Curcumin nanoformulations

Review
Curcumin nanoformulations: A review of pharmaceutical properties
and preclinical studies and clinical data related to cancer treatment
Ornchuma Naksuriya
a
,
b
, Siriporn Okonogi
a
, Raymond M. Schiffelers
c
, Wim E. Hennink
b
,
*
a
Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Suthep Rd, Mueang, Chiang Mai 50200, Thailand
b
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, Utrecht 3805 TB, The Netherlands
c
Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands
article info
Article history:
Received 28 November 2013
Accepted 22 December 2013
Available online 15 January 2014
Keywords:
Curcumin
Cancer
Nanoformulation
Drug delivery

Nanomedicine
Clinical studies
abstract
Curcumin, a natural yellow phenolic compound, is present in many kinds of herbs, particularly in Cur-
cuma longa Linn. (turmeric). It is a natural antioxidant and has shown many pharmacological activities
such as anti-inflammatory, anti-microbial, anti-cancer, and anti-Alzheimer in both preclinical and clinical
studies. Moreover, curcumin has hepatoprotective, nephroprotective, cardioprotective, neuroprotective,
hypoglycemic, antirheumatic, and antidiabetic activities and it also suppresses thrombosis and protects
against myocardial infarction. Particularly, curcumin has demonstrated efficacy as an anticancer agent,
but a limiting factor is its extremely low aqueous solubility which hampers its use as therapeutic agent.
Therefore, many technologies have been developed and applied to overcome this limitation. In this re-
view, we summarize the recent works on the design and development of nano-sized delivery systems for
curcumin, including liposomes, polymeric nanoparticles and micelles, conjugates, peptide carriers, cy-
clodextrins, solid dispersions, lipid nanoparticles and emulsions. Efficacy studies of curcumin nano-
formulations using cancer cell lines and in vivo models as well as up-to-date human clinical trials are also
discussed.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Curcumin is a natural yellow colored phenolic antioxidant and
was first extracted in an impure form by Vogel et al. [1]. The
structure of curcumin was elucidated and it was synthesized by
Milobedeska et al. and Lampe et al., respectively [2,3]. Many
different plant species synthesize curcumin and the commercial
product (such as from SigmaeAldrich) is isolated from the rhizome
of Curcuma longa Linn. in which it is present in relatively high
concentrations. The chemical structure of curcumin is shown in
Fig. 1. It should be mentioned that the commercially available
curcumin products also contain structurally related compounds
(w17% demethoxycurcumin, and 3% bisdemethoxycurcumin).
Sandur et al. reported that the potency for the suppression of tumor

necrosis factor (TNF)-induced nuclear factor-kappaB (NF-
k
B) acti-
vation ranked curcumin > desmethoxycurcumin > bisdesme-
thoxycurcumin suggesting a critical role of the methoxy groups on
the phenyl rings [4]. Moreover, curcumin has the highest car-
dioprotective, neuroprotective and antidiabetic activities of the
three curcuminoids shown in Fig. 1 [5e7]. Interestingly, the
mixture of curcuminoids has increased nematocidal activity as
compared to the individual compounds, suggesting a synergistic
effect [8].
For many centuries, curcumin in its crude form has been used as
spice and dietary supplement as well as component of many
traditional Asian medicines [9]. In recent studies, it has been shown
that curcumin exhibits a wide range of pharmacological activities
against many chronic diseases including type II diabetes, rheuma-
toid arthritis, multiple sclerosis, Alzheimer’s disease and athero-
sclerosis. It also inhibits platelet aggregation, suppresses
thrombosis and inhibits human immunodeficiency virus (HIV)
replication. Further, curcumin enhances wound healing and pro-
tects against liver injury, cataract formation, pulmonary toxicity
and fibrosis [10e20]. Finally, the anti-cancer activity of curcumin
has been extensively investigated and it has been suggested as a
potential agent for both prevention and treatment of a great variety
of different cancers, including gastrointestinal, melanoma, genito-
urinary, breast, lung, hematological, head and neck, neurological
and sarcoma [20e23]. At a molecular level, curcumin not only in-
hibits cell proliferation and metastasis, but also induces apoptosis
by modulating several pro-inflammatory factors (e.g. interleukin
(IL)-1, IL-1

b
, IL-12, tumor necrosis factor (TNF)-
a
and interferon
*
Corresponding author. Tel.: þ31 30 253 6964; fax: þ31 30 251 7839.
E-mail address: (W.E. Hennink).
Contents lists available at ScienceDirect
Biomaterials
journal homepage: www.elsevier.com/locate/biomaterials
0142-9612/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
/>Biomaterials 35 (2014) 3365e3383
(INF)-
g
), growth factors (e.g. epidermal growth factor (EGF), he-
patic growth factor (HGF) and platelet-derived growth factor
(PDGF)), receptors (e.g. epidermal growth factor receptor (EGFR),
human epidermal growth factor receptor (HER)-2, IL-8R and Fas-R),
transcription factors (e.g. signal transducer and activator of tran-
scription (STAT) 3, nuclear factor (NF)-
k
B, Wilms’ tumor (WT-1)
and peroxisome proliferator-activated receptor (PPAR)
g
) and
protein kinases, e.g. extracellular signal-regulated kinases (ERK),
mitogen-activated protein kinases (MAPK), protein kinase A (PKA)
B (PKB) and C (PKC) [20e25].
An overview of the different indications for which curcumin has
been investigated is shown in Fig. 2. It has been suggested that,

because of its many pleiotropic properties, curcumin can be more
effective than single pathway targeted anticancer drugs [26,27].
Many preclinical studies have demonstrated that curcumin has
anti-inflammatory and anticancer activity [27e30]. In a recent
clinical study it appeared that oral administration of curcumin was
well tolerated at doses of 12 g/day which indicates that curcumin is
safe [31]. Curcumin can freely pass through cellular membranes
due to its lipophilicity (log P ¼ 2.5) [32]. It should however be
mentioned that curcumin has a very low aqueous solubility of only
0.6
m
g/ml and is susceptible to degradation particularly under
alkaline conditions [33e35]. These characteristics are the cause for
its very low bioavailability resulting in suboptimal blood concen-
trations to achieve therapeutic effects [21,34e36]. For instance, in a
study in rats reported by Yang et al. a maximum serum concen-
tration of 0.36 Æ 0.05
m
g/ml after an intravenous injection of 10 mg/
kg was reached, whereas 500 mg/kg orally administered curcumin
gave a maximum plasma concentration of 0.06 Æ 0.01
m
g/ml,
indicating that oral bioavailability was only 1% [37]. Similarly,
Shoba et al. showed a maximum serum concentration of
1.35 Æ 0.23
m
g/ml at 1 h after administration of an oral dose of 2 g/
kg to rats, whereas healthy man volunteers (weighing 50e75 kg)
receiving a single dose of 2 g curcumin (4 capsules of 500 mg each)

showed an extremely low serum concentration of
0.006 Æ 0.005
m
g/ml at 1 h [38]. An obvious approach to improve
the poor biopharmaceutical properties of curcumin is to improve
its aqueous solubility using nanocarriers. Nanocarriers have a small
size (typically 10e100 nm) and can, besides for solubilization, also
be used for the targeted delivery of drugs [39e44]. Nanocarriers
can improve the circulation time of the loaded therapeutic agent
and may improve its accumulation at the pathological site
exploiting the so-called ‘enhance permeation and retention (EPR)
effect’ [45e48]. During the last decades, various types of nano-
carriers, such as polymeric micelles and nanoparticles, liposomes,
conjugates, peptide carriers etc., for drug delivery/targeting have
been investigated and some systems have reached clinical evalua-
tions and applications [49e52]. Many studies, as summarized in the
next sections, have shown that nanocarriers are suitable for
increasing curcumin’s bioavailability and its targeted delivery to
tumors and other sites of disease. This review focuses on the design
and development, the evaluation in preclinical and clinical trials of
curcumin nanoformulations, particularly focused on cancer ther-
apy. In the next section, different curcumin nanoformulations are
discussed with emphasis on their pharmaceutical properties. In the
final section of this review the results of curcumin nano-
formulations in preclinical studies and clinical evaluations are
summarized and discussed.
2. Curcumin nanoformulations
The nanoformulations discussed in this section primarily aim to
achieve increased solubilization of curcumin, but at the same time
protect curcumin against inactivation by hydrolysis. The formula-

tion should be efficiently prepared and loaded and should retain
curcumin for the required time period. Some formulations are
aimed for a prolonged release of curcumin, while others have
additional mechanisms for cellular delivery or intracellular release.
2.1. Liposomes
Liposomes consist of one or more phospholipid bilayers sur-
rounding an aqueous core. Both lipophilic compounds/drugs (sol-
ubilized in the liposomal bilayer) and hydrophilic compounds
(soluble in the aqueous core) can be loaded into liposomes. Different
types of liposomes for targeted drug delivery have been developed
and some systems have reached clinical practice [53e56].
Many liposomal curcumin formulations have been developed in
recent years (Table 1) and a few studies are highlighted. Karewicz
et al. prepared curcumin loaded liposomes composed of egg yolk
phosphatidyl choline (EYPC), dihexyl phosphate (DHP), and
cholesterol prepared by the film evaporation technique [57].
Because of its lipophilicity, curcumin is solubilized in the lipophilic
bilayer. By using fluorescent probes, the authors showed that it was
indeed located at the hydrophobic acyl side chain and positioned
closely to the glycerol groups. It was shown that curcumin loaded
into the EYPC/DPH/cholesterol liposomal bilayer stabilizes the
system proportionally to its content. In a follow up study, the li-
posomes were coated with the cationic lipid/polymer conjugate N-
dodecyl chitosan-N-[(2-hydroxy-3-trimethylamine) propyl]
(HPTMA) chloride. The obtained liposomes with a size of 73 nm
were able to bind to and penetrate cells due to their cationic nature.
These coated liposomes released their content in a sustained
manner in about 10 h. Further, the formulations showed a slightly
better cell killing activity than free curcumin, likely due to the
improved cellular internalization of the cationic liposomes [58].

