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Fluorescence nanoparticles “quantum dots” as drug delivery system and their toxicity: A review


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Fluorescence nanocrystals or quantum dots (QDs) are engineered nanoparticles (NP) that have shown great promise with potential for many biological and biomedical applications, especially in drug delivery/activation and cellular imaging. The use of nanotechnology in medicine directed to drug delivery is set to expand in the coming years. However, it is unclear whether QDs, which are defined as NPs rather than small molecules, can specifically and effectively deliver drugs to molecular targets at subcellular levels. When QDs are linked to suitable ligands that are site specific, it has been shown to be brighter and photostable when compared with organic dyes. Interestingly, pharmaceutical sciences are exploiting NPs to minimize toxicity and undesirable side effects of drugs. The unforeseen hazardous properties of the carrier NPs themselves have given rise to some concern in a clinical setting. The kind of hazards encountered with this new nanotechnology materials are complex compared with conventional limitations created by traditional delivery systems. The development of cadmium-derived QDs shows great potential for treatment and diagnosis of cancer and site-directed delivery by virtue of their size-tunable fluorescence and with highly customizable surface for directing their bioactivity and targeting. However, data regarding the pharmacokinetic and toxicology studies require further investigation and development, and it poses great difficulties to ascertain the risks associated with this new technology. Additionally, nanotechnology also displays yet another inherent risk for toxic cadmium, which will enter as a new form of hazard in the biomedical field. This review will look at cadmium-derived QDs and discuss their future and their possible toxicities in a disease situation.
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In recent years, there has been vast growth and expansion
of research and applications in the eld of nanoscience
and nanotechnology. e outcomes in these disciplines
are materials known as NPs. NPs include fullerenes,
buckyballs, carbon tubes, liposomes (Malam et al. 2009),
nanoshells, dendrimers, quantum dots (QDs) (Iga et al.
2007; Jamieson et al. 2007), superparamagnetic NPs
(Riyahi-Alam et al. 2010), gold, and silver (Chaloupka
et al. 2010) NPs.
It is expected to bring great benets as applied to bio-
medicine in areas as diverse as diagnosis and treatment
of disease. Potential applications in the eld of medicine
include drug delivery, clinical diagnostics, diet industry,
and improved biocompatible materials. Nanomaterials
are potential tools that can facilitate some of these
applications. Research and development have focused
on the synthesis, solubilization, and bioconjugation of
highly luminescent stable QD. Structurally, QD possesses
a metallaloid crystalline core, which ultimately depend-
ing on its composition and size will confer the type of u-
orescence it will emit. e core is composed of materials
from including cadmium–selenium (CdSe), cadmium–
tellurium (CdTe),indium–phosphate (InP) or indium–
arsenate (InAs) (Jamieson et al. 2007). A semiconductor
shell typically zinc sulde (ZnS) stabilizes the core, further
improving the optical, physical properties, and bioavail-
ability of the material. Additional capping or coatings of
biocompatible material or polymer layers, such as POSS-
PCU (Kidane et al. 2009) and PEG (Polyhedral Oligomeric
Fluorescence nanoparticles “quantum dots” as drug delivery
system and their toxicity: a review
Shirin Ghaderi1, Bala Ramesh1, and Alexander M. Seifalian1–3
1Centre for Nanotechnology and Regenerative Medicine, Division of Surgery and Interventional Science, University College
London, UK 2London Centre for nanotechnology, London, and 3Royal Free Hampstead NHS Trust Hospital, London, UK
Fluorescence nanocrystals or quantum dots (QDs) are engineered nanoparticles (NP) that have shown great promise
with potential for many biological and biomedical applications, especially in drug delivery/activation and cellular
imaging. The use of nanotechnology in medicine directed to drug delivery is set to expand in the coming years.
However, it is unclear whether QDs, which are dened as NPs rather than small molecules, can specically and
eectively deliver drugs to molecular targets at subcellular levels. When QDs are linked to suitable ligands that are
site specic, it has been shown to be brighter and photostable when compared with organic dyes. Interestingly,
pharmaceutical sciences are exploiting NPs to minimize toxicity and undesirable side eects of drugs. The unforeseen
hazardous properties of the carrier NPs themselves have given rise to some concern in a clinical setting. The kind of
hazards encountered with this new nanotechnology materials are complex compared with conventional limitations
created by traditional delivery systems. The development of cadmium-derived QDs shows great potential for
treatment and diagnosis of cancer and site-directed delivery by virtue of their size-tunable uorescence and with
highly customizable surface for directing their bioactivity and targeting. However, data regarding the pharmacokinetic
and toxicology studies require further investigation and development, and it poses great diculties to ascertain
the risks associated with this new technology. Additionally, nanotechnology also displays yet another inherent
risk for toxic cadmium, which will enter as a new form of hazard in the biomedical eld. This review will look at
cadmium-derived QDs and discuss their future and their possible toxicities in a disease situation.
Keywords: Quantum dots, toxicity, cancer, drug delivery, imaging
Address for Correspondence: Prof. Alexander M. Seifalian, Centre for Nanotechnology and Regenerative Medicine, University College
London, London, UK. E-mail:
(Received 11 June 2010; revised 17 September 2010; accepted 20 September 2010)
Journal of Drug Targeting, 2011; 19(7): 475–486
© 2011 Informa UK, Ltd.
ISSN 1061-186X print/ISSN 1029-2330 online
DOI: 10.3109/1061186X.2010.526227
476 S. Ghaderi et al.
Journal of Drug Targeting
Silsesquioxane-Polycarbonateurethane, Polyethylene
Glycol), to the QD core-shell promotes water solubility
and desired bioactivity (Figure 1). e polymer coatings
have either –COOH or –NH2 surface groups available for
covalent coupling of bioactive molecules. e excellent
optical properties of CdSe and CdTe QDs have received
great interest in biological applications. In addition to
these distinctive structural and uorescence properties,
QD shows a direct, relationship between their physical
size and the energy of the exciton (electron–hole pairs)
and the wavelength of emitted uorescence. is unique
property of size-tunable uorescence allows QD to have
a common excitation prole spanning the ultraviolet
(UV), visible, and near-mid infrared regions of the elec-
tromagnetic spectrum but dierent uorescent emission
maxima (Yaghini et al. 2009).
Cadmium metal toxicity in health has been studied
and investigated for over 50 years. eir unique struc-
tures such as size, shape, and chemical composition and
their interaction with light or other external stimuli gives
rise to a concern, as they have detrimental eect to the
environment. Currently, cadmium is classed as category
1 carcinogen, and studies carried out in bacteria have
shown that there is no direct genotoxic or mutagenic
eect. Metals generally produce their toxicity by form-
ing complexes called “ligands” with organic compounds.
e modied molecules lose their ability to function e-
ciently leading to the malfunction or death of the aected
cells. Metals commonly bind to biological compounds
containing oxygen, sulfur, and nitrogen, which might
inactivate certain enzyme systems or aect protein struc-
ture. e mechanism involved in cadmium toxicity is via
genome stability involving free-radical damage to DNA.
Most toxicity studies are based on the leaching of
toxic heavy metals not only from initial colloidal form
but can also occur from intrinsic properties such as size
and surface chemistry of these NPs making them as
ecient energy donors. Potentially, they are capable of
transferring energy to nearby oxygen molecules and give
rise to the formation of reactive oxygen species. ese
can promote cell inammation, damage, and death.
In addition to these toxic properties emanating from
molecular leaching and surface area, these QDs also
possess large surface area that can bind and transport
therapeutic drugs. Despite extensive studies on cad-
mium toxicity, more studies are forthcoming regard-
ing intracellular damage and environmental exposure
(Yaghini et al. 2009).
As mentioned earlier, cadmium NPs are those of
CdSe or CdTe, entombed in various coatings in the form
of semiconductor QDs. e chemical composition of
the NPs core and the composition of the outer capping
layer are vital factors inuencing QD toxicity. In terms
of chemical properties, CdTe QDs are signicantly more
toxic than core shell (CdSe/ZnS) NPs. e evolution of
nanotechnology has introduced new aspects of cadmium
toxicity as applied to clinical settings.
Using the apparatus of nanotechnology, drug delivery
techniques in the nanometer-sized parameters can be
exploited and developed to modify both pharmacological
and therapeutic properties of drug molecules. By virtue of
their small size, QD as drug delivery vehicle oers great
advantages in the areas of pharmacokinetic properties
and ecient payload compared with traditional systems.
A further advantage is modifying their surface chemistry
to suit attachment of targeting and therapeutic molecules
for clinical applications.
In this review, uorescent NPs “quantum dots” have
been discussed as potential drug delivery vehicle with
possible reduction in its inherent toxicity before clinical
application can be anticipated.
Engineered fluorescent QDs
Currently, there are many methods in the synthesis of
QD, which include organic and aqueous synthesis in pre-
paring highly luminescent nanocrystals. Traditionally,
high-quality nanocrystals are prepared in organic sol-
vents and they cannot be used directly in biosystems due
to their hydrophobicity. Water dispersible QD that sus-
tain strong uorescence can now be prepared by ligand
exchange with a hydrophilic moiety. However, it is a dif-
cult procedure, but a direct synthesis can be carried out
in an aqueous environment for biological applications.
