Perspective

Therapeutic
Delivery
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Clay-based drug-delivery systems: what

does the future hold?

Clays for drug delivery have been used from ancient time due to the large availability Giuseppe Lazzara†,1, Serena
of clay minerals and their unprecedented properties. The empirical use of nanoclays Riela†,2 & Rawil F Fakhrullin*,3
from the past is converted in a stimulating scientific task aimed at building up
1
Dipartimento di Fisica e Chimica,
Università degli Studi di Palermo, Viale
nanoarchitectonic vehicles for drug delivery in a targeted and stimuli-responsive
delle Scienze, pad. 17, 90128 Palermo,
fashion. Here the historical aspects are discussed; next the modern examples of Italy
applications of different clay-based materials are discussed. A special focus is given to 2
Dipartimento STEBICEF, sezione di
halloysite clay nanotubes, which are an emerging and very promising nanomaterial for Chimica, Università degli Studi di
drug-delivery purposes due to its special morphology and unique chemical properties. Palermo, Viale delle Scienze, pad. 17,
90128 Palermo, Italy
Advantages and limitations of these natural nanomaterials are critically discussed 3
Institute of Fundamental Medicine and
pointing out the future perspectives and directions for further research. Biology, Kazan Federal University, Kreml
uramı 18, Kazan, Republic of Tatarstan
Keywords:  drug delivery • halloysite • nanoclay • nanotubes 420008, Russian Federation
*Author for correspondence:
kazanbio@ gmail.com
Nanoclays for medical purposes: d­ifferent m­ inerals for medicinal uses and †
Authors contributed equally
from the past to modern regulations were listed, and this was also the
applications first mineralogical classifications.
Nowadays there is a simultaneous and grow- There are several naturally occurring min-
ing interest in the development of innovative erals with tubular morphologies (chrysotile,
process technologies and new materials that cylindrite, tochilinite, among others) whose
can reduce the environmental impact on the structure, occurrence and properties are
ecosystems  [1–3] . Specifically, the researchers extensively reported.
have focused their attention on renewable From the mineralogical viewpoint, nano-
and nontoxic natural resources to face key clays belong to the family of phyllosilicates
environmental problems such as the accumu- composed of tetrahedral and octahedral
lation of wastes and water pollution. sheets. The tetrahedral sheet consists of sili-
Pharmaceutical technology is not an con–oxygen tetrahedra linked to neighboring
exception and natural source excipients are tetrahedra by sharing three corners, which
recovering positions against the synthetic results in a hexagonal network; the remain-
materials  [4,5] . Due to their large availability, ing fourth oxygen of each tetrahedron also
clay minerals are known for medical appli- belongs to the adjacent octahedral sheet.
cation since a very long time [6] . Mixture The latter is usually composed of aluminum
of clay and iron hydroxides have been used or magnesium in sixfold coordination with
by prehistoric ancestors not only for paint oxygen from the tetrahedral sheet and with
caves but also to cure wounds. The clay use hydroxyl groups. The thickness of each layer
is documented in ancient Egypt as anti- is ca. 1 nm and the lateral dimensions may
inflammatory agents and antiseptics. Later change from tenth of nanometers to several
on, in the middle age, Ibn al-Baitar discussed microns. Several layers may be joined in a
eight kinds of medicinal earth. When Phar- clay crystallite by electrostatic force, Van der
macopoeia appeared in Renaissance, clays Waals force, interlayer cations or by hydrogen
have been classified among other drugs. The bonding. These layers organize themselves to part of