Re et al. developed curcumin loaded liposomes composed of
bovine brain sphingomyelin, cholesterol, and 1,2-stearoyl-sn-glyc-
ero-3-phosphoethanolamine-N-[maleimide(poly(ethylene glycol)-
2000)] and surface functionalized with the apolipoprotein E
(ApoE) peptide as targeting ligand. The liposomes were prepared by
the fi
lm evaporation technique and non-incorporated curcumin
Fig. 1. Chemical structures of curcumin (A), demethoxycurcumin (B) and bisdeme-
thoxycurcumin (C).
O. Naksuriya et al. / Biomaterials 35 (2014) 3365e33833366
was removed by size-exclusion chromatography using a PD-10
column. The recovery of lipids was about 90% and the liposomes
had a mean size of w130 nm. It was shown these ApoE-liposomes
enhanced the transport of their curcumin payload through RBE4
brain capillary endothelial cells making these nanocarriers inter-
esting for brain targeting [59]. In another study, a cationic lipo-
someepolyethylene glycol (PEG)epolyethylenimine (PEI) complex
(lipoePEGePEI complex, LPPC) was used for the encapsulation of
curcumin. Morphological analysis by transmission electron micro-
scopy (TEM) showed a spherical shape of the liposomal nano-
particle with hair like projections on the surface likely originating
from PEG and PEI. The size of curcumin loaded LPPC was w260 nm
and the encapsulation efficiency of curcumin was 45%. In vitro,
these LPPC released curcumin within 120 h [60].
2.2. Polymeric nanoparticles
Different polymers, particularly biodegradable ones, have been
used for the preparation of curcumin loaded nanoparticles [65] .
PLGA (poly(D,L-lactic-co-glycolic) is widely used for drug delivery
purposes due to its biocompatibility and biodegradability [66e72].
Shaikh et al. reported on curcumin loaded PLGA nanospheres pre-

pared byemulsion-evaporation method usingPVA as surfactant.The
obtained particles had a size of 264 nm and 77% entrapment effi-
ciency resulting in 15% loading capacity of curcumin. The particles
showed a biphasic release pattern characterized by a relatively rapid
initial release of about 24% of the loading in 24 h followed by sus-
tained releaseof about 20%ofthe loading duringthe next 20days. An
in vivo study in rats revealed that the curcumin loaded PLGA nano-
spheres improved the oral bioavailability of curcumin at least 9 fold
when compared to curcumin administered with piperine. The latter
compound was co-administered to improve curcumin availability as
it inhibits curcumin inactivation by hepatic and intestinal glucur-
onidation [73]. Yallapu et al. encapsulated curcumin in PLGA nano-
particles by a nanoprecipitation method using poly(vinyl)alcohol
(PVA) and poly(
L
-lysine) as stabilizers (nano-CUR 1e6) [74].Itwas
found that the size ofthenanoparticles decreased from 560 to76 nm
with increasing PVA concentration. Further, the particles had a
neutral zeta-potential, although for poly(
L
-lysine) coated nano-
particle a positive zeta-potential is expected. The absence of charge
on the particle surfaces might be ascribed by the improper way the
measurements were done (in distilled water with no pH control),
whereas a low ionic strength buffer is preferred [75] or even the
absence of the polylysine coating. The nanoparticles showed after a
small burst of around 20% of the loading a sustained release of cur-
cumin for 25 days (Fig. 3). The particles prepared with the highest
concentration of PVA showed the slowest release and the authors
hypothesized that the surface adsorbed PVA acts as a barrier and

consequently controls the release rate. The Nano-CUR6 formulation
that released 64% of the loaded curcumin in 25 days was selected for
further in vitro studies (outcome discussed in section 3) [74]. Ghosh
et al. developed curcumin-loaded PLGA nanoparticles (Nano Cur) for
the treatment of diethylnitrosamine (DEN) induced hepatocellular
carcinoma (HCC) in rats. Nano Cur was prepared by emulsion-
diffusion-evaporation method and atomic force microscopy (AFM)
showed that the particles had an average diameter of 14 nm. The
optical density of Nano Cur was measured at
l
max
of 422 nm to
calculate the encapsulation efficiency which was 78%. Fourier
transform infrared (FTIR)analysis revealed that there were no strong
interactions between curcumin and the polymer matrix, but no
Fig. 2. Indications for which curcumin has been investigated.
O. Naksuriya et al. / Biomaterials 35 (2014) 3365e3383 3367
release data were reported. It was also not commented why the
particles had a small size, but probably the strong surfactant
(didodecyldimethylammonium bromide) in combination with the
high-speed homogenizer that was used to produce the emulsions
might be an explanation [76]. Anand et al. prepared curcumin-
loaded PLGA nanospheres using a nanoprecipitation method and
polyethylene glycol (PEG)-5000 as stabilizer. Curcumin was almost
quantitatively entrapped in particles of 81 nm. However, no in vitro
release data were reported [77]. Polylactic-co-glycolic acid (PLGA)
and PLGAepolyethylene glycol (PLGAePEG) nanoparticles contain-
ing curcumin were obtained by a single-emulsion solvent evapora-
tion technique [78]. The encapsulation efficiency was over 70% and
particles with asize w150 nm were formed.ThePLGAePEG particles

released 21% of curcumin in 24 h, followed by a sustained release to
57% of the loading over 9 days. On the other hand, the PLGA particles
showed a continuous release of 40% of the loading in 9 days. The
authors hypothesized that the faster release of curcumin from the
PLGAePEG nanoparticles is attributed the higher water-absorbing
capacity of this matrix compared to PLGA only [78]. NIPAAm, N-vi-
nyl-2-pyrrolidone, poly(ethyleneglycol) monoacrylate and N,N
0
,-
methylene bis acrylamide were copolymerized in water resulting in
crosslinked nanoparticles with a size of 50 nm. An aqueous disper-
sion of thesenanoparticleswas vortexed with asolutionof curcumin
in CH
3
Cl and a very high 90% entrapment efficiency was obtained.
The loaded nanoparticles released 40% of their content in 24 h [79].
Natural polymers have also been used to prepare curcumin
nanomedicines. Liu et al. developed curcumin loaded chitosan/
poly(Ɛ-caprolactone) (chitosan/PCL) nanoparticles by a precipita-
tion method. The mean diameter of the obtained nanoparticles was
between 220 and 360 nm whereas the encapsulation efficiency and
loading of curcumin were 71 and 4%, respectively. The curcumin
chitosan/PCL nanoparticles released 68% of their content over 5 days
in a sustained manner [80]. Rejinold et al. described chitosan-g-
poly(N-isopropylacrylamide) for the development curcumin-
loaded nanoparticles [81]. This polymer is temperature sensitive
because of the presence of the pNIPAAm grafts [82,83]. Below the
lower critical solution temperature (LCST) (38

C), chitosan-g-

poly(N-isopropylacrylamide) was fully soluble in water whereas
the polymer solution became turbid above the LCST. Particles of
Table 1
Some recent curcumin liposomal formulations.
Formulation Entrapment
efficiency
(%)
Size
(nm)
Release kinetics Status of
investigation
Observations Reference
Curcumin loaded liposomes
coated with N-dodecyl
chitosan-HPTMA chloride
Not
reported
73 >80% in 10 h In vitro Non-toxic for murine fibroblasts
(NIH3T3) whereas toxic for
murine melanoma (B16F10) cells.
[58]
Curcumin loaded liposomes
coupled with the ApoE
peptide
Not
reported
132 Not reported In vitro Increased accumulation of
curcumin in RBE4 cell brain
capillary endothelial cells.
[59]

Curcumin loaded lipoe
PEGePEI complex
45 269 90% in 120 h In vitro/vivo The cytotoxic activity of the
nanoformulation was higher
than free curcumin on both
curcumin-sensitive cells and
curcumin-resistant cells.
60e90% inhibition of tumor
growth in mice inocolated with
CT-26 or B16F10 cells.
[60]
Curcumin loaded silica-
coated flexible liposomes
91 157 Not reported In vivo Increased 3.3-fold bioavailability
compared with curcumin loaded
liposomes in mice through
gavage administration.
[61]
Curcumin-conjugated
nanoliposomes
Not
reported
207 Not reported In vivo Down regulated the secretion
of amyloid peptide (A
b
) and
partially prevented A
b
induced
toxicity in mouse model of

Alzheimer disease.
[62]
Curcumin loaded soybean
phosphati-dylcholine
liposomes
Not
reported
176 37% in 48 h In vivo Decreased parasitemia and
increase survival of Plasmodium
berghei infected mice (anti-malarial
therapy).
[63]
Curcumin loaded egg
phosphatidyl-choline
liposomes
Not
reported
Not
reported
Not reported In vivo Exhibited cytoprotection for
renal ischemiaereperfusion injury.
[64]
Fig. 3. Curcumin release profiles of nano-CUR 1e6. The red circle indicates the burst
release. Nano-Cur 1 to 6 were prepared with different concentrations of PVA in the
aqueous phase (0e1% w/v). Reprinted from Journal of Colloid and Interface Science, Vol.
351/1, M.M. Yallapu, B.K. Gupta, M. Jaggi, S.C. Chauhan, Fabrication of curcumin
encapsulated PLGA nanoparticles for improved therapeutic effects in metastatic cancer
cells, pp. 19e29, Copyright (2010), with permi ssion from Elsevier. (For interpretation of
the references to colour in this figure legend, the reader is referred to the web version
of this article.)

