD and 1:10 SD formulations was
compared to that of pure CUR. There was significant statis-
tical difference between the Cmax value of the pure CUR and
1:10 SD. The increment was approximately 6-fold from 1:10
SD as compared to pure CUR. AUC0–12h was increased by
approximately 5-fold in the case of 1:10 SD as compared
to pure CUR.
CUR and Cellulose The SD consisting of CA brought about the transformation 105
acetate (CA) of CUR from the crystalline to the amorphous state with in-
creased solubility. The water insolubility of the carrier ef-
fectively controlled the drug release. Sustained-release
profiles of CUR from the SDs were ideally controlled in vitro
up to 12 h. The optimized formulation provided improved
pharmacokinetic parameters (Cmax = 187.03 ng/ml, tmax =
1.95 h) in rats as compared to pure drug (Cmax = 87.06 ng/
ml, tmax = 0.66 h).
HPMC-AS: hydroxypropyl methylcellulose acetate succinate, PEG 400: polyethylene gly-
col 400, PG: propylene Glycol, Cmax: maximum concentration of curcumin observed after its
administration, Tmax: time taken by curcumin to reach Cmax¸ AUC (area under curve of the drug
concentration time profile): extent of bioavailability

FIGURE 8. General representations of the typically used microcapsule and microsphere for en-
capsulation of curcumin. Microcapsules are comprised of a solid or liquid core carrying curcumin
that is bordered by a polymeric shell. Whereas microspheres are solid polymeric particles having
curcumin embedded in its matrix. Both the formulations have a size in range of 1–1000 mm.
bioactivity of released drug revealed that microcapsules were cytocompatible while the
extract of capsules loaded with curcumin showed severe cytotoxicity on mouse fibro-
blast cells, indicating that the released curcumin was active.109 Another group reported
that curcumin retained the broad spectrum inhibitory activity of the curcumin after the
microencapsulation process against food-borne pathogens and spoilage microbes, such
as E. coli, Y. enterocolitica, S. aureus, B. subtilis, B. cereus, A. niger, P. notatum, and S.
cerevisiae. The maintenance inhibition ratio of microcapsule curcumin was about 85%,
the maximum value 90.8 ± 0.97% was that of microcapsule curcumin against A. niger,
while the minimum value 80.6 ± 4.25% was against E. coli. Its antibacterial activity was
more pronounced against gram-positive bacteria than gram-negative bacteria. Further-
more, its antifungal activity was found better than its antibacterial activity.110 Mukerjee
et al. prepared curcumin-loaded nanospheres that were found to be smooth and spheri-
cal, exhibiting high yield and drug-entrapment efficiency. The in vitro curcumin release
studies from the nanospheres showed that curcumin was released in a sustained manner
over a prolonged period of time. Intracellular uptake and cell viability assays also dem-
onstrated efficient uptake and high efficiency in arresting cell growth as compared to free
curcumin in prostate cancer cell lines. Nanospheres were able to inhibit NF-κB function
to a greater degree as compared to free curcumin.25 In a recent study, curcumin-loaded
lipid-core nanocapsules (C-LNCs) were synthesized with the aim to improve the anti-
glioma activity of curcumin in vitro and in vivo. The cytotoxicity of C-LNC was found to
be equivalent with nonencapsulated curcumin only after 96 h against C6 cells, whereas
C-LNCs were more cytotoxic than nonencapsulated curcumin after 24 h of incubation in
U251MG cells. In rats bearing C6 gliomas, C-LNC (1.5 mg/kg/day, i.p.) decreased the
tumor size and malignance and prolonged animal survival when compared to the same

dose of nonencapsulated drug.111 The same formulation was assessed for its defensive ac-
tion against cigarette smoke–induced cognitive impairment. It was seen that both free and
C-LNC were efficient in reversing the decrement of Na+, K+-ATPase, and Ca2+-ATPase
stimulated by cigarette smoke exposure. Remarkably, owing to superior bioavailability,
a low dose (4 mg/kg) of C-LNC reproduced results similar to that of higher doses of free
curcumin. C-LNC was also effective in treating oxidative stress that was a consequence
of cigarette smoke–induced damage to antioxidant defense systems.112
G. Miscellaneous Preparations
To improve the overall therapeutic profile of curcumin, continuous research efforts are
devising novel strategies for administration of curcumin with improved efficacy. Apart
from the aforesaid strategies, researchers have explored numerous other possibilities to
improve the biological activity of curcumin. These include the use of hybrid nanogels,
hydrogel NPs, metallocomplexes, nanodisks, yeast cells, etc.
1. Nanogels
Wu et al. reported the synthesis of curcumin-containing water-dispersible hybrid nano-

gels by coating the Ag/Au bimetallic NPs with a hydrophobic polystyrene (PS) gel layer
as the inner shell and a subsequent thin hydrophilic nonlinear poly(ethylene glycol)
(PEG)–based gel layer as the outer shell for intracellular delivery of hydrophobic cur-
cumin. These multifunctional hybrid nanogels were found to be compatible for in vivo
studies and clinical trials.113 In another study, Dandekar et al. investigated the prepara-
tion of hydrogel NPs using a combination of hydroxylpropyl methyl cellulose and poly-
vinyl pyrrolidone for utilization in antimalarial therapy and toxicological evaluation. In
vivo antimalarial studies showed significant activity of CUR-loaded hydrogel nanopar-
ticles over crude curcumin when mice were administered orally at the dose of 25 mg/
kg body weight.114 Recently, curcumin-loaded chitin nanogels (CCNGs) were shown as
having the ability to treat skin cancer115 (Fig. 9).
2. Nanodisks
Ghosh et al. discussed the formulation and characterization of nanodisks (nanoscale

disk-shaped phospholipid bilayers whose edge is stabilized by apolipoproteins) synthe-
sized from bioactive polyphenol curcumin at 6:1 phospholipid-to-curcumin molar ratio.
These nanodisks had the potential to solubilize curcumin and indicated having potent in
vivo therapeutic applications116 (Fig. 9).
3. β-Cyclodextrin–Curcumin Complexes
A novel poly (β-cyclodextrin)/curcumin self-assembly was described to enhance cur-

cumin’s water solubility, stability, and bioavailability for improving its anticancer

FIGURE 9. Miscellaneous drug delivery formulations for curcumin. (a, b) Nanogel formulations
(hybrid and hydrogel) are highly cross-linked porous structures essentially made up of hydrophilic
polymers with a diameter in the range of 10 to100 nm. The pores of the nanogel act as the carri-
ers of curcumin and its release can be controlled through various mechanisms depending on pH
response, thermoresponse, and photochemical degradation response. (c) Yeast cells (Saccharo-
myces cerevisiae) can carry curcumin integrated in its cell membrane and hydrogen bonded with
the permeable cell wall. (d) Nanodisks are disk-shaped structures made up of phospholipids car-
rying curcumin in their core. Their size ranges up to 50 nm and is stabilized by an apolipoprotein
scaffold.
efﬁcacy to treat prostate cancer. The new complex was said to be highly useful for
bringing about improvements in the biological action and therapeutic efficacy of cur-
cumin against prostate cancer.117 The same authors in another investigation reported the
effectiveness of (β-cyclodextrin)/curcumin self-assembly as an anticancer agent. The
formulation showed solubility of 1.84 mg/ml as against 20 μg/ml for crude curcumin in
phosphate buffered saline solution. Apart from this, cyclodextrin-curcumin preparations
showed increased uptake of curcumin in prostate cancer cells with superior therapeutic
efficacy compared to free curcumin.118

4. Yeast Cell–Encapsulated Curcumin
Paramera et al. reported the encapsulation of curcumin inside the cell membrane of
Saccharomyces cerevisiae and some part was found to be hydrogen bonded with the
cell wall.119 In another investigation, the stability of yeast cell–encapsulated curcumin
was evaluated with regard to environmental factors such as light, humidity, and heat.
It was found that yeast cells appreciably confined curcumin from detrimental effects
of light, as well as from oxidative degradation at elevated relative humidity120 (Fig. 9).
5. Curcumin Metallocomplexes
Barik et al. reported the preparation of two stoichiometrically different copper (II) com-
plexes of curcumin (1:1 and 1:2 for copper:curcumin). On the basis of the structure of
the two complexes, they were found to possess different superoxide dismutase (SOD)
activities, free radical neutralizing abilities, and antioxidant potentials.121
IV. STABILITY OF NANOCURCUMIN
Maintaining the stability of the drug inside the nanocarrier is the most challenging and
essential aspect that is considered during the synthesis of nanometric drugs. The stabil-
ity of a nanodrug ensures its sustained release and targeted delivery while maintaining
its properties under different conditions (buffer, serum, blood, etc). Stability rests on
numerous factors such as particle size, charge (zeta potental), morphology, dosage form
(nanosuspension versus dry solid), dispersion medium (aqueous versus nonaqueous),
delivery route (oral, inhalation, IV, or other routes), nature of drug (small molecules
versus large biomolecules), and storage.122
Different nanoencapsulated formulations of curcumin have been reported as showing
enhanced stability over native curcumin. Mohanty and Sahoo observed that on incuba-
tion of free curcumin and nanoparticulate curcumin in PBS, the former endured rapid
degradation (only 6% of curcumin remained intact after 6 h of incubation) on account of
hydrolysis and biotransformation. Whereas, 90% of nanoparticulate curcumin was stable
under the same condition.123 Similar results were given by liposomal and PLGA formula-
tions of curcumin resulting in improved curcumin stability in PBS in contrast to its native
form.46,124 In another study, it was observed that only 5% of free curcumin remained intact
after an incubation of 8 h in PBS, whereas 94% of curcumin encapsulated in the pluronic/
polycaprolactone micelles remained intact indicating higher stability profile.84
Zeta potential also directly determines the long-term stability of drug-loaded nano-
carriers since it prevents particle aggregation by creating electric repulsion or steric
barriers between them. The formulation of curcumin in solid lipid NPs described by
Wang et al. had a zeta potential of −20.7 ± 1.2 mV, which was high enough to make the
NPs repel each other, thereby avoiding particle aggregation and keeping the long-term
stability of the nanoparticles. In another study, the zeta potential value for the cur-
cumin-loaded thermoresponsive chitosan-g-poly (nisopropylacrylamide) copolymeric