In nanotechnology, one of the main precursors used in
the assembly of QDs is cadmium and tellurium forming
the core that are approximately 2 to 10 nm (200-10,000
atoms) in diameter (Green & Howman 2005; Smith et al.
2008). At these small sizes, QDs show some unique and
fascinating optical properties, such as sharp, symmetri-
cal emission spectra, high quantum yield, chemical and
photostability, and tunabilityof size-dependent emission
wavelength. eir intrinsic brightness is often of many
orders that observed for traditional organic uorophores.
eir large surface to mass ratio confers the particles
Coating agent
Such as; POSS-
Polyethylene Glycol
Peptide ligand
such as;
CdTe, CdSe
shell, such
as; ZnS.
To stabilize
the core.
Figure 1. Structure of quantum dot with bioactive agents.
Materials such as POSS-nanocomposite have been used to coat
the QD to eliminate its toxicity and facilitate covalent conjugating
of bioactive molecules (such as ligands, antibodies and peptides)
to QD. is schematic gure was generated by authors.
Quantum dots as drug delivery system and their toxicity 477
© 2011 Informa UK, Ltd.
the ability to absorb and carry many compounds. NPs
have relatively large (functional) surface able to bind,
adsorb, and carry compounds such as drugs, probes,
and proteins. Based on these desirable properties, QDs
have the potential to improve the sensitivity of biological
imaging at the cellular level that includes cancer detec-
tion (Figure 2), progression and treatment, radio- and
chemo-sensitizing agents, electron and x-ray contrast
agent, and targeted drug delivery. However, caution have
to be exercised with these attractive applications as QD
contain substantial quantities of cadmium that are reac-
tive in an ionic state, and only limited studies are avail-
able about health risk of exposure to NPs (Juzenas et al.
2008; Smith et al. 2008).
In natural semiconductor bulk material, a suciently
strong stimulus will cause electrons to be raised into the
conduction band and will stay there momentarily before
falling back across the band gap to their natural, valence
energy levels. As the electron falls back down across the
band gap, electromagnetic radiation is emitted with a
wavelength corresponding to the energy lost in the tran-
sition. However, if the size of a semiconductor crystal
becomes small enough that it approaches the size of the
material’s exciton Bohr radius, a quantum connement
phenomena occurs, and under these conditions, it ceases
to resemble the bulk and instead it is now known as QD.
Hence, with QD, the size of the band gap is dependent
on the size of the dot and wavelength of the emitted pho-
tons. Because the emission frequency of QD depend on
the band gap, it is therefore possible to control the output
wavelength of the QD with extreme precision (Alivisatos
Relative QDs are larger than organic uorescent dye,
which favors easy coupling of targeting groups to the
surface. CdSe and CdTe have been the material of choice
for QD with bioimaging, bioanalytical, and optical appli-
cations. By virtue of their large surface area, atoms are
exposed with some incomplete molecular orbital that
causes some degree of instability. ese are termed as
defective sites, which can be highly reactive in a biologi-
cal microenvironment.
QDs have great advantages in which they are pho-
tostable and possess a long half-life over conventional
organic dyes that are photounstable and have a short
half-life. ese properties are desirable in QD as they
can retain their brightness and have potential for imag-
ing, monitoring, and tracking the drug pathway. Organic
dyes such as QDs are excited by light, but due to their
narrow excitation wavelength and overlapping emitting
uorescence spectrum are limited in their use. QD can
be excited by broad spectrum wavelength with narrow
emission wavelength that causes no overlapping with a
broad stokes shift. us, it has advantages in imaging that
give rise to sharp resolution with reduced background
To stabilize the QD, another semiconductor with a
wider band gap is sometimes co-crystalized to form a
shell over the core. ZnS with a wider band gap is a semi-
conductor of choice and can been shown to increase u-
orescence eciency and minimize the toxicity inherent
in the reactive core. e ZnS shell acts as an antioxidant
and protects the core from photobleaching and maxi-
mizes chemical stability. Naked QDs are hydrophobic
when synthesized and they tend to precipitate in aque-
ous environment and are limited in biological applica-
tions. QDs are mostly synthesized in nonpolar organic
solvents. To render them water soluble, functionalization
with secondary coatings or capping materials such as
mercaptopropionic acid, mercaptosuccinic acid, PEG,
and POSS-PCU are used, which also maintains the QD
in a monovalent form (Figure 3). With these types of
coating, conjugation with targeting molecules such as
antibodies, peptides, or receptor ligands can promote
the QD to home in to specic tissues or organs. is has
been demonstrated in vivo imaging of breast cancer and
prostate tumor in mice using CdSe/ZnS-QD coated with
targeting peptides. QD also accurately located the tumors
and tracked metastases with appropriate imaging tech-
niques. is work has led to extensive developments in
the use of QD in vivo detection of cancer, image-guided
surgery, and drug delivery. An attractive feature of QD is
that they possess energy levels in the range of 1 to 5 eV
and can also function as photosensitizers that absorb
high-energy photons from x-rays or gamma radiation,
thus improving and focusing radiation therapy (Juzenas
et al. 2008). Overall, QDs have the potential to detect and
treat cancer and enhance medical therapy. e possible
risk of QD with its toxic Cd composition potentially can
cause undesirable biological eects, unless care is taken
in pharmacological and toxicological parameters.
QD-related toxicity
ere is no consistent data on QD toxicity as there
are many varieties of QD synthesized. Each QD type
Figure 2. Quantum dot nanocrystals can highlight colorectal
cancer cells by photoexcitation. is experimental data obtained
from current research was carried out to investigate the in vivo
application of QD.
478 S. Ghaderi et al.
Journal of Drug Targeting
possesses its own inherent physicochemical proper-
ties, which in turn dictates its potential toxicity or lack
of it. Currently, there are no reliable information in the
literature regarding the toxicity of QD, and this can be
attributed to a number of factors: absence of proper
toxicology-based studies, the many types of QD dos-
age/exposure concentrations reported in scientic
literature, and the diverse physicochemical properties
of individual QD (Hardman 2006). Data from studies
primarily designed for toxicological assessment (e.g.,
dose, duration, frequency of exposure, and mechanism
of action) are far and few. To summarize QD toxicity, we
can discuss general concepts pertaining to core, core
shell and coating toxicities, and animal studies. In this
review, there are two tables that currently summarize
some of the literature survey performed on QD toxicity
(Tables 1 and 2).
Core material toxicity
e potential and main area of QD toxicity is from
cadmium located at the core of the nanocrystal. Data
from uncoated QD and free Cd present in the colloid
suspensions and core have aected cells intracellularly
(Kirchner et al. 2005) concluded that CdTe QDs were
cytotoxic in rat pheochromocytoma cells (PC12) at 1
µg/ml level of concentration that induced apoptotic
type of cell death with chromatin condensation and
membrane fragmentation. e toxicity eect observed
in these studies resembled Cd ions toxicity. Data col-
lected from incubation of uncoated nanocrystals in
rat hepatocytes cells suggest that cadmium is released
via surface oxidation by biodegradation (Derfus et al.
2003). is study suggests that cadmium toxicity is
from the core and is likely to contribute signicantly to
QD toxicity.
6.80 nm
20 nm
Direct Mag: 300000x
Royal Free Hospital
Microscopist: Innes
Print MAg: 598000x @ 7.8 in
164-06 CD Tell Ctrl_003.tif
164-06 CD-Tellurium Control
5.39 nm
8.61 nm
5.61 nm
5.77 nm
5.77 nm
8.88 nm
6.21 nm
9.22 nm
7.13 nm
6.40 nm
10.1 nm
5.36 nm
8.51 nm 5.70 nm
8.51 nm
9.96 nm
9.16 nm
6.88 nm
7.03 nm
10.5 nm 7.43 nm
8.35 nm
7.58 nm
Figure 3. Transmission electron microscopy photomicrographs showing average size of CdTe nanocrystals (5–6 nm), with biocompatible
POSS-PCU (Bakhshi et al. 2009) nanocomposite coating. is experimental data obtained from current research was carried out in
development of QD for biomedical application.
Quantum dots as drug delivery system and their toxicity 479
© 2011 Informa UK, Ltd.
QDs derived from CdTe and CdSe are electronically
active and as such are prone to photo and air oxidation,
which could potentially promote free-radical formation
that can instigate cytotoxicity (Ipe et al. 2005). ere is
evidence that free cadmium ions do not promote free-
radical formation but can increase oxidative stress,
whereas the QD core does contribute to free radical
generation. Studies have shown that using cadmium
reactive dyes in cell culture, the cytotoxicity was not
linked to cadmium release from QD but to free-radical
generation (Cho et al. 2007). ere is also evidence that
free-radical generation promote DNA damage in the
absence and presence of light photon activation (Green
& Howman 2005). Photoactivation of QD by visible or
UV light or air oxidation was shown to increase free-
radical formation. e mechanism involved in these
environments is that a photon of light excites the QD
generating an excited electron that migrates to molecu-
lar oxygen generating singlet oxygen. In the presence
of water and biological molecules, singlet oxygen read-
ily initiates free-radical formation. is is the rationale
behind photodynamic therapy in cancer applications
when QD are the participating material and its toxic-
ity needs assessing when distributed to normal tissues.
