hạt nano kim loại và thuốc chữa bệnh

1179
ISSN 2041-599010.4155/TDE.13.74 © 2013 Future Science Ltd
Ther. Deliv. (2 013 ) 4 (9 ), 1179–119 6
Review
Nanostructured metallic films approximately
200–500 nm thick have been a part of ceramic
decorations ‘luster’ since the medieval period.
The homogeneous dispersion of silver and cop-
per nanoparticles over glazed pottery results in
a colored iridescence called luster, a technique
very popular in the Middle East, Egypt, Persia
and Spain. In 1685, Andreas Cassius invented
a recipe of glass coloring pigment called Purple
of Cassius. He made the purple precipitates by
dissolving gold particles in aqua regia and then
added a piece of tin to it. The pigment is famous
for its use in high-quality porcelain ware. A Vien-
nese chemist, Richard Zsigmondy was awarded
the Nobel Prize in Chemistry in 1925 for discov-
ering that colloidal gold adsorbed on stannous
hydroxide base makes Purple of Cassius. Michael
Faraday (1857) prepared gold sols, whose size was
found out by JM Thomas in 1988 to be 3–30 nm
in diameter, when he reproduced those gold
nanoparticles. Industrial nanotechnology was
initiated in 1930 with the manufacturing of sil-
ver coatings for photographic films. At around
this time imaging techniques such as ultrasound,
MRI, computed tomography, positron emission
tomography and surface enhanced raman spec-
troscopy were becoming popular for imaging

various disease states and magnetic nanopar-
ticles came to the rescue as contrast agent with
unique physicochemical properties. The 1980s
took nanomaterials to higher strata by introduc-
ing fullerenes and scanning tunnel microscopes.
In the mid-1980s, when growth technologies
such as molecular beam epitaxy tied nuptials
with electron-beam lithography to confine
electron motion in all three (x-y-z) directions,
quantum dots (Q-dots) were produced. These
metallic nanoparticles have been embraced by
nanotechnology for more than four decades now.
Today, with Q-dots as new nanoball bearings,
aluminosilicates as nanowire gauges, cochle-
ates as nanocrystalline delivery trucks and iron
nanoparticles as new biomagnets, it is no wonder
that nanoscience thinks about metals in terms
of size control, spatial resolution, chemical reac-
tivity and engineering their relationship at the
cellular level in real time.
Metal nanoparticles can be easily prepared to
the nanometer scale, they possess fundamentals
of light matter interaction and are highly suitable
Metallic nanoparticles and their medicinal
potential. Part II: aluminosilicates,
nanobiomagnets, quantum dots and cochleates
Metallic miniaturization techniques have taken metals to nanoscale size where they can display fascinating properties
and their potential applications in medicine. In recent years, metal nanoparticles such as aluminium, silicon, iron,
cadmium, selenium, indium and calcium, which find their presence in aluminosilicates, nanobiomagnets, quantum
dots (Q-dots) and cochleates, have caught attention of medical industries. The increasing impact of metallic

nanoparticles in life sciences has significantly advanced the production techniques for these nanoparticles. In this
Review, the various methods for the synthesis of nanoparticles are outlined, followed by their physicochemical
properties, some recent applications in wound healing, diagnostic imaging, biosensing, assay labeling, antimicrobial
activity, cancer therapy and drug delivery are listed, and finally their toxicological impacts are revised. The first half
of this article describes the medicinal uses of two noble nanoparticles – gold and silver. This Review provides further
information on the ability of aluminum, silicon, iron, selenium, indium, calcium and zinc to be used as nanoparticles
in biomedical sciences. Aluminosilicates find their utility in wound healing and antibacterial growth. Iron-oxide
nanoparticles enhance the properties of MRI contrast agents and are also used as biomagnets. Cadmium, selenium,
tellurium and indium form the core nanostructures of tiny Q-dots used in cellular assay labeling, high-resolution
cell imaging and biosensing. Cochleates have the bivalent nano ions calcium, magnesium or zinc imbedded in their
structures and are considered to be highly effective agents for drug and gene delivery. The aluminosilicates,
nanobiomagnets, Q-dots and cochleates are discussed in the light of their properties, synthesis and utility.
Leena Loomba
1
& Tiziano
Scarabelli*
2,3
1
Punjab Agricultural University,
Ludhiana, Punjab, India
2
Center for Heart & Vessel Preclinical
Studies, St. John Hospital & Medical
Center, Wayne State University
School of Medicine, Detroit, MI, USA
3
Medical Center, Wayne State
University School of Medicine,
MI, USA
*Author for correspondence:

E-mail:
For reprint orders, please contact
Review | Loomba & Scarabelli
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for conjugation with drugs, ligands, antibod-
ies and genes, as well as functional groups of
interest. Excitation and relaxation of conduction
band electrons in metallic nanoparticles results
in plasmon resonance – a unique phenomenon
responsible for energy dissipation and optical
effects. An effective cellular communication,
the invincible ability of nanometals provides
immense possibility for their growth and devel-
opment in biomedicine. Nanoparticles have been
synthesized, tested, used and modified over the
years to function as agents for gene therapy, DNA
sequencing, cancer detection, cellular tracking,
targeted drug delivery and biomedical imaging.
The versatile attitude of metallic nanoparticles
attracts scientific research and clinical appli-
cations under the stream of nanotechnology
(Table 1).
Aluminosilicate nanoparticles
 Types, properties & synthesis of
aluminosilicate nanoparticles
Types
Aluminosilicates are broadly classified into the
following categories (FiguRe 1):


Orthosilicates with [AlO
6
]
3-
anions connected
by isolated (SiO
4
)
4-
clusters; for example,
andalusite (Al
2
SiO
5
) and its polymorphs,
kyanite and sillimanite;

Phyllosilicates with tetrahedral and octahedral
layers in two dimensions; for example,
kaolinite, smectite and illite;

Cyclosilicates with tetrahedral clusters of
(Si
3
O
7
)
6-
, (Si

4
O
12
)
8-
or (Si
6
O
18
)
12-
arranged in
a cyclic manner; for example, bentonite
(BaTi[Si
3
O
9
]) and beryl (Be
3
Al
2
[Si
6
O
18
]).
Properties
Aluminosilicates are minerals consisting of alu-
minium and silicon oxides. Silicates are tetra-
hedrally clustered polymers of (SiO

4
)
4-
anions.
The positively charged ions of Al
3+
can either
substitute silica atoms in the silicate tetrahedra
or connect outside the anionic framework, to
form aluminosilicates. In nature, magma solid-
ifies to form aluminosilicates such as feldspar
(xAl[Al,Si]
3
O
8
, where x can be Na, K or Ca),
mica, beryl or wollastonite. In feldspar the Al
3+

ion replaces the Si
4+
cation of (SiO4)
4-
, leaving
behind a negative charge on the 3D framework.
The positively charged ions neutralize this
negative charge, for example, K
+
in microcline
(KAlSi

3
O
8
) and Na
+
in albite (NaAlSi
3
O
8)
,
both K
+
and Na
+
in sanidine ([K,Na]AlSi
3
O
8
]
4
)
and Ca
2+
in Anorthite (Ca[AlSi
2
O
8
]). The
weather plays its role to convert feldspar to clay
kaolin (Al

2
Si
2
O
5
[OH]
4
) or montmorillonite
([Na,Ca]
0.33
[Al,Mg]
2
[Si
4
O
10
][OH]
2
.nH
2
O).
Naturally occurring aluminosilicate nanopar-
ticles exist as nanotubes called imogolites, or
hollow 3–5 nm spherical allophanes. Both these
aluminosilicates have on identical chemical com-
position (Al
2
SiO
3
[OH])

4
, but with different
structures depending on the Al/Si ratio.
Clay has negatively charged sites that can
attract and hold positively charged particles
and this is called ‘cation exchange capacity’; it
is the measure of how many negatively charged
sites are available on a nanoparticles surface.
These exchange reactions are rapid, reversible
and stoichiometric with respect to charge:
2{K
+
-Soil} + Ca
2+
→ 2K
+
+ Ca
2+
–(Soil)
2

equaTion 1
Aluminosilicate nanoparticles undergo ion
exchange readily, that is, adsorbed cations can
be replaced by a large quantity of other com-
peting ions, which superimpose their strength
and resistance. The layered sheet-like structure
of aluminosilicate nanoparticles provides addi-
tional surface area as well as the ability to hold
substances for targeted delivery.

