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Journal of Biomaterials and Nanobiotechnology, 2011, 2, 173-180
doi:10.4236/jbnb.2011.22022 Published Online April 2011 (http://www.scirp.org/journal/jbnb)
Copyright © 2011 SciRes. JBNB
Microscopic Observation of the Intercellular
Transport of CdTe Quantum Dot Aggregates
Lan Mi1, Rongling Xiong1, Yu Zhang1, Zheng Li1, Weidong Yang2, Ji-Yao Chen3 , Pei-Nan Wang1*
1Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Department of Optical Science and Engineering,
Fudan University, Shanghai, China; 2Department of Biological Sciences, Center for Photochemical Sciences, Bowling Green State
University, Bowling Green, USA; 3Surface Physics Laboratory (National key laboratory), Department of Physics, Fudan University,
Received December 9th, 2010; revised February 10th, 2011; accepted February 14th, 2011.
Various inorganic nanopa rticles are being con sidered for applications in life science as fluor escent labels and for such
therapeutic app lications as drug d elivery or targ eted cell destructio n. It is of importance to understand their intercellu-
lar transport behaviors and mechanisms. Here, the intercellular transport of internalized CdTe quantum dot (QD) ag-
gregates through tunneling-nanotubes (TNTs) between human hepatocellular carcinoma cells was studied by
time-resolved confocal fluorescence microscopy. TNTs are known to connect eukaryotic cells to provide important
pathways for intercellular communications. The formation, shrinkage, elongation and rupture of TNTs were clearly
observed by microscopy. We found TNTs contained only F-actin or both microtubules and F-actin. Two transport mod-
es for QD aggregates through the TNTs were observed: the microtubule-based bidirectional motion and the ac-
tin-depen d ent un idirectio na l m o tion. Th e mea n squ a r e di spla ce m ent analyses revealed that the intercellula r transporta-
tions of QDs along TNTs were mediated by active processes. The bidirectional intercellular transport of QDs within
lysosomes through the TNT was also observed.
Keywords: Q uantum Dot, Tunnel i n g -Nanotubes, Active Transport, Fluorescence, Microtubule, Filament
The tunneling-nanotubes (TNTs) were originally de-
scribed by Gerdes et al for cultured rat neuronal PC12
cells in 2004 . The TNTs are thin tubular protrusions
formed from the plasma membranes that connect eu-
karyotic cells. The lengths of TNTs can reach several cell
diameters . They were observed in a variety of cell
types both in vivo and in vitro, including the mouse cor-
neal , neuronal [1,3], myeloid [4-7], immune [6-11],
epithelial [1,12-15] and mast cells . A multitude of
cargos, including calcium fluxes , , bacteria ,
nucleic acids , virus [8,11], endosomal vesicles [1,7],
lysosomes [3,7], mitochondria [7,17,18], and QDs 
were observed to be transported through TNTs. Thus,
TNTs play an important role in cell-to-cell communica-
tion and represent a general mechanism for functional
connectivity between living cells. The communications
mediated by these long-range physical connections among
living cells are more widespread than previously thought.
Recently, a great variety of inorganic nanoparticles
(NPs) was synthesized and widely applied in life science
as fluorescent labels and in therapeutic applications as
drug delivery or targeted cell destruction [20-22]. While
intercellular transport can enhance the effectiveness of
NP therapeutics, it also potentially results in toxicity to
the tissue. Undoubtedly, nanotoxicology has to be ma-
tured as a scientific discipline to enable the widespread
application of NPs. Hence, it is of great importance to
understand the behavior and mechanism of the intercel-
lular transport of NPs.
In the present work, the morphological changes of
TNTs and the intercellular transport of the internalized
CdTe QD aggregates with relatively larger sizes along
the TNTs between human hepatocellular carcinoma
(QGY) cells were study by means of differential inter-
ference contrast (DIC) imaging and confocal fluores-
174 Microscopic Observation of the Intercellular Transport of CdTe Quantum Dot Aggregates Through Tunneling-Nanotubes
cence microscopy. The QDs are sufficiently bright and
photostable for the long term tracking of intercellular
2. Materials and Methods
2.1. Cell Culture
QGY-7703 cells obtained from the Cell Bank of Shang-
hai Science Academy were seeded into a Petri dish con-
taining DMEM-H medium with 10 % fetal bovine serum,
100 μg·mL–1 streptomycin and 100 μg·mL–1 neomycin.
The cells were then cultured in a fully humidified incu-
bator at 37℃ with 5 % CO2 for 24 h.
