Determining the Size and Shape
Dependence of Gold Nanoparticle
Uptake into Mammalian Cells
B. Devika Chithrani,†,‡Arezou A. Ghazani,†,‡and Warren C. W. Chan*,†,‡,§
Institute of Biomaterials & Biomedical Engineering, UniVersity of Toronto, 4 Taddle
Creek Road, Toronto, Ontario M5S 3G9, Canada, Terrence Donnelly Center for
Cellular and Biomolecular Research, UniVersity of Toronto, 160 College Street, 4th
Floor, Toronto, Ontario M5S 3E1, Canada, and Materials Science and Engineering,
UniVersity of Toronto, 184 College Street, Toronto, Ontario M5S 3E4, Canada
Received December 4, 2005; Revised Manuscript Received February 14, 2006
We investigated the intracellular uptake of different sized and shaped colloidal gold nanoparticles. We showed that kinetics and saturation
concentrations are highly dependent upon the physical dimensions of the nanoparticles (e.g., uptake half-life of 14, 50, and 74 nm nanoparticles
is 2.10, 1.90, and 2.24 h, respectively). The findings from this study will have implications in the chemical design of nanostructures for
biomedical applications (e.g., tuning intracellular delivery rates and amounts by nanoscale dimensions and engineering complex, multifunctional
nanostructures for imaging and therapeutics).
The chemical design and synthesis of nanoparticles have
fueled the growth of nanotechnology. The foundation of
nanotechnology research is based on the size and shape of
the structures, where distinct optical, electronic, or magnetic
properties can be tuned during chemical synthesis. There is
an enormous interest in exploiting nanoparticles in various
biomedical applications since their size scale is similar to
that of biological molecules (e.g., proteins, DNA) and
structures (e.g., viruses and bacteria). Furthermore, useful
properties can be incorporated into the design of the
nanoparticles for manipulation or detection of biological
structures and systems. Nanoparticles are currently used in
imaging,1-6biosensing,7-9and gene and drug delivery.10-12
As the field continues to develop, quantitative and qualita-
tive studies on the cellular uptake of nanoparticles, with
respect to their size and shape, are required in order to
advance nanotechnology for biomedical applications. This
will be important for assessing nanoparticle toxicity (i.e., if
nanoparticles do not enter cells, they are less prone to killing
cells or altering cellular function), for advancing nanopar-
ticles for imaging, drug delivery, and therapeutic applications
(i.e., how to maximally accumulate nanoparticles in cells,
tumors, and organs?), and for designing multifunctional
nanoparticles (i.e., are there dimensional limits to designing
nanoparticles that can target and kill diseased cells?). Detailed
studies of uptake kinetics of nanoparticles by cells have not
been well characterized and quantified as a function of their
size and shape (i.e., trends have not been determined). Most
studies have focused on liposomes
particles,17,18which are generally larger than 100 nm.
Furthermore, metallic, semiconductor, and carbon-based
nanoparticles can be synthesized with greater size and shape
variabilities than liposome and polymer particles.
We selected gold nanoparticles as the model system for
our studies; the rationale being that gold nanoparticles could
be synthesized at a large size (1-100 nm diameter) and shape
range (1:1 to 1:5 aspect ratio). Gold nanoparticles are also
easy to characterize by the techniques of UV-vis spectro-
photometry, inductively coupled plasma atomic emission
spectroscopy (ICP-AES), and transmission electron micros-
copy (TEM). Furthermore, gold nanoparticles have recently
been demonstrated in cell imaging,19,20targeted drug deliv-
ery,21and cancer diagnostics and therapeutic applications.22-25
These studies appear to be representative of the initial
applications of nanoparticles in biology and medicine. In this
paper, we studied the effect of nanoparticle size, shape,
concentration, and incubation time on their cellular uptake
kinetics. In the first part of the paper, the effect of
nanoparticle size, concentration, and incubation time on the
cellular uptake is discussed using colloidal gold nanoparticles
with sizes varying between 14 and 100 nm. The second part
of the paper is focused on the effect of nanoparticle shape
on cellular uptake.
* Corresponding author. E-mail: firstname.lastname@example.org.
†Institute of Biomaterials & Biomedical Engineering.
‡Terrence Donnelly Center for Cellular and Biomolecular Research.
§Materials Science and Engineering.