10.4155/tde-2017-0041 © 2017 Future Science Ltd Ther. Deliv. (2017) 8(8), 633–646 ISSN 2041-5990 633
Perspective  Lazzara, Riela & Fakhrullin
form stacks with a regular gap called the interlayer or
the gallery. The different arrangement of the tetrahedral
and octahedral sheets allowed us to classify the clays in
three categories: 1:1, 2:1 and 2:1:1 phyllosilicates. The
1:1 phyllosilicates, such as kaolinite and halloysite, have
one tetrahedral and one octahedral sheet per clay layer;
as concerns the 2:1 clay minerals, each layer consists of
one octahedral sheet sandwiched between the two tet-
rahedral sheets. Examples are given by montmorillon-
ite (MTM), and illite. Finally, the 2:1:1 phyllosilicates,
such as cloisite, are composed of an octahedral sheet
adjacent to a 2:1 layer. Because of the isomorphous sub-
stitutions, the clay may have a charge in the sheets.
Drug molecules are encapsulated in clay minerals to
modify the rate, the time and to target the site of drug
release. Moreover, this strategy can be useful to protect
drugs against aging due to chemical and enzymatic
degradation. On this basis, a new concept of ‘excipient’
is generated for clay minerals as they are not inert fillers
but, instead, they can have a functionality providing
targeting release, prevention or reduction of side effects
and increasing the product shelf-life [7] .
Many polymeric materials have been widely inves-
tigated with the same aim, but frequently their prop-
erties need to be improved by addition of inorganic
f­illers, as, again, natural mineral clays.
Immediate release
Prolonged zero order release
100
Drug release (%)
Toxic concentration
Plasma concentration
Minimum effective concentration
no effects
Figure 1. Correlation between drug-release profiles and plasma concentration.
634 Ther. Deliv. (2017) 8(8)
Clays represents a class of old materials that has
never been out of attracting scientific interest due to
the chemical tunability and multiple possible uses in
medical sciences.
Nanoclay for adsorption & sustained release
of drugs
Since last century, controlled drug-delivery systems
(DDS) are a recognized protocol to prepare materi-
als that can efficiently encapsulate drug molecules,
and release them at the target site for a defined period
of time and in a controlled manner. Usually release
dosage forms are known to provide an initial burst
release of the drug, without control upon the release
rate. In order to reach and maintain the therapeutic
plasmatic concentrations a control in the dosage con-
trol is needed. Such a strategy is necessary to avoid
significant fluctuations in the drug on molecular
levels. Indeed, DDS can reduce the patient expenses
as well as the risks of toxicity, while it can improve
the drug efficacy, specificity, therapeutic index and
tolerability of corresponding drugs [8] . Therefore,
the development of both stimuli-responsive and con-
trolled-release systems is crucial for the development
of both clinical medicine and fundamental science
(Figure 1) .
Time
Adverse effects
Therapeutic interval
Time
future science group
 Clay-based drug-delivery systems: what does the future hold?  Perspective
Nanomaterials are considered to be important in
refining drug delivery, and they may be pharmaceuti-
cals as well as diagnostics. In the years several nanoma-
terials, both natural and synthetic, have been consid-
ered and tested as system for synthetize controlled drug
carrier and delivery. Among the plethora of nanomate-
rials, clay minerals are an important, widely abundant,
low-cost and nontoxic class of materials with unique
properties such as intercalation, swelling, ion exchange
and adsorption properties [9] . Normally, in the USA,
clay minerals are used as excipients in commercial-
ized pharmaceutical products [6,10–12] and indicated
as ‘Inactive Ingredient Database’ [13] . Clay minerals
used as ingredients can have some advantages [14–17] .
For example, MTM was used: by Choy et al. for taste
masking of sildenafil improving its organoleptic quali-
ties  [18] ; by Choy et al. for both the taste masking and
solubility enhancement of aripiprazole [19] ; and by
Ambrogi et al. for the photostabilization of photolabile
piroxicam [20] . Furthermore, clay minerals are promis-
ing materials that could be employed as new drug car-
rier and delivery systems in fundamental science and
clinical medicine [21,22] . Indeed, they could be used
to administer drugs to reach the site of action and to
minimize temporal variation in drug concentration,
maintaining a constant release, during the treatment
(Figure 2) [23] .
Until the 1965s, Sorby et al. noted that oral admin-
istration of promazine was reduced by co-administra-
tion of attapulgite clay; indeed, it was observed that
the presence of the clay slowed the appearance of drug
in the urine, confirming the interaction between the
drug and the clay, and they concluded that the adsorp-
tion interaction is important to the effect obtained
in vivo  [24,25] . Up to now the safety proof data of clay
minerals clearly suggest them to be nontoxic for trans-
dermal application, oral administration and so on [26] .
Most of the research concerning the applications of
clay minerals for medical purpose is focused on kaolin
(Si/Al oxide, 1:1), MTM and sepiolite (SPT) (Si/Al
oxide, 2:1), where ca. 1 nm-thick clay alumino-silicate
sheets are stacked in bulky platelets or processed with
exfoliation to bilayer sheets. Halloysite (HNT) (Si/Al
oxide, 1:1) is another nanoclay with great potentials,
where the most common morphology is constituted by
elongated tubule (Figure 3) . Indeed, these clays have
high surface areas, colloidal dimensions of their par-
ticles and an empty cavity, in the case of HNT, that
can encapsulated drug molecules.
Figure 4 reflects the increasing interest of the scien-
tific community toward the use of halloysite nanotubes
as drug carrier and delivery. It is interesting to note
as the percentage (%) of the number of publications
on halloysite as drug carrier (Figure 4B) is duplicate
future science group
Natura
l
Bio
compa
tibility
Increa
se
solubil d
No ity
injecta
ble
High
absorp
No stu tion
die
in hum s
ans
Sustain
ed
releas
e
Figure 2. Comparison between advantages and
disadvantage of clays used as drug carrier.
with respect to the total % on halloysite publications.
Indeed, this interest is confirmed by the highest % of
patent respect to journal publications (Figure 4C), con-
firming the interest to use it in industrial scale.
The preparation of clay–drug complex is usually
carried out mixing, in a proper volume ratio, an aque-
ous dispersion of clay with a solution (water/organic
solvent) of drug. The resulting mixture is allowed to
equilibrate for a suitable time under favorable pH con-
ditions, usually at room temperature; afterward the
solid phase is filtered off, washed several times with the
appropriate solvent to ensure the removal of the physi-
cally adsorbed drug and, finally, dried under vacuum.
There are many mechanisms that can be involved
in the interaction between clay and drug molecules.
They depend on the clay mineral involved as well as
on the physical–chemical and functional groups of
the drugs, which can generate different interactions
such as hydrogen bonding, hydrophilic/hydrophobic
interaction, ion exchange and so on. Clay minerals
are either negatively/positively charged, which is the
main reason for their ion exchange capacity. The so-
called cationic clay minerals (e.g., kaolin, MTM, hal-
loysite) possess an overall mean negative charge due to
the external surface contribution, but also a positive
charge in their interlayer space where interstitial water
molecules are also located. These clays are able to ion
exchange with basic drugs in solution. Furthermore, in
order to develop clay mineral systems for controlled-
release of drugs, a simple procedure is related to the
intercalation of drugs into the clay minerals interlayers.
The possibility of intercalate drugs in the interlayers of
www.future-science.com 635
Perspective  Lazzara, Riela & Fakhrullin
A B
C
Figure 3. Structure of halloysite nanotubes. (A) Schematic representation
of the rolled structure of halloysite; (B) transmission electron microscopy
and atomic foce microscopy images of halloysite nanotube edges;
Reproduced with permission from [26] © Wiley (2015). (C) Field emission
scanning electron microscopy image of halloysite on Si-wafer (left)
and schematic illustration of crystalline structure of halloysite (right).
Reproduced with permission from [27] © The American Chemical Society
(2012).
silicate minerals allows a good opportunity to prepare
inorganic and organic hybrids that possess the typical
features of both the organic guest and inorganic host
in a single material. The drug encapsulation efficacy
(%) and drug content (%) in the clay–drug hybrid are
obtained according to equations (1) and (2) from spectro-
photometric investigations and/or t­hermogravimetric
analysis.
Mass of the drug loaded in the clay
Drug encapsulation efficiency (%) =
Mass of the total drug added
Drug content (%) =
Mass of the drug loaded in the clay
×100
Mass of the clay − drug composite synthesized
The anticancer drug doxorubicin (DOX) was intro-
duced in both kaolin and HNT, reducing toxicity and
increasing the efficiency of release of the drug. A very
high loading capacity, of the drug, was observed in
the two clays (∼54 and 80 wt% in kaolin and HNT,
respectively) at neutral pH. The driving forces, of the
clay–DOX interaction, are predominantly electrostat-
ics between the negative charge present on the siloxane
face of clays and positive DOX. The highest value of
the loading in HNT with respect to that for kaolin
is probably due to the possibility of encapsulate DOX
in the nanotube lumen. The acidity of solutions, in
both cases, shows significant effect on DOX release
from clay-DOX hybrid confirming that the electro-
static interactions occur in both hybrids; indeed, under
imulated tumor intracellular conditions (pH 5.5),
­ HNT promotes the loading of ibuprofen by creating
636 Ther. Deliv. (2017) 8(8)
clay–DOX showed a faster DOX release rate, with
cumulative release of approximately 30% over 30 h
respect to neutral conditions were only a 5% of drug
released was observed [28,29] .
The kinetics of drug release from clay are complex
mechanisms. Generally, the active molecules release
profiles can be described by several kinetics models, as
summarized in Table 1.
Ft indicates the drug release fraction at time t, k is
the kinetic release constant of the respective equations,
t is the release time and n is the characteristic diffusion
exponent, depending on the release mechanism and the
geometry of the device. If Fickian diffusion occurs, n
decreased to 0.5 for slab/cylinder/sphere. If non-Fick-
ian (anomalous) diffusion dominates, the n value is
between the above value corresponding to the polymer
chain relaxation (n < 1) for slab/cylinder/sphere. Thus,
the drugs release mechanism can be identified through
determination of the n value. It should be noted that
clays have at least two different chemistry surfaces pro-
viding at least two different binding mechanisms that
make the release kinetics complex.
With regard to DEM model, it describes a mecha-
nism consisting of two parallel reactions involving spe-
cies adsorbed into two different sites [37,38] . Finally, the
Hill model assumes that adsorption is a cooperative
phenomenon where the ligand binding ability at one
site on the substrate may influence different binding
sites on the same substrate [34] .
Sciascia et al. evaluated the potential applicability as
DDS of MTM and Tween 20-MTM with respect to the
cinnamic acid drug. The adsorption isotherms of cin-
namic acid onto both the MTM and organoclay follow
a sigmoidal shape where the affinity of the drug toward
×100
the clays increases with the amount of adsorbed drug.
The data were analyzed by several models, and it turned
out that the Hill equation represents the most reliable
model. Differently, under conditions that mimic oral
drug administration and the consequent physiological
release (pH 1 and 6.8, at 37.0°C) the system followed a
DEM release profile [39] . Turco Liveri et al. immobilized
commercial Vitamin A (VitA) in MTM and SPT by
impregnation. The studies of kinetic release showed that
the release of VitA depends on the nature of the support
as well as on the pH. Besides the controlled release, it
was demonstrated that the SPT is able to prevent the
oxidative degradation of the VitA [40] . An improvement
in the solubility, and in the control/release of ibuprofen,
with high permeability and low solubility, was archived
by loading it with several clays such as kaolin [41] ,
MTM  [42] , HNT and covalently modified HNT with
3-aminopropyltriethoxysilane  [43–45] . It is worth not-
ing that organosilane modification of external face of
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 Clay-based drug-delivery systems: what does the future hold?  Perspective