O. Naksuriya et al. / Biomaterials 35 (2014) 3365e33833368
chitosan-g-poly(N-isopropylacrylamide) with a size of 180e220 nm
were formed by ionic crosslinking using pentasodium tripoly
phosphate (TPP)in the presence of curcumin addedto the mixtureas
a solution in ethanol. Only 5% of the loaded amount of curcumin was
released below the LCST in 35 h, whereas above this temperature
100% drug release was observed within 35 h. The authors hypoth-
esized that below the LCST hydrogen bonds exist between the
phenolic hydroxyl groups of curcumin and the amide groups of the
pNIPAAm blocks that retain curcumin in the polymer matrix. Above
this temperature the interpolymer interactions dominate and as a
consequence curcumin-polymer interactions are weakened, which
in turn results in release of the active [81]. In a recent study of Anitha
et al.,curcumin-loaded nanoparticlesof dextran sulfate and chitosan
were prepared by coacervation method resulting in spherically
shaped and stable nanoparticles of 200 e220 nm which are hold
together by electrostatic interaction between the two oppositely
charged polymers and the curcumin encapsulation efficiency and
loading capacity were 74 and 5%, respectively [84]. The drug release
pattern was characterized by a burst release in the first 3 h followed
by a sustained release of curcumin that reached 70% of the loaded
amount within 120 h. The release was faster at pH 5 than at pH 7 due
to the protonation of the amine groups of chitosan at low pH
resulting in swelling of the polymer matrix [84].
2.3. Polymeric micelles
Polymeric micelles are composed of amphiphilic block co-
polymers that spontaneously form micelles with a size ranging
between 20 and 100 nm in aqueous solution above the critical
micellar concentration (CMC). The hydrophobic core can accom-
modate hydrophobic drugs and therefore polymeric micelles have

been extensively used for solubilization and targeted delivery of
drugs [85e92]. Song et al. loaded curcumin into micelles of
amphiphilic methoxy poly(ethylene glycol)-b-poly(Ɛ-capro-
lactone-co-p-dioxanone) by a solid dispersion method [93]. These
micelles had a small size (30 nm) with a narrow size distribution,
whereas the entrapment efficiency was more than 95% and the
loading capacity was 12%. The micelles slowly released w80% of
their content without a burst in 300 h [93]. A poly(
D
,
L
-lactide-co-
glycolide)-b-poly(ethylene glycol)-b-poly(
D
,
L
-lactide-co-glycolide)
(PLGAePEGePLGA) triblock copolymer was synthesized by ring-
opening polymerization of
D
,
L
-lactide using PEG as macroinitiator
[94]. Curcumin loaded triblock copolymer micelles were prepared
by a dialysis method and it was shown that the CMC at room
temperature was 2.8 Â 10
À2
mg/ml. The drug loading capacity and
entrapment efficiency were 4 and 70%, respectively. TEM analysis
showed that the micelles were spherically shaped and had a size of

26 nm which was con firmed by dynamic light scattering mea-
surements [94]. No release data were reported, but these nano-
particles were evaluated in vivo (discussed in Section 4). Zhao et al.
used a central composite design to optimize a formulation of mixed
micelles composed of Pluronics P123 and F68 [95]. The average size
of the mixed micelles was 6 8 nm, and the encapsulation efficiency
and loading capacity for curcumin were 87% and 7%, respectively. It
was shown that 50% of the loaded curcumin was released from the
micelles in 72 h demonstrating that this formulation had sustained
release properties [95]. Samanta et al. conducted a molecular dy-
namics study of curcumin with pluronic block copolymers and they
concluded that the hydrophobic PPO chains cover the curcumin
molecule leaving the hydrophilic PEO chains exposed, resulting in
solvation of curcumin in water [96]. Gong et al. reported on the
encapsulation of curcumin in monomethyl poly(ethylene glycol)-
poly(Ɛ-caprolactone) (MPEGePCL) micelles by a one-step solid
dispersion method [97]. Micelles with a mean diameter of 27 nm
were obtained that were well dispersible in water after freeze-
drying. The encapsulation efficiency and drug loading capacity
were 99 and 15%, respectively. The release study was done by
dialysis method using phosphate buffered saline (PBS) and 0.5% of
tween 80 as external medium, and these micelles released about
58% of the loading in 14 days [97]. Ma et al. loaded curcumin in
micelles of different PEO-PCL block copolymers by a cosolvent
evaporation technique [98]. It was reported that the PEO
5000
-
PCL
24500
showed the highest solubilization capacity whereas

PEO
5000
-PCL
13000
had the best drug retention capacity resulting in
the slowest release kinetics. The authors also found that the release
was faster in the presence of HSA which is probably due to the high
affinity of curcumin for HSA [98].
2.4. Conjugates
Conjugation of curcumin to small molecules (particularly amino
acids) and as well as to both natural and synthetic hydrophilic
polymers has been exploited to increase its aqueous solubility.
Several amino acids among which proline, glycine, leucine,
isoleucine, alanine, phenylalanine, phenyl glycine, valine, serine
and cysteine were coupled to curcumin [99]. These conjugates were
synthesized in dry dioxane using e.g. N,N
0
-dicyclohex-
ylcarbodiimide (DCC) as coupling agent, and (4-dimethylamino-
pyridine (DMAP) and triethylamine (TEA)) as catalysts, and purified
by column chromatography. These amino acid conjugations
increased curcumin’s aqueous solubility to 1e10 mg/ml [99]. Manju
et al. reported on the conjugation of hyaluronic acid and curcumin
both dissolved in a water/DMSO mixture using DCC and DMAP as
coupling agent and catalyst, respectively [100]. Although hyal-
uronic acid is very well soluble in water, the conjugates were
amphiphilic due to the hydrophobic curcumin groups and as a
result they self-assembled into particles with a size between 300
and 600 nm and a negative zeta-potential (À25 to À75 mV). It was
found that curcumin conjugated to hyaluronic acid remained intact

for 90% once incubated in aqueous solution at pH 7.4 for 8 h
whereas free curcumin showed 60% degradation within 25 min
[100]. Tang et al. conjugated curcumin to two short oligo(ethylene
glycol) chains via
b
-thioester bonds that are labile in the presence
of intracellular glutathione and esterases (Curc-OEG; Fig. 4B (top))
[101]. These Curc-OEG conjugates contained 25% by weight cur-
cumin and formed micelles with a size of 37 nm that released less
than 12% of the conjugated amount of curcumin by hydrolysis in
24 h at pH 7.4 and 5.0 indicating a good stability of this system in
PBS. On the other hand, Fig. 4B (bottom) shows that more than 25%
of the conjugated curcumin at pH 7.4 and 35% at pH 5.0 was
released within 10 h in a medium containing reduced glutathione
(GSH) and more than 80% of Curc-OEG hydrolyzed within 2 h at pH
7.4 in medium containing 30 U esterase. The authors argued that
Curc-OEG will be stable in the blood circulation and release cur-
cumin once in the cell catalyzed by a combination of GSH and
esterase [101]. In a recent study, three curcumin molecules were
covalently linked to the distal end of a block copolymer of methoxy
poly(ethylene glycol) (mPEG) and PLA via a tris (hydroxyl methyl)
aminomethane (Tris) spacer (mPEGePLAeTriseCur) (Fig. 5) [102].
Also, a block copolymer of (mPEG) and PLA to which one molecule
of curcumin was coupled was synthesized. Micelles with a size from
60 to 100 nm were prepared by a dialysis method and they con-
tained both conjugated and solubilized curcumin with a high
loading (up to 20%; only 2% loading for mPEGePLA micelles). The
release was studied using a Franz cell and PBS (pH 7.4) containing
5% sodium dodecyl sulfate as the acceptor medium. It was found
that the release of curcumin was due to a combination of diffusion

of physically loaded curcumin and hydrolysis of the ester bond that
connects curcumin and the polymer (Fig. 5). The authors reported
that mPEGePLAeCur and mPEGePLAeTriseCur showed a rapid
O. Naksuriya et al. / Biomaterials 35 (2014) 3365e3383 3369
release of curcumin during the first 12 h which then leveled off. The
authors argued that the release was controlled by hydrolysis of the
ester bond connecting the active and the polymer but that simul-
taneously degradation of released curcumin occurred resulting in a
steady state concentration of the compound. However, no
convincing data were presented to substantiate this explanation
[102]. Wichitnithad et al. coupled curcumin via different carboxylic
ester spacers to mPEG 2000. The authors reported a log-linear
release of curcumin in time for all conjugates tested. Further, it
was shown that as compared to the half-life of free curcumin
(0.56 h at pH 7.4 and 37

C), PEG bound curcumin had a substantial
better stability (t
1/2
is w3to13h)[103].
2.5. Peptide/protein carriers
Beta casein, an amphiphilic polypeptide with molecular mass
of 24,650 Da, spontaneously forms micelles (CMC at 37