Vol. 6, No. 4
10.1021/nl052396o CCC: $33.50
Published on Web 03/01/2006
© 2006 American Chemical Society
Spherical and rod-shaped nanoparticles with diameters of
14, 30, 50, 74, and 100 nm and length by width of 40 × 14
nm and 74 × 14 nm, respectively, were prepared using
standard solution techniques (see Supporting Information
sections 1 and 2).26-29The spherical gold nanoparticles were
free from aggregation (as determined by TEM, spectropho-
tometry, and gel electrophoresis) and had a size variation of
(10%. The surface of the spherical gold nanoparticles was
not modified, and therefore, they were stabilized by citric
acid ligands. Rod-shaped nanoparticles were synthesized
using seed mediated growth as demonstrated by El-Sayed
and Murphy and their co-workers.28,29After synthesis, the
presence of rod-shaped, pyramid, and sphere-shaped nano-
particles was apparent in the TEM images. The majority of
the nanoparticles were rod shaped (>75%) with a size
variation of (10%. The surface of the rod-shaped gold
nanoparticles was modified by chemical exchange so that
the cetyl trimethylammonium bromide (CTAB) was replaced
by citric acid ligands. Fourier transform infrared (FTIR)
spectroscopy showed the presence of citric acid on the
surface of the nanoparticles; however, we cannot verify the
complete removal of the rod-shaped gold nanoparticle’s
surface CTAB molecules due to the lack of available
In these experiments, we incubated HeLa cells with gold
nanoparticles with various sizes and shapes for 6 h in
Dulbecco Minimum Essential Media (DMEM) plus 10%
serum. After the allotted time, we detached the cells from
the Petri dish surface using the enzyme trypsin, homogenized
the cells, and measured the concentration of Au by the
technique of ICP-AES. We used the following equations to
convert the number of gold atoms to number of gold
nanoparticles from the ICP-AES measurements. For a sphere
of diameter D, the number of atoms (U) fitting into each
volume of gold nanoparticles was determined. In this
Figure 1. Dependence of cellular uptake of gold nanoparticles as
a function of size.
Figure 2. Transmission electron microscopy imaging and measurements of gold nanoparticles in cells. (A) The graph of number of gold
nanoparticles per vesicle diameter vs nanoparticle size. (B-F) TEM images of gold nanoparticles with sizes 14, 30, 50, 74, and 100 nm
trapped inside vesicles of a Hela cell, respectively. (TEM images were recorded at a voltage of 75 kV with a Hitachi H7000.)
Nano Lett., Vol. 6, No. 4, 2006 663
calculation, a refers to the edge of a unit cell, which has a
value of 4.0786 Å on the edge; there are four gold atoms
per unit cell. M is the measured number of gold atoms from
All results were further verified by UV-vis spectrophotom-
etry, where gold nanoparticles have a distinctive absorbance
spectrum. Also, for all experiments the concentrations of the
gold nanoparticles were equalized before incubation with
In Figure 1, a plot of the number of gold nanoparticles
in/on cells versus size of gold nanoparticles shows cellular
uptake was heavily dependent upon the size. The maximum
uptake by a cell occurred at a nanoparticle size of 50 nm. In
agreement with our results, Osaki et al. qualitatively showed
that 50 nm semiconductor nanoparticles entered cells via
receptor-mediated endocytosis more efficiently than smaller
nanoparticles. Figure 2 shows TEM images of gold nano-
particles with sizes between 14 and 100 nm inside cells and
trapped in vesicles in the cytoplasm. They did not enter the
nucleus. For a single cell, multiple vesicles containing gold
nanoparticles are readily observed (see Supporting Informa-
tion section 3). Within the vesicles, the nanoparticles
appeared to be monodisperse (see Figure 2B-F). Figure 2A
shows that the number of nanoparticles per vesicle diameter
is related to the size of the gold nanoparticles. We used the
unit of gold nanoparticles per vesicle size (area) because of
vesicle size variations; this method allowed standardization
of measurements. Further studies with gold nanoparticles
coated with the specific ligand transferrin have a similar
intracellular uptake trend as the citrate acid stabilized gold
nanoparticle (see Supporting Information section 4). Trans-
ferrin is one of the many proteins in serum, and it enters
cells via receptor-mediated endocytosis. However, the num-
ber of transferrin-coated gold nanoparticles entering the cells
is ca. three times less than that of the citrate-stabilized gold
nanoparticles. Finally, we conducted a trypan blue exclusion
staining assay to determine cellular viability. Our results did
not indicate any cellular toxicity due to uptake of gold
nanoparticles (98% viability), which is in agreement with
results by other research groups.31-33
Figure 3A shows the uptake of the nanoparticles signifi-
cantly increased for the first 2 h, but the uptake rate gradually
slowed and reached a plateau at 4- 7 h, depending on size.