When normal tissue takes up QD NPs and when acti-
vated by photons of light or other oxidative stress, free
radical production can have detrimental eects on the
To circumnavigating this problem, tissue culture stud-
ies can provide some understanding of the process but
unfortunately correlating the outcome to in vivo can over-
estimate or underestimate toxicity eects. Uncoated QDs
have also contributed to cytotoxicity comparable with
cadmium toxicity and oxidative damage. Perturbations
in gene expression and biochemical processes have all
been implicated with QD toxicity, suggesting a need for
more thorough long-term studies of the eects of QD on
cell signaling. is is vital for future applications, as long
transit times encountered by QD in tissues and cells may
cause damage.
With the current knowledge based on uorescent
organic dyes to determine the fate of intracellular biomol-
ecules, care has to be exercised. Numerous NPs with their
innate active electronic structure can interact with com-
monly used organic dyes. It is of utmost importance to
conduct suitable controls to include data that NP activity
is not due to its electronic interaction with organic dyes
present in assays.
Encapsulated QDs and their toxicity
Studies have shown that encapsulation of the QD
core with ZnS or alternative capping material tends to
reduce toxicity, although more work in this area needs
investigating. Work on human breast cancer MCF-7
cell culture has shown that CdTe Cd cellular damage
similar to cadmium toxicity, whereas CdTe/ZnS core
shells or CdTe capped with mercaptopropionic acid,
cysteamine, and n-acetylcysteine minimized the eect,
indicating that ZnS shells and capping materials are
eective in the time scale studied (Bakalova et al. 2005).
In the above studies, free cadmium ion in the intrac-
ellular compartment was also minimized by ZnS and
capping. e presence of ZnS shell not only reduced
the process of apoptosis and biochemical activation of
processes but also eliminated release of cadmium ions
in aqueous environment. It also showed that ZnS shells
could also reduce free-radical production generated by
air oxidation. is clearly demonstrates that capping
QD with ZnS or other capping material reduces toxic-
ity implicated with free-radical production or release
of free cadmium. It is important to emphasize that to
evaluate toxicity of shell or capped particles, the deg-
radation of the shell or capping material is taken into
consideration together with its cytotoxicity (Chan et al.
Previous studies have shown that uorescence inten-
sity of CdSe/ZnS decreased with time along with a shift
toward the blue spectra within live cells over time. is
indicates that ZnS core shell biodegrades within the
intracellular milieu. Some studies have indicated that
ZnS shell did not fully eliminate cytotoxicity when air
or photooxidation was involved and that CdSe/ZnS-QD
may have promoted free-radical production. It has been
proposed by some researchers that although the ZnS
shell shielded the CdSe core from oxidation, it could not
inhibit the electron-induced radical generation in the
aqueous environment suggesting that the ZnS underwent
slow oxidation in the presence of air or water generating
the sulte (SO2−) radical (Kirchner et al. 2005).
Applying capping materials such as ZnS to insulate
QD core to reduce toxicity has been undertaken in many
applications. In one study, CdTe QD coated with mer-
captopropionic acid or cysteamine required a higher
concentration to become toxic in PC12 cells as com-
pared with uncoated QD. Equally using the amino acid
derivative N-acetylcysteine as coating agent on CdTe, a
reduction in the induction of Fas upregulation involved
in apoptosis (Lovric et al. 2005a) and a decrease in cyto-
toxicity in neuroblastoma cells were observed. Using
dihydroxylipoic acid coating on CdSe/ZnS (Voura et al.
2004) have shown reduction in toxicity of QD in several
cell lines while maintaining the uorescence for over a
week with no adverse eects. Using a large protein such
as bovine serum albumin (BSA) coating on QD has also
shown reduced toxicity.
e majority of the eective capping materials all
belong to antioxidants and this demonstrates the exis-
tence of oxidative stress in cadmium-based QD toxicity.
Capping materials in themselves must also be taken
into account as potential toxic substances and several
groups have shown increased toxicity associated with
mercaptoacetic acid and Topo-tri-n-octylphosphine
oxide. Accumulated data suggest that the stability of
shell and capping materials as well as toxicity requires
intensive investigation for dierent QD preparations
(Smith et al. 2008).
480 S. Ghaderi et al.
Journal of Drug Targeting
Table 1. Summary of quantum dots toxicity studies in vitro.
type Shell Coating agent
QD size
(nm) Concentration
Biological model
tested Assay used
time (h) Evaluated toxicity Outcome Year
CdSe ZnS DHLA NR 400–600 nM NR Dictyostelium
discoideum and
HeLa cells
NR <1 Cell growth was
Not applicable.
420–680 and Abso is
350 nm
et al. 2003)
CdSe ZnS None NR 10 pmol QD
Approx 10 nM
Eλ= 550 HeLa cells NR 10 Day 10 nM had minimal
eect on cell so no
Not applicable. 2004 (Chen
H2/OH, NH2,
NR 1–2 µM
WTK1 cells
cultures of rat
NR 12
DNA damage was
detected when exposed
to 2 mM QD-COOH at
2 h so there is a sign of
inuence was cytotoxic.
ere is no sign of
cytotoxicity by capping
the QD with ZnS.
Not applicable. 2004
et al. 2004b)
CdSe ZnS MUA NR 0–0.4 mg/ml Eλ= 640 Vero and HeLa
cell culture,
primary cultures
of human
NR 24 Vero cells showed
toxicity at 0.2 mg/ml,
whereas, HeLa cells
and hepatocytes at
0.1mg/ ml.
Not applicable. 2004
et al. 2004)
CdSe ZnS SSA NR 0.1–0.4
Eλ= 520 EL-4 cells
NR 0-24 Cell growth was aected
at 0.1 mg/ml.
Not applicable. 2004
et al. 2004a)
CdTe None None 2.3, 2.2,
5.7, 5.2
Eλ= 605
Aλ= 518
Rat pheochromo-
cytoma and
microglial cell
MTT assay 2-24 At 10 µg/ml is cytotoxic. Pr-incubation of
cells with antioxident
and bovine serum
albumin signicantly
reduced QD induced
cell death, also size
plays an important
part in cytotoxicity.
2005 (Lovric
et al. 2005b)
CdTe None None 2(green),
4 (yellow),
0–100 µM NR Hep G2 (human
hepatom) a cell
MTT assay 48 Concentrations in
the range of 3.0 µM,
4.8 µM and 19.1 µM
induced reduction of
50% in MTT activity,
respectively. Free
Cd was implicated
in the observed cell
Cytotoxicity is
related to the size
of QD. Higher
cytotoxicity was
related to smaller
size than the larger
QD in this particular
Green 520 nm and
yellow 519 nm
2005 (Lovric
et al. 2005b)
Table 1. continued on next page
Quantum dots as drug delivery system and their toxicity 481
© 2011 Informa UK, Ltd.
type Shell Coating agent
QD size
(nm) Concentration
Biological model
tested Assay used
time (h) Evaluated toxicity Outcome Year
CdSe ZnS PEG Silanized NR 0, 8, 80 nM NR Human HSF-42
(skin broblast)
and INR-90 (lung
broblast) cell
and cell
48 No cytotoxicity.
Minimal eect on cells
integrity and molecular
response of QD exposed
to cell lines.
Exposed QD were
endocytosed by
human skin and lung
Gene expression was
altered approximately
0.2% of genes QD
stimulated skin
broblast compared
with controls.
2006 (Zhang
et al. 2006)
CdSe ZnS Peptide NR 15–250 nM Eλ=
HEK 239T/17
and COS-1
(African green
monkey) cell
Cell titer
96 cell
1 and 24 Low toxicity at 1 hr
High toxicity at 24 hr
e toxicity is
dependent on
exposure duration
and concentration.
et al. 2006)
ZnS Cysteine,
acid, N-acetyl
NR 10 µg/ml Eλ=
MCF-7 (human
breast cancer)
cell culture.
MTT and
Trypan blue
cell assays.
1-24 Treatment of cells with
all forms of CdTe QD
resulted in signicant
cell death. erefore,
cytotoxicity has been
e CdTe QD is
more toxic than
CdSe/ZnS QD. It
was established
that free Cd is from
CdTe induces cell
death by free radical
2007 (Cho
et al. 2007)
CdSe None None 2.38 1, 10,20 nM NR Primary rat
cell culture
MTT assay 24 Cells exposed with QD:
1 nM - no toxicity, 10, 20
reduced cell viability.
Reactive Oxygen
species has been
caused the toxicity.