NPs was found to be +25 mV. These values lie in the stable range, indicating that the
NP systems were stable.56 Similar findings were reported in the form of curcumin-O-
carboxymethyl chitosan NPs and curcumin-loaded dextran sulphate–chitosan nanopar-
ticles for which the zeta potential value was found to be −30mV, which lies in the stable
range.26,34
Moreover, lyophilization has been reported as a means of imparting stability and
improved shelf life during storage over long periods of the developed curcumin nano-
formulations.37,63
V. BIOLOGICAL APPLICATIONS OF NANOCURCUMIN
Recently, a lot of emphasis has been given to reap health benefits from naturally occur-
ring medicinal sources both for preventive and curative purposes. This is mainly due to
their low cost and limited side effects in comparison to conventional medical sources
that often show undesirable secondary effects apart from health benefits. Curcumin is
one such promising phytodrug that has been known since antiquity of possessing re-
markable medicinal and therapeutic properties.125 But it is only recently that its potential
is being realized globally and efforts are being made to make use of its anticancer,126
anti-inflammatory,127 antioxidant,128 antimicrobial,129 antimalarial,130 antiasthma,131 and
antiparasitic132 properties. Saying this, curcumin also suffers from a major drawback of
low aqueous dispersion that hinders its journey from kitchen shelf to pharmacist shelf.
However, numerous sincere and dedicated efforts made in the last few years to increase
the aqueous solubility of curcumin by formulating it in the nanometric range have dras-
tically improved its image. These nanoscale preparations have been reported as show-
ing the same properties as promised by free curcumin but with better efficiency and at
a much lower dose. Various researches have been carried out worldwide to explore the
medicinal prospects of nanocurcumin.
A. Anticancer Action of Nanocurcumin
Although the role of curcumin in prevention and treatment of various kinds of cancer is
a highly explored and comprehensively published topic, its actual implementation for
clinical treatment regimes is severely hampered due to its low bioavailability. Nanocur-
cumin, on the other hand, has paved the way for showing exciting possibilities leading
to clinical translation of curcumin by improving all the drawbacks associated with free
curcumin. The anticancer ability of curcumin arises primarily because of its ability to
selectively induce apoptosis in the cancerous cells. Moreover, it can also suppress the
action of misregulated NF-κB that can also result in cancer.133,134
Large numbers of in vitro experiments have been conducted, effectively indicat-
ing the beneficial role of nanocurcumin in impeding the progression of cancer.18,28,31,33,92
However, in vivo experiments are limited in this context. Bisht et al.135 synthesized poly-
meric NPs encapsulating curcumin (Nanucurc) that substantially improved its bioavail-
ability without compromising its therapeutic properties. On parenteral administration of

Nanocurc, significant inhibition was seen in the growth of pancreatic cancer xenografts
in both subcutaneous and orthotopic settings. In addition, combinatorial administration
of Nanocurc with gemcitabine caused a much heightened inhibition response of tumor
growth in comparison to the lone effect of either of the agents. This suggested an addi-
tive therapeutic influence in vivo.135 In another study, carried out on a rodent chemical
carcinogenesis model, a similar formulation of curcumin (Nanocurc) given via an in-
traductal approach further confirmed its ability to cure cancer.136 Gou et al. investigated
the effects of curcumin encapsulated in monomethoxy poly(ethylene glycol)-poly(3-
caprolactone) (MPEG-PCL) micelles and reported that this formulation successfully
inhibited the proliferation of subcutaneous C-26 colon carcinoma in vivo in contrast to
free curcumin.86 The same effect was seen in vivo by cationic liposome-PEG-PEI com-
plex (LPPC) in suppressing the tumor growth in mice bearing CT-26 or B16F10 cells.33
B. Anti-Inflammatory Action of Nanocurcumin
Curcumin can effectively treat inflammation by practicing its suppressive action against
PLA-2, COX-2, LOX, TNF-α, IFN-γ, and NF-κβ activities that have been regarded as
the major underlying mechanisms that lead to inflammation.137 On the same note, nanor-
ange formulations of curcumin have reproduced the same results with appreciably better
proficiency owing to its improved pharmacokinetic profile. Liposomal curcumin was
reported to be synthesized using phosphatidylcholine vesicles for the treatment of vagi-
nal inflammation. The formulation was found to have two- to six-fold more potency for
controlling the inflammation than corresponding curcuminoids.138 Sun et al.139 gave evi-
dence that the anti-inflammation activity of curcumin is enhanced by encapsulating it in
NP exosomes. This preparation enhances the solubility, stability, and bioavailability of
curcumin in connection with an increased delivery of curcumin to activated monocytes.
This scheme of curcumin delivery protected mice from lipopolysaccharide-induced sep-
tic shock.139 A new investigation conducted on a diabetic mouse model proved the anti-
inflammatory activity of curcumin-loaded nanofibers, which illustrated its wound heal-
ing ability.140 In another research, the anti-inflammation activity of nanosized curcumin
encapsulated oil-in-water (O/W) emulsions was studied. It was seen that curcumin O/W
emulsions substantially improved the inhibition of edema in the mouse ear inflamma-
tion model in comparison to curcumin dispersed in Tween 20 water solution.91 Rogers
et al. gave an insight into the possibility of liposomal curcumin–mediated amelioration
of renal ischaemia-reperfusion (IR) injury that is associated with graft rejection. This
injury usually arises during renal transplantation and is induced by generation of oxida-
tive stress and inflammation (mediated by activation of NF-κB pathway) together with
the synthesis of cytokine and chemokine.141
C. Antioxidative Action of Nanocurcumin
Extensive evidence is available that supports the antioxidative nature of curcumin, but
the exact mechanism behind this property still remains unclear. It is still controversial

whether the phenolic group or CH2 group in the heptadienone link is responsible for an-
tioxidant activity. Recent studies have emphasized more on the phenolic hydroxyl group
for imparting curcumin with its free radical scavenging mechanism.142,143 Regardless of
the mechanism involved, nanocurcumin has been found to amplify this very property
with much superior ability than free curcumin.
Yen et al. explained the development of a novel curcumin NP system (CURN) us-
ing polyvinylpyrrolidone as the hydrophilic carrier and assessed its antioxidative ability
in vitro in comparison to native curcumin. The nanoformulation exhibited superior free
radical scavenging ability with enhanced antilipid peroxidation effect than curcumin.144
In another experiment, liposome-encapsulated curcumin (LEC) was prepared from leci-
thins and was comparatively assessed with free curcumin for its antioxidant properties.
LEC was found to have significantly higher antioxidant activity than its usual free form.50
Sonkaew et al. reported the development of curcumin NPs (Ccm-NPs) through rapid ex-
pansion of subcritical solutions into liquid solvents (RESOLV) and later on its incorpora-
tion into cellulose-based films. Both preparations had much higher antioxidant activity
than the solutions of curcumin in ethanol and water (Ccm-EtOH and Ccm-H2O).145
D. Antiamyloid Action of Nanocurcumin
Curcumin has been found to prevent the formation of β-amyloid oligomer aggregates in
brain parenchyma regions. This peptide is regarded as the sole reason for the progres-
sion of Alzheimer’s disease (AD). Various studies have disclosed the proficiency of
curcumin to impede the pathogenesis of AD by targeting several related mechanisms
suggesting its preventive and remedial action.146,147
NP formulation of curcumin has shown similar effects with heightened response
against the accumulation of β-amyloid aggregates inside brain. An exploration conduct-
ed by Kakkar et al. for the first time reported the curative role of curcumin against the
AD-like symptoms and induced cognition losses on its inclusion into SLNs.69 In another
approach, nanoliposomes decorated with a curcumin derivative were prepared using a
click chemistry reaction that presented very high affinity toward β-amyloid aggregates.
This suggested a direction that can be considered for the possible cure of AD.148 Mulik et
al. devised apolipoprotein E3-mediated poly(butyl) cyanoacrylate NPs containing cur-
cumin (ApoE3-C-PBCA) and studied its in vitro therapeutic efficacy against β-amyloid
SH-SY5Y neuroblastoma cells. In comparison to curcumin solution, ApoE3-C-PBCA
showed better anti-amyloidogenic activity suggesting a great advantage in the treatment
of β-amyloid-induced cytotoxicity.57,149 An investigation conducted on both cell culture
(human SK-N-SH cells) and animal model (athymic mice) confirmed the amelioration
of ROS-mediated damage by Nanocurc that promised a huge step forward for the treat-
ment of AD.150 In another study, water-soluble PLGA-coated curcumin NPs tagged with
Tet-1 peptide were investigated for its anti-amyloid activity in vitro. The Tet-1–tagged
NP formulation could easily cross the blood brain barrier and had higher affinity toward
neurons that facilitated an improved destruction of the amyloid aggregates, showing its
potential to treat AD.151