Kaolinites are 1:1 aluminium phyllosilicates
having the chemical formula Al
2
Si
2
O
5
(OH)
4
.
Clays such as kaolinite, dichite, nacrite and hal-
loysite fall under this category. They have SiO
4

tetrahedrons and AlO
4
octahedrons arranged in
Table 1. Examples of metallic nanoparticles used as drugs and diagnostic agents.
Metallic nanoparticles Element Use
Aluminosilicate nanoparticles Al, Si Faster blood clotting in open wounds
Nano biomagnets Fe Helps in targeted drug delivery
Q-dots Cd, Se, In Medical imaging
Cochleates Ca, Zn, Mg Oral drug delivery of drugs encapsulated in a
nanocrystalline structure
Metallic nanoparticles & their medicinal potential | Review
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a 2D hexagonal array. This arrangement twists
the tetrahedral sheet, flattens the octahedral

sheet and compels the hexagonal arrangement
to distort in a ditrigonal manner.
Smectites and illites are 2:1 bonded sheets of
aluminium phyllosilicates with an octahedral
sheet sandwiched between two tetrahedral sheets
(TOT). The space between two TOT sheets is
occupied by cations and/or water molecules. The
arrangement can be designated as TOT (H
2
O/
cations) TOT. Smectites have the chemical for-
mula: Na
0.3
Al
2
(Si
3.7
Al
0.3
)O
10
(OH)
2
and examples
include montmonrillonite, nantronite, saponite
and hectorite. They have high cation exchange
capacity, a very large chemically active surface area
and an unusual tendency to hold water molecules
in the interlamellar surface. Illites have the chemi-
cal formula K

0.7
Al
2
(Si
3.3
Al
0.7
)O
10
(OH)
2
. The cat-
ion exchange capacity of the illite group is midway
between that of kaolinite and smectite, but their
hydration capacity is low due to the replacement
of Na
+
ions by K
+
ions.
Synthesis
Mesoporous aluminosilicate nanoparticles with
narrow size distribution (30–50 nm) are syn-
thesized by a hydrothermal method using cet-
yltrimethylammonium bromide as a template
and polyethylene glycol as a means to tailor the
nanoparticles [1]. The aluminium salt, alumi-
num nitrate nonahydrate, catalyzes the hydroly-
sis of the silica precursor tetraethyl orthosilicate.
The hydrolyzed species can be rapidly assembled

into mesostructured nanocomposites under the
direction of cationic micelles with the addition
of basic ammonia water. The nonionic polyeth-
ylene glycol shields the formed nanoparticles
through hydrogen-bonding interactions, thereby
tuning the grain size distribution of mesoporous
nanoparticles. A sol–gel route has been used to
synthesize aluminosilicates, with varying alu-
mina–silica ratios. The process uses boehmite
and tetraethyl orthosilicate as alumina and silica
precursors, respectively [2].
 Aluminosilicate nanoparticles in medicine
Clay has been popular since the prehistoric era
in bath spas to preserve complexion; in ochres to
cure wounds caused by serpents, to reduce the
flow from the lachrymal ducts; against hemor-
rhage, inflammation, gastrointestinal infections
and kidney diseases; and even to make mum-
mies. Modern physicians use the same clay parti-
cles at a nanoscale level in bandages, antibacterial
ointments and pharmaceutical carriers.
Kaolinites are known for wound healing
Kaolin clay has long been used for curing inju-
ries, festering inflammations and healing wounds.
From the 1950s kaolin has been an activating
agent for a clotting test that doctors perform
routinely. The clay is predominantly rich in alu-
minosilicate nanoparticles that have the ability
to reduce staunch bleeding by absorbing water;
resulting in quick blood clotting [101]. The surgical

dressings, impregnated with kaolin, are sold under
the tradename ‘QuickClot
®
’ and are used to com-
bat life-threatening hemorrhage on the battlefield.
The presence of kaolin on the surface of nonwo-
ven rayon gauge leads to enhanced transformation
of factor XII, factor XI and prekallikrein to their
activated forms; this activation further initiates
the coagulation cascade of hemostasis. Chemists
at the University of California (Santa Barbara,
CA, USA), realized that the aluminosilicate
nanoparticles could be used to halt severe nose
bleeds. The inorganic specks, which are derived
from kaolin clay, when infused with a bandage,
Aluminiosilicates
Orthosilicates
Phyllosilicates
Cyclosilicates
Examples: andalusite, kyanite, sillimanite
(used in ceramics, boiler furnaces
and kiln linings).
Examples: kaolinite, smectite, illite
(used in wound healing, burns,
sepsis and inflammation)
Examples: bentonite, beryl
(used as a laxative and
anti-inflammatory agents)
Figure 1. Various types of aluminosilicates and their uses.
Review | Loomba & Scarabelli

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trigger the body’s natural clotting process. The
bandage stops the bleeding immediately, when
rolled up and inserted in the nose [102].
Smectites & illites possess antibacterial ability
Smectites are famous for their tendency to
absorb the carcinogenic metabolite aflatoxin
B1, produced by the fungi Aspergillus flavus in
animal diet [3]. The nanoparticles of smectites–
illites and reduced iron present in natural clay
have the potential to eliminate Escherichia coli
and even antibiotic-resistant bacteria such as
methicillin-resistant Staphylococcus aureus. The
hydrated clay leaches into the bacterial cell mem-
brane to increase bacterial iron and phosphorous
levels and metabolic activity of the membrane.
The regulatory proteins subsequently come into
action to oxidize Fe
2+
to Fe
3+
and even produce
hydroxyl radicals, which enter the cytoplasm
and cause cell death [4].
The in vitro antibacterial activity of clay min-
erals has proven effective against Buruli ulcer
and b-lactamase E. coli. The mineral surfaces of
aluminosilicates in clay alter pH and oxidation

states in bacterial membranes to control redox
reactions, resulting in cell lysis [5]. The layered
metal hydroxides of clay behave as excellent
pharmaceutical carriers. The lamellar surfaces
of various layers can easily hybridize nano-
medicines in their 2D structure. For example,
methotrextate – a folate antagonist anticancer
drug – is unstable and also has a short plasma
half-life. The drug, when layered in Mg and Al
hydroxides of clay, specifically suppresses growth
of human osteosarcoma cancer cells [6].
Bentonite: a versatile aluminisilicate
Bentonite is a chemically inert, absorbent alu-
minium phyllosilicate consisting of montmoril-
lonite. Bentonite supports good digestion and
acts as a laxative. In the gastrointestinal tract of
animals bentonite reduces bacterial mucolysis
and inflammation. The granular form of benton-
ite is used under the commercial name ‘Wound-
Stat™’, in battlefields for wound dressings. It
reduces pain associated with stings, burns and
cuts, promotes detoxification and also shields
against urushiol – the oil found in poison ivy.
Nanobiomagnets
 Types, properties & synthesis of
nanobiomagnets
Types
The nanosized, biocompatible, paramag-
netic iron oxides that serve as biomagnets are
magnetite (Fe

3
O
4
), maghemite (g-Fe
2
O
3
) and
haematite (a-Fe
2
O
3
); of which magnetite,
because of its biocompatibility, is very promis-
ing. Iron oxide nanoparticles (IONps) are avail-
able in various dimensions and shapes such as
nanorods, nanotubes, hollow fibers, rings and
snowflakes.
The iron oxide nanorods demonstrate higher
incident photon-to-current conversion compared
with nanospheres, which is further improved
by surface modification and doping with Zn.
The nanoparticle size imposes a huge impact on
superparamagnetism and, in turn, their usage.
Generally, iron oxide nanoparticles ranging from
1 to 25 nm are highly efficient models. Super-
paramagnetic iron oxide nanoparticles are of
particular interest in MRI; examples include:

AMI-227 (Sinerem, Combidex

®
) and SHU-
55C – a 20 nm sized iron oxide nanoparticle
coated with carbodextran. It demonstrates
excellent T2 relaxivities of 151.0 mmol/sec
and has been used for lymph node and bone
marrow imaging.