2008 (Tang
et al. 2008)
CdSe ZnS PEG NR 0.84–105 µM NR CaCo-2
(human colon
carcinoma) cell
MTT assay 24 ere is low cytotoxicity e toxicity of coated
QD is increased with
acid treatment due
to the free Cd ions.
2008 (Wang
et al. 2008)
CdTe CdS,
None NR 0.2–3.0 µM NR K562 and HEK
293T human cell
MTT assay 48 Cells treated with CdTe
and CdTe/CdS QD
were mostly nonviable.
erefore, it has shown
cytotoxicity. However,
no cytotoxicity has seen
in CdTe/CdS/ZnS QD.
ZnS shells may
prevent the release
of Cd2+ ions causing
ere is evidence
that residual
organic solvents in
nonaqueous QD
preparations may
have resulted in
QD independent
cytotoxic eects in
other reports.
2009 (Su
et al. 2009)
Keys: MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide); MUA: Mercaptoundecanoic acid; NR: not reported.
Table 1. Continued.
482 S. Ghaderi et al.
Journal of Drug Targeting
Table 2. Summary of quantum dots toxicity studies in vivo.
QD type Shell Coating agent
QD size
(nm) Concentration
Biological model
tested Assays used
Incubation time
toxicity Outcome Year
InAs ZnSe DHLA/PEG 8.7 NR No longer than
and IV injected in
to rats and mice.
NR 5 min Toxicity was not
QD were accumulated
to SLNs when
they were applied
However, QD injected
intravenously were
shown to extralvasate
from the vasculature.
(Zimmer et al.
CdSe ZnS MAA/targeting
peptides± PEG
3.5 and
NR Eλ= 750–920 IVD into the tail of
NR 20 min Toxicity was not
PEG prevents the
nonspecic uptake of
QD into the liver and
spleen. erefore, PEG
has an important role
in QD.
(Zimmer et al.
QD525 and
ZnS ±PEG 21 and
25 pmol Eλ= 525 IVD in the mouse. NR 15 min ere is no sign
of toxicity in this
QDPEG coated had
a 6-min circulation
time and without the
2 min. Presence of
QD in the liver and
spleen. e size of
QD had no eect on
(Schipper et al.
CdTe ZnS Monoclonal Ab
for lung
NR NR NR IVD into the
NR Up to 144 No acute toxicity
was observed.
e QD was removed
from the body in a slow
(Woodward 2007)
25, 80 5 nmol Eλ= 430
Aλ= 350
injection into the
NR 240 No toxicity was
BSA coated QD was
almost distributed
to the liver, spleen
and other tissues in
approximately less
than 2 h.
CdSe CdS PEG 37 NR Eλ= 610–621 Intradermal
injection into the
NR 24 Not toxicity was
QD mainly stayed
in the injected site,
they were detected in
lymph nodes shortly
(Gopee et al.
CdSe ZnS SSA/MUA NR 0.1 mg/ml NR EL-4 cells,
injected into
NR Up to 168 h Not toxicity NR 2004
(Hoshino et al.
CdTe None None 6 2 mM NR IVD into rat. Physiological,
assessment with
24 According to this
paper, there are
some signs of
toxicity that can
be observed.
NR 2007
(Zhang et al.
Keys: IVD: Intravenously delivered.
Quantum dots as drug delivery system and their toxicity 483
© 2011 Informa UK, Ltd.
Functional coatings and toxicity of QDs
QD incorporating shell and capping materials contain
functional groups to target specic cells or tissues.
ese functionalized QD will need their toxicity and
physicochemical parameters investigated as they may
reduce toxicity when targeted to specic locations. e
specicity of the targeting material needs evaluating,
as migration to nontargeted tissue may generate toxic-
ity especially when QD function as a photosensitizing
agent or drug carrier. Despite many studies in the use of
functionalized QD in vitro and in vivo, no detailed stud-
ies has been conducted to ascertain the toxicity of these
NP derivatives or their presence in nontargeted tissues.
Data as to the biostability of the coatings, their half-life
in vivo, and nonspecic targeting need further investi-
gation. All these queries need answering before use of
coated QD in human applications can be undertaken
(Derfus et al. 2003).
Toxicity studies of QDs in vivo
Toxicity can be exploited for its benet in regards to
biomedical applications especially in directing cellular
death of tumors or metastases (Juzenas et al. 2008). One
can envisage QD being designed with a photoactivat-
able coating and a site-specic ligand. Toxicity induced
by photoactivation is directed to specic sites (such as
tumors). After excitation by a photon, QD can impart an
excited electron to a molecular oxygen in the vicinity,
thus initiating a chain reaction of free-radical generation
promoting cell death. Photodynamic therapy in oncol-
ogy uses this rationale, and it must be borne in mind
that nonspecic distribution of QD to noncancerous
tissue such as skin or retina exposed to light taken into
QD pharmacology and toxicology pertaining to ani-
mal studies are still lacking in detail. Uncoated CdTe QD
injected in rats produced inconclusive results relating to
toxicity and organ damage, and a thorough histological
evaluation was absent. Disturbances to the motor func-
tion, was visible after injection of uncoated QD, indicat-
ing potential toxic eect to neural function (Zhang et al.
2008a). Future investigation should focus in this area.
Further long-term exposure studies need addressing.
Studies with injected amphiphilic polycyclic acid poly-
mer and PEG-coated QD in mice of 20 m−1g−1 animal
weight have indicated nonlethality until necropsy (133
days) and no indication of necrosis or damage at injec-
tion sites and no signs of QD degradation in vivo. Mice
injected with 20 nM and 1 µM CdSe/ZnS showed no
noticeable adverse eects (Larson et al. 2003). Absence of
overt adverse eects is no indication that there is no tox-
icity. QD with polymer and amphiphilic coatings when
injected was found to retard degradation of coatings over
time in vivo, aecting uorescence over time, indicating
that toxicological eects can alter with residence time
of QD in tissues. Studies have shown that depending on
the coatings, such as mercaptoundecanoic acid, lysine,
and BSA-coated CdSe/ZnS-QD, when injected into rats
shows regional distribution. Interestingly, detection of
QD in the urine or feces were absent over the duration of
10 days, indicating long transit time in the body. e par-
ticles indicated nontoxicity but not eliminated from the
system either. e existing few studies show the need for
short- and long-term toxicity assessment that monitors
multiorgan systems before QD was evaluated accurately
(Gao et al. 2004).
Parameters involved in elimination toxicity
of QD
QD just as pharmaceutical drugs undergo similar toxicity
evaluation in terms of size, dose, and exposure, empha-
sizing the importance of stringent physicochemical
characterization of QD. Particle size evaluation is vital to
biological actions of NPs. Numerous studies have dem-
onstrated that for QD, particle size inuences toxicity
at the intracellular and animal level. Some studies have
indicated that in cellular studies, 2.2 nm CdTe QD had
greater toxicity as compared with larger 5.2 nm particles
(Lovric et al. 2005b). Interestingly, smaller particles were
localized in and around the nucleus of the cell, whereas
the larger particles (approximately 2.5 nm) were located
within the cytoplasm.
At the nanoscale level, size and dose plays an impor-
tant role, since surface area is critical for NP properties.
In one study, it concluded that structure might play an
important role in its activity when delivered via the der-
mal route. Relevant information needed for toxicological
studies as applied to humans are the level of exposure
and dose (Zhang et al. 2008b). Studies done in vitro
using milligram or microgram per milliliter quantities
may indicate a high dose to correlate with physiological
context, as QD used at low concentration when targeted.
Until dosing parameters are standardized, current stud-
ies should include a wide range of concentrations, high-
est to the lowest and incorporate estimations of surface
area and the number of particles delivered (Ryman-
Rasmussen et al. 2007).
Finally, exposure parameters require further evalu-
ation. Most NPs including QD have a tendency to dis-
tribute widely in tissues unless targeted, and most have
minimal level of metabolism or excretion. Evidence of
long residence time in tissues, and long-term studies are
vital to establish toxicological risk (Zhang et al. 2008a).
In relevance to QD, the presence of electronically active
cadmium in the structure may reside in tissues for a long
duration perhaps years. As has been established that
QD promote toxicity via the eects of cadmium and free
radical generation, alteration on transcription, DNA syn-
thesis, and signal transduction can go on for a long time.
Recent studies have shown how relevant, low levels of
free radical formation are integral to signal transduction
pathways, and hence low-level radical production from
QD may participate and alter with these pathways over
time, as the various layers coating the toxic cadmium
core are biodegraded (Tonks 2005).
484 S. Ghaderi et al.
Journal of Drug Targeting
Passing QDs through blood-brain barrier
Blood-brain barrier (BBB) is a barrier that prevents diu-
sion of any unwanted substances to enter the vasculature
of the brain due to tight junctions. e disadvantage of
this is that therapeutic drugs cannot reach the brain.
ere are special receptors or specic transporters that
depend on the integrity of the capillaries for the transport
of compounds across the barrier (Lockman et al. 2002).