2.2. Cell Uptake of QDs and Living Cell Staining
The water-soluble thiol-capped CdTe QDs with the
emission peak at 601 nm were prepared via the modified
hydrothermal route using the thioglycolic acid as a stabi-
lizer . When the cells reached 80 % confluence, the
QDs aqueous solution was added into the culture dish to
reach a final concentration of 50 - 100 μg·mL–1. The cells
were then incubated for 15-30 min in the incubator for
uptake of QDs.
For imaging of lysosomes, the QD loaded cells were
further incubated with 50 nM LysoTracker Green
DND-26 in growth medium (Invitrogen, Molecular
Probes) for another 15 min to stain lysosomes. After in-
cubation, the Petri dish with the adhered living cells was
washed with phosphate-buffered saline (PBS) three times
to remove the unbound QDs and fluorescent probes.
During the microscopic examination, the cells were kept
at 37℃/5% CO2 in a temperature controller mounted on
the microscope stage (Olympus).
2.3. Fixation and Immunostaining
The QGY cells were fixed with 4% paraformaldehyde
(Sigma) for 30 min at room temperature, and then ex-
tracted with 0.1% (v/v) Triton X-100 in 4% paraformal-
dehyde for 15 min. After washing three times with PBS,
the Petri dishes with attached cells were treated with 1%
BSA block for 2 h at 4℃, and then incubated in 2 μg·mL–1
affinity purified anti-α-tubulin (DM1A; eBioscience)
overnight at 4℃. After washing three times with 0.05%
Tween20/PBS, the cells were stained with 2 μg·mL–1
R-Phycoerythrin conjugated goat anti-mouse IgG (Mul-
tiSciences) for α-tubulin labeling and 5 - 10 nM Alexa
Fluor® 488 phalloidin conjugate (Invitrogen, Molecular
Probes) for F-actin labeling for 2 h at room temperature.
Meanwhile, to reduce nonspecific background staining,
1% BSA was added to the staining solution. The dishes
with attached cells were washed three times with 0.05%
Tween20/PBS before microscopic observation.
The three-dimensional (3-D) fluorescence images and the
DIC micrographs were acquired by a laser scanning
confocal microscope (Olympus, FV-300, IX71) using a
488 nm Ar+ laser (MELLES GRIOT) as the excitation
source and a 60× oil objective to focus the laser beam.
The fluorescence images of QDs and lysosomes were
recorded simultaneously in two channels of the micro-
scope with a 585-640-nm bandpass filter for QDs and a
505-550-nm bandpass filter for lysosomes. Using the
t-scan mode (15-180 seconds interval per frame with
2.8-second exposure time for each image) of the micro-
scope, the dynamic morphological change of TNTs and
the intercellular transportation of QDs were recorded.
Similar method was used to detect the F-actin and mi-
crotubes in TNTs. The fluorescence images of F-actin
and microtubes were recorded simultaneously in two
channels with a 505-550-nm and a 585-640-nm bandpass
3. Results and Discussion
3.1. TNT Structures
The QGY cells connected by TNTs were observed in
both differential interference contrast (DIC) micrographs
and F-actin stained fluorescence images (Figure 1). The
TNTs stretched between interconnected cells at their
nearest distance. Typically, a seamless transition of the
membrane from the TNT to both connected cells was
observed, such as those shown in Figure 1(a,b). The
junction border between the protrusion of one cell and
the membrane of the other connected cell was rarely ob-
served in this work. The DIC image (Figure 1(a)) dem-
onstrates that the protrusions from the two neighboring
cells met with each other to form a TNT and the joining
point can be seen in the middle of the TNT as marked
with an arrowhead. The fluorescence image (Figure 1(c))
shows a 3-D confocal micrograph of the F-actin-stained
QGY cells, where the main image exhibits the TNTs in
the X-Y plane and the lower part shows an X-Z profile
along the TNT in the main image marked with a pair of
red arrows. It can be seen clearly that the TNT hovers in
the medium and has no contact to the substratum, which
is a criterion described for TNTs [1,25]. Interestingly, a
TNT from a cell branched into two TNTs connecting one
nearby cell as shown in Figure 1(d).