OMP (Abdoscan
®
) and AMI-121 (Lumirem
®
,
GastroMARK
®
) are 300 nm sized iron oxide
nanoparticles (IONps) coated with silica.
Their oral administration finds utility as a
gastrointestinal contrast.
Properties
In magnetite, Fe
3+
ions are placed at all tetrahe-
dral sites, whereas both ferrous and ferric ions
occupy octahedral sites of inverse spinel struc-
ture. Maghemite is the oxidized form of mag-
netite having 56 ions in each unit cell, of which
32 are O
2-
ions, eight Fe

3+
ions in tetrahedral
sites and 16 Fe
3+
in octahedral sites. Magne-
tite is a spin-polarized black crystal containing
both Fe (II), Fe (III) and absorbs throughout
the UV–vis–IR spectrum, while maghemite is
an insulator. Both phases are ferrimagnetic.
Haematite, a-Fe
2
O
3
, has a 3D framework built
up of trigonally distorted octahedra FeO
6
, with
oxygens in hexagonal closest-packing. The tri-
valent iron ions are closely packed between
two oxygen layers. This arrangement makes
the structure neutral with no excess charge.
Haematite has antiferromagnetic properties
and an absorption spectrum in the visible range
between 295 and 600 nm. The magnetic behav-
ior of these oxides is due to their stereochem-
istry that triggers internal superexchange com-
petition between tetrahedral and octahedral
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sites. At room temperature both magnetite
and maghemite are superpara magnetic, which
means an external magnetic field can easily
magnetize the nanoparticles.
The IONps need to be superparamagnetic,
biocompatible and nontoxic to be useful for
molecular imaging purposes. They also need to
bind to a range of metabolites. The zero point
charge value of seven makes oxides stable only
in highly acidic or basic aqueous media. This
drawback in their surface chemistry causes con-
siderable aggregation and precipitation in solu-
tion phase. Also, low hole mobility, electron-
hole recombination and electon-trapping, and
oxygen-deficient iron sites yield poor photocur-
rent efficiency. However, coating the particles
with silica, dextran, carbodextran, poloxamines
or poly(ethylene glycol) followed by their bio-
conjugation with various ligands gives them
both stability and specificity. Magnetic iron-
oxides need high r1 and r2 relaxivities, as well
as surface engineering, to fine tune their size
and structure, before being used for in vivo
applications [7].
The ferromagnetic nanoparticles magnetiza-
tion fluctuates with temperature, fluctuations
are generally larger at higher temperatures and
smaller at lower temperatures. When the time
between two magnetization fluctuations (Néel

relaxation time) is shorter than the time used to
measure the magnetization of the nanoparticles,
in the absence of external magnetic field, the
nanoparticles show an average zero magnetiza-
tion. This is called superparamagnetism. Mate-
rials having superparamagnetism have a high
saturation magnetization and zero coercivity
and remanence.
The Néel relaxation time is highly tempera-
ture dependent, it fluctuates randomly by ther-
mal fluctuation at high enough temperatures.
The thermal energy decreases at lower tempera-
tures and blocks the magnetic moments. This
temperature is called the blocking temperature.
It is a function of the particle size and increases
with increasing particle size. Thus, superpara-
magnetism increases with the decrease in size
of the nanoparticle. Below blocking tempera-
ture, the preferred direction of magnetization
of superparamagnetic material is lost in zero
magnetic fields. When the temperature rises
above the blocking temperature, the nanopar-
ticles show no hysteresis. With these fascinating
superparamagnetic properties, IONps find their
utility in ferrofluids, hyperthermia and MRI
contrast agents.
Synthesis
Reverse micelle and precipitation are two com-
monly used techniques for the synthesis of iron
oxides [8]. The simplest of all the methods to

prepare IONps is the coprecipitation of a 2:1
stoichiometric mixture of Fe
2+
/Fe
3+
salts in an
aqueous medium of pH between 8 and 14. The
magnetite forms black colored precipitates. The
overall reaction is written as:
Fe
2+
+ 2Fe
3+
+ 8OH
-
→ Fe
3
O
4
+ 4H
2
O
equaTion 2
The particle size depends on numerous fac-
tors such as Fe
3+
/Fe
2+
ratio, temperature, ionic
strength, nature of salts, pH and addition of che-

lating agents. Generally, the nanoparticle size
decreases with an increase in the pH, Fe
3+
/Fe
2+

ratio and ionic strength of the medium.
The aqueous iron salt solutions essentially
form reverse micelles with the hydrophilic head
towards the core of the micelle and the hydro-
phobic tail directed outwards. Reverse micelles
solubilize large amounts of water, which can be
controlled, for nanoparticle production. A wide
range of iron oxide nanoparticles can be syn-
thesized by altering the nature and amount of
surfactant, solvent and cosurfactant.
They can also be synthesized using techniques
such as sonochemistry, microwave irradiation
and autogenic pressure reactor [9]. A new method
to produce nanocrystals is glass crystallization
[10]. In total, 15–20 nm sized, monodisperse,
Fe
3
O
4
nanoparticles are synthesized by decom-
position of iron (II) acetate at 400°C. IONps of
desired size and dispersity are also synthesized by
heating iron-oleic complex at 320°C in 1-octa-
decene for 30 min. Hydrothermal treatment of

iron powder and iron chloride solution in urea
solution for 20 h at 130–150°C yields iron rods
of nearly 80 nm.
 Photoelectrochemical applications of
biomagnets
The chemistry of iron oxide nanoparticles can
be manipulated to have magnetic properties
that find their importance in magnetic reso-
nance imaging, biotechnology and effective
hyperthermia (FiguRe 2).
Iron-oxide nanoparticles as hyperthermia
& MRI contrast agents
MRI is a noninvasive technique that combines
the characteristics of high spatial resolution,
Review | Loomba & Scarabelli
The r. Del iv. (2013) 4(9)
1184
future science group
nonionizing radiation and multiplanar tomog-
raphies in cellular imaging. Superparamagnetic
iron oxide nanoparticles comprise a class of
novel MRI contrast agents that are composed
of a ferrous iron (Fe
2+
) and ferric iron (Fe
3+
) core,
and a layer of dextran or other polysaccharide
coating [11]. The iron nanoparticles have a very
large magnetic moment, which leads to local

magnetic field inhomogeneity. Consequently,
they serve to enhance the image contrast and,
thus, improve the sensitivity and specificity of
MRI in mapping information from tissues [12].
In vivo, nonspecific superparamagnetic iron
oxide nanoparticles are mainly captured by the
reticuloendothelial system, and they are more
suitable for liver, spleen and lymph node imaging
[13]. Because of their long plasma half-life, super-
paramagnetic iron oxides are also used as blood
pool agents in magnetic resonance angiography.
Haematite nanoparticles, 1.8 nm in size,
when coated with polysaccharides such as chi-
tosan and alginate, respond superparamagneti-
cally with very low coercivity. These nanopar-
ticles can either be converted to magnetite by
reduction or used directly for imaging [14].
The intensity of magnetic field of iron-based
nanoparticles, having a layer of bis-carboxyl-ter-
minated poly(ethylene glycol) on them, induces
more effective hyperthermia than uncoated
iron particles. They are far better MRI contrast
agents and provide a focused approach for in vivo
applications and cancer therapy [15]. Iron oxide
nanoparticles manipulated with Herceptin
®
–
an antibody present in breast cancer cells – or
chlorotoxin – a peptide that binds MMP-2 in
gliomas, show enhanced in vivo tumor-targeting

properties [16]. Mammary tumors contain over-
expressed levels of urokinase-type plasminogen
activator. Amino-terminal fragment conjugated
IONps can effectively bind the over expressed
receptors in breast cancer tissues and help in vivo
imaging [17]. The nanocomposites of maghemite,
such as those with bentonite and raffinose-mod-
ified trypsin, are used as MRI contrast agents for
the gastrointestinal tract and magnetic carriers
for trypsin immobilization, respectively [18]. Flu-
orescence and magnetism can be uniquely com-
bined over maghemite nanoparticles. Congo-red
or rhodamine dyes hybridize with g-Fe
2
O
3
to
serve as biomarkers for in vivo Alzheimer’s dis-
ease diagnosis [19]. Ferrite nanoparticles ranging
from 20 to 200 nm in diameter are being used
for biosensing and as contrast agents for MRI,
when attached with europium these spheres can
emit fluorescent radiations at 618 nm to help
detect cancer [20].
Nanobiomagnets in biotechnology
Biotechnology can rely on the magnetic powers
of IONps to separate specific proteins from a
group of biomolecules. For example, dopamine
grafted IONps can be used for protein separa-
tion. The bidentate enediol ligands of the dopa-

mine molecule tightly bind with unsaturated
iron sites. The nanostructures so produced
enhance specificity for protein separation and
provide tremendous stability to heating and high
salt concentrations. In the same manner, mag-
netic nanoparticles are ideal candidates for gene
detection. In the diagnosis of diseases involving
genetic expression, the separation of rare DNA/
mRNA targets with single-base mismatches
in a mixture of various bio complexes is criti-
cally important. Genomagnetic nano capturers
have been formulated using IONps to detect
DNA/RNA molecules with one single-base dif-
ference. Nanobiomagnets can transfer drugs
into the body and are held at the target site by
an external magnet. The purpose of this is to
concentrate the drug at the tumor site for long
enough for it to be absorbed and release the drug
on demand. The control of drug delivery using
biomagnets can reduce the dosage by 60–75%,
thus enhancing drug efficacy while decreasing
Nanobiomagnets
Magnetite
Maghemite
Haematite
Used in hyperthermia,
in biotechnology as genomagnetic
capturer, as MRI contrast agents
and to magnetically focus
the drug at tumor sites