Cis
8m
M
). When curcumin was loaded in the hydrophobic core of
these casein micelles, its solubility increased 2500 fold [104].
However, no data regarding size and release properties were re-

ported. Nanoparticles of cross-linked human serum albumin (HSA)
have shown good biocompatibility and have been used for drug
delivery purposes [105,106]. Kim et al. presented curcumin-HSA
nanoparticles that were prepared by homogenization of a
mixture of HSA in water and curcumin in chloroform [107]. The
mean size of curcumin-loaded HSA particles was 135 nm and the
loading capacity was 7.2%. The authors speculated that the parti-
cles were formed by crosslinking of albumin molecules via disul-
fide exchange due to heating associated with cavitation produced
by the high-pressure homogenizer. Curcumin was likely solubi-
lized in hydrophobic cavities of albumin [108,109] resulting in a
300 fold increase in solubility. However, the release characteristics
of the nanoparticles were not investigated [107].
2.6. Cyclodextrins
Cyclodextrins are cyclic oligosaccharides with a hydrophilic
outer surface and a lipophilic cavity that can solubilize hydrophobic
drugs and other small hydrophobic compounds such as curcumin
[110,111]. Yadav et al. used 2-hydroxypropyl-
g
-cyclodextrin
(HP
g
CD) to complex curcumin by a pH shift method. Curcumin was
dissolved in an alkaline solution containing HP
g
CD and subse-
quently the pH was adjusted to 6.0 [112]. Due to this pH change
curcumin becomes hydrophobic and consequently partitioned in
Fig. 4. Synthesis of curcumin amino acid conjugates (A). Reprinted from Food Chemistry, Vol. 120/2, K. Parvathy, P. Negi, P. Srinivas, Curcumineamino acid conjugates: Synthesis,
antioxidant and antimutagenic attributes, pp. 523e530, Copyright (2010), with permission from Elsevier. (B) top; chemical structure of Curc-OEG, middle; synthesis of Curc-OEG,

bottom; degree of hydrolysis of Curc-OEG at different conditions (B). Reproduced from Nanomedicine, Volume 5, Issue 6, pp. 855e865 with permission of Future Medicine Ltd.
O. Naksuriya et al. / Biomaterials 35 (2014) 3365e33833370
the hydrophobic cavity of the CD. Yallapu et al. developed a
b
-
cyclodextrin (
b
-CD)-curcumin inclusion complex by solvent evap-
oration method.
b
-Cyclodextrin (CD) was dissolved in deionized
water and varying amounts of curcumin in acetone were added
while stirring overnight to evaporate acetone. Then,
b
-cyclodextrin
(
b
-CD)-curcumin inclusion complexes were recovered by freeze
drying. Analysis showed that 1e2 curcumin molecules were
encapsulated per
b
-CD cavity [113]. The same group synthesized
poly(
b
-CD) (molecular weight from 2900 to 4100 Da) which was
subsequently loaded with 5e10% of curcumin. Poly(
b
-CD)/curcu-
min self-assembled formulations were prepared by drop-wise
precipitation method [114]. TEM analysis showed that a curcu-

min/poly(
b
-CD) inclusion complex (loading: 10e30%) self assem-
bled into nanoparticles with a size of 250 nm. An in vitro stability
study was performed in PBS and it was noted that >70% of the
loaded curcumin was retained in the nanoparticles during 72 h of
incubation at pH 7.4 and 37

C, demonstrating a good compatibility
of curcumin and its carrier [114].
2.7. Solid dispersions
Solid dispersions are dispersions of a drug/compound (either
molecularly dissolved in amorphous or (semi) crystalline form) in
an inert matrix [115,116]. Solid dispersions are prepared by melt
method or solvent evaporation technique and used to enhance the
solubility and dissolution rate of poorly water-soluble drugs [117e
120]. Lyophilized 2-hydroxypropyl-
b
-cyclodextrin (HP-
b
-CD)-cur-
cumin co-precipitates were prepared by a solid dispersion method
[121].HP-
b
-CD and curcumin (molar ratios from 0.5 to 2.8) were
dissolved in methanol and converted into an amorphous co-
precipitate which was subsequently lyophilized. The lyophilisates
had a porous structure that showed enhanced hydration and
dissolution. It was further shown that solutions of the curcumin
solid dispersions showed a pronounced decrease in curcumin

concentration up to 90% of the loaded amount af ter storage for
168 h, indicating that supersaturated curcumin solutions were
formed upon dissolution of the lyophilisates. These HP-
b
-CD-cur-
cumin co-precipitates significantly inactivated Escherichia coli after
exposure to blue light (400e500 nm), most likely caused by the
photosensitizing activity of curcumin [121]. Seo et al. reported on
curcumin-polyethylene glycol-15-hydroxystearate (Solutol
Ò
HS15)
solid dispersions which were prepared by a solvent evaporation
method and it was shown that the solubility of curcumin increased
to 560
m
g/ml. Upon incubation in buffer, 90% the loaded amount of
curcumin released/dissolved within 1 h [122].
2.8. Miscellaneous nanoformulations
Mohanty et al. prepared curcumin loaded nanoparticles
composed of glycerol monooleate and Pluronic F127 [123]. The
entrapment efficiency was around 90% and size of the nano-
particulates was 192 nm with a high negative zeta potential
(À32 mV) that ensured long term stability and avoided aggregation
of the particles. When dispersed in buffer, these nanoparticles
enhanced the stability of curcumin by protecting it against hydro-
lysis [123]. Anuchapreeda et al. prepared a curcumin nanoemulsion
Fig. 5. mPEGePLAeTriseCur: synthetic route and loading and release of curcumin. Reprinted from Pharmaceutical Research, Vol. 29/12, R. Yang, S. Zhang, D. Kong, X. Gao, Y. Zhao, Z.
Wang, Biodegradable polymerecurcumin conjugate micelles enhance the loading and delivery of low-potency curcumin, pp. 3512e3525, Copyright (2012), with permission from
Springer.
O. Naksuriya et al. / Biomaterials 35 (2014) 3365e3383 3371

based on soybean oil, hydrogenated l-
a
-phosphatidyl choline from
egg yolk and co-surfactants (tween 80 and polyoxyethylene hy-
drogenated castor oil 60, Cremophor-HR30) with a mean particle
diameter of 47e55 nm and with a concentration of curcumin of
0.9 mg/ml. This formulation was stable for 60 days at 4

C. Further,
25% of the loaded amount was released from these nanoemulsions
in 72 h when dispersed in PBS, pH 7.4, containing 25% human
serum [124]. In another study, curcumin-loaded lipid-core poly(Ɛ-
caprolactone) nanocapsules coated with polysorbate 80 (C-LNCs)
were prepared by interfacial deposition of preformed polymer. The
particles had a mean size of 96 nm, a negative zeta potential of
wÀ10 mV and showed 100% encapsulation efficiency [125]. These
C-LNCs released 35% of the loaded amount within 2 h [125].
3. In vitro studies of curcumin nanoformulations
The cytotoxicity of curcumin nanoformulations has been stud-
ied in many types of cancer cell lines. Interpretation of the rele-
vance of the results is often difficult due to the prolonged exposure
of cells to high static concentrations of curcumin (either in its free
for or as nanoformulation) that however are not necessarily related
to the concentrations achieved in vivo.
Yallapu et al. demonstrated that the intracellular drug retention
of Nano-CUR6 formulation was better than free curcumin (dis-
solved in DMSO) due to the sustained release of the active. This
formulation also increased the cellular uptake 2 and 6 fold in MDA-
MB-231 metastatic breast cancer cells and A2780CP cisplatin
resistant ovarian cancer cells, respectively, compared to free cur-

cumin. The 50% inhibitory concentrations (IC
50
) of Nano-CUR6
were 13.9 and 9.1
m
M
against A2780CP and MDA-MB-231 cells,
respectively, whereas the IC
50
’s of free curcumin were higher than
Nano-CUR6 (15.2
m
M
and 16.4
m
M
against A2780CP and MDA-MB-
231 cells, respectively) [74]. Apoptosis induction of KBM-5 human
chronic myeloid leukemia cells upon incubation with curcumin-
loaded PEG-5000-PLGA nanoparticles was investigated by Anand
et al. [77]. Curcumin-loaded PEG-5000-PLGA nanoparticles were
more potent than free curcumin in inducing apoptosis which could
be related to the higher intracellular curcumin concentration upon
Fig. 6. Viability of different cancer cells after incubation with curcumin loaded PEG-5000-PLGA for 24 h. Reprinted from Biochemical Pharmacology, Vol. 79/3, P. Anand, H.B. Nair, B.
Sung, A.B. Kunnumakkara, V.R. Yadav, R.R. Tekmal, B.B. Aggarwal, Design of curcumin-loaded PLGA nanoparticles formulation with enhanced cellular uptake, and increased
bioactivity in vitro and superior bioavailability in vivo, pp. 330e338, Copyright (2010), with permission from Elsevier.
O. Naksuriya et al. / Biomaterials 35 (2014) 3365e33833372
incubation with the nanoparticles due their excellent cellular
internalization as compared to intracellular concentrations ob-
tained after exposure to free curcumin. The uptake of curcumin-

loaded PEG-5000-PLGA nanoparticles and free curcumin by KBM-
5 cells was investigated by fluorescence microscopy. PEG-5000-
PLGA nanoparticles were taken up already after 5 min exposure
and reached a maximum at 30 min. In contrast, the uptake of free
curcumin could only be detected after 30 min incubation. The
mechanism of cellular uptake of the nanoparticles was not inves-
tigated, but they most likely entered the cells by endocytosis
[126,127]. However, no differences in viability were observed after
explore of the cells to either free curcumin or curcumin-loaded
PEG-5000-PLGA nanoparticles (Fig. 6). The authors explained that
apoptosis was examined after 24 h of incubation, whereas prolif-
eration was examined at 72 h. [77]. Liu et al. reported that
curcumin-loaded chitosan/polycarpolactone nanoparticles exhibi-
ted cytotoxicity on HeLa cervical cancer cells and OCM-1 human
choroidal melanoma cells to the same extent as free curcumin after
48 h incubation [80]. Furthermore, Wichitnithad et al. revealed that
mPEG 2000ecurcumin conjugates had IC
50
values in the range of
3e6
m
M
against Caco-2 colon adenocarcinoma cells and IC
50
values
in the range of 1e3
m
M
against KB oral epidermoid carcinoma, MCF7
breast adenocarcinoma, and NCIeH187 small lung carcinoma cells.

mPEG 2000ecurcumin conjugates showed a potency comparable
to free curcumin (IC
50
values in the range of 1e3
m
M
) on all cancer
cells used in this study [103]. These studies demonstrate that
nanoparticle-encapsulation of curcumin is not always beneficial.
This is also underlined by cytotoxicity studies of curcumin-loaded
nanoemulsions on B16F10 mouse melanoma and leukemic cell
lines (K562, Molt4, U937 and HL60) by Anuchapreeda et al. [124].It
was shown that the 50% inhibitory concentration values (IC
50
)
ranged from 3.5 to 53.7
m
M
. On the other hand, free curcumin dis-
solved in DMSO showed lower IC
50
in B16F10 cells and also in
leukemic cell lines as compared to that of curcumin-loaded nano-
emulsions. The authors argued that the lower activity of curcumin-
loaded nanoemulsions was due to the incomplete release during
24e72 h (incubation time of the formulations with the cells). In the
same study, it was shown that leukemic cell lines were less sensi-
tive to curcumin both in its free form and as nanoemulsion than
B16F10 cells. It was hypothesized by the authors that the pheno-
type of B16F10 melanoma cells is responsible for this difference.