A
Halloysite
Kaoline
Montmorilonite
Sepiolite
Other

B C

6% 11%
27%
Halloysite
Kaoline Journal
Montmorilonite Patent
ite

e
Sepiolite
ys

lin

e
nit

lite
llo

o
Ka

ilo
Ha

pio
or
56%

Se
ntm
Mo

Figure 4. Increasing interest of the scientific community toward the use of halloysite nanotubes as drug carrier
and delivery. Comparison of the number of scientific publications on the (A) ‘halloysite’, ‘kaolin’, ‘montmorillonite’
and ‘sepiolite’ terms, and (B) ‘halloysite’, ‘kaolin’, ‘montmorillonite’ and ‘sepiolite’ refined each with the term
‘drug’; (C) distribution (%) of scientific publications in ‘patent’ and ‘journal’ for each clay investigated. Data
analysis of publications, as on February 2017, was done using the SciFinder Scholar search system using as
‘Document type’ the ‘Journal’ and ‘Patent’, only.

an electrostatic attraction between the carboxyl groups
present in the drug molecule and the grafted aminopro-
pyl groups in the clay. The electrostatic attraction was
stronger than the hydrogen bonding interactions in the
ibuprofen–HNT hybrid (Figure 5).
Halloysite nanotubes
Halloysite as nanocontainer
Toxicity studies on halloysite nanotubes toward living
organisms have been widely reported and the general
outcome is that HNTs can be considered a safe materi-
als in a very wide concentration range [46,47] . Halloysite
has an advantage over other clays because it does not
need exfoliation, which is typically time consuming
and expensive, and can be easily dispersed in pharma
formulations. Phytotoxic study on Raphanus sativus
L proved a low impact on plant life by halloysite [48] .
HNT is proved to be a biocompatible material also
for human cell cultures such as breast cancer cells [49] ,
thyroid cancer cells [17,38,50] , hepatic cancer cells [51,52]
and epithelial adenocarcinoma cells [49] . It was dem-
onstrated that concentration up to 0.2 g/dm3 can
be considered safe, this value is typical for i­norganic
inclusions. The interaction of halloysite nanotubes
with microscopic algae Chlorella pyrenoidosa was inves-
tigated and no penetration of the nanomaterials into
cell interior was observed [53] . It was also reported that
halloysite nanotubes were safe for one of the most
common fresh water ciliate protist Paramecium cauda-
tum  [54] . Similarly, HNTs exhibits no toxicity toward
Escherichia coli bacteria [55] and yeast cells [56] .
Toxicity in vivo tests were reported for free living
nematodes (worms) Caenorhabditis elegance [46] , proved
that HNTs did not enter the worms as they accumu-
lated within the intestines, inflicting only mechanical
stress onto the alimentary system (Figure 6) .
Based on the safety concerns of bare HNTs, research
was devoted to their use as carrier for drugs. The most
attractive feature of halloysite is its inner lumen with a
diameter capable of entrapping chemical agents such
as macromolecules, including drugs, DNA, proteins
and other chemically active agents, for example, anti-
corrosion for protective coating [57–59] . In this context
the empty lumen of halloysite acts as a nanocontainer
for processes that benefit from suitable molecules
s­ustained release  [60–65] .

future science group www.future-science.com 637

Perspective  Lazzara, Riela & Fakhrullin
Table 1. Kinetic and isotherm equations.
  Equation
First-order kinetic
Ft = M ∞ (1 − e − kt )
Higuchi square kinetic
Ft = kt1/ 2
Korsmeyer–Peppas model
Ft = kt n
DEM
Ft = Fe′ ⋅ (1 − e − k′t ) + Fe′′⋅ (1 − e − k′′t )
Hill
Q m ⋅ ( K H ⋅ Ce ) ⋅ n
Qe =
1 + ( K H ⋅ Ce ⋅ n )
Langmuir
K L Q m Ce
Qe =
1 + K L Ce
Freundlich
Q e = K F Ce
1/ n
DEM: Double exponential model.
Electrostatic interactions can be used to target the
adsorption site of specific molecules. In this context,
Lvov  et al. reported the immobilization of laccase,
glucose oxidase, lipase and pepsin at inner or outer
n­anotube surface  [66] .
Besides drug immobilization in HNT inner
lumen, some inorganic salts can be loaded and release
from halloysite lumen [67] . Complete release of the
inorganic compounds from halloysite nanotubes is
achieved within 1–2 h. The introduction of anionic
surfactant in the inner lumen is a possible strategy
to obtain hydrophobic cavity [68,69] . Loading dioctyl
sulfosuccinate sodium salt allowed to use HNT as
cargo to stabilize oil-in-water emulsions [70] . Reverse
micelles for water-in-oil emulsion were prepared by
using cationic surfactant adsorbed selectively onto
the external surface [71] .
The introduction of targeting moieties on halloysite
surface can generate an accumulation of halloysite into
the cell, with specific interaction including high pro-
pensity to cross-cell membranes penetrating even into
the cell nucleus. This aspect will be discussed in the
next paragraph.
Halloysite-based smart nanocomposites with
stimuli responsive features
More recently, the research was devoted to find more
complex nanoarchitectures to approach a stimuli
responsive drug release, compatibilization of the drug
carrier, multiple drug delivery or a combination of such
features. With this aim, HNT-based n­anocomposites
638 Ther. Deliv. (2017) 8(8)
Ref.
[30]
[31]
[32]
[33]
[34]
[35]
[36]
and/or its chemical modification is needed. Fakhrul-
lin et al.  [72] fabricated a novel DDS based on HNTs
loaded with brilliant green, as a drug model, and coated
with dextrin to clog the tube opening until the cell
absorbs these nanocarriers where sugar can be cleavable
by intercellular glycosyl hydrolases. Such a strategy
allowed the accumulation and enzymatically induced
release of drug in cells with higher proliferation rates,
which is a characteristic of tumoral cells (Figure 7) .
The curcumin (Cur) selective release was achieved by
covalent linking on halloysite external surface through
glutathione or pH responsive bonds (HNT‑Cur
p­rodrug)  [51] .
Under normal physiological conditions, the
h­a lloysite prodrug showed relatively good stability, and
as a consequence of the dual stimuli-responsive nature
of this nanomaterial, enhanced release of Cur was
observed upon exposure of the prodrug to acidic or
glutathione-rich conditions similar to the cellular
microenvironment of hepatic cancer cells (Figure 8) .
Stimuli responsive polymers are another class of
compounds whose conformation varies upon an
external stimulus such as temperature, change in
light, pH and so on. Therefore, covering halloysite
surface with these types of polymers could generate
novel materials with lots of applications in the field of
scaffolds for tissue engineering, biosensors and DDS.
In particular, thermo-responsive system was
obtained by introducing a thermo-responsive poly-
mer such as poly(N-isopropylacrylamide) on halloy-
site surface [52] . This polymer was attached, by amide
future science group
 Clay-based drug-delivery systems: what does the future hold?  Perspective