Photoelectrochemical
applications
Figure 2. Nanobiomagnets and their photochemical applications.
Metallic nanoparticles & their medicinal potential | Review
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1185
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unwanted systemic uptake. This mechanism can
find its utility in control of insulin-dependent
diabetes. Recent studies report that the iron
oxide nanoparticles can adhere to red blood cell’s
surface for nearly 4 months. This can help to
release drugs slowly into the body and can lead
to controlled treatment of many immunogenic
diseases.
Q-dots
 Types, properties & synthesis of Q-dots
Types
Q-dots are tiny particles, traditionally chal-
cogenides (selenides or sulfides) of metal such
as cadmium or zinc (CdSe/ZnS) ranging
from 2 to 10 nm. The electrons and holes of
the semiconductor cores being confined to a
point significantly modifies the energy spec-
trum of the carriers. Q-dots have a metallic
core made of semiconductors, noble metals,
and magnetic transition metals, shielded by a
shell. Depending on the variation in the con-
stituents of the core, Q-dots are classified into
various groups:


Group II–IV series Q-dots contains ZnS,
ZnSe, CdSe and CdTe cores;

Group III–V series Q-dots have InAs, InP,
GaAs and GaN cores;

Group IV-VI series Q-dots have PbTe, SnTe,
SnS and SnS
2
cores.
Q-dots are also classified as Type-I, Reverse
Type-I and Type-II:

Type-I Q-dots have a core that simultaneously
traps electrons and holes giving rise to
contravariant band layout so that both the
conduction and valence band edges of the core
lie within the bandgap of the shell; for example,
CdSe/CdS, CdSe/ZnS and InAs/CdSe;

For reverse Type-I Q-dots, the bandgap of the
core is wider than the shell, and the conduc-
tion and valence band edges of the shell lie in
the core; for example, CdS/HgS, CdS/CdSe
and ZnSe/CdSe;

Type-II Q-dots have one type of charge carrier
in the core while the shell carries the other
type. It maintains covariant band layout in

which the valence and conduction band edge
are either lower or higher than the band edges
of the shell; for example, Type-II Q-dots that
attract holes are GaSb/GaAs and Ge/Si, and
those that attract electrons are InP/InGaP and
InP/GaAs.
Properties
Q-dots are basically made of three parts – a
core, a shell and the outer coating (FiguRe 3).
The core region, when excited by a photon,
triggers its electron in the semiconductor band
gap, leaving behind a positive hole in the lower
energy band. An increase in excitation increases
the absorption in the band gap giving rise to
broad absorption spectrum. Since the energy
gap between higher and lower energy bands is
responsible for emission energy, and the energy
gap is low, the emission spectrum is narrow.
The shell covers the surface defects of the elec-
tron–hole nanocore, and thus protects it from
oxidation, fluorescence and chemical reactions.
The shells having large energy gaps increase the
quantum yield and enhance photostability. A
Q-dot core
(CdSe)
Shell (ZnS)
Cap (disulfide
bridge, silane)
S
Biomolecule

(protein/DNA)
Biological applications
Cellular and
assay labeling
High-resolution
cell imaging
Q-dot-FRET
biosensing
Figure 3. A biofunctional quantum dot and its biological applications.
FRET: Fluorescence resonance energy transfer; Q-dot: Quantum dot; S: Sulfide bridge.
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coating of functional ligands over the Q-dot
shell improves their solubility in polar solvents
and also labels them. The mono or dithiol dihy-
drolipoic acid ligands improve stability for over
1–2 years; phospholipids induces stability over a
wide pH range while thiolated peptides or poly
histidine residues provide both dispersion and
bio-functionalization.
The electronic properties of Q-dots are inter-
mediate between those of bulk semiconductors
and discrete molecules. The most apparent of
these is the emission of photons under excitation,
which are visible to the human eye as light. The
wavelength of these photon emissions depends
on their size. The smaller the dot, the closer it is
to the blue end of the spectrum and the larger

the dot, the closer to the red end. The charac-
teristics of Q-dots that attract the attention of
biomedicine are brightness, time resolved imag-
ing because of 20 s lifetime of fluorescence, and
the ability to image many colors simultaneously
without overlapping, due to narrow fluorescence
emission. Moreover, Q-dots require a mini-
mum amount of energy to induce fluorescence,
resulting in high quantum yields. Their core-
shell structure makes them highly stable against
photobleaching.
Synthesis
The binary semiconductor nanocrystals
such as cadmium selenide, cadmium sulfide,
indium arsenide and indium phosphide could
be synthesized by fabrication, colloidal syn-
thesis or as viral assembly. Bulk quantities of
semiconductor dots are produced by colloidal
synthesis based on a three-component system
composed of precursors, organic surfactants
and solvents. The high temperature turns the
reaction medium to monomers [21]. Fabrica-
tion produces 5–50 nm sized dots, defined by
lithographically patterned gate electrodes, or by
etching on 2D electron gases in semiconductor
heterostructures [22 ]. The biocomposite struc-
tures of Q-dots could be genetically engineered
using bacteriophage viruses (TMV, M13 or Fd)
[23]. Subjecting the organometallic precursors
(CdO, Cd-acetate) and solvent-ligand (trioctyl

phosphine–tri octyl phosphine oxide) mixture
to high temperatures yields CdSe Q-dots with
high crystalline cores.
 The utility of Q-dots in medicine
The initial Q-dot bioconjugate was reported
in 1998. Over the past decade, the study of
Q-dots has extended from high-resolution
cellular imaging to labeling, tumor targeting,
and diagnostics.
Q-dots in cellular & assay labeling
When introduced in cells, Q-dots found applica-
tions in cell tracking, immunoassays, determin-
ing the metastatic potential of cells and unleash-
ing various cellular and metabolic processes.
The labeling of cells and assays with Q-dots is
an initial step of imaging processes and can be
achieved by extracellular or intracellular modes.
The proteins as well as receptors associated
with membranes help in extracellular labeling
of Q-dots to understand biological pathways
such as signal transduction, chemotaxis, cel-
lular organization and diffusion behavior of
metabolites. Studies have been successfully
carried out with biotinylated-coated dots and
glycosyl–phosphatidyl–inositol conjugated avi-
din Q-dots to understand the diffusive behavior
of the plasma membrane [24].
To demonstrate intracellular labeling, cells
can be microinjected or incubated with Q-dots
via nonspecific endocytosis. The peptide-medi-

ated intracellular delivery of Q-dots allows pas-
sive intake of biomolecules, such as cytokeratin,
mortalin, microtubules, liposomes and oligonu-
cleotides, into the cells. The streptavidin–biotin
complex links easily, through covalent bonding
to the Q-dot surface to control intracellular
delivery.
The difference between invasive and non-
invasive cancer cell lines can be demonstrated
by in vitro cell motility assay based on the phago-
kinetic uptake of Q-dots. The cell lines move
across the homogeneous layer of Q-dots and
leave a fluorescent-free trail. On calculating the
ratio of trail-to-cell area, the tumor invasiveness
can be easily distinguished.
Q-dots coated with DNA serve as probes for
the detection of multiallele DNA and human
metaphase chromosomes. They also act as spe-
cific DNA labels for highly sensitive in situ
hybridizations [25]. Multiple toxin ana lysis in
immunoassays and marking Her2 breast cancer
cells has been possible by conjugating Q-dots
with antibodies [26]. Q-dots have also been used
to diffuse glycine receptors in neurons and in
near-infrared emission identification of lymph
nodes during live animal surgery [27].
Recently, CdTe Q-dots have been reported
to control the nerve cells. Light energy excites
electrons in the Q-dot, which causes the
immediate environment to become negatively

