surface biomarkers (active targeting) (Fig. 1b) [8]. Figure 1c (bottom) shows no
tumor signals detected with QD-COOH (no specific targeting), and the only weak
signals were observed for QD-PEG (passive targeting); however, very intense
signals were detected for QD-PSMA (active targeting). These results indicate the
active tumor targeting is more efficient than passive targeting [5].
Since this groundbreaking work, there have been studies to show the surfacemodified QDs with a variety of biological targeting moieties (e.g., small molecule
[9], peptide [10, 11], aptamer [12]) allowed successful identification with high
resolutions for tumor cells in vivo. Further recent studies for QDs for optical imaging
have been particularly focused on improving the imaging sensitivity with use of
near-infrared (NIR)-emitting QDs or decreasing the toxicity by using Cd-free QDs.
QDs that emit in the near-infrared (NIR) region (700–900 nm) can minimize the
problems of endogenous fluorescence of tissues (autofluorescence) and increase
tissue penetration, which is particularly suitable for in vivo animal imaging
[14, 15]. In a pioneering study, Bawendi and coworkers first reported core/shell
(CdTe/CdSe) QDs with fluorescence emission at 840–860 nm while preserving the
absorption cross section (Fig. 2a, b) [13]. These NIR-emitting QDs were then
rendered soluble and stable in serum by polydentate phosphine coating and used
for to identify cancer cells in lymph nodes during surgery (sentinel lymph node
mapping). As shown in Fig. 2c, when these QDs (10 pmol) were intradermally
injected to the mouse, they entered the lymphatics and migrated within minutes to an
axillary sentinel lymph node (SLN) that could be detected using intraoperative NIR
fluorescence imaging system. Furthermore, even in a large animals (pigs), the
authors found NIR fluorescence from intradermally injected ODs (400 pmol) was
sensitive enough for imaging SLN 1 cm deep in real time and ensuring complete
resection of the SLN under optical image guidance (Fig. 2d) [13].
Second near-infrared (NIR-II) window is nearly biologically transparent due to its
much less optical scattering from endogenous molecules (e.g., hemoglobin, melanin,
lipids), and thus NIR-II imaging can afford deeper anatomical penetration at high
spatial resolution, compared to NIR-I imaging [17]. Hence, in 2010, the Dai group
has developed single-walled carbon nanotubes (SWCNTs) as sensitive NIR-II
fluorescent probes for whole-body imaging as well as real-time intravital small
vessel imaging. Here, SWCNTs were emitted in the NIR-II region
(1,000–1,400 nm) upon excitation by a 785 nm laser, with large Stokes shift up to
~400 nm (Fig. 3a) and thus allowed for high spatial (~30 mm) and temporal
(<200 ms per frame) resolution for small-vessel imaging at 1–3 mm deep in the
hind limb (Fig. 3b) [16]. Also, these NIR-II-emitting SWCNTs have permitted the
high through-skull fluorescence imaging of mouse cerebral vasculature to a depth of
>2 mm in mouse brain with sub-10-μm resolution [18]. However, the optical cross
section of SWCNT is a bit limited, and thus Ag 2 S QDs have been developed with 5.6
times higher photoluminescence quantum yield than SWCNT for emission in the
NIR-II region. These probes also have negligible cytotoxicity [19] and the potential
for deep tissue imaging (with theoretical penetration depth of 5 cm) [20]. Ag 2 S QDs
can be used to study angiogenesis mediated by a tiny tumor (2–3 mm in diameter)
[21]. More recently, Bawendi and coworkers introduced InAs-based, core/shell QDs
58
T. Kim and J. V. Jokerst
tumor signals detected with QD-COOH (no specific targeting), and the only weak
signals were observed for QD-PEG (passive targeting); however, very intense
signals were detected for QD-PSMA (active targeting). These results indicate the
active tumor targeting is more efficient than passive targeting [5].
Since this groundbreaking work, there have been studies to show the surfacemodified QDs with a variety of biological targeting moieties (e.g., small molecule
[9], peptide [10, 11], aptamer [12]) allowed successful identification with high
resolutions for tumor cells in vivo. Further recent studies for QDs for optical imaging
have been particularly focused on improving the imaging sensitivity with use of
near-infrared (NIR)-emitting QDs or decreasing the toxicity by using Cd-free QDs.
QDs that emit in the near-infrared (NIR) region (700–900 nm) can minimize the
problems of endogenous fluorescence of tissues (autofluorescence) and increase
tissue penetration, which is particularly suitable for in vivo animal imaging
[14, 15]. In a pioneering study, Bawendi and coworkers first reported core/shell
(CdTe/CdSe) QDs with fluorescence emission at 840–860 nm while preserving the
absorption cross section (Fig. 2a, b) [13]. These NIR-emitting QDs were then
rendered soluble and stable in serum by polydentate phosphine coating and used
for to identify cancer cells in lymph nodes during surgery (sentinel lymph node
mapping). As shown in Fig. 2c, when these QDs (10 pmol) were intradermally
injected to the mouse, they entered the lymphatics and migrated within minutes to an
axillary sentinel lymph node (SLN) that could be detected using intraoperative NIR
fluorescence imaging system. Furthermore, even in a large animals (pigs), the
authors found NIR fluorescence from intradermally injected ODs (400 pmol) was
sensitive enough for imaging SLN 1 cm deep in real time and ensuring complete
resection of the SLN under optical image guidance (Fig. 2d) [13].
Second near-infrared (NIR-II) window is nearly biologically transparent due to its
much less optical scattering from endogenous molecules (e.g., hemoglobin, melanin,
lipids), and thus NIR-II imaging can afford deeper anatomical penetration at high
spatial resolution, compared to NIR-I imaging [17]. Hence, in 2010, the Dai group
has developed single-walled carbon nanotubes (SWCNTs) as sensitive NIR-II
fluorescent probes for whole-body imaging as well as real-time intravital small
vessel imaging. Here, SWCNTs were emitted in the NIR-II region
(1,000–1,400 nm) upon excitation by a 785 nm laser, with large Stokes shift up to
~400 nm (Fig. 3a) and thus allowed for high spatial (~30 mm) and temporal
(<200 ms per frame) resolution for small-vessel imaging at 1–3 mm deep in the
hind limb (Fig. 3b) [16]. Also, these NIR-II-emitting SWCNTs have permitted the
high through-skull fluorescence imaging of mouse cerebral vasculature to a depth of
>2 mm in mouse brain with sub-10-μm resolution [18]. However, the optical cross
section of SWCNT is a bit limited, and thus Ag 2 S QDs have been developed with 5.6
times higher photoluminescence quantum yield than SWCNT for emission in the
NIR-II region. These probes also have negligible cytotoxicity [19] and the potential
for deep tissue imaging (with theoretical penetration depth of 5 cm) [20]. Ag 2 S QDs
can be used to study angiogenesis mediated by a tiny tumor (2–3 mm in diameter)
[21]. More recently, Bawendi and coworkers introduced InAs-based, core/shell QDs
58
T. Kim and J. V. Jokerst