IBU loading (mass %)

Hydrogen bonding
0
11.7% Halloysite

ln (%release)
-1
11.8% Heated halloysite
In vitro release
IBU curve of IBU -2
12.7%

APTE8-modified halloysite Modified Korameyer-Pappas model

f = af + b -3

14.8%
-1 0 1 2 3 4
APTE8-modified and Electrostatic attraction
ln (time)
heated halloysite

Figure 5. Schematic representation of ibuprofen loading and release on halloysite and modified halloysite.
Reproduced with permission from [44] © Elsevier (2014).

c­
ondensation, on external HNT surface previously undergoes a coil-to-globule transition at the lower crit-
modified with 3-aminopropyltrimethoxysilane. A ical solution temperature, around 32°C, temperature-
large surface density of polymer onto the nanotubes responsive features were observed. This material was
was endowed by the synthetic route adopted in this used for Cur delivery; the drug was loaded onto the car-
work. As the poly(N-isopropylacrylamide) corona rier at 25°C, whereas the drug release was investigated

Mouth
A B C D
Intestine Uterus Intestine
Procorpus
Vulva
Eggs Rectum
Metacorpus
Eggs
Isthmus

E F G
Cumulative number of worms (%)

Cumulative survival of worms

% of eggs refer to control

Body weight (µm) HNTs (mg/ml) Time (days)

Figure 6. Dark-field microscopy imaging of distribution of halloysite in Caenorhabditis elegance worms. (A) Inside the foregut;
(B and C) in the midgut (no nanotubes in embryos, uterus and vulva were detected); (D) inside the hindgut. (Bottom images)
In vivo effects on C. elegance growth and fertility: (A) the cumulative curves of body length of nematodes treated with increasing
concentrations of halloysite (mg ml-1); (B) the influence of tube concentration on fertility in adult hermaphrodites; (C) cumulative
survival curve for increasing concentrations of halloysites (mg ml-1).
Reproduced with permission from [46] © The Royal Society of Chemistry (2015).

future science group www.future-science.com 639

Perspective  Lazzara, Riela & Fakhrullin

A
BG Dextrin
Dextrin
stoppers

Loaded BG

B C D E

Figure 7. Halloysite-based prototype nanocontainers for drug delivery. (A) Fabrication of BG-loaded HNTs and the subsequent
coating with dextrin stoppers. (B) Transmission electron microscopy (TEM) image of BG-loaded halloysite; (C) scanning electron
microscopy image of a dextrin cap on the end of the functionalized nanotube; (D) TEM images of A549 cell incubated with dextran-
coated clay nanotubes; (E) resazurin assay results demonstrating the medial lethal dose (LD50 ) value of BG-loaded halloysite for A549
cells. The insets show atomic force microscopy images of the distribution of doxorubicin-halloysite in the A549 cells.
BG: Brilliant green.
Reproduced from [72] under Creative Commons license (2015).

at 37°C in a media that simulate the gastrointestinal This novel nanomaterial represents an example of a
transit (Figure 9) . The in vitro release tests showed a prolonged antioxidant synergistic protection where the
targeted and sustained release of the active species into antioxidant function was attributed to Trolox, which is
the intestine. grafted on the HNT external surface, whereas querce-
A synergic nanoantioxidant was proposed using tin, supramolecular loaded in the inner lumen, acts as
Trolox covalently linked on the external surface of a second co-antioxidant (Figure 10) .
h­a lloysite and quercetin loaded into HNT lumen [74] . Recently, the development of a dual drug delivery
is an important task of scientific community since it
MeO OH offers remarkable advantaged if compared with the
traditional single dosage. Co-delivery, indeed, may
enhance a kind of synergism between different drugs,
O increasing therapeutic target selectivity, reducing
1) HS NH3
Cl O Si N the drug resistance through distinct mechanisms of
O Si SH S S
O
OMe O O
O
OMe action.
2) MeO OMe
HO OH Recently Zhou et al. reported a dual-DDS compris-
O MeO OH ing poly(L-lactide)/HNTs electrospun mats capable of
O Si OH
O
Si OH
O co-delivering hydrophilic (polymixin B) and hydro-
phobic (dexamethasone) drugs [75] . Filling of electro-
HNT-SH HNT-Cur prodrug
HNT-SH HNT-Cur prodrug spun poly(L-lactide) mats with HNTs makes that the
nanocomposite obtained presents an increase in the
Figure 8. Schematic representation of the synthesis of the halloysite
nanotubes-curcumin prodrug.
breaking stress and, in addition, the mats degraded
HNT: Halloysite nanotubes. more rapidly if compared with pure electrospun mats,
Reproduced with permission from [73] © The Royal Society of Chemistry (2017). under the same conditions. Moreover, the presence

640 Ther. Deliv. (2017) 8(8) future science group

 Clay-based drug-delivery systems: what does the future hold?  Perspective

PNIPAAM

Loading Release
Functionalization
25°C, pH 7.4 37°C, pH 6.8

Figure 9. Schematic representation of temperature-triggered loading and release of curcumin into halloysite
nanotubes modified with poly(N-isopropylacrylamide).
Reproduced with permission from [73] © The Royal Society of Chemistry (2017).