This plateau effect is in agreement with a previous study by
Desai et al.34The uptake half-life determined by the slope
of Figure 3a for the different-sized gold nanoparticles was
2.10, 1.90, and 2.24 h at a rate of 622, 1294, and 417
nanoparticles per hour for the 14, 50, and 74 nm gold
nanoparticles, respectively. The maximum number of nano-
particles a cell can uptake for sizes 14, 50, and 74 nm are
3000, 6160, and 2988 respectively (see Figure 3B).
Initially, the mechanism of cellular uptake was puzzling
since the overall surface charge of the gold nanoparticles
was negative (due to the citric acid stabilizing ligand).
Anionic molecules and structures bind less efficiently to cell
surfaces than neutral or cationic molecules since electrostatic
repulsion between the negatively charged surface membrane
and cellular environment would repel the nanoparticles from
entering. That is the reason why lysine-rich macromolecules
and positively charged liposomes are commonly used for
transfecting molecules into cells.14
We hypothesize the uptake of gold nanoparticles is
mediated by nonspecific adsorption of serum proteins onto
the gold surface; these proteins induce the nanoparticles to
enter into cells via the mechanism of receptor-mediated
endocytosis. To test out this hypothesis, we incubated gold
nanoparticles with DMEM containing 10% serum, purified
them by centrifugation (10 000 rpm), and analyzed them
using UV-vis absorbance spectrophotometry, FTIR spec-
troscopy, gel electrophoresis, and protein assay (see Figure
The absorbance spectra shows a shift in the surface
plasmon resonance peak of 6 nm (Figure 4A) when the gold
nanoparticles are incubated with DMEM plus 10% serum
(marked in black in Figure 4A); previous studies show
proteins adsorbed onto the gold nanostructures could cause
similar shifts in the surface plasmon resonance.35The FTIR
spectroscopy was used to verify the attachment of proteins
on the surface of the gold nanoparticles. For gold nanopar-
Figure 3. Cellular uptake kinetics of gold nanoparticles. (A)
Cellular uptake of gold nanoparticles as a function of incubation
time for three different size gold nanoparticles (nanoparticle
diameters 14, 50, and 74 nm). (B) Dependence of cellular uptake
of gold nanoparticles as a function of concentration (nanoparticle
diameters 14, 50, and 74 nm).
Nano Lett., Vol. 6, No. 4, 2006
ticles modified with serum protein, the peaks at 1550 and
1407 cm-1indicate the presence of the primary amine on
the nanoparticle surface. Broad band 3300 cm-1is an
indication of the bonded NH or NH2groups on the surface
(see Figure 4B). The gel bands indicate loss of mobility (see
lane 2 in Figure 4C) after incubation; alteration of nanopar-
ticle surface charge or size can slow their mobility in a gel.
Finally, a ninhydrin-based protein assay was conducted to
verify that proteins are on the surface of gold nanoparticles.
In the presence of high concentrations of primary and
secondary amines (from amino acids), the solution becomes
purple when incubated with the organic molecule ninhydrin
after 10 min. Figure 4D shows vials of gold nanoparticles
incubated in a ninhydrin solution after incubation in citrate
buffer, DMEM, and DMEM plus serum followed by
purification. Clearly, the vial of gold nanoparticles incubated
with DMEM plus serum is purple. Of note, incubated gold
nanoparticles with only DMEM lead to aggregation after 1
h. These data suggest that the surface of the gold nanopar-
ticles was modified by nonspecific adsorption of serum
proteins. This is likely since citric acid stabilizers are weakly
bound to the surface of gold nanoparticles and could be
desorbed from the metal surfaces by proteins. This adsorption
process appears to be instantaneous.