Nevertheless, the feasibility of the use of NPs for drug
delivery or even imaging of the brain through the BBB
has great potential. NPs with appropriate ligands are
able to cross the BBB to deliver therapeutic drug mol-
ecules into the brain as well as maintaining their stabil-
ity. Additionally, slow release of the drug may prevent
or decrease the peripheral toxicity, which is the second
desirable property of the NP. Because of lack of research
in this area, there are many factors that have to be con-
sidered to use the NPs for labeling purposes. In the late
19th century, BBB work was carried out using Trypan
blue dye injected into small animals intravenously and
results showed that the blue dye had been absorbed into
the entire body except the brain. In the 1950s, similar
experiments done on bigger animals such as rabbits and
dogs when injected directly into the cerebrospinal uid
and electron microscopy showed trace of the blue dye
in the brain. Finally, there is lack of data in the studies
currently conducted on QD and BBB. e lack of data in
this area is because of inability of QD to cross the BBB or
uptake and clearance by the reticuloendothelial system
(RES) from the circulation. More experiments in this area
with QDs have to be explored and established (Longmire
et al. 2008).
Residence of QDs in vivo
It is important to consider the physiological aspect of NPs
to understand their clearance mechanism. Kidneys and
liver are responsible for clearing the QD from dierent
organs when taken up. It must be established that the
injected QDs have been removed from the body as they
contain heavy metal such as cadmium and selenium.
According to dierent reviews, QDs have varied half life.
As one study has shown that the existence of ODs in the
liver and kidney for 28 days, and another study detected
the trace of QD in the lymph node and bone marrow
of mice for 133 days, when QD injected intravenously
(Ballou et al. 2004; Hardman 2006).
NPs face several processes that eliminate it from the
body through renal clearance. ese processes involve
glomerular ltration, tubular secretion, and nally elimi-
nation of the molecule (Deen et al. 2001). In addition to
size, surface charge plays an important part in clearance
of NPs. e rate of ltration of NPs depends on their
hydrodynamic diameter in the glomerular ltration.
Renal clearance of QD has been studied in the past by
monitoring the body uid such as urine, bile, and feces
(Choi et al. 2007). NPs with diameter less than 6 nm are
freely ltered, whereas size between 6 and 8 nm can be
ltered depending on the surface charge (Ohlson et al.
2001). Larger NPs with size of 8 nm cannot be removed
by renal route; however, studies have shown that RES was
involved in the uptake (Choi et al. 2007), Renal clearance
of QD). Additionally, the hepatobiliary system take rst
priority in removing the large NPs (>8 nm). Renal system
plays a vital part in the removal of QD from the body with
hydrodynamic diameter ranging between 4 and 6 nm. It
can be deduced that as the size of QD increases, the renal
clearance decreases. One study has shown that the clear-
ance of QD exhibited high level of QD conjugated with
BSA in the liver (Schipper et al. 2007).
By analyzing the amount of QD retained in the body,
dimensions of the nanocrystal were estimated (Pelley
et al. 2009). Excretion of QD from body circulation is
inverse linked to their toxicity. High amount of QD in the
body causes signicant toxicity. is was conrmed by
work done by one group by Lin et al (2008). Data obtained
by experiments, involving injecting intravenously the
QD705 (commercial Qtracker 705 QD; Invitrogen, Inc.,
CA) into mice and monitoring for a period of 6 months
showed no evidence of excretion or metabolism of
QD705 within 28 days. is study implied that QD705
was a toxic NP. In comparison, there was another study of
biodistribution and excretion of CdSe coated with silica
QD (Chen et al. 2008) intravenously injected into mice
gave contrary results from QD705. In this study, major-
ity of the QD have been cleared from mice through both
urine and feces within 5 days.
Overall, more research is needed to gain a better
understanding and thorough insight into this topic.
One needs to address a number of fundamental issues.
For instance, details as to how QD are excreted from the
human body need to be determined.
Conclusion and future perspectives
Nanotechnology is a rapidly expanding area of science
and NPs such as QDs have potential to revolutionize in
the area of medicine and research. Once the potential
toxicity is reduced or eliminated, it has the potential for
multifuntional applications in the eld of biomedicine
that includes cancer detection, drug delivery, imaging,
and real-time monitoring of cellular processes in a dis-
ease state. Explorative work in the area of toxicity and
safe use of NPs in a clinical setting will contribute to our
understanding of its properties. To reduce toxicity, more
research and investigation on non-cadmium QD and
novel biocompatible would be desirable.
e authors acknowledge the nancial support of Samuel
Sebba Trust and EPSRC in development of QDs for bio-
medical application.
Declaration of interest
e authors report no conict of interest.
Quantum dots as drug delivery system and their toxicity 485
© 2011 Informa UK, Ltd.
Alivisatos P. (2004). e use of nanocrystals in biological detection.
Nat Biotechnol, 22, 47–52.
Bakalova R, Zhelev Z, Jose R, Nagase T, Ohba H, Ishikawa M, Baba Y.
(2005). Role of free cadmium and selenium ions in the potential
mechanism for the enhancement of photoluminescence of
CdSe quantum dots under ultraviolet irradiation. J Nanosci
Nanotechnol, 5, 887–894.
Bakhshi R, Edirisinghe MJ, Darbyshire A, Ahmad Z, Seifalian AM. (2009).
Electrohydrodynamic jetting behaviour of polyhedral oligomeric
silsesquioxane nanocomposite. J Biomater Appl, 23, 293–309.
Ballou B, Lagerholm BC, Ernst LA, Bruchez MP, Waggoner AS. (2004).
Noninvasive imaging of quantum dots in mice. Bioconjug Chem,
15, 79–86.
Chaloupka K, Malam Y, Seifalian AM. (2010). Nanosilver as a new
generation of nanoproduct in biomedical applications. Trends
Biotechnol (In Press).
Chan WH, Shiao NH, Lu PZ. (2006). CdSe quantum dots
induce apoptosis in human neuroblastoma cells via
mitochondrial-dependent pathways and inhibition of survival
signals. Toxicol Lett, 167, 191–200.
Chen FQ, Gerion, D. (2004). Fluorescent CdSe/ZnS
nanocrystal-peptide conjugates for long-term, nontoxic imaging
and unclear targeting in living cells. Nano Lett, 4, 1827–1832.
Chen Z, Chen H, Meng H, Xing G, Gao X, Sun B, Shi X, Yuan H,
Zhang C, Liu R, Zhao F, Zhao Y, Fang X. (2008). Bio-distribution
and metabolic paths of silica coated CdSeS quantum dots. Toxicol
Appl Pharmacol, 230, 364–371.
Cho SJ, Maysinger D, Jain M, Röder B, Hackbarth S, Winnik FM. (2007).
Long-term exposure to CdTe quantum dots causes functional
impairments in live cells. Langmuir, 23, 1974–1980.
Choi HS, Liu W, Misra P, Tanaka E, Zimmer JP, Itty Ipe B, Bawendi MG,
Frangioni JV. (2007). Renal clearance of quantum dots. Nat
Biotechnol, 25, 1165–1170.
Deen WM, Lazzara MJ, Myers BD. (2001). Structural determinants
of glomerular permeability. Am J Physiol Renal Physiol, 281,
Delehanty JB, Medintz IL, Pons T, Brunel FM, Dawson PE, Mattoussi H.
(2006). Self-assembled quantum dot-peptide bioconjugates for
selective intracellular delivery. Bioconjug Chem, 17, 920–927.
Derfus AM, Chan WCW, Bhatia SN. (2003). Probing the cytotoxicity of
semiconductor quantum dots. Nano Letters, 4, 11–18.
Gao X, Cui Y, Levenson RM, Chung LW, Nie S. (2004). In vivo cancer
targeting and imaging with semiconductor quantum dots. Nat
Biotechnol, 22, 969–976.
Gopee NV, Roberts DW, Webb P, Cozart CR, Siitonen PH, Warbritton AR,
Yu WW, Colvin VL, Walker NJ, Howard PC. (2007). Migration of
intradermally injected quantum dots to sentinel organs in mice.
Toxicol Sci, 98, 249–257.
Green M, Howman E. (2005). Semiconductor quantum dots and free
radical induced DNA nicking. Chem Commun (Camb), 1, 121–123.
Fischer HC, Liu LC, Pang KS, Chan WC. (2006). Pharmacokinetics of
nanoscale quantum dots : In vivo distribution, sequestration, and
clearance in the rat. Adv Funct Mater, 16, 1299–1305.
Hardman R. (2006). A toxicologic review of quantum dots : toxicity
depends on physicochemical and environmental factors. Environ
Health Perspect, 114, 165–172.
Hoshino A , Hanaki K, Suzuki K, Yamamoto K. (2004a). Applications
of T-lymphoma labeled with uorescent quantum dots to cell
tracing markers in mouse body. Biochem Biophys Res Commun,
314, 46–53.