of HNTs in the fibers facilitated tunable release of
polymixin B and dexamethasone that is interesting in
p­roducing wound-dressing materials.
Another dual-drug loaded HNT delivery system
was obtained by the covalent linkage of β-cyclodextrin
(β-CD) units on HNT external surface [76] . CDs are
well known in drug delivery due to their capacity
to entrap hydrophobic drugs. Thanks to the pres-
ence of two different cavities, it is possible to encap-
sulate two or more drug molecules s­imultaneously.
In this context different systems were developed
(Figure 11) . Such a multicavity nanomaterial was used
for the simultaneous co-delivery of quercetin and
silibinin  [38] . Experimental data highlighted that the
quercetin molecules interact preferentially with the
hydrophobic CD cavity, while the silibinin only with
the HNT lumen. The interaction between cells and
the carrier revealed that the materials were taken up
into cells surrounding the nuclei.
The introduction of targeting functionalities as
well as glycocluster effect on halloysite/CD systems
were achieved by attaching on the β-CD core several
m­annose units  [50] .
The final aspect to clarify in a possible future use
of halloysite as drug carrier and delivery systems is
related to the real possibility to use these nanoma-
terials in pharmaceutical science. Since halloysite is
not biodegradable nanomaterial it cannot be injected
intravenously. The use of modified halloysite is
li­mited as an active ingredient in external medical
treatment with slow release of encapsulated drugs
(e.g., in implants, creams or wound treatment of
t­issues)  [10,65] .
In this context, the modification of HNT external
surface with amino acid derivatives allows to obtain
nanohybrids that can be incorporated in a peptide
hydrogel to obtain novel drug carrier applicable in
transdermal therapy [77] . HNT-NH 2 nanomaterial
was used as intermediate to covalent link Fmoc-
phenylalanine (f-HNT). This amino acid is able to
give hydrogels featured by the presence of uniform
entangled fibers. Unlike in the case of silane-mediate
aminogroup tailoring [78] the presence of the amino
acidic functionality on HNT surface allows specific
π–π interaction between modified HNT and Fmoc-
phenylalanine-generating hybrid supramolecular

A B
Stoichiometric coefficient

HNT-Trolox Quc

ROO• DPPH•
HNT-Trolox HNT-Trolox/Quc

Figure 10. (A) Schematic representation of quercetin loading into HNT–Trolox. (B) Synergic effect in HNT–Trolox/
Que: experimental stoichiometric coefficient in MeCN (blue bars, ±SD, N = 3) compared with theoretic one, as
calculated from the sum of contributions of HNT–Trolox (green bars) and HNT/Que (red bars) alone.
HNT: Halloysite nanotubes.
Reproduced with permission from [73] © The Royal Society of Chemistry (2017).

future science group www.future-science.com 641

Perspective  Lazzara, Riela & Fakhrullin

OTBDMS
7

O
O
MeO S
O
Si O
O O O
O O

OAc
AcO
O
AcO
1) AcO HNT-βCD
SH n SH
2) MeONa/MeOH
3) BF3OEt2

HO
HO O
HO
OH OTBDMS
HO
S 7 7

n S O
O O
O
MeO S
MeO S O
O Si O
Si O S O O O O S
O O O O O n
O HO
HO O S
n
O S
HO S S
HO HO S
HO
O S S n S n
HO
HO O
HO O
HO HO HO OH

n
OH
OH HO HO OH
OH
OH
HNT multicavity
HNT-CD
Drugs Drugs
Drugs Drugs

Figure 11. Schematic representation of the synthesis of the halloysite nanotubes multicavity and halloysite
nanotubes-cyclodextrin.

h­ydrogel with peculiar physico-chemical properties. halloysite clay is concerned, another difficulty that is
Deep investigation of hybrid gel properties, indeed, worth of being investigated in the future is the pos-
showed that the introduction of HNT filler in the sibility to ‘clean’ HNT samples obtaining more uni-
hydrogel matrix induced decreased thermal stabil- form nearly monodisperse nanotubes. This is crucial
ity but, in general, a concomitant increase in the in applications as release properties are influenced
gel strength. The hybrid hydrogel was employed for by the HNT deposit and polydispersion distribution
camptothecin delivery. Release tests in physiologi- in sizes. On the other hand, Halloysite used as DDS
cal conditions showed a synergistic action of HNTs could have an advantage due to the biocompatibility,
and gel matrix, as accounted for by the best drug low cost and natural resources of the material and the
d­ispersion and the slower rate of release as a conse- simple methods used to prepare dosage forms. These
quence of the HNTs incorporation in the gel phase. characteristics should allow for quick industrial scale-
up. The goal should be to increase the use of halloysite
Conclusion & future perspective clay nanotubes in DDS suitable for different routes of
Clay minerals-based materials are very promising for administration. In the near future, we foresee its usage
the development of DDS. Although there are a number in medical cosmetic formulations, animal treatment,
of papers on this direction, there are still several issues in dental resins, for timed-release antimicrobial spray
to be solved and other opportunities to be investigated. and as a tableting excipient. The possibility to prepare
Due to their inorganic nature, the route of adminis- smart caps as well as the possibility to use HNT inter-
tration are somehow limited as the blood injection is layers beside its cavity are also opening bright perspec-
not yet considered safe unless further in vivo tests are tives for developing controlled/targeted delivery sys-
able to find a possible route for the elimination of this tems. In this context, HNTs could be used as a tablet
inorganic material from the blood flow. As far as the for delivery and controlled-release of several drugs.

642 Ther. Deliv. (2017) 8(8) future science group

 Clay-based drug-delivery systems: what does the future hold?  Perspective

Financial & competing interests disclosure
This work was funded by the subsidy allocated to Kazan Fed-
eral University for the state assignment in the sphere of scien-
tific activities (16.2822.2017/4.6). The work was performed
according to the Russian Government Program of Competi-
tive Growth of Kazan Federal University. The work was par-
tially supported by the University of Palermo, FIRB 2012 (prot.
RB‑FR12ETL5). The authors have no other relevant affiliations
or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject mat-
ter or materials discussed in the manuscript apart from those
disclosed.
No writing assistance was utilized in the production of this
manuscript.