As to the mechanism of entrance, our results show that
the gold nanoparticles entered the cells via the receptor-
mediated endocytosis pathway (RME). In RME, a ligand
binds onto a receptor on the cell’s surface and enters the
cell when the membrane invaginates. Eventually, the receptor
recycles back, meaning that it takes the ligand into the cell,
releases the ligand, and then comes back onto the membrane
surface. Cells have a maximum receptor density (number of
receptors per cell surface area) on the membrane; the
unbound or available receptors determine whether and how
much a molecule or structure enters a cell via this mecha-
nism. Since RME is dependent upon temperature, we
compared the uptake of gold nanoparticles at 37 versus 4
°C. Our results show a vast difference in absorbance signal
between cells incubated with gold nanoparticles at 37 versus
4 °C (A560 nm per cell of 3 × 10-6versus 1.54 × 10-6,
respectively). The background absorbance signal (A560 nm) for
a cell is 1.22 × 10-6. These results are in agreement with
previous RME studies, where ligands did not enter cells at
4 °C but were only bound to the cell membrane.36We
Figure 4. Determining the nonspecific adsorption of serum proteins on gold nanoparticles. (A) Absoption spectra of citrate-capped gold
nanoparticles (marked in red) and gold nanoparticles capped with serum protein (marked in black). (B) FTIR spectra of serum protein
capped gold nanoparticles (marked in black) in comparison to citrate-capped gold nanoparticles (marked in red). (C) Electrophoretic mobilty
of citrate stabilized gold nanoparticles (lane 1) and serum protein stabilized gold nanoparticles (lane 2) in agarrose gel. Gel electrophoresis
of citric acid stabilized gold nanoparticles in DMEM (without serum) was not studied due to aggregation of the gold nanoparticles in
media. (D) Vials of citrate-capped gold nanoparticles (left most), serum protein capped gold nanoparticles (middle), and serum protein
capped gold nanopaticles after incubation in a ninhydrin solution (right most). The purple color of the solution indicates the detection of
primary and secondary amines (which are commonly in proteins). For brevity, we show data for the 50 nm gold nanoparticles. Similar
results were found for other sizes and shapes.
Nano Lett., Vol. 6, No. 4, 2006665
conclude that serum proteins are adsorbed on the nanoparticle
surface and dictate the uptake of the nanoparticles.
To study the effect of nanoparticle shape on cellular
uptake, we used spherical and rod-shaped gold nanoparticles.
Figure 5A shows that nanoparticle uptake is dependent upon
shape and that the uptake of rod-shaped gold nanoparticles
is lower than their spherical counterpart. For example, cells
took up 500 and 375% more 74 and 14 nm spherical gold
nanoparticles than 74 × 14 nm rod-shaped gold nanopar-
ticles, respectively. The difference in the surface chemistries
(from the stabilizing ligand from the synthesis) between the
spherical and rod-shaped gold nanoparticles may be one of
the reasons for the difference in uptake. However, cellular
uptake of rod-shaped structures with lower aspect ratio (1:
3) is greater than higher aspect ratio (1:5) nanoparticles (both
of these rod-shaped gold nanoparticles are synthesized in
the presence of CTAB). In every TEM image, we observed
a high population of nonrod-shaped nanoparticle byproducts
in the cells along with rod-shaped nanoparticles (see Figure
5). Yet, spherical, cuboidal, and triangular-shaped gold
nanoparticles constituted only 25% of the nanoparticle
population after synthesis. We have included more images
of rod-shaped nanoparticles taken up by the cells in the
Supporting Information to show this low concentration in
the vesicles was not an anomaly (see Supporting Information
section 3). This suggests the actual number of rod-shaped
gold nanoparticles entering cells is less than that depicted
in Figure 5. ICP-AES does not discriminate the size and
shape, and it is difficult to separate the different shaped
nanoparticles before use in cell experiments. This result
supports our claim that spherical-shaped particles have a
higher probability of entering the cell in comparison to rod-
On the basis of our results, we can speculate on the
mechanisms that govern size- and shape-dependent intra-
cellular uptake of nanoparticles. Clearly, nonspecific adsorp-
tion of serum proteins mediates the uptake of the nanopar-
ticles. The presence of these proteins on the surface of the
nanoparticles dictates uptake half-life, rates, and amount. A
quantitative comparison of citrate-stabilized gold nanopar-
ticles versus transferrin-coated nanoparticles clearly shows
greater uptake of citrate-stabilzed gold nanoparticles. Since
serum proteins contain a diverse set of proteins, the surface
of the citrate-stabilized gold nanoparticles probably contains
a variety of serum proteins on its surface. Many of the serum
proteins (e.g, R- and ?-globulin proteins) are known to be
taken up by cells. Therefore, the diversity of the proteins
may allow entrance into the cells via multiple receptors as
compared to transferrin (which only has two corresponding
receptors37). We want to note that the saturation rate of uptake
Figure 5. The effect of shape of the nanoparticles on cellular uptake and transmission electron microscopy images of rod-shaped gold
nanoparticles internalized within the cells. (A) Comparison of uptake of rod-shaped nanoparticles (with aspect ration 1:3 and 1:5) and
spherical shaped nanoparticles, the transmission electron microscopy images of rod-shaped gold nanoparticles with aspect ratio 1:3 (B) and
1:5 (C) internalized inside vesicles of Hela cells.