E. Antimicrobial Action of Nanocurcumin
Like curcumin, its nano form is also able to prevent and eradicate the growth of microbes
such as bacteria, fungi, and parasites. Bhawana et al. ascertained the improved suppressive
role of aqueous dispersion of nanocurcumin compared to curcumin against Staphylococcus
aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Penicillium notatum,
and Aspergillus niger.10 Synthesized microcapsule curcumin was reported that showed broad
spectrum inhibitory effects against bacterial and fungal food-borne pathogens and spoilage
microbes such as Escherichia coli, Yersinia enterocolitica, Staphylococcus aureus, Bacillus
subtilis, Bacillus cereus, Aspergillus niger, Penicllium notatum, and Saccharomyces cerevi-
siae.110 In another study, curcumin-encapsulated chitosanpoly(vinyl alcohol) silver nanocom-
posite films significantly inhibited the growth of E. coli.152 In a similar manner, curcumin-
loaded sodium carboxyl methyl cellulose silver nanocomposite films (SCMCSNCFs) also
noticeably inhibited the growth of E. coli.153 Dandekar et al. prepared a curcumin-containing
hydrogel NPs using hydroxyl propyl methyl cellulose and polyvinyl pyrrolidone and estab-
lished its advanced in vivo efficacy over curcumin regarding the control of parasites involved
in the pathogenesis of malaria.114 Similar results were produced by Akhtar et al. showing
that the oral delivery of curcumin-loaded chitosan NPs to mice infected with a lethal strain
of Plasmodium yoelii made all the mice survive. On the contrary, native curcumin displayed
only a one-third survival rate.154
F. Antifibrotic Action of Nanocurcumin
Fibrosis refers to a condition that involves the replacement of the normal fibrous tissues
of any organ by excessive and unnecessary invasion of fibrous connective tissues. Nor-
mally, the formation of fibrous connective tissues occurs for the repair purpose to heal
any damaged tissue that arises because of some injury or infection.155 Any abnormality
in this process can lead to fibrosis. The most well-documented examples of fibrosis
include cystic fibrosis (which affects the mucus of organs such as lungs, liver, and pan-
creas, and intestines, making the mucus layer thick and sticky), pulmonary fibrosis, and
liver cirrhosis. Curcumin has been known as a natural compound that can act to inhibit
the progression of uncontrolled fibrosis by acting primarily in two ways. First, it can
restrain the signaling pathways initiated by various cytokines and chemokines that di-
rectly result in fibrosis, and second, through the induction of apoptosis in stellate cells
of affected organs.156–159
Preparation of nanocurcumin has augmented the prevailing low healing profile of
curcumin against fibrosis by bringing amplification in its systemic bioavailability in the
target organs. Cartiera et al. described the formulation of poly lactic-co-glycolic acid
(PLGA) NPs encapsulating curcumin with improved bioavailability that resulted in par-
tial correction of a subset of cystic fibrosis symptoms in vivo with better efficiency than
free curcumin.65 In another study, parenteral administration of Nanocurc could success-
fully reverse the harmful effects of carbon tetrachloride (CCl4)–induced liver injury and
subsequent fibrosis in rodents. It was observed that on nanoencapsulation, curcumin still

retained its ability to channelize the apoptosis of profibrotic stellate cells coupled with
inhibition of proinflammatory cytokines.160
G. Metal Chelation Action of Nanocurcumin
The structure of curcumin confers a great advantage with regard to the treatment of
heavy metal toxicity. Its 1,3-diketone moiety on its transformation into keto-enol tau-
tomeric form can readily chelate various metal ions forming complexes facilitating the
removal of metal ions primarily through urine.161 Curcumin can effectively chelate lead,
cadmium, arsenic, aluminium, and mercury ions.162–165
Considering this property of curcumin, Yadav et al. attempted to further improve its
chelating efficacy through the synthesis of water-soluble curcumin NPs (ECNPs) made
from chitosan. These ECNPs were then tested for the treatment of arsenic-induced tox-
icity in rats in comparison with free curcumin. The much pronounced effect of ECNPs
was seen to revert back the adverse changes that appeared on account of oxidative stress
induced by arsenic. Furthermore, these NPs had superior chelating potential even at low
dose (1.5 mg/kg) in contrast to free curcumin (15 mg/kg).166 Recently, our group re-
ported the preventive efficacy of bulk and nanocurcumin against lead-induced oxidative
stress in mice. It was observed that nanocurcumin showed superior ability in removing
lead from blood and soft tissues (brain, kidney, and liver). Compared to bulk curcumin,
it also efficiently increased the depleted delta-aminolevulinic acid dehydratase (ALAD)
levels in blood arising due to lead exposure. A similar higher competence of nanocur-
cumin was seen in reversal of lead-induced altered biochemical parameters (ROS, GSH,
GSSG, and TBARS) indicative of oxidative stress in brain, kidney, and liver.167
H. Other Biological Activities of Nanocurcumin
Apart from the above-discussed therapeutic action of nanocurcumin, its role in several
other biological activities has been reported. Nanocurcumin has shown signs of over-
coming the multidrug resistance that usually arises on administration of a diverse range
of conventional and novel chemotherapeutic agents that proves to be a significant bottle-
neck in the treatment of several diseases, especially cancer.168–170 In another study, chi-
tosan-coated NPs loaded with curcumin showed their ability as a mucoadhesive agent
through heightened interaction with mucin.171 Li et al. synthesized a curcumin-loaded
nanocomposite hydrogel made from N,O-carboxymethyl chitosan and oxidized alginate
with a significant potential of wound healing ability.172 An exploration demonstrated
the capability of curcumin-loaded glyceryl monooleate NPs to cross the blood-brain
barrier and facilitating apoptosis in glioma cells that are associated with severe tumors
of brain and central nervous system.173 Luz et al. established the in vitro ability of cur-
cumin-containing poly(lactic-co- glycolic) acid (PLGA) nanospheres to act as a schis-
tosomicidal agent competent to treat human schistosomiasis (a dreadful disease caused
by parasites of the genus Schistosoma).174 The role of curcumin-loaded apotransferrin
NPs was confirmed in vitro in blocking the HIV replication through its ability to target

the endocytosis-promoting cellular receptor.175 The anticonvulsant activity of liposome-

entrapped curcumin was assessed and reported by a research group against increasing
current electroshock seizures (ICES) test, pentylenetetrazole (PTZ)-induced seizures,
and status epilepticus in mice.176
VI. CLINICAL STUDIES AND PATENTS
A search carried out on www.clinicaltrials.gov revealed about 75 clinical trials related

to curcumin that are either underway or have been completed to evaluate its therapeutic
potential as an effective clinical medicine. The trials take into account a wide variety of
medical conditions such as cancer, inflammatory conditions (dermatitis, irritable bowel
disease, colitis), Alzheimer’s disease, rheumatoid arthritis, osteoarthritis, diabetes, asth-
ma, and cardiovascular diseases.177
Of these, there are two clinical trials dealing specifically with nanoformulations of
curcumin. The first one is liposomal curcumin, which aims at the assessment of the safe-
ty, tolerability, and pharmacokinetics of increasing doses of intravenous liposomal cur-
cumin in healthy subjects (ClinicalTrials.gov Identifier: NCT01403545; Phase I; Status:
Completed; Sponsor: SignPath Pharma, Inc). The second one is Surface-Controlled Wa-
ter Soluble Curcumin (Theracurmin CR-011L) aiming at the determination of the high-
est tolerable doses of Theracurmin that can be given to patients with advanced cancer
(ClinicalTrials.gov Identifier: NCT01201694; Phase I; Status: Ongoing; Sponsor: M.D.
Anderson Cancer Center). Table 7 gives a list of patented technologies of nanocurcumin.
VII. CONCLUSION AND FUTURE DIRECTIONS
Curcumin, a naturally occurring phenolic compound of turmeric, is regarded as one of

the most versatile phytodrugs that is capable of healing a wide range of diseases through
its anticancer, antioxidative, anti-inflammatory, antifibrotic, antimicrobial, and metal
chelating actions. In spite of such extraordinary capabilities, its specific implementation
as a potential pharmaceutical and chemopreventive drug is still far from being achieved.
TABLE 7. List of Patented Technologies of Nanocurcumin