However, in the same study it was shown that there were no dif-
ferences in the IC
50
values of free and curcumin-loaded lipid
nanoemulsion in four leukemic cell lines (K562, Molt4, U937 and
HL60) [124]. It was found by Bisht et al. that the cytotoxicity of
curcumin loaded micelles based on cross-linked random co-
polymers of NIPAAm with N-vinyl-2-pyrrolidone and poly(-
ethyleneglycol) monoacrylate (nanocurcumin) against pancreatic
XPA-1 cells was lower than curcumin in its free form [79]. Dhule
et al. developed curcumin loaded HP-
g
-cyclodextrin liposomes that
showed 50% encapsulation efficiency with a size of 98 nm [128].
The cytotoxic activity of these liposomes against KHOS osteosar-
coma and breast cancer MCF-7 cell lines (IC
50
¼ 6 and 12
m
g/ml,
respectively) was higher than that of curcumin in DMSO (IC
50
¼ 23
and 20
m
g/ml, respectively). Interestingly, non-cancerous mesen-
chymal stem cells and skin fibroblasts were unaffected by the
nanoformulation but were affected by free curcumin, indicating an
improved safety profile. Of note, a RFOS osteosarcoma cell line
derived from an untreated osteosarcoma patient was resistant

against free curcumin as well as its nanomedicine formulation. The
authors argued that this resistance was because of the low curcu-
min uptake (either in free form or as nanoformulation) because
RFOS cells have a very slow growth rate and a low uptake capacity
which is caused by the low metabolic activity of the cell [129].Ina
recent study, it was shown that curcumin loaded Pluronic/
polycaprolactone (Pluronic/PCL) block copolymer micelles with a
size of 196 nm released 60% of the loaded amount in 108 h [130].
The loaded Pluronic/PCL micelles were evaluated for their uptake
by Caco 2 cells using fluorescence microscopy based on curcumin’s
intrinsic fluorescence. Cells incubated with the curcumin-loaded
micelles showed a higher fluorescence intensity than those incu-
bated with free curcumin, demonstrating good cellular internali-
zation of the micelles, that, as hypothesized by the authors,
occurred via endocytosis. They argued that the insertion of the
hydrophobic part of pluronic block copolymers into the lipid bi-
layers of cell membranes resulted in a lower membrane micro-
viscosity and internalization of micelles [130]. Park et al. loaded
curcumin into nanoparticles based on the R7L10 peptide which is
composed of a 7-arginine stretch and a 10-leucine stretch which
were prepared by an oil-in-water (O/W) emulsion/solvent evapo-
ration method [131]. The cationic arginine groups of these peptide
micelles were used to make complexes with plasmid DNA. Inter-
estingly, the authors found synergistic effects of curcumin on
transfection (Fig. 7). The authors hypothesized that the hydro-
phobic curcumin stabilizes the structure of the complexes by
facilitating the formation of R7L10 micelles. These stable R7L10e
curcumin plasmid complexes may show increased endocytosis and
cellular internalization resulting in enhanced transfection. The
R7L10ecurcumin plasmid complexes also showed anti-

inflammatory activity by reducing the TNF-
a
levels of LPS-
activated Raw264.7 macrophage cells. Moreover, it was shown
that after intratracheal injection of this R7L10-curcumin formula-
tion, a stronger decrease in TNF-
a
levels in lung tissue in an acute
lung injury mouse model was observed than after administration of
free curcumin whereas no liver toxicity was detected [131]. Yallapu
investigated the hemocompatibility of various curcumin nano-
formulations based on PLGA,
b
-cyclodextrin, cellulose, poly-N-
isopropylacrylamide and polyamidoamine dendrimer [132].It
was found that the curcumin dendrimer nanoparticles adsorbed
more proteins than the other mentioned formulations and had
higher lytic activity towards red blood cells, likely caused by the
positive surface charge of the dendrimer particles [132].
Several studies have given evidence that drug-resistant cancer
cells are sensitive to curcumin. Zhang et al. demonstrated that
curcumin showed a similar cytotoxic effect against A549/DDP
multidrug-resistant human lung adenocarcinoma cells compared
to non-resistant cells [133]. The IC
50
of curcumin at 48 h was 16
m
M
for A549 cells and 18
m

M
for A549/DDP cells indicating that the
multidrug resistant cells were still sensitive to curcumin. The au-
thors also found that curcumin inhibited the expression of miR-
186*, a miRNA that targets caspase-10 mRNA. Inhibition of this
miRNA resulted in increased apoptosis as a result of the increased
caspase-10 activity in these cells [133]. Duan et al. co-encapsulated
doxorubicin and curcumin in poly(butyl cyanoacrylate) nano-
particles (CUR-DOX-PBCA-NPs, size 133 nm) prepared by emulsion
polymerization and interfacial polymerization [134]. The results
showed that CUReDOXePBCA-NPs inhibited the growth of multi-
drug resistant human breast cancer cells (MCF-7/ADR) for 97%
which was substantially higher than observed for cells incubated
with a cocktail of free curcumin and doxorubicin (cell growth in-
hibition was only 20%). It is important to notice that the adminis-
tration of a nanoformulation loaded with both doxorubicin and
curcumin achieved the strongest down-regulation of P-glycopro-
tein activity, which is considered to be a major mechanism in
multidrug resistance in MCF-7/ADR cells, compared to the combi-
nation of free curcumin and doxorubicin. This higher cytotoxicity
was ascribed by the authors to the high concentration of curcumin
near the cell membrane that bound to P-glycoprotein resulting in
inhibition of the dox efflux [134]. In another study, the cytotoxicity
of cationic PEGePEI liposomes loaded with curcumin against
O. Naksuriya et al. / Biomaterials 35 (2014) 3365e3383 3373
different cell lines, curcumin-resistant B16F10 murine melanoma
cells and CT26 colorectal adenocarcinoma cells (obtained by
continuously culturing the parental tumor cells in growth media
containing 5
m

M
of curcumin) was investigated [60]. It was found
that this liposome formulation, likely because of its rapid cellular
internalization, was substantially more cytotoxic (IC
50
of w1
m
M
)
than free curcumin (IC
50
of w25
m
M
). Also, these liposomes showed
antitumor activity in tumor bearing mice after intravenous
administration (Fig. 8) [60].
4. In vivo studies of curcumin nanoformulations: kinetics and
efficacy
The pharmacokinetic, biodistribution and therapeutic efficacy of
different curcumin nanoformulations have been investigated in
many animal studies in order to get insight into the potential value
of these systems for the treatment of different diseases. It has been
shown in many studies that oral or intravenous administration of
curcumin nanoformulations resulted in a larger area under the
concentrationetime curve (AUC) than after administration of cur-
cumin in its free form. A more than 40 fold increase in the maximum
concentration (C
max
) and a 10 fold increase in AUC in mice were

observed after an oral dose of 1 g/kg of a curcumin nano-emulsion
composed of PEG 600 and Cremophor EL when compared with a
suspension of curcumin in 1% methylcellulose [135]. Khalil et al.
showed that curcumin loaded PLGA and curcumin loaded PLGAe
PEG nanoparticles displayed better pharmacokinetics profiles
compared to a curcumin aqueous dispersion after a single oral dose
of 50 mg/kg in rats (Fig. 9) [78]. The mean half-lives of curcumin
loaded PLGA and curcumin loaded PLGAePEG nanoparticles were 4
and 6 h, respectively, compared to a half-life of free curcumin of 1 h.
It was also shown that for the same formulations the C
max
values
were 2.9 and 7.9 fold, respectively, higher than free curcumin and
the AUCs were 15.6 and 55.4 fold, respectively, higher than free
curcumin. According to the authors, the better performance of the
PLGAePEG nanoformulation was due to the more rapid release of
curcumin from PLGAePEG nanoparticles than from PLGA nano-
particles making the drug quicker available in blood. They also
refered to the lack of interaction of the PEGylated systems with
Fig. 7. Comparison of transfection activity of R7L10-curcumin/pDNA formulation with other carriers as measured by luciferase assay. Reprinted from Biomaterials, Vol. 33/27, J.H.
Park, H.A. Kim, J.H. Park, M. Lee, Amphiphilic peptide carrier for the combined delivery of curcumin and plasmid DNA into the lungs, pp. 6542e6550, Copyright (2012), with
permission from Elsevier.
Fig. 8. The effect of curcumin/LipoePEGePEI complex (LPPC) on tumor growth in vivo.
(A) Balb/c mice were inoculated with CT26 cells and subsequently treated with 2.1 mg/
kg of free curcumin, cationic PEGePEI liposomes (LPPC) or curcumin/LPPC; (B) C57BL/
6J mice bearing B16F10 tumors were treated with 40 mg/kg of curcumin or curcumin/
LPPC. Reprinted from Nanomedicine : Nanotechnology, Biology and Medicine, Vol. 8/3,
Y.L. Lin, Y.K. Liu, N.M. Tsai, J.H. Hsieh, C.H. Chen, C.M. Lin, K.W. Liao, A LipoePEGePEI
complex for encapsulating curcumin that enhances its antitumor effects on curcumin-
sensitive and curcumin-resistance cells, pp. 318e327, Copyright (2012), with permis-