charged. This cause the ion channels to open
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in the cancerous tissue, allowing the thorough-
fare of ions in and out of the cells. The ion
channel openings generate action potential over
nerve cells, which in turn can be controlled by
external voltage on Q-dots to depolarize the
unwanted cells [28].
High-resolution cell imaging with the help
of Q-dots
Q-dots have the ability to overcome the limi-
tations of fluorescence imaging of live tissues,
which is greatly hindered by the poor trans-
mission of visible light. Q-dots act as the inor-
ganic fluorophore for intra-operative detection
of tumors using fluorescence spectroscopy as
they are 20-times brighter and 100-times more
stable than the traditional fluorescent report-
ers [29]. The improved photostability of Q-dots
allows the acquisition of many consecutive focal
plane images that can be reconstructed into a
high-resolution 3D image. The extraordinary
stability makes them a probe to track cells or
molecules over extended periods of time. The
ability to image single-cell migration in real-
time renders their importance in embryogen-
esis, cancer metastasis, stem-cell therapeutics,

lymphocyte immunology and in vitro imaging
of prelabeled cells [30]. Fluorescent Q-dots can
be tagged to antibodies that target cancerous
cells or cells infected with tuberculosis or HIV
[31], and could also be used to diagnose malaria
by making them target the protein that forms a
mesh in the blood cell’s inner membrane. The
shape of this protein network changes when
cells are infected with malaria, so scientists are
able to spot malaria infection from the shape
produced by the dots [32]. Q-dots have earned
success in sentinel lymph node biopsy, a tech-
nique that locates the first draining lymph node
at the cancer site. The background tissue auto-
fluorescence is an avid limitation of blue dye and
radioisotopes used in biopsy, which is overcome
by Q-dots emitting at the near-IR range. This
allows surgeons to undertake biopsy with high
accuracy and minimum invasiveness.
Q-dot-fluorescence resonance energy transfer
biosensors
A fluorescence resonance energy transfer
(FRET) is an energy transfer between two chro-
mophores through dipole–dipole interactions.
The process of energy transfer enjoys an inverse
relationship to the sixth power of the distance
between donor and acceptor molecules. FRET
can wonderfully detect molecular interactions
and conformations in biological systems. Q-dots
can transfer their energy to quencher analytes

through FRET, thus minimizing the fluores-
cence from the Q-dot donor. Gold rods read-
ily quench the fluorescence from the Q-dots.
This exciting property of FRET between Q-dots
and the surface of gold nanoparticles helps to
explore many DNA properties [33]. The friend-
ship between FRET technology and Q-dots can
reduce background signal due to time-gating
and increase the possibility of measuring long
distances.
FRET-based Q-dots biosensors have been
developed to detect Aspergillus amstelodami.
The Q-dots conjugated to IgG antibodies
transfer their energy to quencher-labeled ana-
lytes through FRET. The high-affinity target
analytes replace the quencher analytes during
detection to increase Q-dot fluorescence sig-
nal. The sandwich immunoassay then detects
Aspergillus, as low as 103 spores/ml, in 5 min.
The idea can be further exploited to detect other
biological threats [34]. Multiple colored Q-dots
can tag various antibodies uniquely. Recently,
researchers demonstrated a novel idea to multi-
plex the utility of Q-dot biosensors, by applying
simultaneous FRET to five different Q-dots on
terbium complex with emission maxima at 529,
565, 604, 653 and 712 nm [35].
CdSe-ZnS core-shell Q-dots coated with
dihydrolipoic acid and conjugated with human
phosphoinositide-dependent protein kinase-1

have been designed to identify selective inhibi-
tors of protein kinases. The response of this bio-
sensor is tested in molecular dyad incorporating
an ATP ligand and a chromophore. The organic
dye allows nonspecific adsorption on the surface
of nanoparticles promoting FRET from Q-dot
to quencher dye. The assay demands study of
new strategies to prevent energy adsorption on
the nanoparticle donor surface [36].
Cochleates
 Types, properties & synthesis of
cochleates
Types
Cochleates are multilayered delivery vehicles
made of alternating layers of divalent counter
ions (Ca
2+
/Zn
2+
) and bridging phospholipid
bilayers, all rolled up in a spiral [37]. They are
made up of three constituents: the lipid bilay-
ers, the cations and the agent to be delivered;
on varying one or more of these constituents,
various permutation combinations are possible,
as shown in box 1.
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Properties
Cochleates are rod-like, rigid, internally hydro-
phobic sheets made from small unilamellar lipo-
somes condensed by bivalent cations. The positive
charge on cations such as Zn
2+
, Ca
2+
, Mg
2+
and
Ba
2+
interacts with negatively charged lipid to con-
dense it and rolling further makes them resistant
to their immediate environment. The high ten-
sion at the bilayer edges of cochleates is the driv-
ing force of cochleate’s interaction with the tissue
membrane [38]. The cell membranes fuse with the
lipid bilayer structure of cochleates, which unfolds
to release the internal contents into cells. Another
hypothesis put forward is the idea of phagocytosis
for nanocochleates’ delivery. The phosphatidylser-
ine receptors are common between the liposomal
membranes of macrophages as well as those of
cochleates. When in close proximity, the liposome
membrane and the outer cochleate layer fuse to
release the drugs into cell cytoplasm.
The alternating lipid layers entrap the drug
molecules without chemically bonding to it and

potentially protect it from digestive enzymes in
the stomach. Encochleation is a medium to
extend the shelf-life of drugs because the cochle-
ate cores are resistant to water and oxygen, two
components that act as leading agents of drug
decomposition and degradation.
Synthesis
Cochleates can be produced in submicron size
using methods known as hydrogel-isolated
cochleation, trapping, binary aqueous–aqueous
emulsion, liposome before cochleates dialysis,
direct calcium dialysis, or simply by increasing the
ratio of multivalent cationic peptides over nega-
tively charged liposomes. The hydrogel method
immerses unilamellar liposomes loaded with drug
in two sets of immiscible polymers. The polymer
miscibility results in a two-phase aqueous system,
which is crosslinked by a cation salt. The tiny
cochleates so formed are washed and then sus-
pended in a buffer. The trapping method involves
dropwise addition of calcium salt and water phase
to the formative layer of phosphatidylserine lipo-
somes. The binary aqueous–aqueous emulsion
method injects the primary dextran–liposome
phase into a secondary non-miscible polyeth-
ylene glycol polymer. The divalent cations are
then diffused from one phase to another forming
cochleates, less than 100 nm in size.
The liposome before cochleates dialysis
method suspends a detergent–lipid mixture in

a two-phase polymer system. The mixture is dia-
lyzed with a buffer to form protein–lipid vesi-
cles. The cochleate precipitates from the vesicles
by addition of calcium ions. Large needle-shaped
cochleates are formed by the direct calcium dial-
ysis method, in which lipid detergent mixture is
dialyzed against CaCl
2
solution [39].
 The cochleate technology for
nanomedicine
Cochleate means spiral shell. In 1975 Papah-
adjopoulos and Wilschut discovered cigar-like
nanocochleates nearly 500 nm in size. Since
then, cochleates have been used to formulate a
variety of biologically active molecules, mediate
effective oral drug bioavailability and reduce
toxicity. There is a budding interest of scientists
to explore cochleate efficacy in gene delivery.
Effective drug delivery by cochleates
Cochleate technology is a new means of over-
coming the poor oral absorption of drugs such as
amphotericin B and to facilitate the bioral drug
delivery of cochleate-administered oral doses of
amphotericin B, ranging from 0 to 40 mg/kg of
body weight/day fortnightly in a murine model of
systemic aspergillosis. This leads to a reduction of
more than two logs of colony counts in hepatic,
pulmonary and renal organs [40]. Cochleates
increase the efficacy of antibacterial drugs such as

clofazimine used against tuberculosis. To protect
mice from lethal acute graft-versus-host disease
the immunosuppressive, water-insoluble com-
pound 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-
1H-1,2,4-triazole was subcutaneously adminis-
tered through an oily vehicle. The oral admin-
istration of 10 mg/kg of this compound after
encochleation reduced lethality, and increased
the survival rate to 100%, whereas the control
with empty nanocochleates was inactive [41].
Cochleates serve as delivery vehicles for anti-
inflammatory drugs such as naproxen, ibupro-
fen and acetaminophen. Macrophages use the
Box 1. The various constituents of a cochleate.
Cations Lipids Drugs
Zn
2+
, Ca
2+
, Mg
2+
, Ba
2+
Phosphotidylserine
phosphatidic acid
Phosphotidylinosotol
Phosphotidyl Glycerol
Phosphotidylcholine
Phosphotidylethanolamine
Diphosphotidylglycerol