Executive summary
Nanoclays for medical purposes: from the past to modern applications
• Clay minerals have been known for medical applications since a very long time from ancient Egypt to
Renaissance.
• Drug molecules are encapsulated in clay minerals to modify the rate, the time and to target the site of drug
release.
• Clay minerals as they are not inert fillers but, instead, they can have a functionality providing targeting
release, prevention or reduction of side effects and increasing the product shelf-life.
Nanoclay for adsorption & sustained release of drugs
• Drug-delivery system is a recognized protocol to increase the drug specificity, efficacy, tolerability and
therapeutic index.
• Clay minerals are used as excipients in commercialized pharmaceutical products and indicated as ‘Inactive
Ingredient Database’.
• Most of the research concerning the applications of clay minerals for medical purpose is focused on kaolin,
montmorillonite, sepiolite and, more recently, halloysite nanotubes.
• Interaction between clay and drug molecules depend on functional groups of the drugs, which can generate
different interactions such as hydrogen bonding, hydrophilic/hydrophobic interaction, ion exchange and so on.
• The kinetics of drug release from clay are complex mechanisms as clays have at least two different chemistry
surfaces providing at least two different binding mechanisms.
Halloysite nanotubes
• Halloysite as a nanocontainer.
• Halloysite nanotubes can be considered a safe materials toward living organisms such as plant, human cell,
microscopic algae Chlorella pyrenoidosa, ciliate protist Paramecium caudatum, Escherichia coli bacteria, yeast
cells and free living nematodes (worms) Caenorhabditis elegance.
• The most attractive feature of halloysite is its inner lumen with a diameter capable of entrapping chemical
agents. Electrostatic interactions can be used to target the adsorption site of specific molecules.
Halloysite-based smart nanocomposites with stimuli-responsive features
• Complex nanoarchitectures can be achieved to approach a stimuli responsive drug release, compatibilization
of the drug carrier, multiple drug delivery or a combination of such features.
• Halloysite nanotubes coated with dextrin was a strategy to clog the tube opening until the cell absorbs these
nanocarriers where sugar can be cleavable by intercellular glycosyl hydrolases.
• The drug selective release was achieved by covalent linking on halloysite external surface through glutathione
or pH responsive bonds.
• Covering halloysite surface with these types of polymers could generate novel materials with lots of
applications in the fields of scaffolds for tissue engineering, biosensors and drug-delivery systems.
• A synergic nanoantioxidant was proposed using Trolox covalently linked on the external surface of halloysite
and quercetin loaded into HNT lumen to regenerate the main antioxidant and afford a prolonged synergistic
protection.
• Dual-drug loaded halloysite nanotubes delivery system was obtained by the covalent linkage of β-cyclodextrin
units on nanotubes external surface. The presence of two cavities offers the remarkable possibility for a
simultaneous encapsulation of two or more drug molecules with different physico-chemical properties,
followed by a different release path.

2 Abe H, Liu J, Ariga K. Catalytic nanoarchitectonics for

References environmentally compatible energy generation. Mater.
Papers of special note have been highlighted as: • of interest
Today 19(1), 12–18 (2016).
1 Kazuhiko M, Kazunari D. Development of novel
3 Kuwahara Y, Tamagawa S, Fujitani T, Yamashita H.
photocatalyst and cocatalyst materials for water splitting
Removal of phosphate from aqueous solution using layered
under visible light. Bull. Chem. Soc. Jpn 89(6), 627–648
double hydroxide prepared from waste iron-making slag.
(2016).
Bull. Chem. Soc. Jpn 89(4), 472–480 (2016).

