Chemistry Reference
In-Depth Information
proliferation was evident in cells that underwent 24 h of labelling. Further
in vivo
testing will be required to ensure that
labelling with these dual-modality MRI/optical agents does not perturb the cells' function.
a lipophilic agent composed of gd-DTPa, a fluorescent dye, and a 16-carbon alkyl chain for intercalative labelling of
low-density lipoprotein (lDl) particles was reported for
in vivo
detection of lDl receptors (lDlR) by MRI and
in vitro
monitoring of cellular localisation by confocal fluorescence microscopy [111]. While no significant membrane-associated
fluorescence signal was observed, differential shortening of T
1
relaxation time was found in normal liver (>70%) when com-
pared to lDlR
-/-
liver (12%) in mice. In addition, uptake of labelled lDl particles in subcutaneously implanted B16 mela-
noma tumours in mice led to a modest decrease in T
1
relaxation time of the tumour.
In another report, a chemoselective reaction was employed to synthesise an agent that contains a peptidic targeting ligand,
gd-DTPa, and a fluorescent dye Oregon green 488 [112]. The cyclic peptide used in this study contains the asparagine-
glycine-arginine motif (NgR), which can bind to an angiogenesis-related protein CD13 [113, 114]. However,
in vitro
and
in vivo
behaviour of this agent was not reported.
a bifunctional agent that contains a gd chelate and fluorescein has been developed and investigated [115].
In vitro
studies
in NIH-3T3 mouse fibroblast cells demonstrated a concentrated-dependent increase in fluorescence as well as significant
increase in T
1
, suggesting cell binding and uptake of the agent. However, the use of fluorescein made it only suitable for
cell-based assays but not
in vivo
imaging, due to the short excitation/emission wavelength. Cyanine dyes have been cova-
lently attached to gd-DTPa-polylysine of an extended, uncoiled conformation for fluorescence imaging of preclinical sub-
cutaneous and orthotopic mammary gland tumours [116]. When a wide-field illumination camera system was used, this
agent could allow for intraoperative delineation of the tumour margin.
gadophrin-2, composed of a porphyrin ring and two covalently linked gd-DTPa, has been investigated as a MRI contrast
agent in various studies [117-120]. In one report, it was also used to label and trace intravenously injected human hemato-
poietic cells in athymic mice [121]. unlike the use of covalently linked fluorophores in other dual-modality MRI/optical
imaging agents described above, the fluorescence properties of the porphyrin ring within gadophrin-2 was used for optical
imaging. after intravenous injection, the distribution of gadophrin-2-labelled cells in nude mice was visualised by MRI,
optical imaging, and fluorescence microscopy (Figure 15.9).
In these abovementioned reports, the ratio of gd:dye is quite low, in many cases 1:1. Due to the very low sensitivity of
gd-based MRI, such composition is not optimal for
in vivo
imaging applications. a class of polymer-based MRI/optical
agents has been reported that contains multiple copies of gd in each molecule [122, 123]. However, since these agents fall
into the category of nanoparticle-based dual-modality imaging agents, they will not be discussed in this chapter.
albumin has been conjugated to multiple imaging tags for MRI/optical tracking of labelled fibroblasts in animal tumour
models to understand the role of fibroblastsin tumour differentiation, tumour angiogenesis, and vessel maturation [124]. It
was demonstrated that this contrast agent can be internalised into intracellular granules via caveolae-mediated endocytosis,
which leads to MRI signal enhancement [125]. Interestingly, similar gd
3+
-containing albumin-based agents that contain
Congo Red as the fluorophore have also been reported for detection of amyloid plaques in alzheimer disease (aD) [126].
Because the amyloid deposits detected by the probe were found to be comparable to the amyloid deposits detected by an
amyloid-specific mab, it was suggested that this agent may be useful for detection of individual senile plaques and diagnosis
of aD.
In the NIR region, the absorbance of all biomolecules reaches a minimum and provides a clear window for
in vivo
optical
imaging [127]. Furthermore, there is also significantly less tissue autofluorescence in this region. Poly(l-glutamic acid)
conjugated with gd-DTPa and a NIRF dye NIR813 (emission maximum: 813 nm) has been used for SlN mapping in
normal and tumour-bearing mice [128]. It was reported that there were more than 50 gd-DTPa units per polymer chain.
after subcutaneous injection, axillary and branchial lymph nodes were clearly visualised with both T
1
-weighted MRI and
optical imaging within 3 minutes, even at the lowest dose tested (2 μmolof gd/kg and 4.8 nmol of NIR813). after intralin-
gual injection in tumour-bearing mice, both MRI and NIRF imaging identified most of the superficial cervical lymph nodes.
Histopathologic examination of the SlNs resected under NIRF imaging guidance revealed micrometastases in all SlNs
identified.
a MRI/optical agent has been developed and evaluated for imaging of gRPR in prostate cancer [129]. This agent is con-
sisted of gd
3+
complexed with a chelator abbreviated as TTDa-NP, the NIR dye Cy5.5, and a bombesin peptide. Both MRI
and NIRF imaging displayed good tumour contrast of the agents (i.e., gd-TTDa-NP-BN and gd-TTDa-NP-BN-Cy5.5;
Figure 15.10) in PC-3 tumour-bearing mice.
In a recent report, an MRI/optical agent has been developed for both imaging and photodynamic therapy of tumours
[130]. The fluorophore used in this agent, 3-(1′-hexyloxyethyl)pyropheophorbide-a (abbreviated as HPPH), is a photosensi-
tiser that displayed the best photodynamic therapy efficacy
in vivo
when it was conjugated with multiple gd
3+
-DTPa che-
lates. It was suggested that this multifunctional agent has the potential for screening, diagnosis, treatment monitoring, as
well as image-guided intervention of cancer.