sion from Elsevier.
O. Naksuriya et al. / Biomaterials 35 (2014) 3365e33833374
digestive enzymes present in the gastrointestinal tract as a possible
reason for the better bioavailability of the nanofomulations and
hypothesized that the nanoparticles might be taken up by M cells of
Peyer’s patches or might be taken by enterocytes via a transcellular
mechanism [136,137]. Whether this would imply that the entire
nanoparticle dose translocates to the blood stream is however un-
clear. Song et al. evaluated the pharmacokinetic and biodistribution
of curcumin loaded PLGAePEGePLGA micelles as well as that of a
curcumin aqueous solution also containing 15% of dimethylaceta-
mide, 45% PEG 400 and 40% dextrose [94]. A single dose of 10 mg/kg
of curcumin loaded PLGAePEGePLGA micelles and curcumin so-
lution were intravenously injected into mice. This study revealed
that curcumin loaded PLGAePEGePLGA micelles substantially
improved the AUC, mean residence time, clearance half-life and
distribution halflife (1.3, 2.7, 2.5 and 4.5 fold,respectively) compared
to free curcumin. In another study also supported that the sustained
release of curcumin from the PLGAePEGePLGA micelles resulted in
improved pharmacokinetic parameters [138]. The biodistribution
analysis showed that curcumin loaded PLGAePEGePLGA micelles
yielded higher curcumin concentrations in lung, brain and kidney
and lower curcumin concentrations in spleen and liver than
observed after administration of free curcumin. The authors
remarked that the small size of curcumin loaded PLGAePEGePLGA
micelles (26 nm) and PEG composition of the outer shell avoid up-
take by macrophages of the reticuloendothelial system of liver and
spleen. Particles with a size of less than 50 nm and a neutral or
negative charge are crucial for disposition of nanoparticles in the
brain [139]. Thus, curcumin loaded PLGAePEGePLGA micelles could

permeate through the blood brain barrier and accumulate in the
brain because of their small size and their nearly neutral charge
(zeta potential was À0.7 mV). The authors also suggested that the
accumulation of curcumin loaded PLGAePEGePLGA micelles in the
lungs was due to their small size by which they could pass through
the vascular endothelium and reach the pulmonary alveoli [94,140].
In another study, curcumin was encapsulated into glycerol mono-
oleate based nanoparticles (GMO NP) and showed a 1000 fold
higher peak concentration compared to free curcumin dissolved in
1% v/v of tween 20 at 60 min after intravenous injection in mice.
Furthermore, curcumin from the tween 20 formulation was not
detectable in mice serum 60 min post-administration. Surprisingly,
the peak concentration was not reached at earlier time-points, as
would be expected after intravenous administration, which could
point to a peripheral accumulation of the nanocarrier from which
curcumin (possibly in the form of particles) was subsequently
released [123]. Gao et al. studied the pharmacokinetics and bio-
distribution of a curcumin nanosuspension composed of TPGS (
D
-
a
-
tocopheryl polyethylene glycol 1000 succinate) with a size of
210 nm after an intravenous dose of 15 mg/kg in rabbits and 20 mg/
kg in mice [141]. They reported that the AUC and the mean residence
time of the curcumin nanosuspension were 700
m
g/ml.min and
194 min, respectively. For free curcumin administered in dimethy-
lacetamide and PEG 400 diluted isotonic dextrose solution, the AUC

was 145
m
g/ml min and the residence time 16 min, meaning that
AUC and mean residence time were approximately a factor 4 and 11
higher after nano-encapusulation. It was further shown that 10 min
post injection, the curcumin nanosuspensions deposited in the
lungs, resulting in a high concentration of 10
m
g curcumin per gram
of organ tissue, as well as in the spleen (8
m
g/g) and liver (6
m
g/g).
After administration of free curcumin, the highest concentrations
were measured in the lung (0.5
m
g/g) whereas the levels in liver and
spleen were very low (w0.1
m
g/g). The authors argued that the
curcumin nanosuspensions were phagocytosed by macrophages of
the reticuloendothelial system present in liver, spleen and lung. The
nanoparticles might dissolve in these phagocytic cells and subse-
quently slowly released curcumin in the blood circulation [141]. Zou
et al. prepared polymeric nanoparticles (‘nanocurcumin’) composed
of N-isopropylacrylamide (NIPAAm), vinylpyrrolidone (VP), acrylic
acid (AA), with a size of 92 nm which were loaded with curcumin
(loading capacity of w1% w/w) [142]. This formulation was
administered via a catheter into the left jugular vein of male Spra-

gueeDawley (SD) rats to evaluate the pharmacokinetics of curcu-
min and the tissue distribution of the nanoparticles. The
administration of this nanocurcumin formulation (dose: 10 mg/kg)
resulted in a w1750 greater C
max
of curcumin (25.5 Æ 6
m
g/ml) as
compared to curcumin administered as DMSO/PBS (1:1) formula-
tion. The AUC of curcumin from nanocurcumin group was 51 Æ 14 h.
m
g/ml, while curcumin after administration of the DMSO/PBS
formulation was only detectable 15 min post-injection (14.6 Æ 4 ng/
ml). At the same time point, 8% of the injected dose of the nano-
formulation was circulating which was likely caused by the rapid
burst release of curcumin. The authors discussed that although the
burst release is a limitation for the target delivery for this nano-
curcumin formulation, it still has substantial advantages over free
curcumin because it did not accumulate in lungs and the relatively
small dose of circulating nanocurcumin is available for targeting to a
tumor via the EPR effect [142].
From the studies summarized above, it is evident that nano-
formulations can improve the half-life and AUC of curcumin. Their
small size and slow release profiles contribute to the prolongation
of the elimination time and also the hydrophilic PEG shell present
on the surface of many curcumin nanoformulations may give the
particles ‘stealth’ properties [143e148]. Irrespective of the pres-
ence a PEG-coating, nanoparticles to a large extent, finally end up
in cells of the reticuloendothelial system. Subsequently, they may
degrade slowly in these cells and successively release the active

into the blood circulation [43,149]. Many recent in vivo studies
have demonstrated that curcumin, particularly as nano-
formulation, has chemopreventive as well as chemotherapeutic
effects against various types of cancers. Gong et al. showed that
MPEGePCL polymeric micelles loaded with curcumin more effi-
ciently inhibited angiogenesis in a transgenic zebrafish model than
free curcumin [97]. The same formulations were also evaluated for
efficacy in tumor bearing mice. Fig. 10 demonstrates that the
Fig. 9. Plasma curcumin concentration of different formulations after oral adminis-
tration in rats. Reprinted from Colloids and Surfaces B : Biointerfaces, Vol. 101, N.M.
Khalil, T.C.F.d. Nascimento, D.M. Casa, L.F. Dalmolin, A.C.d. Mattos, I. Hoss, M.A.
Romano, R.M. Mainardes, Pharmacokinetics of curcumin-loaded PLGA and PLGAePEG
blend nanoparticles after oral administration in rats, pp. 353e360, Copyright (2013),
with permission from Elsevier.
O. Naksuriya et al. / Biomaterials 35 (2014) 3365e3383 3375
intravenous injection of these curcumin micelles (dose of 25 mg/
kg of curcumin every 2 days for 14 days) indeed inhibited the
growth of subcutaneous LL/2 pulmonary carcinoma in mice more
effectively than free curcumin [97]. In another study, tumor-
bearing mice were injected intraperitoneally every day for 3
weeks with 12.5 mg/kg body weight of a curcumin nano-
formulation composed of a nonionic biodegradable dendrimeric
glycol ester. This formulation significantly reduced tumor growth
in comparison with free curcumin. Further, longer survival of mice
receiving this dendrosomal curcumin formulation was observed
compared to mice that received free curcumin (70 and 54 days,
respectively) [150]. Recently, Zanotto-Filho et al. developed
curcumin-loaded lipid nanocapsules for the treatment of gliomas
[125]. They showed that these curcumin nanoformulations, when
administered intraperitoneally at a dose of 1.5 mg/kg/day for 14

days, decreased tumor growth as well as the incidence of intra-
tumoral hemorrhages, necrosis and lymphocytic infiltration better
than intraperitoneal administration of a substantial higher dose of
free curcumin dissolved in DMSO (50 mg/kg/day) [125]. Dhule
et al. reported that the intratumoral injection of curcumin loaded
g
-cyclodextrin liposomal nanoparticles administered every 48 h
for 2 weeks effectively induced apoptosis in a xenograft osteo-
sarcoma mouse. However the efficacy of this formulation was not
compared with that of free curcumin [128]. In another study it was
shown that weekly oral administration of curcumin loaded PLGA
nanoparticles (Nano Cur) for 16 weeks (dose 20 mg curcumin/kg)
induced cancer cells apoptosis in diethylnitrosamine (DEN)
induced hepatocellular carcinoma (HCC) rats [76]. Further, Nano
Cur prevented mitochondrial ROS generation, reduction of mem-
brane fluidity and the reduction of antioxidant enzyme levels
(superoxide dismutase, catalase) and reduced glutathione in he-
patic tissues indicating a hepatoprotective effect. Histological ex-
amination of liver tissues further showed that Nano Cur decreased
the formation of hyperplastic nodules and atypical nuclei in the
Nano Cur treated rats, whereas the same dose of free curcumin did
not show these beneficial effects. The authors argued that the
small particle size of Nano Cur (14 nm) might be the reason for its
encouraging efficacy because of the attractive circulation kinetics
and ability to target the liver tumor(s). It should be remarked that
the mechanism by which the nanoparticles reached the circulation
after oral administration was neither investigated nor discussed by
the authors [76]. Murphy et al. reported that curcumin-PEG (dose
of 0.5 mg in 0.1 ml of PBS after intravenous injection) had various
effects on the reproductive system of female and male mice such