Hoshino A, Fujioka K, Oku T, Suga M, Sasaki YF, Ohta T, Yasuhara M,
Suzuki K, Yamamoto K. (2004b) Physicochemical properties and
cellular toxicity of nanocrystal quantum dots depend on their
surface modication. Nano Letters, 4, 2163–2169.
Iga AM, Robertson JH, Winslet MC, Seifalian AM. (2007). Clinical
potential of quantum dots. J Biomed Biotechnol, 2007, 76087.
Ipe BI, Lehnig M, Niemeyer CM. (2005). On the generation of free
radical species from quantum dots. Small, 1, 706–709.
Jaiswal JK, Mattoussi H, Mauro JM, Simon SM. (2003). Long-
term multiple color imaging of live cells using quantum dot
bioconjugates. Nat Biotechnol, 21, 47–51.
Jamieson T, Bakhshi R, Petrova D, Pocock R, Imani M, Seifalian AM.
(2007). Biological applications of quantum dots. Biomaterials, 28,
Juzenas P, Chen W, Sun YP, Coelho MA, Generalov R, Generalova N,
Christensen IL. (2008). Quantum dots and nanoparticles for
photodynamic and radiation therapies of cancer. Adv Drug Deliv
Rev, 60, 1600–1614.
Kidane AG, Burriesci G, Edirisinghe M, Ghanbari H, Bonhoeer P,
Seifalian AM. (2009). A novel nanocomposite polymer for
development of synthetic heart valve leaets. Acta Biomater, 5,
Kirchner C, Liedl T, Kudera S, Pellegrino T, Muñoz Javier A, Gaub HE,
Stölzle S, Fertig N, Parak WJ. (2005). Cytotoxicity of colloidal CdSe
and CdSe/ZnS nanoparticles. Nano Lett, 5, 331–338.
Larson DR, Zipfel WR, Williams RM, Clark SW, Bruchez MP, Wise FW,
Webb WW. (2003). Water-soluble quantum dots for multiphoton
uorescence imaging in vivo. Science, 300, 1434–1436.
Lin P, Chen JW, Chang LW, Wu JP, Redding L, Chang H, Yeh TK, Yang CS,
Tsai MH, Wang HJ, Kuo YC, Yang RS. (2008). Computational and
ultrastructural toxicology of a nanoparticle, Quantum Dot 705, in
mice. Environ Sci Technol, 42, 6264–6270.
Lockman PR, Mumper RJ, Khan MA, Allen DD. (2002). Nanoparticle
technology for drug delivery across the blood-brain barrier. Drug
Dev Ind Pharm, 28, 1–13.
Longmire M, Choyke PL, Kobayashi H. (2008). Clearance properties
of nano-sized particles and molecules as imaging agents:
considerations and caveats. Nanomedicine (Lond), 3, 703–717.
Lovric J, Bazzi HS, Cuie Y, Fortin GR, Winnik FM, Maysinger D. (2005).
Dierences in subcellular distribution and toxicity of green and
red emitting CdTe quantum dots. J Mol Med, 83, 377–385.
Lovric J, Cho SJ, Winnik FM, Maysinger D. (2005). Unmodied
cadmium telluride quantum dots induce reactive oxygen species
formation leading to multiple organelle damage and cell death.
Chem Biol, 12, 1227–1234.
Malam Y, Loizidou M, Seifalian AM. (2009). Liposomes and
nanoparticles: nanosized vehicles for drug delivery in cancer.
Trends Pharmacol Sci, 30, 592–599.
Ohlson M, Sörensson J, Lindström K, Blom AM, Fries E, Haraldsson B.
(2001). Eects of ltration rate on the glomerular barrier and
clearance of four dierently shaped molecules. Am J Physiol Renal
Physiol, 281, F103–F113.
Pelley JL, Daar AS, Saner MA. (2009). State of academic knowledge
on toxicity and biological fate of quantum dots. Toxicol Sci, 112,
Riyahi-Alam N, Behrouzkia Z, Seifalian A, Haghgoo Jahromi S. (2010).
Properties Evaluation of a New MRI Contrast Agent Based on
Gd-Loaded Nanoparticles. Biol Trace Elem Res.
Ryman-Rasmussen JP, Riviere JE, Monteiro-Riviere NA. (2007).
Surface coatings determine cytotoxicity and irritation potential of
quantum dot nanoparticles in epidermal keratinocytes. J Invest
Dermatol, 127, 143–153.
Schipper ML, Cheng Z, Lee SW, Bentolila LA , Iyer G, Rao J, Chen X,
Wu AM, Weiss S, Gambhir SS. (2007). microPET-based biodistribution
of quantum dots in living mice. J Nucl Med, 48, 1511–1518.
Shiohara A, Hoshino A, Hanaki K, Suzuki K, Yamamoto K. (2004). On
the cyto-toxicity caused by quantum dots. Microbiol Immunol, 48,
Smith AM, Duan H, Mohs AM, Nie S. (2008). Bioconjugated quantum
dots for in vivo molecular and cellular imaging. Adv Drug Deliv
Rev, 60, 1226–1240.
Su Y, He Y, Lu H, Sai L, Li Q, Li W, Wang L, Shen P, Huang Q, Fan C.
(2009). e cytotoxicity of cadmium based, aqueous phase -
synthesized, quantum dots and its modulation by surface coating.
Biomaterials, 30, 19–25.
Tang M, Xing T, Zeng J, Wang H, Li C, Yin S, Yan D, Deng H, Liu J,
Wang M, Chen J, Ruan DY. (2008). Unmodied CdSe quantum dots
induce elevation of cytoplasmic calcium levels and impairment of
486 S. Ghaderi et al.
Journal of Drug Targeting
functional properties of sodium channels in rat primary cultured
hippocampal neurons. Environ Health Perspect, 116, 915–922.
Tonks NK. (2005). Redox redux: revisiting PTPs and the control of cell
signaling. Cell, 121, 667–670.
Voura EB, Jaiswal JK, Mattoussi H, Simon SM. (2004). Tracking
metastatic tumor cell extravasation with quantum dot nanocrystals
and uorescence emission-scanning microscopy. Nat Med, 10,
Wang L, Nagesha DK, Selvarasah S, Dokmeci MR, Carrier RL.
(2008). Toxicity of CdSe Nanoparticles in Caco-2 Cell Cultures.
J Nanobiotechnology, 6, 11.
Woodward JD, Kennel SJ, Mirzadeh S, Dai S, Wall JS, Richey T,
Avenell J, Rondinone AJ. (2007). In vivo SPECT/CT imaging
and biodistribution using radioactive (CdTe)-Te-125m/ZnS
nanoparticles. Nanotechnology, 18, 175103-175108.
Yaghini E, Seifalian AM, MacRobert AJ. (2009). Quantum dots and
their potential biomedical applications in photosensitization for
photodynamic therapy. Nanomedicine (Lond), 4, 353–363.
Zhang Y, Chen W, Zhang J, Liu J, Chen G, Pope C. (2007). In vitro and
in vivo toxicity of CdTe nanoparticles. J Nanosci Nanotechnol, 7,
Zhang H, Yee D, Wang C. (2008). Quantum dots for cancer diagnosis
and therapy: biological and clinical perspectives. Nanomedicine
(Lond), 3, 83–91.
Zhang LW, Yu WW, Colvin VL, Monteiro-Riviere NA. (2008). Biological
interactions of quantum dot nanoparticles in skin and in human
epidermal keratinocytes. Toxicol Appl Pharmacol, 228, 200–211.
Zhang T, Stilwell JL, Gerion D, Ding L, Elboudwarej O, Cooke PA,
Gray JW, Alivisatos AP, Chen FF. (2006). Cellular eect of high doses
of silica-coated quantum dot proled with high throughput gene
expression analysis and high content cellomics measurements.
Nano Lett, 6, 800–808.
Zimmer JP, Kim SW, Ohnishi S, Tanaka E, Frangioni JV, Bawendi
MG. (2006). Size series of small indium arsenide-zinc selenide
core-shell nanocrystals and their application to in vivo imaging. J
Am Chem Soc, 128, 2526–2527.
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The use of quantum technology to deliver drugs has the potential to increase the efficacy of many rare disease treatments. Semiconductor nanoparticles are a new type of treatment for life-threatening disorders. The term "quantum dots" refers to semiconductor nanoparticles. These quantum dots have a one-of-a-kind shape, size, fluorescence characteristics, and shape-dependent optoelectronic capacities. As a result, we believe that quantum dots' (QDs) has the potential to be destined as medication carriers, biosensors, and similarly much more. Due to improvements in research, medicinal, and clinical domains, an in-depth examination of Quantum dots is now possible. Quantum dots are also classed as carbon-based quantum dots, graphene-based quantum dots, and cadmium-based quantum dots, with variations in their main structure leading to the discovery of more comparable and diversified quantum dots. Semiconductor quantum dots, or QDs, have also made tremendous progress in the field of fluorescence bioimaging research. After examining their in-vitro and in-vivo applications, we may currently use QDs as agents for gene transport, medication delivery, and enhancing the biocompatibility of other medications. This article discusses the significant breakthroughs and challenges in the field of quantum dots as biosensors for bioimaging, surface changes, quantum dots in the treatment of numerous diseases, and future features of quantum dots and their improvements in bio-medical applications.