S. No. U.S. Patent Nos. Assignee Comments
1 13/056,515 Santosh Kumar Kar Curcumin bound to chitosan NPs
2 12/949,897 Signpath Pharma Inc. PLGA nanocurcumin
3 13/129,370 The University of Texas Curumin bound to fibroin polypep-
system tide
4 11/867,918 The Johns Hopkins Univer- Polymeric curcumin nanoparticles
sity (NIPAAM, VP and PEG-A)
5 13/052,822 SignPath Pharma Inc. Liposomal formulations and poly-
mer conjugates of curcumin
6 13/129,424 Laila Pharmaceuticals Pvt Ltd Nanoemulsion of curcumin and
derivatives of curcumin

This is due to its minimal systemic bioavailability on administration that critically hin-
ders its therapeutic nature.
Recently, a diverse array of novel nanorange preparations of curcumin have been
developed that enhances the therapeutic profile of curcumin by modifying several physi-
cochemical characteristics such as particle size, surface charge, surface area, and hydro-
phobicity. The new formulations include nanoliposomes, nanoparticles, microspheres,
microemulsions, solid dispersions, etc. Although the results have been extremely re-
warding, still a more advanced level of investigations are called for further ensuring the
improvements in stability, drug loading and entrapment efficiency, release profile, and
evasion of biological defenses of the body.
Ensuring tissue specificity is an area that needs to be explored as apart from target-
ing the affected cells curcumin also interferes with healthy cells and tissues. Moreover,
toxic effects associated with both curcumin and its carrier needs to be evaluated. Stabil-
ity during storage along with lowering the cost of production are other major challenges
that need proper addressing.
This can be done by bringing about a more thorough exploration of the ingredients
that go into the encapsulation of nanocurcumin, guarantying its minimal cytotoxicity to-
gether with augmented biocompatibility. Moreover, the majority of the studies conducted
so far have emphasized the in vitro effects of nanocurcumin. In order to achieve a more
concrete platform to promote nanocurcumin up to a level of clinical trials, a series of con-
clusive in vivo experiments are indispensible in different disease experimental models.
To conclude, application of nanotherapeutics for the delivery of curcumin is still in
its early stages. Its evolution demands sincere and dedicated efforts through a regime of
ordered and planned experiments based entirely with an intention of strengthening the
beneficial effects of curcumin.
REFERENCES
1. Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory
agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic
diseases. Int J Biochem Cell Biol. 2009;41:40–59.
2. Chattopadhyay I, Biswas K, Bandyopadhyay U, Banerjee RK. Turmeric and curcumin: biological
actions and medicinal applications. Curr Sci. 2004;87:44–53.
3. Maheshwari RK, Singh AK, Gaddipati J, Srimal RC. Multiple biological activities of curcumin: a
short review. Life Sci. 2006;78:2081–7.
4. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems
and promises. Mol Pharm. 2007;4:807–18.
5. Ireson C, Orr S, Jones DJ. Characterization of metabolites of the chemopreventive agent curcumin
in human and rat hepatocytes and in the rat in vivo, and evaluation of their ability to inhibit phorbol
ester-induced prostaglandin E2 production. Cancer Res. 2001;61:1058–64.
6. Lin JK, Pan MH, Lin-Shiau SY. Recent studies on the biofunctions and biotransformations of curcu-
min. Biofactors. 2000;13:153–8.
7. Couvreur P, Fattal E, Alphandary H, Puisieux F, Andremont A. Intracellular targeting of antibiotics
by means of biodegradable nanoparticles. J Controlled Release. 1992;19:259–67.
8. Wahlstrom B, Blennow G. A study on the fate of curcumin in the rat. Acta Pharmacol Toxicol (Co-
penh). 1978;43:86–92.
9. Lao CD, Ruffin MTt, Normolle D. Dose escalation of a curcuminoid formulation. BMC Comple-
ment Altern Med. 2006;6:10.

10. Bhawana, Basniwal RK, Buttar HS, Jain VK, Jain N. Curcumin nanoparticles: preparation, charac-
terization, and antimicrobial study. J Agric Food Chem. 2011;59:2056–61.
11. Gelperina S, Kisich K, Iseman MD, Heifets L. The potential advantages of nanoparticle drug deli-
very systems in chemotherapy of tuberculosis. Am J Respir Crit Care Med. 2005;172:1487–90.
12. Muqbil I, Masood A, Sarkar FH, Mohammad RM,Azmi AS. Progress in nanotechnology based ap-
proaches to enhance the potential of chemopreventive agents. Cancers. 2011;3:428–45.
13. Wang D, Veena MS, Stevenson K. Liposome-encapsulated curcumin suppresses growth of head and
neck squamous cell carcinoma in vitro and in xenografts through the inhibition of nuclear factor
kappaB by an AKT-independent pathway. Clin Cancer Res. 2008;14:6228–36.
14. Kumar V, Lewis SA, Mutalik S, Shenoy DB, Venkatesh, Udupa N. Biodegradable micro-spheres of
curcumin for treatment of inflammation. Indian J Physiol Pharmacol. 2002;46:209–17.
15. Das RK, Kasoju N, Bora U. Encapsulation of curcumin in alginate-chitosan-pluronic composite
nanoparticles for delivery to cancer cells. Nanomedicine. 2010;6:153–60.
16. Gupta V, Aseh A, Rios CN, Aggarwal BB, Mathur AB. Fabrication and characterization of silk fibro-
in-derived curcumin nanoparticles for cancer therapy. Int J Nanomed. 2009;4:115–22.
17. Maiti K, Mukherjee K, Gantait A, Saha BP, Mukherjee PK. Curcumin-phospholipid complex: Pre-
paration, therapeutic evaluation and pharmacokinetic study in rats. Int J Pharm. 2007;330:155–63.
18. Bisht S, Feldmann G, Soni S, Ravi R, Karikar C, Maitra A. Polymeric nanoparticle-encapsulated
curcumin (“nanocurcumin”): a novel strategy for human cancer therapy. J Nanobiotechnology.
2007;5:3.
19. Yallapu MM, Jaggi M, Chauhan SC. Curcumin nanomedicine: a road to cancer therapeutics. Curr
Pharm Des. 2013;19:1994–2010.
20. De Jong WH, Borm PJ. Drug delivery and nanoparticles:applications and hazards. Int J Nanomedi-
cine. 2008;3:133–49.
21. Tsai YM, Chien CF, Lin LC, Tsai TH. Curcumin and its nano-formulation: the kinetics of tissue
distribution and blood-brain barrier penetration. Int J Pharm. 2011;416:331–8.
22. Ma Z, Shayeganpour A, Brocks DR, Lavasanifar A, Samuel J. High-performance liquid chromato-
graphy analysis of curcumin in rat plasma: application to pharmacokinetics of polymeric micellar
formulation of curcumin. Biomed Chromatog. 2007;21:546–52.
23. Mythri RB, Jagatha B, Pradhan N, Andersen J, Bharath MM. Mitochondrial complex I inhibition in
Parkinson’s disease: how can curcumin protect mitochondria? Antioxid Redox Signal. 2007;9:399–408.
24. Muller RH, Keck CM. Challenges and solutions for the delivery of biotech drugs—a review of drug
nanocrystal technology and lipid nanoparticles. J Biotechnol. 2004;113:151–70.
25. Mukerjee A, Vishwanatha JK. Formulation, characterization and evaluation of curcumin-loaded
PLGA nanospheres for cancer therapy. Anticancer Res. 2009;29:3867–75.
26. Anitha A, Deepagan, VG, Divya Rani VV, Menon D, Nair SV, Jayakumar R. Preparation, characte-
rization, in vitro drug release and biological studies of curcumin loaded dextran sulphate–chitosan
nanoparticles. Carbohydrate Polym. 2011;84:1158–64.
27. Mohanraj, VJ, Chen Y. Nanoparticles—a review. Trop J Pharm Res. 2006;5:561–73.
28. Yallapu MM, Maher DM, Sundram V, Bell MC, Jaggi M, Chauhan SC. Curcumin induces chemo/
radio-sensitization in ovarian cancer cells and curcumin nanoparticles inhibit ovarian cancer cell
growth. J Ovarian Res. 2010;3:11.
29. Faisant N, Siepmann J, Benoit JP. PLGA-based microparticles: elucidation of mechanisms and a
new, simple mathematical model quantifying drug release. Eur J Pharm Sci. 2002;15:355–66.
30. Zolnik BS, Burgess DJ. Effect of acidic pH on PLGA microsphere degradation and release. J Control
Release. 2007;122:338–44.
31. Yallapu MM, Gupta BK, Jaggi M, Chauhan SC. Fabrication of curcumin encapsulated PLGA
nanoparticles for improved therapeutic effects in metastatic cancer cells. J Colloid Interface Sci.
2010;351:19–29.
32. Mulik R, Mahadik K, Paradkar A. Development of curcuminoids loaded poly(butyl) cyanoacry-
late nanoparticles: physicochemical characterization and stability study. Eur J Pharm Sci. 2009;37:
395–404.
33. Lin YL, Liu YK, Tsai NM. A Lipo-PEG-PEI complex for encapsulating curcumin that enhances its
antitumor effects on curcumin-sensitive and curcumin-resistance cells. Nanomedicine. 2012;8:318–27.
34. Anitha A, Maya S, Deepa N. Efficient water soluble O-carboxymethyl chitosan nanocarrier for the
delivery of curcumin to cancer cells. Carbohydrate Polymers. 2011;83:452–61.