as uterine hypertrophy, reduction of folliculogenesis, hustling of
the puberty for female mice and diminishing of accessory gland
weights, testicular testosterone concentrations, and spermato-
genesis of male mice. The authors suggested that the estrogen
mimicking activity of curcumin-PEG could contraindicate the
treatment of breast and ovarian cancers, whereas anti-androgenic
effects would be advantageous for the treatment of e.g. prostate
cancer [151].
Fig. 10. Anticancer activity of free curcumin and curcumin loaded MPEGePCL polymeric micelles. Reprinted from Biomaterials, Vol. 34/4, C. Gong, S. Deng, Q. Wu, M. Xiang, X. Wei,
L. Li, X. Gao, B. Wang, L. Sun, Y. Chen, Y. Li, L. Liu, Z. Qian, Y. Wei, Improving antiangiogenesis and anti-tumor activity of curcumin by biodegradable polymeric micelles, pp. 1413e
1432, Copyright (2013), with permission from Elsevier.
O. Naksuriya et al. / Biomaterials 35 (2014) 3365e33833376
As pointed out above, many studies have shown the efficacy of
curcumin nanoformulations for the treatment of different types of
cancer in animal models. It should be noted however that other
studies have shown the therapeutic potential of curcumin nano-
formulations for treatment and prevention of other diseases than
cancer (studies summarized in Table 2).
5. Clinical trials
Curcumin both in its free form and as nanoformulations has
been under investigation in human clinical trials for many years
and it has shown clinical benefits for patients with colorectal
cancer, pancreatic cancer, breast cancer and multiple myeloma
[161e167]. Curcumin is mostly administered orally in the form of
capsules loaded with its powder and is normally administered in
high doses because of its low bioavailability resulting in low plasma
concentrations (Table 3). These high doses are possible because
dose escalation studies revealed no toxicity and no dose-limiting
toxicity of curcumin at doses up to 12 g per day [29,168,169].
Because of its low bioavailability, in recent years also curcumin

nanoformulations have been evaluated in clinical trials. In a human
pharmacokinetic study [171], a single 650 mg curcumin dose of
orally administered solid lipid nanoparticles to healthy volunteers
achieved a mean C
max
of 22 ng/ml, whereas no detectable plasma
curcumin concentrations were detected after administration of the
same dose of the unformulated curcuminoids extract. In the same
study, higher doses of this solid lipid nanoparticle formulation (2, 3
and 4 g with a curcumin content in the range of 20e30%) were also
given to osteosarcoma patients and it was observed that a higher
dose did not result in higher plasma concentrations (C
max
¼ 33 ng/
ml, 31 ng/ml and 41 ng/ml, respectively). The authors explained that
the non-proportional plasma concentration was caused by complex
absorption kinetics and theinterindividual variability in healthyand
osteosarcoma subjects [171]. In another study, a C
max
value of
29 Æ 13 ng/ml was achieved in healthy volunteers after oral
administration of curcumin nano-colloidal dispersion named
THERACURMIN (curcumin dispersed in gum ghatti, glycerin and
water; formulation prepared using a high pressure homogenizer) at
Table 2
Examples of the application of curcumin nanoformulations for prevention and treatment of other diseases than cancer.
Formulation Dose of curcumin Route of
administration
Duration
of study

Animal Disease Observations Reference
Curcumin loaded p(PEGePLA)
micelles
23 mg/kg weekly Oral 3 months Tg2576 transgenic
mouse
Alzheimer Improved working and
cue memory. Improved
curcumin bioavailability
in brain.
[152]
Curcumin and MRI contrast
agent (GdHPDO3A)
loaded apoferritin
63 mg/kg IP 24 h C57BL mouse Hepatitis Protected livers against
thioacetamide induced
hepatitis. Reduced
necro-inflammation.
[153]
CurcuminemPEGechitosan
film
2.7 mg/3 cm
2
Topical 14 days Adult male Spraguee
Dawley) rat
Wound
healing
Increased collagen
synthesis. 90% wound
reduction.
[154]

Curcumin loaded PEGePCL
micelles in hydrogel
1 mg Topical 7 days Adult male Spraguee
Dawley) rat
Wound
healing
Enhanced wound closure.
Higher collagen content,
better granulation and
higher wound maturity.
[155]
PLGAecurcumin
nanoparticles
0.15 mg/30
m
lof
0.9%w/v NaCl
ID 16 days RjHan:NMRI female
mice
Wound
healing
Enhanced wound closure
by the combined effect
of lactic acid from PLGA
and curcumin. Exhibited
anti-inflammatory effect,
re-epithelialization and
granulation tissue formation.
[156]
Curcumin loaded solid

lipid nanoparticles
25, 50 mg/kg/day Oral gavage
and IV
8 days Male Wistar rat Cerebral
ischemia
Inhibition of lipid
peroxidation. Increased
endogenous antioxidant
defense enzymes. Improved
bioavailability.
[157]
Curcumin loaded solid lipid
nanoparticles
10 mg/kg/day
for 7 days
IP 22 days Balb/c mouse Asthma Suppressed airway
hyperresponsiveness and
inflammatory cell infiltration.
Decreased IL-4 and IL-13 levels.
Increased distribution of
curcumin to the lungs.
[158]
Curcumin loaded chitosan
nanoparticles
33 mg/kg per day for
7 days after induced
infection for 3 days
Oral 10 days Female Swiss mouse Malaria Improved bioavailability of
curcumin. Cured Plasmodium
yoelii infection.

[159]
Formulation of curcumin
with glycerin and
gum ghatti
0.5 mg/kg/day Oral 6 weeks Adult male Spraguee
Dawley) rats
Heart
failure
Restored left ventricular
fractional shortening in
post-myocardial infarction.
[160]
Table 3
Curcumin plasma concentrations observed in humans.
Subject Dose of curcumin
(g/day)/duration
Maximum
plasma
curcumin
concentration
(ng/ml)
Reference
Healthy volunteer 2/1 day 6 Æ 5 [38]
Healthy volunteer 12/3 days 57
a
[168]
Patients with
pancreatic cancer
8/with patients
compliance

29e412 [164]
Patients with
colorectal cancer
3.6/4 months 4.1 Æ 0.2 [29]
Patients with
colorectal cancer
3.6/7 days <1 [170]
a
Plasma curcumin level could be detected in only one patient.
O. Naksuriya et al. / Biomaterials 35 (2014) 3365e3383 3377
a single oral dose of 30 mg, whereas oral adminstration of the same
dose of curcumin resulted in substantially lower concentrations
(1.8 Æ 2.0 ng/ml) [172]. Moreover, the same authors also evaluated
the bioavailability and safety of THERACURMIN at a single dose of
150 mg and 210 mg resulting in C
max
of 189 Æ 48 ng/ml and
275 Æ 67 ng/ml, respectively, indicating that THERACURMIN en-
hances the gastrointestinal absorption and bioavailability of cur-
cumin in a dose-dependent manner. Toxicity of curcumin
nanoformulation was not observed in this study [1 72, 173]. At pre-
sent, there are several clinical trials in which different curcumin
nanoformulations are evaluated [ />Intravenous infusion of liposomal curcumin is evaluated for safety,
tolerability and pharmacokinetics in healthy volunteers by
Department of Clinical Pharmacology, Medical University of Vienna
and SignPath Pharma, Inc (ClinicalTrials.gov Identifier:
NCT01403545). Further, the James Graham Brown Cancer Center is
investigating curcumin conjugated plant exosomes (Clinical-
Trials.gov Identifier: NCT01294072). Exosomes are 40e100 nm cell-
derived vesicles which are formed by the inside budding of large

multivesicular bodies in cytosol. Exosomes are released into the
extracellular space when multivesicular bodies fuse with the cell
membrane and are presently under investigation as drug delivery
system [174,175]. The James Graham Brown Cancer Center sug-
gested that these fruit-derived exosomes strongly absorb curcumin
(and other lipophilic drugs) by hydrophobic interactions [176] and
are taken up by the intestine cells as well as the immune cells
present in the intestine and are therefore suitable to treat intestinal
diseases. Tablets containing plant curcumin-loaded exosomes (no
data about the administered dose were provided) as well as tablets
containing 3.6 g of free curcumin were given daily for 7 days (15
patients suffering from colon cancer/group). The primary outcomes
are the comparison of the effect and the concentration of curcumin
in normal and cancerous tissue after administration of the curcumin
formulations. Safety, immune responses and histochemical staining
are also evaluated as secondary outcomes; however no experi-
mental details on the method are provided. A phase I study of
surface-controlled water-soluble curcumin (THERACURMIN CR-
011L) is done by M.D. Anderson Cancer Center (ClinicalTrials.gov
Identifier: NCT01201694). Surface-controlled water-soluble curcu-
min was given to patients with advanced malignancies at a starting
dose of 100 mg, orally, two times a day of a 28-day cycle. The highest
tolerable dose and thus safety are the aimed outcomes of this study.
In a study carried out by Sasaki et al. a THERACURMIN formulation
was evaluated in healthy human volunteers af ter alcohol drinking
[172]. An oral dose of 30 mg THERACURMIN was administered after
0.5 mg/kg of ethanol consumption and the ethanol and acetalde-
hyde levels in blood were measured at different time intervals. The
authors found that THERACURMIN significantly reduced the acet-
aldehyde plasma concentration after alcohol intake [172]. However,

the mechanism behind this effect was not discussed by the authors.
Shimatsu et al. evaluated the efficacy of THERACURMIN adminis-
tered at doses of 30 mg and 60 mg as curcumin twice daily for 4
weeks in healthy female volunteers. This formulation reduced skin
pigmentation and increased the skin moisture content with 15%
relative to baseline levels. Hence, the authors concluded that
THERACURMIN can be used for the treatment of skin damage, such
as ultraviolet irradiation-induced pigmentation, collagen degrada-
tion and abnormal keratinization [177].
6. Conclusions and prospects
The preclinical and clinical studies of curcumin that have been
carried out over the last ten years have shown that curcumin might
act as a chemopreventing and chemotherapeutic agent. Curcumin
showed inhibition of proliferation and inhibition of growth of many
cancer cell lines. It has been demonstrated that curcumin induced
apoptosis of cells derived from malignancies like leukemia, breast,
colon, hepatocellular, and ovarian carcinomas. On the other hand,
cell lines from lung, kidney, prostate, cervix, central nervous system
(CNS) malignancies, and melanomas were insensitive for curcumin.
The cause of resistance of the mentioned cancer cells to curcumin is
possibly due to the high expression of Hsp70, which has been
shown to protect cells from apoptosis [178]. Although curcumin has
shown cytotoxicity towards cancer cell lines, its potency is sub-
stantially less as compared to current chemotherapeutic drugs. E.g.
it has reported that curcumin is 5 fold less potent than cisplatin in
inhibition of growth and DNA synthesis of human oral squamous
carcinoma cell line (SCC-25) and more than
w5000 fold less potent
than paclitaxel in inhibition of cervical carcinoma cell line (HeLa)
(IC