... Quantum dots (QDs), otherwise known as 'artificial atoms' are of the earliest nanotechnologies to be incorporated into the field of biological sciences due to the unique attributes that enable them to be suitable for biological applications [1]. QDs have physical dimensions that are smaller than exciton Bohr radius (2-10 nm) and they command attractive electronic properties such as wide and continuous absorption spectra, high light stability, and narrow emission spectra [2,3]. ...
Therapeutic utilization of biodegradable polymers for controlled drug delivery is a promising approach. The safety of this approach can be enhanced by using a green synthesis technique such as Pulsed Laser Ablation of solids in liquid (PLAL) for the fabrication of the nanoparticles. In this study, polyaspartate, a biodegradable polymer, was prepared by polycondensation of L-aspartic acid (PASP) and the AgNPs were synthesized in water, and solutions of PASP by ablation of silver plate with a Q-switched Nd: YAG laser at a wavelength of 1064 nm. The influence of PASP concentrations on the size and dispersity of the AgNPs were investigated. Antibacterial efficiency of the AgNPs was investigated on some bacterial strains by measuring the inhibition zones in agar using disc diffusion method. The nanoparticles were characterized by techniques such as XRD, TEM, UV–Vis, EDX, XRD, and XPS. The structural analysis revealed spherical shaped and well-dispersed silver nanoparticle quantum dots (Ag QDs) when silver metal was ablated in 0.5 mM of PASP. The Ag QDs/0.5 mM PASP sample showed a good inhibition effect against the bacterium Escherichia coli. The findings suggest that biofriendly PASP can successfully be employed in laser ablation for capping AgNPs, and the resultant material can be deployed as promising growth inhibitors against some pathogenic bacterial strains in relevant fields.
... The fluorescence band depends on the shape and thickness of the shell [19,20]. Quantum dots have become an indispensable tool, especially in biomedical research for fluorescence imaging and detection for a long period [21,22].Quantum dots have become an indispensable tool, especially in biomedical research for fluorescence imaging and detection for a longform. [23,24]. ...
... Generally speaking, quantum dots are nanometer-sized semiconductor/metal-oxide particles (e.g., CdSe/CdTe) that could generate fluorescence emission under external excitation. As shown in Figure 1.6, researchers have developed numerous targeted QD probes by combining QD with antibodies and other bio-ligands [20][21][22]. After being introduced into the tissue or animal bodies, the targeted QD probes can be guided towards the diseased sites and generate additional fluorescence emission for researchers and doctors to locate and quantify the disease regions or the distribution of specific biomolecules and cells. ...
Multimodality imaging technologies have attracted wide attention in both biological researches and clinical practice. However, the low image signal-to-noise ratio (SNR) and the limited capability to label multiple targets are the major challenges to use multimodality imaging in many in vivo biomedical applications. Due to the homogeneity of current optical imaging contrast agents (such as gold and polymer nanoparticles, and fluorophores), only the overall distribution of the targets can be observed. Precise tracking of the trajectory of each individual target is not possible. Microcavity lasers are emerging technologies that have broad applications in biomedical fields. Owing to the high emission intensity, rich spectral information, and narrow linewidth, microcavity lasers may provide a route to achieve deep tissue imaging with a high SNR and track implanted cells with unique identifiers. In this dissertation, I introduce the development of three applications of microcavity lasers in multimodality imaging: ultrasound modulated droplet lasers, in vivo single immune cell tracking, and longitudinal in vivo stem cell tracking for cell therapy. In contrast to fluorescence-based imaging and labeling, our microcavity laser emission-based technologies have demonstrated distinct advantages with significantly improved SNR, sensitivity, multimodality contrast, and unique spectral information for labeling different cells. For ultrasound modulated droplet lasers, this technology leverages both deep penetration depth and high resolution of ultrasound imaging, and the high SNR, imaging contrast and sensitivity of laser emission. I first demonstrated the ultrasound modulated microdroplet lasers in which the laser emission intensity from the whispering gallery mode (WGM) of a micro oil droplet laser can be enhanced up to 20-fold when the ultrasound pressure reaches a certain threshold. This enhancement in laser emission intensity is reversible when the ultrasound is turned off. Furthermore, the ultrasound modulation of the laser output in the frequency domain was achieved by controlling the ultrasound modulation frequency. Finally, I investigated a potential in vivo application of the ultrasound modulated droplet lasing using phantoms vessels containing human whole blood. For in vivo immune and stem cell tracking, I demonstrated a multimodality imaging technology combining optical coherence tomography (OCT), fluorescence microscopy (FM), and lasing emission labeling to longitudinally track the 3D migration trajectories of individual cells transplanted into the subretinal space in vivo. The CdS nanowire lasers, with the distinct lasing spectra generated from the subtle differences in the Fabry-Perot microcavity, were utilized as unique identifiers to label the cells. With strong optical scattering and fluorescence emission, CdS nanowires also served as OCT and FM contrast agents to indicate the spatial locations of the cells. FM could provide the overall 2D cell distribution pattern, whereas the nanowires internalized by cells provide unique lasing emission spectra for differentiating individual cells. Meanwhile, OCT imaging could provide both 3D retinal structure and spatial locations of the cells. By integrating the capabilities of FM, OCT, and lasing emission labeling, longitudinal 3D tracking of individual cells in the subretinal space in vivo was achieved. Our study opens a door to utilize microcavity lasers and multimodality imaging platforms to improve imaging quality and solve real-world clinical problems. In the future, our technologies can also be adopted to support both biological researches and clinical applications such as deep tissue cell tracking, and understanding of the pharmacodynamics (PD) and pharmacokinetics (PK) of cell-based therapies for a comprehensive evaluation of both safety and efficacy.
... However, in multispectral FLI, it is possible to differentiate the FL signals of various probes by analyzing the response from different wavelengths. Recently, several studies using multispectral FLI had been conducted for preclinical and clinical applications including sensitive tumor labeling [70], monitoring drug delivery [71,72], and image-guided surgery [73][74][75]. Recently, several examples of in vivo multispectral FLI have been reported using FL nanoparticles. ...
Biomedical imaging is an essential tool for investigating biological responses in vivo. Among the several imaging techniques, optical imaging systems with multispectral analysis of nanoparticles have been widely investigated due to their ability to distinguish the substances in biological tissues in vivo. This review article focus on multispectral optical imaging techniques that can provide molecular functional information. We summarize the basic principle of the spectral unmixing technique that enables the delineation of optical chromophores. Then, we explore the principle, typical system configuration, and biomedical applications of the representative optical imaging techniques, which are fluorescence imaging, two-photon microscopy, and photoacoustic imaging. The results in the recent studies show the great potential of the multispectral analysis techniques for monitoring responses of biological systems in vivo.
At present, the content of antipsychotics in samples is always analyzed by traditional detection methods, including mass spectrometry (MS), spectrophotometry, fluorescence, capillary electrophoresis (CE). However, conventional methods are cumbersome and complex, require a large sample volume, many pre-processing steps, long analysis cycles, expensive instruments, and need well-trained detection capabilities personnel. In addition, patients with schizophrenia require frequent and painful blood collection procedures, which adds additional treatment costs and time burdens. In view of these factors, electrochemical methods have become the most promising candidate technology for timely analysis due to their low cost, simple operation, excellent sensitivity and specificity. As we all know, nanomaterials play an extremely important role in electrochemical sensing applications. As the sensor modifiers, nanomaterials enable electrochemical analysis to overcome the time-consuming and labor-intensive shortcomings of traditional detection methods, and greatly reduce the research cost. Nanomaterials modified electrodes can be used as sensors to determine the concentration of antipsychotics in organisms quickly and accurately, which is a bright spot in the application of nanomaterials. The combination of different nanomaterials can even form a nanocomposite with a synergistic effect. This paper firstly reviews the application of nanomaterials-modified sensors on the basis of research in the past ten years, reviews the use of nanomaterial-modified sensors to quickly and accurately determine the concentration of antipsychotics in biological samples, and demonstrates a new idea of using nanomaterials sensors for drug monitoring and determination. At the end of this review, a brief overview is given of the limitations and the future prospects of nanomaterial sensors for the determination of antipsychotics concentrations.
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Radioactive cadmium telluride/zinc sulfide (Cd125mTe/ZnS) nanoparticles were targeted to mouse lung with antibody to mouse lung endothelium and quantified using radiological histology in order to test the in vivo targeting efficacy of a nanoparticle–antibody (NP–mAb) system. The nanoparticles were linked to either a monoclonal antibody to mouse lung thrombomodulin (mAb 201B) or a control antibody (mAb 33), and injected into groups of 6-week-old Balb/C female mice. Animals were sacrificed at 1, 4, 24, 72 and 144 h post-injection, and biodistribution in major organs was determined. Full body microSPECT/CT imaging was performed on a pair of mice (experimental and control) providing visual confirmation of the biodistribution. The Cd125mTe/ZnS NPs conjugated to mAb 201B principally target the lungs while the nanoparticles coupled to mAb 33 accumulate in the liver and spleen. These data provide, for the first time, a quantitative measurement of the in vivo targeting efficacy of an inorganic nanoparticle–mAb system.