35. Rejinold NS, Muthunarayanan M, Divyarani VV. Curcumin-loaded biocompatible thermorespon-

sive polymeric nanoparticles for cancer drug delivery. J Colloid Interface Sci. 2011;360:39–51.
36. Mittal G, Sahana DK, Bhardwaj V, Ravi Kumar MN. Estradiol loaded PLGA nanoparticles for oral
administration: effect of polymer molecular weight and copolymer composition on release behavior
in vitro and in vivo. J Control Release. 2007;119:77–85.
37. Shaikh J, Ankola DD, Beniwal V, Singh D, Kumar MN. Nanoparticle encapsulation improves oral
bioavailability of curcumin by at least 9-fold when compared to curcumin administered with pipe-
rine as absorption enhancer. Eur J Pharm Sci. 2009;37:223–30.
38. de Villiers MM, Aramwit P, Kwon GS. Nanotechnology in drug delivery. New York: Springer; 2008.
39. Prokop A, Kozlov E, Carlesso G, Davidson J. Hydrogel-based colloidal polymeric system for prote-
in and drug delivery: physical and chemical characterization, permeability control and applications.
filled elastomers drug delivery systems. Berlin: Springer; 2002. p. 119–73.
40. Hu CM and Zhang L. Nanoparticle-based combination therapy toward overcoming drug resistance
in cancer. Biochem Pharmacol. 2012;83:1104–11.
41. Wang AZ, Gu F, Zhang L. Biofunctionalized targeted nanoparticles for therapeutic applications.
Expert Opin Biol Ther. 2008;8:1063–70.
42. Zhang L, Gu FX, Chan JM, Wang AZ, Langer RS, Farokhzad OC. Nanoparticles in medicine: thera-
peutic applications and developments. Clin Pharmacol Ther. 2008;83:761–9.
43. Malam Y, Loizidou M, Seifalian AM. Liposomes and nanoparticles: nanosized vehicles for drug
delivery in cancer. Trends Pharmacol Sci. 2009;30:592–9.
44. Makino K, Shibata A. Surface properties of liposomes depending on their composition. In: Liu AL,
editor. Advances in planar lipid bilayers and liposomes. New York: Academic Press; 2006. p. 49–77.
45. Terreno E, Delli Castelli D, Cabella C. Paramagnetic liposomes as innovative contrast agents for
magnetic resonance (MR) molecular imaging applications. Chem Biodivers. 2008;5:1901–12.
46. Chen C, Johnston TD, Jeon H. An in vitro study of liposomal curcumin: stability, toxicity and bio-
logical activity in human lymphocytes and Epstein-Barr virus-transformed human B-cells. Int J
Pharm. 2009;366:133–9.
47. Lu Y, Ding N, Yang C, Huang L, Liu J, Xiang G. Preparation and in vitro evaluation of a folate-
linked liposomal curcumin formulation. J Liposome Res. 2012;22:110–9.
48. Orr WS, Denbo JW, Saab KR. Liposome-encapsulated curcumin suppresses neuroblastoma growth
through nuclear factor-kappa B inhibition. Surgery. 2012;151:736–44.
49. Kunwar A, Barik A, Pandey R, Priyadarsini KI. Transport of liposomal and albumin loaded cur-
cumin to living cells: an absorption and fluorescence spectroscopic study. Biochim Biophys Acta.
2006;1760:1513–20.
50. Takahashi M, Uechi S, Takara K, Asikin Y, Wada K. Evaluation of an oral carrier system in rats:
bioavailability and antioxidant properties of liposome-encapsulated curcumin. J Agri Food Chem.
2009;57:9141–6.
51. Thangapazham RL, Puri A, Tele S, Blumenthal R, Maheshwari RK. Evaluation of a nanotechnolo-
gy-based carrier for delivery of curcumin in prostate cancer cells. Int J Oncol. 2008;32:1119–23.
52. Li L, Braiteh FS, Kurzrock R. Liposome-encapsulated curcumin: in vitro and in vivo effects on
proliferation, apoptosis, signaling, and angiogenesis. Cancer. 2005;104:1322–31.
53. Narayanan NK, Nargi D, Randolph C, Narayanan BA. Liposome encapsulation of curcumin and
resveratrol in combination reduces prostate cancer incidence in PTEN knockout mice. Int J Cancer.
2009;125:1–8.
54. Faraji AH, Wipf P. Nanoparticles in cellular drug delivery. Bioorg Med Chem. 2009;17:2950–62.
55. Doane TL,Burda C. The unique role of nanoparticles in nanomedicine: imaging, drug delivery and
therapy. Chem Soc Rev. 2012;41:2885–911.
56. Rejinold NS, Sreerekha PR, Chennazhi KP, Nair SV, Jayakumar R. Biocompatible, biodegradable
and thermo-sensitive chitosan-g-poly (N-isopropylacrylamide) nanocarrier for curcumin drug deli-
very. Int J Biol Macromol. 2011;49:161–72.
57. Duan J, Zhang Y, Han S. Synthesis and in vitro/in vivo anti-cancer evaluation of curcumin-loaded
chitosan/poly(butyl cyanoacrylate) nanoparticles. Int J Pharm. 2010;400:211–20.
58. Singh DK, Jagannathan R, Khandelwal P, Abraham PM, Poddar P. In situ synthesis and surface functiona-
lization of gold nanoparticles with curcumin and their antioxidant properties: an experimental and density
functional theory investigation. Nanoscale. 2013;5:1882–93.
59. Manju S, Sreenivasan K. Gold nanoparticles generated and stabilized by water soluble curcumin-polymer

conjugate: blood compatibility evaluation and targeted drug delivery onto cancer cells. J Colloid Interface
Sci. 2012;368:144–51.
60. Kumar A, Glaum M, El-Badri N. Initial observations of cell-mediated drug delivery to the deep lung. Cell
Transplant. 2011;20:609–18.
61. Anitha A, Maya S, Deepa N, Chennazhi KP, Nair SV and Jayakumar R. Curcumin-Loaded N,O-Car-
boxymethyl Chitosan Nanoparticles for Cancer Drug Delivery. J Biomater Sci Polym Ed. 2011;23:
1381–400.
62. Anand P, Nair HB, Sung B. Design of curcumin-loaded PLGA nanoparticles formulation with enhanced
cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo. Biochem Phar-
macol. 2010;79:330–8.
63. Sun M, Gao Y, Guo C. Enhancement of transport of curcumin to brain in mice by poly(n-butylcyanoac-
rylate) nanoparticle. J Nanopart Res. 2010;12:3111–22.
64. Khalil NM, do Nascimento TC, Casa DM. Pharmacokinetics of curcumin-loaded PLGA and PLGA-PEG
blend nanoparticles after oral administration in rats. Colloids Surf B. 2013;101:353–60.
65. Cartiera MS, Ferreira EC, Caputo C, Egan ME, Caplan MJ, Saltzman WM. Partial correction of cystic
fibrosis defects with PLGA nanoparticles encapsulating curcumin. Mol Pharm. 2010;7:86–93.
66. Wissing SA, Kayser O, Müller RH. Solid lipid nanoparticles for parenteral drug delivery. Adv Drug De-
livery Rev. 2004;56:1257–72.
67. Uner M, Yener G. Importance of solid lipid nanoparticles (SLN) in various administration routes and
future perspectives. Int J Nanomed. 2007;2:289–300.
68. Mukherjee S, Ray S, Thakur RS. Solid lipid nanoparticles: a modern formulation approach in drug deli-
very system. Indian J Pharm Sci. 2009;71:349–58.
69. Kakkar V, Kaur IP. Evaluating potential of curcumin loaded solid lipid nanoparticles in aluminium in-
duced behavioural, biochemical and histopathological alterations in mice brain. Food Chem Toxicol.
2011;49:2906–13.
70. Wang W, Zhu R, Xie Q. Enhanced bioavailability and efficiency of curcumin for the treatment of asthma
by its formulation in solid lipid nanoparticles. Int J Nanomed. 2012;7:3667–77.
71. Kakkar V, Singh S, Singla D, Kaur IP. Exploring solid lipid nanoparticles to enhance the oral bioavailabi-
lity of curcumin. Mol Nutr Food Res. 2011;55:495–503.
72. Mulik RS, Monkkonen J, Juvonen RO, Mahadik KR, Paradkar AR. Transferrin mediated solid lipid na-
noparticles containing curcumin: enhanced in vitro anticancer activity by induction of apoptosis. Int J
Pharm. 2010;398:190–203.
73. Tiyaboonchai W, Tungpradit W and Plianbangchang P. Formulation and characterization of curcuminoids
loaded solid lipid nanoparticles. Int J Pharm. 2007;337:299–306.
74. Yan YD, Kim JA, Kwak MK, Yoo BK, Yong CS, Choi HG. Enhanced oral bioavailability of curcumin
via a solid lipid-based self-emulsifying drug delivery system using a spray-drying technique. Biol Pharm
Bull. 2011;34:1179–86.
75. Arruebo M, Fernández-Pacheco R, Ibarra MR, Santamaría J. Magnetic nanoparticles for drug delivery.
Nano Today. 2007;2:22–32.
76. Chin SF, Iyer KS, Saunders M. Encapsulation and sustained release of curcumin using superparamagnetic
silica reservoirs. Chemistry. 2009;15:5661–5.
77. Konwarh R, Saikia JP, Karak N, Konwar BK. ‘Poly(ethylene glycol)-magnetic nanoparticles-
curcumin’ trio: directed morphogenesis and synergistic free-radical scavenging. Colloids Surf B.
2010;81:578–86.
78. Kratz F. Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control
Release. 2008;132:171–83.
79. Wang S, Tan M, Zhong Z, Chen M, Wang Y. Nanotechnologies for curcumin: an ancient puzzlerme-
ets modern solutions. J Nanomater. 2011;5.
80. Kim TH, Jiang HH, Youn YS. Preparation and characterization of water-soluble albumin-bound
curcumin nanoparticles with improved antitumor activity. Int J Pharm. 2011;403:285–91.
81. Kwon GS. Polymeric micelles for delivery of poorly water-soluble compounds. Crit Rev Ther Drug
Carrier Syst. 2003;20:357–403.
82. V.K. Mourya NI, R.B. Nawale, S.S. Kulthe. Polymeric Micelles: General Considerations and their
Applications. Indian J Pharm Educ Res. 2010;45:128–38.
83. Huh KM, Lee SC, Cho YW, Lee J, Jeong JH, Park K. Hydrotropic polymer micelle system for deli-
very of paclitaxel. J Control Release. 2005;101:59–68.