50
of curcumin ¼ 18
m
M
,IC
50
of paclitaxel ¼ 3n
M
), lung adeno-
carcinoma cell line (A549) (IC
50
of curcumin ¼ 30
m
M
,IC
50
of
paclitaxel ¼ 4n
M
) and colon adenocarcinoma cell line (HT-29) (IC
50
of curcumin ¼ 13
m
M
,IC
50
of paclitaxel ¼ 3n
M
) [60,179,180].How-
ever, most current anticancer therapies involve the modulation of a

single target. It should be mentioned that main drawbacks of such
monotargeted therapies are the ineffectiveness due to induction of
drug resistancy and frequently observed severe side effects [17,21].
Curcumin overcomes the multidrug resistance (MDR) of cancer
cells most likely due to its multi-targeted property. Mechanistically,
it has been demonstrated that curcumin can reverse drug resis-
tance of cancer cells by down-regulating the expression of P-
glycoprotein (P-gp), multidrug resistance associated protein 1
(MRP-1), and mitoxantrone resistance protein (ABCG2) which are
three major proteins responsible for the high drug efflux in
multidrug-resistant cancer cells [181,182]. The multiple pharma-
cological activity of curcumin has therefore gained much attention,
including its combination with ‘normal’ chemotherapeutic drugs
such as doxorubicin, paclitaxel, docetaxel gemcitabine and cisplatin
for improvement of antitumor effects and reduction of dosee
limiting toxicity [183e185]. It has indeed been reported that cur-
cumin in combination with doxorubicin and cisplatin resulted in
additive and synergistic cytotoxic effects on hepatic cancer cells
[186]. In another study, it was shown that the combination of
curcumin and gemcitabine significantly down-regulated the
expression of the cell proliferation marker Ki-67 in tumor tissues of
nude mice indicating a chemosensitizing effect of curcumin [187].
In an in vivo study, mice with multidrug-resistant ovarian tumors
were treated with curcumin in its free form and in combination
with docetaxel for 4 weeks. Treatment with curcumin alone and
combined with docetaxel resulted in significant reductions in tu-
mor growth, 47% and 58%, respectively [188]. As summarized in this
paper, nanoformulations of curcumin have shown superior thera-
peutic effects compared to free curcumin. It is therefore a logical
step that in future (clinical) studies, curcumin nanoformulations

are combined with classical cytostatic drugs such as paclitaxel and
doxorubicin [134,189,190]. These drugs can either be given in their
free form or, preferably, be formulated in the same particle or in
different particles. Indeed, a recent study of Boztas et al. showed
that curcumin and paclitaxel encapsulated in poly(
b
-cyclodextrin
triazine) (PCDT) had synergistic effects on cytotoxicity against
A2780 human ovarian cancer cell lines, SKOV-3 human ovarian
cancer cell lines and the H1299 human nonsmall cell lung carci-
noma cell line [191]. The combination of curcumin-PCDT and
paclitaxel-PCDT also induced both apoptosis and necrosis in the
mentioned cancer cell lines. The IC
50
value of the combination of
paclitaxel-PCDT and curcumin-PCDT was substantially lower than
that of paclitaxel-PCDT alone (approximately 30 fold, 10 fold, 2.5
fold on A2780, SKOV-3 and H1299, respectively). The authors
explained that the higher cytotoxicity was due to the enhanced
intracellular delivery of the two drugs [191].
O. Naksuriya et al. / Biomaterials 35 (2014) 3365e33833378
Liposomes, polymeric micelles and polymeric nanoparticles
have been shown to be attractive systems for the formulation of
curcumin because of their high loading capacity (15e20%) and
small size of 10e100 nm. Although nanoformulations of curcumin
showed good safety profiles in both animals and humans, more
attention should be given on the toxicity of nanoformulations of
curcumin, particularly after (repeated) administration of high dose
formulations. High concentrations of curcumin may increase the
reactive oxygen species (ROS) levels in cells which in turn might

play a role in carcinogenesis [192]. It has also been shown that the
unsaturated ketone tautomeric form of curcumin can bound
covalently to thiol group of cysteine residues of proteins which
subsequently can induce DNA damage and inactivate the tumor
suppressor protein p53 [193,194]. The repeated administration of
PEG-coated nanoformulations should also be considered because it
has been reported that anti-PEG IgM’s are formed after the first
dose of PEGylated nanoparticles [195e199]. This is referred to as
the accelerated blood clearance (ABC) phenomenon [200e202]
which depends on size, surface charge, PEG density, and PEG mo-
lecular weight, but the exact mechanism of this ABC phenomenon
is still unclear [203e205]. Therefore, the development of alterna-
tive surface modifying agents is needed to avoid immune responses
and improve the therapeutic efficiency of pegylated nano-
formulations. Most nanoformulations are developed to avoid up-
take by macrophages of the mononuclear phagocyte system (MPS),
but there was a study published in which macrophages were the
target cells. Sou et al. investigated the targeting of curcumin lipid-
based nanoparticles (phospholipid vesicles or lipid-nanospheres
composed of
L
-glutamic acid, N-(3-carboxy-1-oxopropyl)-, 1,5-
dihexadecyl ester (SA) and 1,2-distearoyl-sn-glycero-3-
phosphoethanolamine-N-[monomethoxy poly(ethylene glycol)
(5000)] (PEGeDSPE) containing curcumin to bone marrow or
splenic macrophages for the treatment of oxidative injury and
inflammation [206,207]. Also in other diseases, such as chronic
inflammation and cancer, targeting local macrophages is attractive
because these macrophages can secrete pro-inflammatory media-
tors that contribute to the disease process. Depending on the

location, the nanoparticles can be either short-circulating to reach
the macrophages in liver and spleen, or need to be long-circulating
to passively accumulate in peripheral diseased sites through the
EPR effect [208e21 0]. Hence, the understanding of pathology in
different diseases and the contribution of the stromal cells to the
disease process is an important factor for the selection of proper
target and the design of curcumin nano-delivery systems for cancer
therapy.
Most nanoformulations are administered parenterally. Howev-
er, generally speaking non-invasive routes of administration (such
as oral, transdermal and pulmonary) are preferred for patients. The
appropriate route of administration depends on the targeted region
in the body and the characteristics of the formulations. Also, the
cost-benefit ratio of nanoformulations and (orally administered)
free curcumin should be analyzed.
Besides the nanosystems discussed in this review, also macro-
scopic systems are of interest, particularly for the local delivery of
curcumin. For instance, curcumin was loaded in a 20 amino acid
peptide with alternating lysine and valine residues that due to an
ionic strength trigger folded into a
b
-hairpin hydrogel [211]. The
authors showed that the concentration of the peptide in the
hydrogel can be used to modulate the release rate of curcumin. It
was also reported that 4 m
M
of curcumin loaded in the hydrogel
revealed cytotoxicity against DAOY human medulloblastoma cell
line through apoptosis. In another approach, curcumin polymers
were obtained by an one-step polycondensation of curcumin,

polyethylene glycol and desamino-tyrosyl-tyrosine ethyl ester
(DTE) [212]. DTE is a derivative of a tyrosine dipeptide which was
used to adjust the hydrophobicity and release of the formed PEG/
curcumin hydrogels. Release is due to hydrolysis of the carbonate
bond between PEG and curcumin. In the initial stage, the hydrolysis
produced some free curcumin and various curcumin conjugates
(curcumin conjugated PEG and DTE monomers/oligomers). Then,
the conjugates were further hydrolyzed to yield free curcumin. A
small burst release was observed and the curcumin derived
hydrogels showed sustained release profiles over 80 days. The au-
thors explained that this sustained release of curcumin was due to
the balance between the curcumin diffusion and swelling kinetics
of the gel. This hydrogel was applied as a cancer suppresser and soft
tissue filler after cancer surgery and showed good efficacy [212].
Nanoformations of curcumin are designed to deliver curcumin
to target sites to improve the therapeutic effects and reduce
possible toxic side effects. As summarized in this review, in vivo
models indeed highlight the potential of curcumin nano-
formulations due to the greater bioavailability (after their oral
administration) and targeting. So far, the emphasis of these nano-
formulations is particularly on treatment of cancer, but some
studies have shown that the formulations have also potential for
the treatment of other chronic and life- threatening diseases
including Alzheimer, diabetes, infections, as well as different liver,
kidney and cardiovascular diseases. Extensive human clinical trials
have to be conducted to establish their safety, especially after
chronic and repeated use, and effectiveness for treatment of cancer
and others diseases.
Acknowledgment
The authors are grateful for financial support received from the

Thailand Research Fund (TRF) through the Royal Golden Jubilee
PhD Program (RGJ)Grant No. 5. G. CM/52/D. 2. IN. We also thank the
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical
Sciences (UIPS), Department of Clinical Chemistry and Hematology,
University Medical Center Utrecht, Utrecht University, the
Netherlands and the Graduate school, Chiang Mai University for
their support.
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