future science group www.future-science.com 643

Perspective  Lazzara, Riela & Fakhrullin
4 Ariga K, Ji Q, McShane MJ, Lvov YM, Vinu A, Hill JP.
Inorganic nanoarchitectonics for biological applications.
Chem. Mater. 24(5), 728–737 (2012).
5 Ruiz-Hitzky E, Aranda P, Darder M, Rytwo G. Hybrid
materials based on clays for environmental and biomedical
applications. J. Mater. Chem. 20(42), 9306–9321 (2010).
6 Carretero MI. Clay minerals and their beneficial effects upon
human health. A review. App. Clay Sci. 21(3–4), 155–163
(2002).
7 Aguzzi C, Cerezo P, Viseras C, Caramella C. Use of clays as
drug-delivery systems: possibilities and limitations. App. Clay
Sci. 36(1–3), 22–36 (2007).
8 75/18/Eec D. Quality of prolonged release oral solid dosage
forms. In: Dictionary of Pharmaceutical Medicine.34 (1992).
9 Naumenko EA, Fakhrullin RF. Toxicological evaluation of
clay nanomaterials and polymer-clay nanocomposites. In:
Functional Polymer Composites with Nanoclays.RSC Smart
Materials Lvov Y, Guo B, Fakhrullin RF(Eds). 399–
419 (2017).
10 Yendluri R, Otto DP, De Villiers MM, Vinokurov V,
Lvov YM. Application of halloysite clay nanotubes as a
pharmaceutical excipient. Int. J. Pharm. 521(1–2), 267–273
(2017).
• Demonstrates the fabrication of a versatile halloysite-based
pharmaceutical delivery platform.
11 Bergaya F, Lagaly G. Handbook of Clay Science, Volume 5 2nd
Edition.Bergaya F, Lagaly G (Eds). (2013).
12 Park J-H, Shin H-J, Kim MH et al. Application of
montmorillonite in bentonite as a pharmaceutical excipient
in drug-delivery systems. J. Pharm. Invest. 46(4), 363–375
(2016).
13 FDA. Inactive ingredients database for approved drug
products. FDA/Center for Drug Evaluation and Research.
Office of Generic Drug. Division of Labelling and Program
Support (2009).
14 Mahmoudi M, Adib-Hajbaghery M, Mashaiekhi M.
Comparing the effects of bentonite & calendula on the
improvement of infantile diaper dermatitis: a randomized
controlled trial. Indian J. Med. Res. 142(6), 742–746 (2015).
15 Li S, Jiang C, Chen X, Wang H, Lin J. Lactobacillus
casei immobilized onto montmorillonite: survivability in
simulated gastrointestinal conditions, refrigeration and
yogurt. Food Res. Int. 64, 822–830 (2014).
16 Khediri F, Mrad AI, Azzouz M et al. Efficacy of diosmectite
(Smecta) ® in the treatment of acute watery diarrhoea in
adults: a multicentre, randomized, double-blind, placebo-
controlled, parallel group study. Gastroenterol. Res.
Pract. 2011, 783196 (2011).
17 Riela S, Massaro M, Colletti CG et al. Development and
characterization of co-loaded curcumin/triazole-halloysite
systems and evaluation of their potential anticancer activity.
Int. J. Pharm. 475(1–2), 613–623 (2014).
18 Lee JH, Choi G, Oh YJ et al. A nanohybrid system for taste
masking of sildenafil. Int. J. Nanomedicine 7, 1635–1649
(2012).
19 Oh Y-J, Choi G, Choy YB et al. Aripiprazole-
montmorillonite: a new organic-inorganic nanohybrid
644 Ther. Deliv. (2017) 8(8)
material for biomedical applications. Chemistry 19(15),
4869–4875 (2013).
20 Ambrogi V, Nocchetti M, Latterini L. Promethazine–
montmorillonite inclusion complex to enhance drug
photostability. Langmuir 30(48), 14612–14620 (2014).
21 Viseras C, Cerezo P, Sanchez R, Salcedo I, Aguzzi C.
Current challenges in clay minerals for drug delivery. App.
Clay Sci. 48(3), 291–295 (2010).
22 Ariga K, Abe H, Ji Q, Lvov YM. Halloysite and
related mesoporous carriers for advanced catalysis and
drug delivery. In: Functional Polymer Composites with
Nanoclays. RSC Smart Materials Lvov Y, Guo B, Fakhrullin
RF (Eds). 207–222 (2017).
23 75/318/Eec D. Quality of prolonged release oral solid dosage
forms. (1992).
24 Sorby DL, Liu G. Effects of adsorbents on drug absorption
II: effect of an antidiarrhea mixture on promazine
absorption. J. Pharm. Sci. 55(5), 504–510 (1966).
25 Sorby DL. Effect of adsorbents on drug absorption
I. Modification of promazine absorption by activated
attapulgite and activated charcoal. J. Pharm. Sci. 54(5),
677–683 (1965).
26 Lvov Y, Wang W, Zhang L, Fakhrullin R. Halloysite clay
nanotubes for loading and sustained release of functional
compounds. Adv. Mater. 28(6), 1227–1250 (2015).
27 Yah WO, Takahara A, Lvov YM. Selective modification
of halloysite lumen with octadecylphosphonic acid: new
inorganic tubular micelle. J. Am. Chem. Soc. 134(3),
1853–1859 (2012).
28 Zhang Y, Long M, Huang P et al. Emerging integrated
nanoclay-facilitated drug-delivery system for papillary
thyroid cancer therapy. Sci. Rep. 6, 33335 (2016).
29 Li L, Fan H, Wang L, Jin Z. Does halloysite behave like an
inert carrier for doxorubicin? RSC Adv. 6(59), 54193–54201
(2016).
• A facile and effective method to fabricate anticancer drug-
carrier halloysite platforms using halloysite nanoclay.
30 Gibaldi M, Feldman S. Establishment of sink conditions in
dissolution rate determinations. Theoretical considerations
and application to nondisintegrating dosage forms. J. Pharm.
Sci. 56(10), 1238–1242 (1967).
31 Higuchi T. Mechanism of sustained-action medication.
Theoretical analysis of rate of release of solid drugs dispersed
in solid matrices. J. Pharm. Sci. 52(12), 1145–1149 (1963).
32 Ritger PL, Peppas NA. A simple equation for description of
solute release I. Fickian and non-Fickian release from non-
swellable devices in the form of slabs, spheres, cylinders or
discs. J. Control. Release 5(1), 23–36 (1987).
33 Wilczak A, Keinath TM. Kinetics of sorption and desorption
of copper (II) and lead (II) on activated carbon. Water
Environ. Res. 65(3), 238–244 (1993).
34 Ringot D, Lerzy B, Chaplain K, Bonhoure JP, Auclair E,
Larondelle Y. In vitro biosorption of ochratoxin A on the
yeast industry by-products: comparison of isotherm models.
Bioresour. Technol. 98(9), 1812–1821 (2007).
35 Langmuir I. The constitution and fundamental properties
future science group
 Clay-based drug-delivery systems: what does the future hold?  Perspective
of solids and liquids. part i. solids. J. Am. Chem. Soc. 38(11),
2221–2295 (1916).
36 Wu XL, Zhao D, Yang ST. Impact of solution chemistry
conditions on the sorption behavior of Cu(II) on Lin’an
montmorillonite. Desalination 269(1–3), 84–91 (2011).
37 Sciascia L, Turco Liveri ML, Merli M. Kinetic and equilibrium
studies for the adsorption of acid nucleic bases onto K10
montmorillonite. App. Clay Sci. 53(4), 657–668 (2011).
38 Massaro M, Piana S, Colletti CG et al. Multicavity
halloysite-amphiphilic cyclodextrin hybrids for co-delivery
of natural drugs into thyroid cancer cells. J. Mater. Chem.
B 3(19), 4074–4081 (2015).
39 Calabrese I, Gelardi G, Merli M, Liveri MLT, Sciascia L.
Clay-biosurfactant materials as functional drug-delivery
systems: slowing down effect in the in vitro release of
cinnamic acid. App. Clay Sci. 135, 567–574 (2017).
40 Calabrese I, Turco Liveri ML, Ferreira MJ et al. Porous
materials as delivery and protective agents for Vitamin A.
RSC Adv. 6(71), 66495–66504 (2016).
41 Mallick S, Pattnaik S, Swain K et al. Formation of physically
stable amorphous phase of ibuprofen by solid state milling
with kaolin. Eur. J. Pharm. Biopharm. 68(2), 346–351
(2008).
42 Dziadkowiec J, Mansa R, Quintela A, Rocha F, Detellier C.
Preparation, characterization and application in controlled
release of ibuprofen-loaded guar gum/montmorillonite
bionanocomposites. App. Clay Sci. 135, 52–63 (2017).
43 Li H, Zhu X, Xu J, Peng W, Zhong S, Wang Y. The