Staining for α-tubulin and F-actin revealed that TNTs can
contain only F-actin (Figure 2(a)) or both microtubules and
F-actin (Figure 2(b)). The diameter of the actin-TNT in
Figure 2(a) was estimated around 0.4 - 0.5 μm, while the
microtubule-actin-TNT in Figure 2(b) was relatively
thicker with a diameter around 0.7 - 1 μm. These results
agree with the previously reported observations that micro-
tubules only existed in the thicker TNTs (with a diameter >
0.7 μm) in human monocyte-derived macrophages .
opyright © 2011 SciRes. JBNB
Microscopic Observation of the Intercellular Transport of CdTe Quantum Dot Aggregates Through Tunneling-Nanotubes 175
Figure 1. TNTs connecting QGY cells. TNTs are marked
with arrowheads in all the images. No junction border be-
tween the nanotube and cell surface is observed. (a) DIC
images showing the formation of a TNT, where the joining
point of the protrusions from the two neighboring cells can
be see in the middle of the TNT as marked with an arrow-
head. (b-d) Fixed QGY cells were stained with Alexa Fluor®
488 phalloidin (green) to show F-actin contained TNTs. (c)
The main image exhibits the TNTs in the X-Y plane and the
lower part is an X-Z profile along the TNT in the main im-
age marked with a red arrowhead. (d) A branched TNT
connecting two cells. The enlarged views are shown as insets.
The dynamic morphological changes of TNTs and the
intercellular transport behaviors of QDs via TNTs were
studied using the t-scan mode of the microscope (per
frame with 15-180 seconds interval and 2.8-second ex-
posure time). The rupture of a TNT through apparent
retraction of the nanotube due to the mechanical stress
was demonstrated in Figure 3 (marked with a yellow
arrow). A protrusion from a QGY cell reached the mem-
brane of a neighboring cell and the fusion of the mem-
branes at the contact point formed a continuous mem-
brane bridge can be seen in the same figure (marked with
a red arrow). Interestingly, the TNT was broken when
one of the connected cells died by necrosis as shown in
Both the elongation and shrinkage of TNTs were ob-
served in the time-resolved DIC micrographs. Cell mi-
gration was often observed for the adherent QGY cells in
the Petri dish. Elongation or shrinkage of a TNT oc-
curred when two TNT-connected cells moving apart or
closer. It was suggested that cells maintain a membrane
reservoir, which provides a membrane flow into the
growing or elongating TNT and draws back the mem-
brane from the shortening TNT [26-28]. However, it
seemed that there existed mechanical stress to make
TNTs stretched to straight lines with shortest lengths to
facilitate the cell-to-cell communication.
3.2. Transportation of QDs Along TNTs
The TNTs could also be observed by differential inter-
ference contrast (DIC) microscopy as shown in Figure 5.
With DIC and fluorescence images acquired by the
t-scan mode of the microscope, the intercellular transport
behaviors of QDs via TNTs were studied. The water-
soluble CdTe QDs were incubated with the QGY cells
for 15-30 min. The internalization of QDs was then ob-
served clearly with the 3-D confocal micrographs. The
internalized QDs were not diffusely distributed inside the
cell. A common observation is that QDs tend to aggre-
gate inside living cells and are often trapped in organelles
such as vesicles, endosomes, and lysosomes [29,30]. Mi-
croscopic analysis further revealed that the internalized
QD aggregates could be transported along TNTs. A se-
ries of time-resolved frames selected from a video is
shown in Figures 5(b)-(d) to demonstrate the transport
of a QD aggregate along the TNT. The size of this QD
aggregate was estimated to be about 1.2 μm, which was
in a comparative large size than previously reported car-
gos [5,7,8,11,16,19]. It took 1400 seconds for this QD
aggregate to traverse a distance of 4.6 μm in the TNT,
corresponding to a transport speed of 3.3 nm·s–1.
Unlike the reported actin-dependent unidirectional
transport of cargos through TNTs [1,3,18], our inspec-
tions revealed that the QD aggregate changed speed,
transiently stopped, or changed direction during its
transport along the TNT, corresponding to a bidirectional
manner. Figure 5(e) shows its trajectory along the TNT.
Since the TNT changed its length during the QD trans-
port, the displacement of the QD aggregate was meas-
ured relative to the stationary central point of the TNT. It
can be seen clearly that the motion of QDs was bidirec-
tional, in accord with the previous report of the micro-
tubule-based vesicular traffic .
