Chemistry Reference
In-Depth Information
In several of the abovementioned studies, the reason why imaging was carried out at 24 h after injection for such low
molecular weight agents (which are typically cleared from the circulation in minutes) was unclear. When compared to the
size of either cyclic RgD peptides or c(CgRRaggSC), the
111
In-DTPa complex and the fluorescent dyes are relatively
bulky and may significantly affect receptor binding. Recognising such limitations, several groups have also investigated the
use of dual-labelled antibodies for SPECT/optical imaging using a similar approach.
15.3.3
antibody-Based agents
Overexpression of the human epidermal growth factor receptor (HER) family has been implicated in many cancer types,
because of its multiple roles in signalling pathways that regulate cellular proliferation, differentiation, motility, and survival
[97, 98]. approximately one-third of breast cancer patients overexpress HER2, a member of the HER family [99].
Trastuzumab (Herceptin; genentech, Inc.) is an inhibitory mab developed against the extracellular domain of HER2, which
has been used for cancer therapy in HER2-positive patients [100-102].
In one report, (
111
In-DTPa)
n
-trastuzumab-(IRDye800)
m
was synthesised, and fluorescence confocal microscopy was used
to determine the molecular specificity of (DTPa)
n
-trastuzumab-(IRDye800)
m
in vitro
in SKBr3 (HER2-positive) and
MDa-MB-231 (HER2-negative) breast cancer cells [103]. It was found that (DTPa)
n
-trastuzumab-(IRDye800)
m
had signif-
icantly greater binding to SKBr3 than to MDa-MB-231 cells, and the binding occurred predominantly within the cell mem-
brane, because HER2 is a membrane-bound protein.
In vivo
SPECT and optical imaging of SKBr3 xenografts injected with
(
111
In-DTPa)
n
-trastuzumab-(IRDye800)
m
revealed significantly more uptake in the tumour region than in the contralateral
muscle. This dual-modality agent, (
111
In-DTPa)
n
-trastuzumab-(IRDye800)
m
, may be an effective diagnostic biomarker
capable of tracking HER2 overexpression in breast cancer patients. Several other reports also investigated the potential of
trastuzumab for the development of dual-modality SPECT/optical or PET/optical agents using similar approaches [104,
105]. However, no
in vivo
studies were reported using these agents.
15.4
MrI/optIcal agents
MRI is a noninvasive diagnostic technique based on the interaction of protons (or other MRI-active nuclei) with each other
and with surrounding molecules in a tissue of interest [106]. Different tissues have different relaxation times, which can
result in endogenous MRI contrast. The major advantages of MRI over radionuclide-based imaging are the absence of radi-
ation, higher spatial resolution, and exquisite soft tissue contrast. The major disadvantage of MRI is its inherent low sensi-
tivity, which can be partially compensated for by working at higher magnetic fields (4.7-14 T in small animal models),
acquiring data for a much longer time period, and using exogenous contrast agents. Traditionally, gd
3+
-chelates have been
used to enhance the T
1
contrast [107], and iron oxide nanoparticles have been used to increase the T
2
contrast [108].
generally, the design of non-nanoparticle-based dual-modality MRI/optical imaging agents consists of gd
3+
-chelates that
are covalently conjugated to a fluorescent dye. a tabulated summary of MRI/optical agents is provided in Table 15.3 and
discussed in detail below.
In an early study of dual-modality MRI/optical imaging agents, several groups of compounds with different cell perme-
ability were investigated for such applications [109]. One of these agents, gadolinium rhodamine dextran, was further
studied for its effect on neural stem cells [110]. although no significant effect on cell viability was observed, a decrease in
taBle 15.3
a tabulated summary of dual-modality MrI/optical agents.
Paramagnetic Moiety
Fluorophore
Targeting ligand
Target
References
Rhodamine
-
-
[109, 110]
Dicarbocyanine
lDl
lDl receptor
[111]
Oregon green 488
Cyclic NgR peptide
CD13
[112]
Fluorescein
-
-
[115]
Cyanine dyes
-
-
[116]
gd
3+
-chelates
Porphyrin
-
-
[121]
Fluorescein derivative
albumin
Caveolae
[124, 125]
Congo red
albumin
amyloid plaque
[126]
NIR813
-
-
[128]
Cy5.5
Bombesin peptide
gRPR
[129]
HPPH
-
-
[130]