combination of adsorption by functionalized halloysite
nanotubes and encapsulation by polyelectrolyte coatings
for sustained drug delivery. RSC Adv. 6(59), 54463–54470
(2016).
44 Tan D, Yuan P, Annabi-Bergaya F et al. Loading and in vitro
release of ibuprofen in tubular halloysite. App. Clay Sci. 96,
50–55 (2014).
45 Tan D, Yuan P, Annabi-Bergaya F et al. Natural halloysite
nanotubes as mesoporous carriers for the loading of
ibuprofen. Micropor. Mesopor. Mater. 179, 89–98 (2013).
46 Fakhrullina GI, Akhatova FS, Lvov YM, Fakhrullin RF.
Toxicity of halloysite clay nanotubes in vivo: a Caenorhabditis
elegans study. Environm. Sci. Nano 2(1), 54–59 (2015).
47 Kryuchkova M, Danilushkina A, Lvov Y, Fakhrullin R.
Evaluation of toxicity of nanoclays and graphene oxide
in vivo: a Paramecium caudatum study. Environm. Sci.
Nano 3(2), 442–452 (2016).
• The toxicity of various nanoclays is compared with that of
graphene oxide nanosheets.
48 Bellani L, Giorgetti L, Riela S, Lazzara G, Scialabba A,
Massaro M. Ecotoxicity of halloysite nanotube-supported
palladium nanoparticles in Raphanus sativus L. Environ.
Toxicol. Chem. 35(10), 2503–2510 (2016).
49 Vergaro V, Abdullayev E, Lvov YM et al.
Cytocompatibility and uptake of halloysite clay nanotubes.
Biomacromolecules 11(3), 820–826 (2010).
• This study has pioneered the investigation on uptake and
biodistribution of halloysite nanoclay by human cells in
culture.
future science group
50 Massaro M, Riela S, Baiamonte C et al. Dual drug-loaded
halloysite hybrid-based glycocluster for sustained release
of hydrophobic molecules. RSC Adv. 6(91), 87935–87944
(2016).
• The effective nuclear uptake of drug-loaded polymer-coated
halloysite into cellular nuclei.
51 Massaro M, Amorati R, Cavallaro G et al. Direct chemical
grafted curcumin on halloysite nanotubes as dual-responsive
prodrug for pharmacological applications. Colloids Surf. B.
Biointerfaces 140, 505–513 (2016).
• Delivery of macromolecular prodrug (curcumin) into
human cells.
52 Cavallaro G, Lazzara G, Massaro M et al. Biocompatible
poly(N-isopropylacrylamide)-halloysite nanotubes
for thermoresponsive curcumin release. J. Phys. Chem.
C 119(16), 8944–8951 (2015).
53 Lvov Y, Aerov A, Fakhrullin R. Clay nanotube encapsulation
for functional biocomposites. Adv. Colloid Interface Sci. 207,
189–198 (2014).
54 Kryuchkova M, Danilushkina AA, Lvov YM, Fakhrullin RF.
Evaluation of toxicity of nanoclays and graphene oxide in
vivo: a Paramecium caudatum study. Environm. Sci. Nano 3,
442-452 doi:10.1039/C5EN00201J (2016) (Epub ahead of
print). 
55 Zhang Y, Chen Y, Zhang H, Zhang B, Liu J. Potent
antibacterial activity of a novel silver nanoparticle-halloysite
nanotube nanocomposite powder. J. Inorg. Biochem. 118,
59–64 (2013).
56 Konnova SA, Sharipova IR, Demina TA et al.
Biomimetic cell-mediated three-dimensional assembly of
halloysite nanotubes. Chem. Commun. 49(39), 4208–4210
(2013).
57 Sanchez-Ballester NM, Ramesh GV, Tanabe T et al.
Activated interiors of clay nanotubes for agglomeration-
tolerant automotive exhaust remediation. J. Mater. Chem.
A 3(12), 6614–6619 (2015).
58 Vinokurov VA, Stavitskaya AV, Chudakov YA et al.
Formation of metal clusters in halloysite clay nanotubes. Sci.
Technol. Adv. Mater. 18(1), 147–151 (2017).
59 Abdullayev E, Sakakibara K, Okamoto K, Wei W,
Ariga K, Lvov Y. Natural tubule clay template synthesis of
silver nanorods for antibacterial composite coating. ACS
Appl. Mater. Interfaces 3(10), 4040–4046 (2011).
60 Price R, Gaber BP, Lvov Y. In-vitro release characteristics
of tetracycline HCl, khellin and nicotinamide adenine
dineculeotide from halloysite; a cylindrical mineral. J.
Microencaps. 18(6), 713–722 (2001).
• Demonstrates the encapsulation and release of biologically
active molecules tailored to halloysite nanocontainers.
61 Veerabadran NG, Price RR, Lvov YM. Clay nanotubes
for encapsulation and sustained release of drugs. ACS
Nano 02(02), 115–120 (2007).
62 Dionisi C, Hanafy N, Nobile C et al. Halloysite clay
nanotubes as carriers for curcumin: characterization and
application. IEEE Trans. Nanotechnol. 15(5), 720–724
(2016).
www.future-science.com 645
Perspective  Lazzara, Riela & Fakhrullin
63 Vergaro V, Lvov YM, Leporatti S. Halloysite clay
nanotubes for resveratrol delivery to cancer cells. Macromol.
Biosci. 12(9), 1265–1271 (2012).
64 Vergara D, Bellomo C, Zhang X et al. Lapatinib/paclitaxel
polyelectrolyte nanocapsules for overcoming multidrug
resistance in ovarian cancer. Nanomed. Nanotechnol. Biol.
Med. 8(6), 891–899 (2012).
65 Lvov YM, Devilliers MM, Fakhrullin RF. The application
of halloysite tubule nanoclay in drug delivery. Expert Opin.
Drug Deliv. 13(7), 977–986 (2016).
66 Tully J, Yendluri R, Lvov Y. Halloysite clay nanotubes for
enzyme immobilization. Biomacromolecules 17(2), 615–621
(2016).
67 Abdullayev E, Lvov Y. Halloysite clay nanotubes for
controlled release of protective agents. J. Nanosci.
Nanotech. 11(11), 10007–10026 (2011).
68 Cavallaro G, Lazzara G, Milioto S, Palmisano G, Parisi F.
Halloysite nanotube with fluorinated lumen: non-foaming
nanocontainer for storage and controlled release of oxygen in
aqueous media. J. Colloid Interface Sci. 417, 66–71 (2014).
69 Cavallaro G, Lazzara G, Milioto S. Exploiting the colloidal
stability and solubilization ability of clay nanotubes/ionic
surfactant hybrid nanomaterials. J. Phys. Chem. C 116(41),
21932–21938 (2012).
70 Owoseni O, Nyankson E, Zhang Y et al. Release of
surfactant cargo from interfacially-active halloysite clay
nanotubes for oil spill remediation. Langmuir 30(45),
13533–13541 (2014).
71 Cavallaro G, Lazzara G, Milioto S, Parisi F. Hydrophobically
modified halloysite nanotubes as reverse micelles for water-
in-oil emulsion. Langmuir 31(27), 7472–7478 (2015).
646 Ther. Deliv. (2017) 8(8)
72 Dzamukova MR, Naumenko EA, Lvov YM, Fakhrullin RF.
Enzyme-activated intracellular drug delivery with tubule clay
nanoformulation. Sci. Rep. 5, 10560 (2015).
• Fabrication and in vitro demonstration of anticancer
effect of drug-loaded polymer functionalized halloysite
nanocontainers.
73 Massaro M, Lazzara G, Milioto S, Noto R, Riela S. Covalently
modified halloysite clay nanotubes: synthesis, properties,
biological and medical applications. J. Mater. Chem.
B doi:10.1039/C7TB00316A (2017) (Epub ahead of print).
74 Massaro M, Riela S, Guernelli S et al. A synergic
nanoantioxidant based on covalently modified halloysite-
trolox nanotubes with intra-lumen loaded quercetin. J.
Mater. Chem. B 4(13), 2229–2241 (2016).
75 Zhang X, Guo R, Xu J et al. Poly(l-lactide)/halloysite
nanotube electrospun mats as dual-drug-delivery systems and
their therapeutic efficacy in infected full-thickness burns. J.
Biomater. Appl. 30(5), 512–525 (2015).
• Polymer/halloysite-based 2D nano-to-micro drug delivery
platforms.
76 Massaro M, Riela S, Lo Meo P et al. Functionalized
halloysite multivalent glycocluster as a new drug-delivery
system. J. Mater. Chem. B 2(44), 7732–7738 (2014).
77 Riela S, Rizzo C, Arrigo R et al. Hybrid supramolecular
gels of Fmoc-F/halloysite nanotubes: systems for sustained
release of camptothecin. J. Mater. Chem. B doi:10.1039/
C7TB00297A (2017) (Epub ahead of print).
78 Yuan P, Southon PD, Liu Z et al. Functionalization
of halloysite clay nanotubes by grafting with
γ-aminopropyltriethoxysilane. J. Phys. Chem. C 112(40),
15742–15751 (2008).
future science group