84. Raveendran R, Bhuvaneshwar GS, Sharma CP. In vitro cytotoxicity and cellular uptake of curcumin-
loaded Pluronic/Polycaprolactone micelles in colorectal adenocarcinoma cells. J Biomater Appl.
2012;27:811–27.
]
85. Ma Z, Haddadi A, Molavi O, Lavasanifar A, Lai R, Samuel J. Micelles of poly(ethylene oxide)-
b-poly(ε-caprolactone) as vehicles for the solubilization, stabilization, and controlled delivery of
curcumin. J Biomed Mater Res Part A. 2008;86A:300–10.
86. Gou M, Men K, Shi H. Curcumin-loaded biodegradable polymeric micelles for colon cancer therapy
in vitro and in vivo. Nanoscale. 2011;3:1558–67.
87. Podaralla S, Averineni R, Alqahtani M and Perumal O. Synthesis of novel biodegradable methoxy
poly(ethylene glycol)-zein micelles for effective delivery of curcumin. Mol Pharm. 2012.
88. Song Z, Feng R, Sun M. Curcumin-loaded PLGA-PEG-PLGA triblock copolymeric micelles: Pre-
paration, pharmacokinetics and distribution in vivo. J Colloid Interface Sci. 2011;354:116–23.
89. Zhao L, Du J, Duan Y. Curcumin loaded mixed micelles composed of Pluronic P123 and F68: Pre-
paration, optimization and in vitro characterization. Colloids Surfa B. 2012;97:101–8.
90. Yildiz U, Capek I. Microemulsion polymerization of styrene in the presence of macroinimer. Poly-
mer. 2003;44:2193–200.
91. Wang X, Jiang Y, Wang Y-W, Huang M-T, Ho C-T, Huang Q. Enhancing anti-inflammation activity
of curcumin through O/W nanoemulsions. Food Chem. 2008;108:419–24.
92. Lin HY, Thomas JL, Chen HW, Shen CM, Yang WJ, Lee MH. In vitro suppression of oral squamous
cell carcinoma growth by ultrasound-mediated delivery of curcumin microemulsions. Int J Nano-
med. 2012;7:941–51.
93. Lin C-C, Lin H-Y, Chen H-C, Yu M-W, Lee M-H. Stability and characterisation of phospholipid-
based curcumin-encapsulated microemulsions. Food Chem. 2009;116:923–8.
94. Hu L, Jia Y, Niu F, Jia Z, Yang X, Jiao K. Preparation and enhancement of oral bioavailability of
curcumin using microemulsions vehicle. J Agric Food Chem. 2012;60:7137–41.
95. Cui J, Yu B, Zhao Y. Enhancement of oral absorption of curcumin by self-microemulsifying drug
delivery systems. Int J Pharm. 2009;371:148–55.
96. Setthacheewakul S, Mahattanadul S, Phadoongsombut N, Pichayakorn W, Wiwattanapatapee R. De-
velopment and evaluation of self-microemulsifying liquid and pellet formulations of curcumin, and
absorption studies in rats. Eur J Pharm Biopharm. 2010;76:475–85.
97. Wu X, Xu J, Huang X, Wen C. Self-microemulsifying drug delivery system improves curcumin dis-
solution and bioavailability. Drug Dev Ind Pharm. 2011;37:15–23.
98. Joshi RP, Negi G, Kumar A. SNEDDS curcumin formulation leads to enhanced protection from
pain and functional deficits associated with diabetic neuropathy: An insight into its mechanism for
neuroprotection. Nanomedicine. 2013 (in press).
99. Dhirendra K, Lewis S, Udupa N, Atin K. Solid dispersions: a review. Pak J Pharm Sci. 2009;22:234–
46.
100. Tihanyi K and Vastag M. Solubility, Delivery and ADME problems of drugs and drug-candidates.
Dubai, UAE; Bentham Science Publishers; 2011.
101. Paradkar A, Ambike AA, Jadhav BK, Mahadik KR. Characterization of curcumin–PVP solid disper-
sion obtained by spray drying. Int J Pharm. 2004;271:281–6.
102. Gao Y, Li Z, Sun M. Preparation and characterization of intravenously injectable curcumin nanosus-
pension. Drug Deliv. 2011;18:131-42.
103. Onoue S, Takahashi H, Kawabata Y. Formulation design and photochemical studies on nanocrystal
solid dispersion of curcumin with improved oral bioavailability. J Pharm Sci. 2010;99:1871–81.
104. Seo S-W, Han H-K, Chun M-K, Choi H-K. Preparation and pharmacokinetic evaluation of curcumin
solid dispersion using Solutol® HS15 as a carrier. Int J Pharm. 2012;424:18–25.
105. Wan S, Sun Y, Qi X, Tan F. Improved bioavailability of poorly water-soluble drug curcumin in cel-
lulose acetate solid dispersion. AAPS PharmSciTech. 2012;13:159–66.
106. Li D-C, Zhong X-K, Zeng Z-P. Application of targeted drug delivery system in Chinese medicine. J
Controll Release. 2009;138:103–12.
107. Brown DM. Drug delivery systems in cancer therapy. Totowa, NJ: Humana Press; 2004.
108. Singh MN, Hemant KS, Ram M, Shivakumar HG. Microencapsulation: A promising technique for
controlled drug delivery. Res Pharm Sci. 2010;5:65–77.
109. Manju S, Sreenivasan K. Hollow microcapsules built by layer by layer assembly for the encapsula-
tion and sustained release of curcumin. Colloids Surf B. 2011;82:588–93.