Dioleoyl phosphatidic acid
Distearoyl phosphatidyl serine
Dipalmitoylphosphatidylglycerol
Protein
Peptide
Polynucleotide
Antiviral agent
Anaesthetic agent
Anticancer agent
Immunosuppressant
Anti-inflammatory agent
Tranquilizer
Nutritional supplement
Vitamins or
Vasodilator agent
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enzyme nitric oxide synthase during inflamma-
tion. In vitro studies of encochleated aspirin and
acetaminophen show tenfold more effectiveness
against nitric acid synthase in the macrophage-
derived cell line J774. In vivo data of a third of
aspirin cochleate in carrageenan rat model dem-
onstrated a reduction in gastric inflammation by
nearly 70% compared with the free drug [103].
A naturally occurring, HDL ApoA1 mediates
enzymatic esterification of cholesterol, trans-
porting cholesteryl esters to the liver, thus low-

ering the risk of atherosclerosis and other coro-
nary heart diseases. ApoA1 being a protein, is
ingested by gastrointestinal enzymes, but when
delivered through nanocochleates ApoA1 read-
ily controls high blood cholesterol levels. The
bridging counterions can be easily extracted out
of the inter-bilayer spaces to convert cochleates
to liposomes, making it an excellent delivery
system for insoluble ingredients [42].
Gene delivery through cochleates
Gene therapy is an emerging field of medicine
that combines a DNA plasmid and proteins with
a delivery vehicle to insert into the genome of a
defective cell. Gene transfer was first reported in
animals in 1988. The treatment holds the poten-
tial to cure many genetic disorders such as sickle
cell anemia, cystic fibrosis, hemophilia, Gauch-
er’s disease and many other immunodeficiency
diseases. DNA protein cochleates are handsome
candidates for gene therapy applications. Cochle-
ate formulations facilitate stable gene transfer in
CD34
+
neonatal cord blood cells. In vitro gene
transfer ability of cochleate complexes in human
hematopoietic cells holds latent potential to
treat many genetic and infectious diseases [103].
Scientists have tested for the feasibility of using
rhodamine-labeled cochleates to deliver a green
fluorescent protein (GFP) plasmid in cell lines

and primary cells. They found that cochleates
are efficiently accumulated by macrophages in
both cell lines and primary cells in vitro and
in vivo [43]. In animal models, cochleates have
been reported to be proficient in the delivery of
antisense oligonucleotide for chronic lymphocytic
leukemia [44].
Toxicity of metallic nanoparticles
Even the inert metals gold and silver, at nanoscale
dimensions, bustle with energy compared with
their larger counterparts. A decrease in particle
size increases the surface area to volume ratio,
and in turn raises chemical and physiological
activity. The determination of nanotoxicity is a
crucial subject as it highly affects the relation-
ship of nanometals with humans and the envi-
ronment. A precise knowledge of adverse effects
of nanostructures can help in overcoming health
risks and potential cytotoxicity if inadvertently
released into the human body during clinical
applications. The toxicological consideration
of the aluminosilicates, iron-oxides, Q-dots
and cochleates are presented in the following
sections.
 Aluminosilicate nanoparticles
Aluminosilicates being used in military goods,
as surgical gauges, coatings and propellants,
increase the probability of their exposure to
military personnel. The cellular interaction of
aluminosilicates demonstrates the release of free

radicals and oxidative stress.
Kaolin dust causes in vitro toxicity and DNA
damage in lavaged rat pulmonary alveolar mac-
rophages. The cytotoxic effects are delayed when
the same dust is treated with dipalmitoyl phospha-
tidylcholine – a pulmonary surfactant [45]. Alu-
minosilicate clay kaolin, at concentrations from
0.25 to 1.0 mg/ml, is twice as active as quartz on
a mass basis and about half as active on a surface
area basis. The phagocytotic ability and viability
of cells is greatly hindered. Fetal bovine serum
greatly reduces the toxic effects of the clay parti-
cles [46]. Oscillating bubble tensiometry techinque
has been used to study the influence of benton-
ite, halloysite and mont morillonite nanoparticles
on biophysical activity of pulmonary surfactant.
The study indicates that the aluminosilicate
particles at concentrations 0.1 mg cm
-3
or above
in the pulmonary liquid deviate the minimum
surface tension, stability index and the size of
surface tension hysteresis of the alveolar region.
This alters the dynamic biophysical activity of
the pulmonary surfactant leading to undesirable
health issues [47]. Aluminosilicate nanoparticles,
when exposed to HeLa cells, are known to express
toxicity depending on their size, composition,
dose and shape. Nanozeolites containing alumi-
num-like, ZSM-5, LTL and LTA, demonstrate a

dose-dependent toxicity by inducing cell necrosis
rather than cell apoptosis by the damnification
for the cell membranes. By contrast, pure silica
nanozeolite silicalite-1 at the same concentration
is found to be nontoxic [48] . Microarray-based
toxicogenomics studies on 75 cell cycle-related
genes of adult Drosophila melanogaster, after being
fed with nanoparticles-mixed media for 15 days,
show that silver, zinc oxide and alumino silicate
nano particles adversely influence cell cycle genes,
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whereas gold and silica nanoparticles exert the
least effect on these genes [49].
The opposing face of the aluminosilicates coin
reveals a different story. Raw aluminosilicate
nanoparticles pretreated with iron and manga-
nese salts serve as selective sorbents for anionic
contaminants of As/Sb/Se polluted aqueous
systems. Silica-coated, bismuth-doped, alumi-
nosilicates nanoparticles are not only simple to
prepare, but also exhibit long-lived photolumi-
nescence, high photostability, low toxicity and
smooth penetration into tissues. Pregnant rats
fed on an aflatoxin-contaminated diet (2.5 mg
kg(-1) diet) and then on a diet mixed with 0.5%
(w/w) aluminosilicates and bentonite for 20 days
have not shown any major malformations.

However, aflatoxin alone can lead to toxicity
and growth deformities [50]. The nanosilicate
platelets derived from natural montmorillonite
clay have been tested for genotoxicity using five
strains – TA98, TA100, TA102, TA1535 and
TA1537, of Salmonella typhimurium. The Comet
assay test on Chinese hamster ovary cells in vitro
involving incubation with 1000 µg/ml plate-
lets for 24 h indicates no DNA damage. The
micronucleus assay in vivo and the Salmonella
gene mutation assay results in no micronucleus
induction in the Chinese hamster ovary cells.
Even 3-(4,5-dimethylthiazol-2-yl)-2,5-diphen-
yltetrazolium bromide and lactate dehydroge-
nase release assays on Chinese hamster ovary
cells, after 12 h incubation, demonstrate feeble
cytotoxicity under 1000 µg/ml [51].
Another study conducted recently, involving
lipophilically coated silica nanoparticles and
alumina nanoparticles in the hexagonal close-
packed a structure, found that the nanoparticles
have potential to fight Grasserie, a lethal poly-
organotrophic disease caused by Bombyx mori
nucleopolyhedrovirus, the fifth instar silkworm
larvae. The nanoparticles cause morphological
transformation of Bombyx mori nucleopolyhe-
drovirus polyhedra, and thereby reduce virus-
induced cytopathic effect and plaque formation.
This study can contribute to the development of
new antiviral nanomedicines [52]. In vitro cyto-

toxicity experiments conducted on nanozeolites
and monodisperse amorphous silica nanopar-
ticles of similar size range (25–100 nm) and
concentration (500 µg/ml) report lower toxic-
ity in nanozeolites [53]. The potential toxicity of
organophyllosilicates on cells from lung epithe-
lial cancer, colon epithelial cancer, lung fibro-
blast and skin fibroblast is not apparent even in
the concentration range of 500–1000 µg/ml [54].
Despite the good documentation of respira-
ble-sized aluminosilicates being responsible for
pulmonary diseases, for generations, alumino-
silicates have also been considered as versatile
and benign. A careful methodology involved
in the preparation of aluminosilicates, to avoid
their aggregation or adsorption in the biologi-
cal media, could render them more stable in
nanomedicine.
 Iron oxide nanoparticles
The different types of iron oxides hold different
cytotoxic levels at varying concentrations. Sci-
entists recently studied potential adverse biologi-
cal effects of four different iron nanoparticles,
namely dextran-coated Endorem
®
, carboxydex-
tran-coated Resovist
®
, lipid-coated magnetoli-
posomes and citrate-coated very small iron oxide