Figures 5(f)-(i) show a time-lapse image sequence of
two QD aggregates traveling along a TNT towards the
cell at the right side. The sizes of these two QD aggre-
gates were estimated to around 0.5-0.7 μm in diameter,
smaller than the QD aggregate described above in Fig-
ures 5(a)-(d). Their moving speeds were measured to be
about 28 (yellow arrow) and 21 (green arrow) nm·s–1,
respectively. These transport speeds are much higher than
the net transport speed of the QD aggregate (3.3 nm·s–1) in
the bidirectional manner (Figures 5(b)-(d)). By further
inspection, it is found that the trajectories of the
opyright © 2011 SciRes. JBNB
Microscopic Observation of the Intercellular Transport of CdTe Quantum Dot Aggregates Through Tunneling-Nanotubes
Copyright © 2011 SciRes. JBNB
Figure 2. Fixed QGY cells were stained with Alexa Fluor® 488 phalloidin for F-actin (green) and immunostained with an
antibody against α-tubulin (red). (a) A TNT between QGY cells contains F-actin but no microtubule. (b) A TNT between
QGY cells contains both F-actin and microtubules. Enlarged views of the TNTs are shown in the insets of the figures. The
fluorescence images of F-actin and microtubes were recorded simultaneously in two channels of the microscope with a 505-
550-nm and a 585-640-nm bandpass filter, respectively.
Figure 3. The rupture of a TNT through apparent retraction of the nanotube due to the mechanical stress (marked with a
yellow arrow). It can also be seen that a protrusion from a QGY cell reached the surface of a neighboring cell and the fusion
of the membranes at the contact point formed a continuous membrane bridge (marked with a red arrow).
Microscopic Observation of the Intercellular Transport of CdTe Quantum Dot Aggregates Through Tunneling-Nanotubes 177
Figure 4. The TNT marked with a yellow arrow was broken
when one of the connected cells died by necrosis.
Figure 5. (a) DIC micrograph of two QGY cells connected
by a TNT. (b)-(d) Time-lapse merged images of DIC and
fluorescence micrographs to show the transport of a QD
aggregate (marked with yellow arrowheads) through a TNT.
The red color denotes the fluorescence from QDs. (Scale bar,
5 μm.) (e) Trajectory of the QD aggregate in (b)-(d). Posi-
tion 0 represents the starting position of the QD aggregate
in the TNT once our measurement began. (f)-(i) Time-lapse
images to show two QD aggregates (marked with yellow
and green arrows, respectively) traveling along a TNT.
(Scale bar, 5 μm.) (j) Trajectories of the two QD aggre-
gates in (f)-(i), where (5) corresponds to the QD aggregate
marked with the yellow arrow and (6) the green arrow. (k)
MSD plots for the four periods of continuous moving in (e)
that marked as (1), (2), (3) and (4) and the two unidirec-
tional moving in (j) that marked as (5) and (6). The straight
lines in the plot are the fitted lines. S represents the slope of
the fitted line and R the correlation coefficient.
two QD aggregates were unidirectional as shown in Fig-
ure 5(j), corresponding to the actin-dependent transpor-
When calculating the moving rates of the QD aggre-
gate in the four continuous moving periods in Figure
5(e), it was found that these speeds had the similar value
of 18 ± 4 nm·s–1, which were much faster than the net
speed of the bidirectional motion of the QDs (3.3 nm·s–1)
but were close to the speeds of the unidirectional mo-
tions in Figure 5(j) (28 and 21 nm·s–1). It means the
bidirectional motion greatly reduced the transport
The mean square displacement (MSD) is commonly
used to determine whether the movement is active trans-
port or diffusion . The movement can be attributed to
the free diffusion when the slope of a log–log plot of
MSD as a function of time equals 1, whereas a slope less
than 1 refers obstructed movement, and a slope greater
than 1 indicates an active transport . As shown in
Figure 5(e), there are four periods of the continuous
movements. Three of them were forward movements and
one backward. By choosing these four continuous
movements in Figure 5(e) denoted as (1) to (4) and the
two unidirectional movements in Figure 5(j) denoted as
(5) and (6), we calculated the relationships of log MSD
versus log t. The results are plotted in Figure 5(k), where
the starting time and the displacement of the starting po-
sition for every movement were set as 0. All the simu-
lated slopes (from 1.72 to 3.04) support that the QDs
were transported actively along the TNT.
By estimating the size of the QD aggregate and the
thickness of the TNT in Figure 5(a), we found that the
diameter of the QD aggregate is a little larger than that of
the TNT. As reviewed in Ref. , this phenomenon was
observed previously and called vesicular dilatation. The
vesicle-like dilatations of the TNTs may be formed be-
cause of an organelle, vesicle or supramolecular assem-
bly with a larger diameter being transported inside them.
These dilatations can be transported along the TNT and
then released into the cytoplasm of the second cell
There were two classes of TNTs as shown in Figure
2, which can be distinguished by their cytoskeletal struc-
ture and their functional properties. As reported by On-
felt et al, thin TNTs contained only F-actin, whereas
thicker nanotubes, i.e., those > ~0.7 μm in diameter, con-
tained both F-actin and microtubules . The actin fila-
ments and microtubules are long and directed polymers.