110. Wang Y, Lu Z, Wu H, Lv F. Study on the antibiotic activity of microcapsule curcumin against foodborne
pathogens. Int J Food Microbiol. 2009;136:71–4.
111. Zanotto-Filho A, Coradini K, Braganhol E. Curcumin-loaded lipid-core nanocapsules as a strategy to
improve pharmacological efficacy of curcumin in glioma treatment. Eur J Pharm Biopharm. 2012;83:
156–67.
112. Jaques JA, Doleski PH, Castilhos LG. Free and nanoencapsulated curcumin prevents cigarette smoke-
induced cognitive impairment and redox imbalance. Neurobiol Learn Mem. 2013;100:98–107.
113. Wu W, Shen J, Banerjee P, Zhou S. Water-dispersible multifunctional hybrid nanogels for combined
curcumin and photothermal therapy. Biomaterials. 2011;32:598–609.
114. Dandekar PP, Jain R, Patil S. Curcumin-loaded hydrogel nanoparticles: application in anti-malarial the-
rapy and toxicological evaluation. J Pharm Sci. 2010;99:4992–5010.
115. Mangalathillam S, Rejinold NS, Nair A, Lakshmanan VK, Nair SV, Jayakumar R. Curcumin loaded chitin
nanogels for skin cancer treatment via the transdermal route. Nanoscale. 2012;4:239–50.
116. Ghosh M, Singh AT, Xu W, Sulchek T, Gordon LI, Ryan RO. Curcumin nanodisks: formulation and
characterization. Nanomedicine. 2011;7:162–7.
117. Yallapu MM, Jaggi M, Chauhan SC. Poly(β-cyclodextrin)/Curcumin Self-Assembly: A Novel Approach
to Improve Curcumin Delivery and its Therapeutic Efficacy in Prostate Cancer Cells. Macromolecular
Bioscience. 2010; 10: 1141–51.
118. Yallapu MM, Jaggi M, Chauhan SC. β-Cyclodextrin-curcumin self-assembly enhances curcumin deli-
very in prostate cancer cells. Colloids and Surfaces B: Biointerfaces. 2010;79:113–25.
119. Paramera EI, Konteles SJ, Karathanos VT. Microencapsulation of curcumin in cells of Saccharomyces
cerevisiae. Food Chem. 2011;125:892–902.
120. Paramera EI, Konteles SJ, Karathanos VT. Stability and release properties of curcumin encapsulated in
Saccharomyces cerevisiae, β-cyclodextrin and modified starch. Food Chem. 2011;125:913–22.
121. Barik A, Mishra B, Kunwar A. Comparative study of copper(II)–curcumin complexes as superoxide dis-
mutase mimics and free radical scavengers. Eur J Med Chem. 2007;42:431–9.
122. Wu L, Zhang J, Watanabe W. Physical and chemical stability of drug nanoparticles. Adv Drug Deliv Rev.
2011;63:456–69.
123. Mohanty C, Sahoo SK. The in vitro stability and in vivo pharmacokinetics of curcumin prepared as an
aqueous nanoparticulate formulation. Biomaterials. 2010;31:6597–611.
124. Xie X, Tao Q, Zou Y. PLGA nanoparticles improve the oral bioavailability of curcumin in rats: characte-
rizations and mechanisms. J Agric Food Chem. 2011;59:9280–9.
125. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: from ancient medicine to current clinical
trials. Cell Mol Life Sci. 2008;65:1631–52.
126. Wilken R, Veena MS, Wang MB, Srivatsan ES. Curcumin: A review of anti-cancer properties and thera-
peutic activity in head and neck squamous cell carcinoma. Mol Cancer. 2011;10:12.
127. Menon VP, Sudheer AR. Antioxidant and anti-inflammatory properties of curcumin. Adv Exp Med Biol.
2007;595:105–25.
128. Ak T, Gülçin İ. Antioxidant and radical scavenging properties of curcumin. Chemico-Biological Interac-
tions. 2008;174:27–37.
129. Parvathy KS, Negi PS, Srinivas P. Antioxidant, antimutagenic and antibacterial activities of curcumin-β-
diglucoside. Food Chem. 2009;115:265–71.
130. Mishra S, Karmodiya K, Surolia N, Surolia A. Synthesis and exploration of novel curcumin analogues as
anti-malarial agents. Bioorg Med Chem. 2008;16:2894–902.
131. Karaman M, Firinci F, Cilaker S. Anti-inflammatory effects of curcumin in a murine model of chronic
asthma. Allergol Immunopathol (Madr). 2012;40:210–4.
132. Saleheen D, Ali SA, Ashfaq K, Siddiqui AA, Agha A, Yasinzai MM. Latent activity of curcumin against
leishmaniasis in vitro. Biol Pharm Bull. 2002;25:386–9.
133. Ravindran J, Prasad S, Aggarwal BB. Curcumin and cancer cells: how many ways can curry kill
tumor cells selectively? AAPS J. 2009;11:495–510.
134. Zhang C, Li B, Zhang X, Hazarika P, Aggarwal BB, Duvic M. Curcumin selectively induces apop-
tosis in cutaneous T-cell lymphoma cell lines and patients PBMCs: potential role for STAT-3 and
NF-[kappa]B signaling. J Invest Dermatol. 2010;130:2110–9.
135. Bisht S, Mizuma M, Feldmann G. Systemic administration of polymeric nanoparticle-encapsulated
curcumin (NanoCurc) blocks tumor growth and metastases in preclinical models of pancreatic can-
cer. Mol Cancer Ther. 2010;9:2255–64.

136. Chun YS, Bisht S, Chenna V. Intraductal administration of a polymeric nanoparticle formulation of
curcumin (NanoCurc) significantly attenuates incidence of mammary tumors in a rodent chemical
carcinogenesis model: Implications for breast cancer chemoprevention in at-risk populations. Carci-
nogenesis. 2012;33:2242–9.
137. Hanai H, Sugimoto K. Curcumin has bright prospects for the treatment of inflammatory bowel disea-
se. Curr Pharm Des. 2009;15:2087–94.
138. Basnet P, Hussain H, Tho I, Skalko-Basnet N. Liposomal delivery system enhances anti-inflamma-
tory properties of curcumin. J Pharm Sci. 2012;101:598–609.
139. Sun D, Zhuang X, Xiang X. A novel nanoparticle drug delivery system: the anti-inflammatory acti-
vity of curcumin is enhanced when encapsulated in exosomes. Mol Ther. 2010;18:1606–14.
140. Merrell JG, McLaughlin SW, Tie L, Laurencin CT, Chen AF, Nair LS. Curcumin-loaded poly(epsilon-
caprolactone) nanofibres: diabetic wound dressing with anti-oxidant and anti-inflammatory proper-
ties. Clin Exp Pharmacol Physiol. 2009;36:1149–56.
141. Rogers NM, Stephenson MD, Kitching AR, Horowitz JD, Coates PT. Amelioration of renal ischa-
emia-reperfusion injury by liposomal delivery of curcumin to renal tubular epithelial and antigen-
presenting cells. Br J Pharmacol. 2012;166:194–209.
142. Feng J-Y, Liu Z-Q. Phenolic and enolic hydroxyl groups in curcumin: which plays the major role in
scavenging radicals? J Agri Food Chem. 2009;57:11041–6.
143. Galano A, Álvarez-Diduk R, Ramírez-Silva MT, Alarcón-Ángeles G, Rojas-Hernández A. Role of
the reacting free radicals on the antioxidant mechanism of curcumin. Chem Phys. 2009;363:13–23.
144. Yen FL, Wu TH, Tzeng CW, Lin LT, Lin CC. Curcumin nanoparticles improve the physicochemical
properties of curcumin and effectively enhance its antioxidant and antihepatoma activities. J Agri
Food Chem. 2010;58:7376–82.
145. Sonkaew P, Sane A, Suppakul P. Antioxidant activities of curcumin and ascorbyl dipalmitate nano-
particles and their activities after incorporation into cellulose-based packaging films. J Agric Food
Chem. 2012;60:5388–99.
146. Cole GM, Teter B, Frautschy SA. Neuroprotective effects of curcumin. Adv Exp Med Biol.
2007;595:197–212.
147. Ringman JM, Frautschy SA, Cole GM, Masterman DL, Cummings JL. A potential role of the curry
spice curcumin in Alzheimer’s disease. Curr Alzheimer Res. 2005;2:131–6.
148. Mourtas S, Canovi M, Zona C. Curcumin-decorated nanoliposomes with very high affinity for amy-
loid-beta1-42 peptide. Biomaterials. 2011;32:1635–45.
149. Mulik RS, Monkkonen J, Juvonen RO, Mahadik KR, Paradkar AR. ApoE3 mediated poly(butyl)
cyanoacrylate nanoparticles containing curcumin: study of enhanced activity of curcumin against
beta amyloid induced cytotoxicity using in vitro cell culture model. Mol Pharm. 2010;7:815–25.
150. Ray B, Bisht S, Maitra A, Lahiri DK. Neuroprotective and neurorescue effects of a novel polymeric
nanoparticle formulation of curcumin (NanoCurc) in the neuronal cell culture and animal model:
implications for Alzheimer’s disease. J Alzheimers Dis. 2011;23:61–77.
151. Mathew A, Fukuda T, Nagaoka Y. Curcumin loaded-PLGA nanoparticles conjugated with Tet-1 pep-
tide for potential use in Alzheimer’s disease. PLoS One. 2012;7:e32616.
152. Vimala K MY, Varaprasad K, Redd NN, Ravindra S, Naidu NS, Raju KM. Fabrication of curcumin
encapsulated Chitosan–PVA silver nanocomposite films for improved antimicrobial activity. J Bio-
mater Nanobiotechnol. 2011;2:55–64.
153. Varaprasad K, Vimala K, Ravindra S, Narayana Reddy N, Venkata Subba Reddy G, Mohana Raju
K. Fabrication of silver nanocomposite films impregnated with curcumin for superior antibacterial
applications. J Mater Sci Mater Med. 2011;22:1863–72.
154. Akhtar F, Rizvi MM, Kar SK. Oral delivery of curcumin bound to chitosan nanoparticles cured
Plasmodium yoelii infected mice. Biotechnol Adv. 2012;30:310–20.
155. Lundvig DM, Immenschuh S, Wagener FA. Heme oxygenase, inflammation, and fibrosis: the good,
the bad, and the ugly? Front Pharmacol. 2012;3:81.
156. Ghiassi-Nejad Z, Friedman SL. Advances in antifibrotic therapy. Expert Rev Gastroenterol Hepatol.
2008;2:803–16.
157. Lin YL, Lin CY, Chi CW, Huang YT. Study on antifibrotic effects of curcumin in rat hepatic stellate
cells. Phytother Res. 2009;23:927–32.
158. Punithavathi D, Venkatesan N, Babu M. Curcumin inhibition of bleomycin-induced pulmonary fi-
brosis in rats. Br J Pharmacol. 2000;131:169–72.