particles. They found magnetoliposomes have
the highest level of safe concentrations in cells
followed by Endorem, Resovist and small iron
oxide particles. This study is significant in evalu-
ation of nontoxic concentrations and choice of
particles for cell labeling techniques [55]. Exces-
sive levels of nearly 1000 mg Fe/ml, of these iron
oxide nanoparticles localized in perinuclear sur-
faces of murine C17.2 neural progenitor cells and
human blood outgrowth endothelial cells dem-
onstrate detrimental effects on cell migration
and differentiation [56].
Superparamagnetic iron oxide nanoparticles
(SPIO), which are considered as the gold stan-
dard for MRI cell tracking, have the potential
to perturb the actin cytoskeleton, alter gene/cel-
lular expression, impair cell-cycle regulation and
disturb iron homeostasis and pancreatic func-
tioning. In some cases SPIO-labeled cells pro-
duce hyperintensities on T
2
/T
2
-weighted MRI,
making it difficult to distinguish from other
hypointense regions such as damaged tissues
or blood clots. Also, SPIO are known to cause
inflammation, mitochondrial disintegration,
chromosome condensation and formation of
apoptotic bodies and reactive oxygen species [57].

The SPIOs, Feridex
®
(also known as Endorem
or ferumoxide) and Resovist (also known as clia-
vist) have been known for their utility as T
2
MRI
contrast agents due to their ability to shorten T
2

relaxation times in the liver and spleen, by selec-
tive uptake and accumulation in the cells of the
reticuloendothelial system. These SPIOs being
synthesized in aqueous media have poor crystal-
linity and, in turn, relatively low r
2
relaxivities,
which makes them unfit for ultrasensitive MRI.
Since 2009, both Feridex and Resovist have been
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abandoned from their use in humans due to their
adverse side effects such as severe back pain, leg
pain, vasodilation and paraesthesia [58].
Scientists believe that it is chemical instability
or surface reactivity of metallic nanoparticles that
causes them to produce in vitro toxicity. Nanopar-
ticles that are readily oxidized, reduced or dis-

solved carry good potential to be genotoxic or
cytotoxic. Oxidation of zero valent iron nanopar-
ticles into lepidocrocite (gFeOOH) and magnetite
(Fe
3
O
4
) in contact with E. coli leads to the genera-
tion of reactive oxygen species through the fenton
reaction inducing oxidative stress [59]. Oxidative
stress is considered the main mechanism behind
cytotoxicity and this can be suppressed to some
extent by use of surface coatings such as citrate,
polyvinyl alcohol and meso-2,3-dimercaptosuc-
cinic acid, which reduces the number of oxida-
tive sites and also prevents direct contact between
nanoparticles and cells. Tetramethylammonium
11-aminoundecanoate-coated iron nanoparticles
are found to be nontoxic at 0.110 mg/ml and cyto-
toxic at 100 mg/ml [60]. For clinical utility, efforts
should be made to improve magnetic properties
of iron oxide nanoparticles, and thereby increase
relaxivities by controlling the composition, oxida-
tion state, aggregation and toxicity due to pres-
ence of other harmful transition elements such as
Co and Mn. Very recently, magnetite nano cubes
of 40–120 nm, encapsulated in polyethylene
glycol-phospholipids, have been used as highly
sensitive contrast agents for MRI of single cells
both in vitro and in vivo [61]. Magnetic iron oxide

nanoparticles are toxic at 300 g/ml, but are very
promising in orthopaedic applications at a low
concentration of 20 g/ml [62]. Manganese-doped
SPIO nanocomposites of nearly 80 nm shows T
2

relaxivity of 270 (Mn
+
Fe) mM
-1
s
-1
in a magnetic
field of 1.5 T. The relaxivity is much higher than a
single manganese-doped SPIO nanoparticle con-
taining lipid–PEG micelles and is highly useful to
form ultrasensitive MRI contrast agents for liver
imaging [63]. These high-yield designs, along with
suitable detoxification pathways of nanoparticles,
hold immense implications for safe utility in the
human body.
 Q-dots
The health hazards posed by Q-dots depend
on their size, concentration [64], type of metal-
lic cores [65], bioactivity of outer coating [66]
and their oxidative or photolytic stability [67].
The cytotoxicity of cellular Q-dots is mainly
because of photobleaching in an in vivo aero-
bic environment through irradiation. The high
photobleaching rate occurs in oxygen-rich condi-

tions and at low Q-dot concentration subjected
to high irradiation power density. The photo-
chemical process results in transfer of an elec-
tron to an excited Q-dot oxygen molecule, which
leads to the production of a superoxide anion
that corrodes the nanoparticle surface. The
photooxidation of CdTe has been observed in
Euglena gracilis (EG 277) and human embryonic
kidney (HEK 293) cells [68].
Cadmium-, selenium- and tellurium-contain-
ing Q-dots are toxic due to release of free metal,
production of free radical species, and also intra-
cellular distribution of Q-dot nanoparticles in
cells, causing toxicity in the kidneys, lungs and
nervous system, in addition to DNA damage.
CdSe-incubated Bacillus subtilis have shown
the heavy metal damage [69]. Moreover, each
Q-dot is unique in its composition and physi-
cochemical properties, which makes it difficult
to generalize their biological and toxicological
influence in various models. One study on a
luminous bacteria Photobacterium phosphoreum,
involving a series of Q-dots (CdSe, CdTe and
ZnS-AgInS2), holds surface coating such as
with MAA or dihydrolipoic acid, responsible
for cytotoxicity [70].
Inhibition of the respiratory mechanism or
membrane depolarization, as a result of interac-
tion of metallic components of Q-dots with com-
ponents of the electron transport chain, might be

another cause of toxicity [71]. Dose-dependent cell
motility has been found in Chagas’ disease caus-
ing protozoan Trypanosoma cruzi, where CdTe
Q-dots with concentrations below 20 µM did not
affect cell division of parasites, while 2–200 µM
CdTe Q-dots caused a reduction in the percent-
age of DNA-duplicated parasites. T. cruzi epimas-
tigotes incubated with 200 µM Q-dots, under
ultrastructural analysis, reveal mitochondrial
swelling, intense vacuolization in the cytosol, the
appearance of endoplasmic reticulum profiles sur-
rounding organelles and other cytosolic degraded
structures. The presence of the nanoparticle could
be observed inside the cytosolic vesicles and also
on the epimastigote surface [72]. In vitro vascular
endothelial toxicity, through activation of the
mitochondrial death pathway and induction of
endothelial apoptosis, of mercaptosuccinic acid
(2-sulfanylbutanedioic acid)-capped Q-dots has
been observed in plant cells [73].
The study of cytotoxicity of aqueous synthe-
sized Q-dots, CdTe/CdS and CdTe/CdS/ZnS,
reveals that the cytotoxicity of these Q-dots
not only comes from the release of Cd
2+
ions,
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future science group

but also intracellular distribution of Q-dots in
cells and the associated nanoscale effects [74].
The cadmium leaching from the more soluble
Q-dots is found on examination of multiple
end points on nematodes using core (CdSe) and
core–shell (CdSe/ZnS) Q-dots, at low (10 mg/l
Cd), medium (50 mg/l Cd) and high concen-
trations (100 mg/l Cd). The core–shell Q-dots
exhibit no effect on lifespan, fertility and growth
while the core Q-dots cause acute effects simi-
lar to those found for cadmium salts. The lower
lifecycle exposures to core Q-dots did not carry
enough adverse biological attributes to the prog-
eny compared with those subjected to higher
concentrations [75].
Most of the studies on Q-dots cited in the
literature are in vitro; however, a recent in vivo
study of animal toxicity of CdSe–ZnS Q-dots
does not report significant adverse effects [76].
CdSe Q-dots having a protective coating of tri-n-
octylphosphine oxide, one or two monolayers of
ZnS and bovine serum albumin on their surface,
which virtually eliminates their cytotoxicity [77].
The mobile charges present on the surface of
Q-Dots cause photo brightening and blinking.
A rapid alternation of Q-dots among emitting
and nonemitting states produce blinking, on the
other hand, excessive excitation increases fluo-
rescence intensity to cause photo brightening.
These photophysical limitations, once reduced,