They provide the roadways for the cellular transportation
system. Mitochondria and intracellular vesicles, includ-
ing late endosomes and lysosomes, were detected within
the thicker TNTs transported in a stepwise and bidirec-
tional manner .
opyright © 2011 SciRes. JBNB
178 Microscopic Observation of the Intercellular Transport of CdTe Quantum Dot Aggregates Through Tunneling-Nanotubes
The bidirectional microtubule-based transport mode
has been reviewed by Gross in detail . The transport
modes of cargos along TNTs between cells should be
same due to the similar cytoskeletal structure. There are
three classes of molecular motors which transport cargos
along the actin filaments or the microtubules with a cer-
tain direction: the myosin motors that move along actin
filaments unidirectionally; the kinesin motors that move
along microtubules, predominantly towards the micro-
tubule plus-ends; and the dynein motors that move to-
wards the microtubule minus-ends. For microtubule-
based transport mode, kinesin and dynein motors can
make the cargo move back and forth as a result . The
net or average direction of transport depends on which
kind of motor plays the dominant role at one moment.
For the actin-dependent transport mode, the myosin pro-
tein moves the cargo unidirectionally. Figure 6 shows
the bidirectional and unidirectional transportations of
QDs along a TNT schematically.
3.3. Transportation of QDs Inside lysosomes
As reported, a wide variety of intracellular compartments
was observed to traffic through the TNTs between ma-
crophages and arrive in the cytoplasm of cells . In our
previous work, co-localization of QDs with lysosomes in
living cells has been observed . Lysosomes are one
of the major destinations of internalized QDs. Hence, it is
possible that QDs could transport between cells within
lysosomes. To verify this hypothesis, the lysosomes in
QGY cells were stained with LysoTracker after the cells
were incubated with QDs. The fluorescence images of
QDs and lysosomes were recorded simultaneously in two
Figure 6. Schematic diagram of possible models for TNT-
mediated transport of QDs. For microtubule-based trans-
port, the kinesin motors move the cargo along microtubules,
predominantly towards the microtubule plus-ends and the
dynein motors move the cargo towards the microtubule
minus-ends. These two kinds of motors can make the cargo
move back and forth as a result. While the myosin motors
move the cargo unidirectionally along the actin filament.
with a 585-640-nm bandpass filter for QDs and a 505-
channels of the microscope 550-nm bandpass filter for
lysosomes. In the fluorescence micrographs, the red and
green colors denote the QDs and the lysosomes, respec-
tively, and the yellow color in the overlaid images repre-
sents the mixed fluorescence from LysoTracker and QDs.
As shown in Figure 7(a), a QD aggregate was trans-
ported along a TNT in the bidirectional manner from the
first cell in the upper side of the figure to the second cell
at the lower side. After a while, a QD loaded lysosome
(yellow color) moved backward along the same TNT to
the first cell as shown in Figure 7(b). It means that QDs
can transport between cells within or without lysosomes.
However, the mechanism should be the same since the
internalized QDs are believed to be aggregated inside the
TNTs with different diameters were observed to connect
QGY cells. The TNTs contained only F-actin or both
microtubules and F-actin. The formation, shrinkage, elon-
gation and rupture of TNTs between QGY cells were
observed. The internalized QD aggregates were trans-
ported to the neighboring cells via TNTs either in a bidi-
rectional or a unidirectional manner. The transport of
QDs within lysosomes was also observed. The MSD
analyses revealed that the intercellular transportations of
QDs along TNTs were mediated by active processes. A
fully understanding of the TNT-mediated intercellular
transport mechanism for NPs will provide solid funda-
mental knowledge for the application of NPs in drug de-
Figure 7. Time-lapse micrographs showing the transport of
QD aggregates (marked with yellow arrows) along a TNT
between two QGY cells. The red and green colors denote
QDs and lysosomes, respectively, and the yellow represents
the mixed fluorescence from LysoTracker and QDs, indi-
cating the co-localization of QDs with lysosomes. (a) A QD
aggregate was transported along a TNT in the bidirectional
manner from the first cell in the upper side to the second
cell at the lower side. (b) After a while, a QD loaded ly-
sosome (yellow) moved backward along the same TNT to
the first cell.
opyright © 2011 SciRes. JBNB
Microscopic Observation of the Intercellular Transport of CdTe Quantum Dot Aggregates Through Tunneling-Nanotubes 179
This work is supported by National Natural Science
Foundation of China (61008055, 11074053), the Ph.D.
Programs Foundation of Ministry of Education of China
(20100071120029) and Shanghai Educational Develop-
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