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The growing applications of nanotechnologic products, such as quantum dots (QDs), increase the likelihood of exposure. Furthermore, their accumulation in the bioenvironment and retention in cells and tissues are arousing increasing worries about the potentially harmful side effects of these nanotechnologic products. Previous studies concerning QD cytotoxicity focused on the reactive oxygen species produced by QDs. Cellular calcium homeostasis dysregulation caused by QDs may be also responsible for QD cytotoxicity. Meanwhile the interference of QDs with voltage-gated sodium channel (VGSC) current (I(Na)) may lead to changes in electrical activity and worsen neurotoxicologic damage. We aimed to investigate the potential for neurotoxicity of cadmium selenium QDs in a hippocampal neuronal culture model, focusing on cytoplasmic calcium levels and VGSCs function. We used confocal laser scanning and standard whole-cell patch clamp techniques. We found that a) QDs induced neuron death dose dependently; b) cytoplasmic calcium levels were elevated for an extended period by QD treatment, which was due to both extracellular calcium influx and internal calcium release from endoplasmic reticulum; and c) QD treatment enhanced activation and inactivation of I(Na), prolonged the time course of activation, slowed I(Na) recovery, and reduced the fraction of available VGSCs. Results in this study provide new insights into QD toxicology and reveal potential risks of their future applications in biology and medicine.
Nano-sized particles and molecules possess enormous potential as diagnostic imaging agents and hold promise for the development of multimodality agents with both imaging and therapeutic capabilities. Yet, some of the most promising nano-materials currently under investigation demonstrate prolonged tissue retention and contain heavy metals. This presents serious concerns for toxicity and additionally, prolonged particle retention may interfere with diagnostic imaging and testing modalities. The creation of nano-sized particles and molecules with optimal pharmacokinetics and clearance characteristics will minimize toxicity risks by reducing the duration of exposure to these agents. Given that many types of nanomaterials possess easily modifiable surface chemistry, if nanoparticle characteristics associated with optimal pharmacokinetics and clearance from the body were well established, it would be feasible to design and create agents with more favorable clearance properties. In this talk, based on our experiences of dendrimer-based nano-sized MRI/Optical/Nuclear multimodality imaging agents, I will discuss the physiologic clearance of nano-sized particle and molecule, especially focusing on renal mechanisms, as well as provides an extended view of current research investigating clearance of other types of nano-sized particles and molecules, including dendrimers, quantum dots, and carbon, gold, and silica-based nanoparticles.
One of the biggest challenges in cell biology is the imaging of living cells. For this purpose, the most commonly used visualization tool is fluorescent markers. However, conventional labels, such as organic fluorescent dyes or green fluorescent proteins (GFP), lack the photostability to allow the tracking of cellular events that happen over a period from minutes to days. In addition, they are either toxic to cells (dyes) or difficult to construct and manipulate (GFP). We report here the use of a new class of fluorescent labels, silanized CdSe/ZnS nanocrystal−peptide conjugates, for imaging the nuclei of living cells. CdSe/ZnS nanocrystals, or so-called quantum dots (qdots), are extremely photostable, and have been used extensively in cellular imaging of fixed cells. Most of the studies about living cells so far have been concerned only with particle entry into the cytoplasm or the localization of receptors on the cell membrane. Specific targeting of qdots to the nucleus of living cells has not been reported in previous studies, due to the lack of a targeting mechanism and proper particle size. Here we demonstrate for the first time the construction of a CdSe/ZnS nanocrystal−peptide conjugate that carries the SV40 large T antigen nuclear localization signal (NLS) and the transfection of the complex into living cells. By a novel adaptation for qdots of a commonly used cell transfection technique, we were able to introduce and retain the NLS−qdots conjugate in living cells for up to a week without detectable negative cellular effects. Moreover, we can visualize the movement of the CdSe/ZnS nanocrystal−peptide conjugates from the cytoplasm to the nucleus, as well as the accumulation of the complex in the cell nucleus, over a long observation time period. This report opens the door for using qdots to visualize long-term biological events that happen in the cell nucleus and provides a new nontoxic, long-term imaging platform for observing nuclear trafficking mechanisms and cell nuclear processes.
With their bright, photostable fluorescence, semiconductor quantum dots (QDs) show promise as alternatives to organic dyes for biological labeling. Questions about their potential cytotoxicity, however, remain unanswered. While cytotoxicity of bulk cadmium selenide (CdSe) is well documented, a number of groups have suggested that CdSe QDs are cytocompatible, at least with some immortalized cell lines. Using primary hepatocytes as a liver model, we found that CdSe-core QDs were indeed acutely toxic under certain conditions. Specifically, we found that the cytotoxicity of QDs was modulated by processing parameters during synthesis, exposure to ultraviolet light, and surface coatings. Our data further suggest that cytotoxicity correlates with the liberation of free Cd2+ ions due to deterioration of the CdSe lattice. When appropriately coated, CdSe-core QDs can be rendered nontoxic and used to track cell migration and reorganization in vitro. Our results provide information for design criteria for the use of QDs in vitro and especially in vivo, where deterioration over time may occur.
Advances in nanotechnology research on quantum dots (QDs)-water soluble ZnS-capped, CdSe fluorescent semiconductor nanocrystals-for in vivo biomedical applications have prompted a close scrutiny of the behavior of nanostructures in vivo. Data pertaining to pharmacokinetics and toxicity will undoubtedly assist in designing better in vivo nanostructure contrast agents or therapies. In vivo kinetics, clearance, and metabolism of semiconductor QDs are characterized following their intravenous dosing in Sprague-Dawley rats. The QDs coated with the organic molecule mercaptoundecanoic acid and crosslinked with lysine (denoted as QD-LM) are cleared from plasma with a clearance of 0.59 +/- 0.16 mL min(-1) kg(-1). A higher clearance (1.23 +/- 0.22 mL min(-1) kg(-1)) exists when the QDs are conjugated to bovine serum albumin (denoted as QD-BSA, P<.05 (P = statistical significance). The biodistribution between these two QDs is also different. The liver takes up 40% of the QD-LM dose and 99% of QD-BSA dose after 90 min. Small amounts of both QDs appear in the spleen, kidney, and bone marrow. However, QDs are not detected in feces or urine for up to ten days after intravenous dosing.
Nanocrystal quantum dots (QDs) have been applied to molecular biology because of their greater and longer fluorescence. Here we report the potential cytotoxicity of our characterized QDs modified with various molecules. Surface modification of QDs changed their physicochemical properties. In addition, the cytotoxicity of QDs was dependent on their surface molecules. These results suggested that the properties of QDs are not related to those of QD-core materials but to molecules covering the surface of QDs.
Topical exposure to nanoscale materials is likely from a variety of sources including sunscreens and cosmetics. Because the in vivo disposition of nanoscale materials is not well understood, we have evaluated the distribution of quantum dots (QDs) following intradermal injection into female SKH-1 hairless mice as a model system for determining tissue localization following intradermal infiltration. The QD (CdSe core, CdS capped, poly[ethylene glycol] coated, 37 nm diameter, 621 nm fluorescence emission) were injected intradermally (ID) on the right dorsal flank. Within minutes following intradermal injection, the highly UV fluorescent QD could be observed moving from the injection sites apparently through the lymphatic duct system to regional lymph nodes. Residual fluorescent QD remained at the site of injection until necropsy at 24 h. Quantification of cadmium and selenium levels after 0, 4, 8, 12, or 24 h in multiple tissues, using inductively coupled plasma mass spectrometry (ICP-MS), showed a time-dependent loss of cadmium from the injection site, and accumulation in the liver, regional draining lymph nodes, kidney, spleen, and hepatic lymph node. Fluorescence microscopy corroborated the ICP-MS results regarding the tissue distribution of QD. The results indicated that (1) ID injected nanoscale QD remained as a deposit in skin and penetrated the surrounding viable subcutis, (2) QD were distributed to draining lymph nodes through the sc lymphatics and to the liver and other organs, and (3) sentinel organs are effective locations for monitoring transdermal penetration of nanoscale materials into animals.
Nanosilver (NS), comprising silver nanoparticles, is attracting interest for a range of biomedical applications owing to its potent antibacterial activity. It has recently been demonstrated that NS has useful anti-inflammatory effects and improves wound healing, which could be exploited in developing better dressings for wounds and burns. The key to its broad-acting and potent antibacterial activity is the multifaceted mechanism by which NS acts on microbes. This is utilized in antibacterial coatings on medical devices to reduce nosocomial infection rates. Many new synthesis methods have emerged and are being evaluated for NS production for medical applications. NS toxicity is also critically discussed to reflect on potential concerns before widespread application in the medical field.