can further enhance the efficiency of Q-dots.
 Cochleates
Cochleates are considered safe oily vehicles.
The AFCo1 cochleate produced from proteo-
liposome Neisseria meningitidis B, when tested
for toxicological relevance in Sprague Dawley
rats, was found to be nontoxic and fit for human
consumption through the nasal route [78]. The
efficacy of oral cochleate-amphotericin B to treat
systemic candidiasis is well known. Adminis-
tration of low doses (0.5 mg/kg body weight)
through cochleates completely clears the fungal
infection from kidneys and lungs, leaving behind
no trace of toxicity. Cochleates have introduced a
novel way to empower multidrug resistant bacte-
ria, by working in coordination with membrane
active oligo-acyl-lysyl sequence. The oligo-acyl-
lysy-based cochleates act synergistically with
various antibiotics, to decrease drug toxicity and
increase dose-dependent therapeutic efficacy.
The cochleates encapsulating amphotericin B
do not induce hemolysis of human red blood cells
even at high concentrations of 500 µg of ampho-
tericin B/ml. These cochleates were also found
to be highly effective in treating mice infected
with Candida albicans when administered intra-
peritoneally at doses as low as 0.1 g/kg/day [79].
Cochleates are considered to be highly efficient
lipid-based modules for the treatment of vis-
ceral leishmaniasis, and also a highly reliable

source to deliver nucleic acid-based therapies.
When compared with the conventional drug
amphotericin B deoxycholate, the in vitro activ-
ity of cochleates encapsulating amphotericin B
is similar, having an ED
50
of 0.021 µg/ml and
the latter of 0.017 µg/ml; however, cochleates
encapsulating amphotericin B unlike ampho-
tericin B deoxycholate deoxycholate is not toxic
to macrophages at concentrations as high as
2.5 µg/l [80]. Lipid formulations of amphoteri-
cin B deoxycholate (fungizone) circumscribe the
nephrotoxicity and infusion-related side effects
of this broad-spectrum antifungal drug. The
formulations are available under the names of
AmBisome
®
, a true liposome; Abelcet
®
, ribbon-
shaped; and Amphocil
®
, disc-shaped drug. They
differ in size, shape, visceral diffusion and retic-
uloendothelial clearance but all of formulations
contain amphotericin B with an effective dose
range of 3–5 mg/kg/day [81]. Cochleates encap-
sulating a plasmid (3.75 µg/ml DNA) expressing
GFP, when incubated in vitro in 4T1 murine

mammary adenocarcinoma cells, exhibit GFP
expression of 19.49–10.12% 96 h after addi-
tion; with GFP expression seen for up to 7 days
postaddition [82].
Conclusion
Currently, nanometals are a highly promising
class of nanomaterials for medical progress as
they control infection, inflammation, cancer,
gene therapy and drug delivery, and even bio-
sensing, imaging and labeling techniques. The
biocompatible nature of the miniature-sized
metals, juxtaposed with their photo absorbance
or emission characteristics, renders them a
ubiquitous place in nanomedicine to interplay
both diagnostic and therapeutic properties.
The health benefits of nanometals are no doubt
transforming therapeutics; however, their poten-
tial adverse effects cannot be underestimated.
The success of nanometals in medicine highly
relies on the transition from their risk assessment
to risk elimination. Researchers should con-
sider a thorough investigation of nanoparticle
concentration, distribution, sublethal cellular
changes, cell type and experimental conditions
of the cytotoxic assay; to overcome drawbacks
associated with the applications of nanoparticles.
Metallic nanoparticles & their medicinal potential | Review
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Future perspective
The medicinal potential of nanometals will reach
a new height if they can work synergistically
with biomolecules to be self-guided automatic
machines, having enough force to precisely
reconstruct the molecular structure of damaged
Executive summary
Background

The medicinal industry has seen an amazing growth in nanoscale science over the last four decades; to the extent that products
containing metallic nanoparticles like aluminosilicates, nanobiomagnets, quantum dots (Q-dots) and cochleates have found their utility
in wound healing, antibacterial growth, diagnostic imaging, biosensing, assay labeling, cancer therapy and drug delivery.
Aluminosilicate

Aluminosilicates are aluminium and silicon oxides broadly classified as orthosilicates, phyllosilicates and cyclosilicates and are mainly
synthesized by hydrothermal method or a sol-gel route.

Aluminosilicate nanoparticles are abundantly found in clay. Since time immemorial, kaolin clay has been used to prevent bleeding and
help in the healing of skin wounds. Over the last few years, kaolin impregnated surgical dressings, and QuickClot
®
are being increasingly
used by the medical personnel.

The metal surfaces of aluminosilicates in clay like smectites and illites, prohibit the growth of various microbes including Aspergillus
flavus, methicillin resistant Staphylococcus aureus and b-lactamase Escherichia coli.

Bentonite is another aluminosilicate, with commercial name ‘WoundStat™’, for wound dressings, pain, stings, burns and cuts.
Nanobiomagnets

Magnetite, haematite and maghemite are the various forms of iron oxides that serve as biomagnets. The magnetic behavior of these

iron oxides is due to internal superexchange competition between their different tetrahedral and octahedral sites.

The commonly used techniques to synthesize nanobiomagnets are reverse micelle, precipitation, sonochemistry, microwave irradiation,
autogenic pressure reactor and glass crystallization.

Iron oxide nanoparticles are excellent hyperthermia and MRI contrast agents due to their high magnetic moment, which leads to local
magnetic field inhomogeneity. Iron oxide nanoparticles are effective tools for separating proteins and detection of DNA/RNA molecules
with a single-base difference.
Q-dots

Q-dots are 2–10 nm sized chalcogenides of cadmium or zinc. They constitute the metallic core of semiconductors, noble metals and
magnetic transition metals shielded by a shell that cover surface defects and a coating of functional ligands as a cap.

The electronic excitations in the semiconductor band gap of Q-dots bring forth a broad absorption spectrum, narrow emission spectrum,
brightness, time resolved imaging, high quantum yield and stability against photobleaching.

Biomedicine utilize the properties of Q-dots in cell tracking, immunoassays, determining the metastatic potential of cells, high resolution
cell imaging and fluorescence resonance energy transfer-based biosensing.
Cochleates

Cochleates are rod-like multilayer entities having unilamellar liposomes condensed by bivalent cations as zinc, calcium, magnesium and
barium.

These highly efficient drug-delivery vehicles are encochleated into a spiral by hydrogel method, trapping, binary aqueous–aqueous
emulsion and dialysis.

The internal environment of cochleate sheet is hydrophobic, which helps to safely administer the drugs even with poor oral absorption.

Gene transfer into a genome of defective cell or hematopoietic cells can be done by combining a DNA plasmid and proteins with
cochleates. Many genetic disorders can be cured using this methodology.

Toxicity of metallic nanoparticles

The relationship of metallic nanoparticles with humans and the environment is greatly governed by their toxicity levels.

The amount of oxidative stress and free radicals released during their interaction with living tissues, and the concentration at which they
are least destructive, are the points worth consideration before they are used for biomedical purposes.
Conclusion

Nanometals have earned their position in medical sciences to be used as both diagnostic and therapeutic agents. However, a lot needs
to be done to eliminate the risk factors associated with them.
Future perspective

If scientists today can make a nanoscale car with chassis, wheels and UV-driven engine that can ferry drug molecules, we can dream of
nanometals as self-guided automatic machines having enough potential to tailor the damaged cells. The need to overcome the practical
challenges of cytotoxicity, economical issues and lengthy clinical trials will help the tiny nanometallic-caterpillar to come out of its
cocoon as a beautiful butterfly.
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cancer cells and perform surgeries. The real chal-
lenge lies in producing nanoparticles that can
function in close proximity to cells and can use
digital data such as ribosomes to lead synthesis of
the genome with predictable and tailored prop-
erties. Since there is a large disparity in size and
shape of these tiny metals, the biggest hurdle is
to produce nanometallic medicines on a large
scale with the same accuracy every time and
with a strong control over their physicochemical

properties. A thorough insight into the interac-
tion of these metals with biochemical pathways,
their toxicological effects, economical issues and
exposure pathways, will allow future medicine
to use them with confidence. The bright future
of nanometals in medicine needs to emerge from
the clouds of lengthy clinical trials, risk assess-
ment, long product approval processes and high
associated expenses.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial
involvement with any organization or entity with a
financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript. This
includes employment, consultancies, honoraria, stock
ownership or options, expert t estimony, grants or patents
received or pending, or royalties.
No writing assistance was utilized in the production of
this manuscript.
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