159. Shu JC, He YJ, Lv X, Ye GR, Wang LX. Curcumin prevents liver fibrosis by inducingapoptosis and
suppressing activation of hepatic stellate cells. J Nat Med. 2009;63:415–20.
160. Bisht S, Khan MA, Bekhit M. A polymeric nanoparticle formulation of curcumin (NanoCurc) ame-
liorates CCl4-induced hepatic injury and fibrosis through reduction of pro-inflammatory cytokines
and stellate cell activation. Lab Invest. 2011;91:1383–95.
161. Zhao X-Z, Jiang T, Wang L, Yang H, Zhang S, Zhou P. Interaction of curcumin with Zn(II) and
Cu(II) ions based on experiment and theoretical calculation. J Mol Struct. 2010;984:316–25.
162. Agarwal R, Goel SK, Behari JR. Detoxification and antioxidant effects of curcumin in rats experi-
mentally exposed to mercury. J Appl Toxicol. 2010;30:457–68.
163. Daniel S, Limson JL, Dairam A, Watkins GM, Daya S. Through metal binding, curcumin protects
against lead- and cadmium-induced lipid peroxidation in rat brain homogenates and against lead-
induced tissue damage in rat brain. J Inorg Biochem. 2004;98:266–75.
164. Sethi P, Jyoti A, Hussain E, Sharma D. Curcumin attenuates aluminium-induced functional neuroto-
xicity in rats. Pharmacol Biochem Behav. 2009;93:31–9.
165. Yadav RS, Sankhwar ML, Shukla RK. Attenuation of arsenic neurotoxicity by curcumin in rats.
Toxicol Appl Pharmacol. 2009;240:367–76.
166. Yadav A, Lomash V, Samim M, Flora SJ. Curcumin encapsulated in chitosan nanoparticles: A novel
strategy for the treatment of arsenic toxicity. Chem Biol Interact. 2012;199:49–61.
167. Flora G, Gupta D, Tiwari A. Preventive efficacy of bulk and nanocurcumin against lead-induced
oxidative stress in mice. Biol Trace Elem Res. 2013;152:31–40.
168. Das M,Sahoo SK. Folate decorated dual drug loaded nanoparticle: role of curcumin in enhancing
therapeutic potential of nutlin-3a by reversing multidrug resistance. PLoS One. 2012;7:e32920.
169. Ganta S, Amiji M. Coadministration of Paclitaxel and curcumin in nanoemulsion formulations to
overcome multidrug resistance in tumor cells. Mol Pharm. 2009;6:928–39.
170. Misra R, Sahoo SK. Coformulation of doxorubicin and curcumin in poly(D,L-lactide-co-glycoli-
de) nanoparticles suppresses the development of multidrug resistance in K562 cells. Mol Pharm.
2011;8:852–66.
171. Mazzarino L, Travelet C, Ortega-Murillo S, Otsuka I, Pignot-Paintrand I, Lemos-Senna E, Borsali
R. Elaboration of chitosan-coated nanoparticles loaded with curcumin for mucoadhesive applicati-
ons. J Colloid Interface Sci. 2012;370:58–66.
172. Li X, Chen S, Zhang B. In situ injectable nano-composite hydrogel composed of curcumin,
N,O-carboxymethyl chitosan and oxidized alginate for wound healing application. Int J Pharm.
2012;437:110–9.
173. Kundu P, Mohanty C, Sahoo SK. Antiglioma activity of curcumin-loaded lipid nanoparticles and
its enhanced bioavailability in brain tissue for effective glioblastoma therapy. Acta Biomater.
2012;8:2670–87.
174. Luz PP, Magalhaes LG, Pereira AC, Cunha WR, Rodrigues V, Andrade ESML. Curcumin-loa-
ded into PLGA nanoparticles: preparation and in vitro schistosomicidal activity. Parasitol Res.
2012;110:593–8.
175. Gandapu U, Chaitanya RK, Kishore G, Reddy RC, Kondapi AK. Curcumin-loaded apotransfer-
rin nanoparticles provide efficient cellular uptake and effectively inhibit HIV-1 replication in vitro.
PLoS One. 2011;6:e23388.
176. Agarwal NB, Jain S, Nagpal D, Agarwal NK, Mediratta PK, Sharma KK. Liposomal formulation
of curcumin attenuates seizures in different experimental models of epilepsy in mice. Fundam Clin
Pharmacol. 2011;27:169–72.
177. Henrotin Y, Priem F and Mobasheri A. Curcumin: a new paradigm and therapeutic opportunity for
the treatment of osteoarthritis: curcumin for osteoarthritis management. Springerplus. 2013;2:56.

Các D NG Nano Curcumin

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Các D NG Nano Curcumin

Uploaded by

Copyright:

Available Formats

Critical Reviews™ in Therapeutic Drug Carrier Systems, 30(4), 331–368 (2013)

Nanocurcumin: A Promising Therapeutic

School of Biotechnology, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, M.P., India

*Address all correspondence to: Gagan Flora; Email: gaganflora@gmail.com

ABSTRACT: Curcumin, a naturally occurring polyphenolic compound, is known to have a

KEY WORDS: curcumin, nanotherapeutics, nanocurcumin, bioavailability

0743-4863/13/$35.00 ©2013 Begell House, Inc. www.begellhouse.com 331

products (di-, tetra-, hexahydrocurcumin and hexahydrocurcuminol) and their glucuro-

FIGURE 1. Chemical structure of curcumin. Curcumin is a member of linear diarylheptanoid

Critical Reviews™ in Therapeutic Drug Carrier Systems

lated in liposomes,13 biodegradable microspheres,14 chitosan,15 and silk microspheres,16

II. PHYSICOCHEMICAL PROPERTIES OF NANOCURCUMIN ENHANCES ITS

Volume 30, Number 4, 2013

circulation of curcumin in the body is limited since a substantial amount of curcumin

Critical Reviews™ in Therapeutic Drug Carrier Systems

E. Entrapment and Loading Efficiency

Volume 30, Number 4, 2013

Total amount of drug with in the carrier

Total mass of drug with in the carrier

A survey of literature available on different formulations of nanocurcumin have

III. NOVEL DELIVERY SYSTEMS FOR CURCUMIN: A NANOTHERAPEUTIC AP-

Recent advances in nanotechnology have given a very committed platform to improvise

Critical Reviews™ in Therapeutic Drug Carrier Systems

another study, different liposomal formulations of curcumin (LCs) demonstrated very

Volume 30, Number 4, 2013

TABLE 1. Studies Showing Comparatively Superior Therapeutic Efficacy of Liposomal

substantial improvement in solubility and pharmacokinetic profile. Owing to their small

Critical Reviews™ in Therapeutic Drug Carrier Systems

Volume 30, Number 4, 2013

other polymers such as N-isopropylacrylamide (NIPAAM), chitosan, and silk fibroin

Critical Reviews™ in Therapeutic Drug Carrier Systems

Furthermore, Anitha et al.61 administered curcumin in a carboxymethyl chitosan (CMC)

2. Solid Lipid Nanoparticles (SLNs)

3. Magnetic Nanoparticles (MNPs)

Volume 30, Number 4, 2013

TABLE 2. Studies Showing Comparatively Superior Therapeutic Efficacy of Curcumin-

Critical Reviews™ in Therapeutic Drug Carrier Systems

In an attempt to formulate curcumin-loaded magnetic NPs, encapsulation of cur-

Volume 30, Number 4, 2013

TABLE 3. Studies Showing Comparatively Superior Therapeutic Efficacy of Curcumin-

Kim et al. described the preparation of curcumin-loaded HSA NPs (CCM-HSA-NPs)

Critical Reviews™ in Therapeutic Drug Carrier Systems

Volume 30, Number 4, 2013

D. Microemulsions and Nanoemulsions

Microemulsions and nanoemulsion are attributed with having a number of properties

Critical Reviews™ in Therapeutic Drug Carrier Systems

TABLE 4. Studies Showing Comparatively Superior Therapeutic Efficacy of Curcumin-

Volume 30, Number 4, 2013

Table 5 summarizes the studies94–98 that showed comparatively superior therapeutic

E. Solid Dispersion (SD)

Solid dispersion is essentially a molecular dispersion of two different compounds; usu-

Critical Reviews™ in Therapeutic Drug Carrier Systems

TABLE 5. Studies Showing Comparatively Superior Therapeutic Efficacy of Curcumin-

Whereas, solid dispersion showed complete dissolution within 30 min.101 In another

Volume 30, Number 4, 2013

F. Nanospheres and Microcapsules

TABLE 6. Studies Showing Comparatively Superior Therapeutic Efficacy of Curcumin

Critical Reviews™ in Therapeutic Drug Carrier Systems

Volume 30, Number 4, 2013

Wu et al. reported the synthesis of curcumin-containing water-dispersible hybrid nano-

Ghosh et al. discussed the formulation and characterization of nanodisks (nanoscale

A novel poly (β-cyclodextrin)/curcumin self-assembly was described to enhance cur-

Critical Reviews™ in Therapeutic Drug Carrier Systems