Nano Lett., Vol. 6, No. 4, 2006
may also depend on the number of available proteins (that
are not adsorbed onto the gold nanoparticles in the DMEM
+ serum) since these unbound proteins can compete for
receptor sites on the cell surface against protein-adsorbed
nanoparticles. Saturation curves, such as Figure 3, are
commonly observed for receptor-mediated endocytosis. Since
serum proteins are important in the internalization of gold
nanoparticles, a further detailed study will be needed. This
will provide a greater understanding of how citrate-stabilized
gold nanoparticles enter the cell.
Even with the serum proteins dictating uptake, the size
and shape of the nanoparticles appear to matter in the uptake
scheme. We observed a large difference in the uptake of the
different size and shaped gold nanoparticles. For example,
the uptake concentrations for 74 × 14 nm rod-shaped
nanoparticles were different than those for 74 or 14 nm
spherical nanoparticles. At this point, we can only speculate
as to the reasons. One reason could be the difference in the
curvature of the different-shaped nanoparticles. For example,
the rod-shaped nanoparticles can have larger contact area
with the cell membrane receptors than the spherical nano-
particles when the longitudinal axis of the rods interacts with
the receptors. This, in effect, could reduce the number of
available receptor sites for binding. A second reason could
be the amount of CTAB surfactant molecules adsorbed onto
the rod-shaped nanoparticle surface during synthesis. If the
CTAB was still on the surface, the serum protein may not
be able to bind onto the gold nanoparticle surface efficiently.
Also, the protein coating on the surface of the rod-shaped
gold nanoparticles may not be homogeneous. In such a case,
the ligands on the surface of the rod-shaped gold nanopar-
ticles may not bind to receptors on the cell surface as strongly
(due to a lack of multivalent binding). This would affect the
uptake of the nanoparticles. More studies will be required.
The results strongly suggest that nanoparticle size and shape
can mediate receptor-ligand binding constants, receptor
recycling rates, and exocytosis.
Many important applications of nanotechnology would not
be achievable without the proper design of nanoparticles.
As the integrative field of biomedical nanotechnology
evolves, more systematic approaches for the chemical design
of nanoparticles and structures will be required. Fundamental
studies on the interface of nanostructures with biological
systems will provide guidance. As researchers start to
construct multifunctional nanostructures, issues of size and
shape and surface chemistry will be important. In this study,
we show that size and shape of the nanoparticles and
nonspecific adsorption of proteins are important for maximal
intracellular uptake. These results suggest that we can tune
the delivery of proteins, drugs, and oligonucleotides using
nanoparticles for diagnostic and therapeutic applications by
the size and shape of the nanometer-scale structure. As to
the broad issues of nanotoxicity, the nonspecific adsorption
of serum protein(s) may dictate the cellular fate, uptake,
metabolism, and clearance of nanoparticles. As new tools
and probes emerge from nanotechnology research, such
fundamental studies will be important.
Acknowledgment. W.C.W.C. would like to acknowledge
CIHR, NSERC, CFI, OIT, and University of Toronto for
financial support. D.B. and A.A.G. would like to thank
NSERC and OGS for fellowships. We acknowledge Mrs.
Tanya Hauck and Mr. Justin Chan for informative discus-
sions on nanoparticle preparation and ICP-AES analysis. We
acknowledge Mr. Battista Calvieri for his support in process-
ing cells for transmission electron microscopy.
Supporting Information Available: The methods and
experimental procedures and TEM images and absorption
spectra of gold nanoparticles and TEM images of Hela cells
with internalized nanoparticles. This material is available free
of charge via the Internet at http://pubs.acs.org.
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