Chemistry Reference
In-Depth Information
results. The approach which has been quite successful in incorporating Gd to
porphyrin-based compounds has been to link the tetrapyrrolic system to diethylene
triamine pentaacetic acid (DTPA) or 1,4,7,10-tetraazacyclododecane-1,4,7,10-
tetraacetic acid (DOTA) in which Gd can easily be chelated. Gadoporphyrin-2
[
60
], in which the paramagnetic metal was chelated to DTPA side chains, showed a
favorable safety profile with high stability. Additionally, it showed remarkable
target specificity to necrotic tumor tissue. For the last few years, the Roswell Park
group has been developing dual-function imaging agents (MR/fluorescence) with
an option of NIR PDT. In their initial study, HPPH was conjugated with variable
number of Gd-DTPA [
61
]. The synthetic methodologies for HPPH-2Gd(III)DTPA
and HPPH-3Gd(III)DTPA are illustrated in Schemes
3
and
4
, respectively. It was
observed that by increasing the number of Gd(III)DTPA, moiety enhances the
tumor contrast to some extent (Table
2
). Among the conjugates investigated
containing 2 to 6 Gd(III)DTPA moieties [
62
,
63
], both 2- and 3-Gd(III)DTPA-
HPPH conjugates showed excellent tumor-imaging (MR and fluorescence) and
PDT efficacy in tumored mice and rats (Figs.
6
,
7
,
8
, and
9
). However, the conjugate
with 3-Gd(III)DTPA was easier to formulate in PBS and was selected for a detailed
investigation. Interestingly, the conjugate even at 8-fold higher than the imaging
dose did not show any normal organ toxicity. Compared to Magnevist (current
clinical standard), the MR imaging dose of HPPH-3Gd(III)DTPA was 10-fold
lower and provides a unique opportunity to develop a single agent for both cancer
imaging and therapy.
Shim and coworkers [
64
] extended this approach and synthesized a series of Gd
(III)DTPA-based purpurinimide analogs, in which one or two moieties of purpurin-
18-
N
-(2-aminoethyl) were conjugated with DTPA, which on further reaction with
gadolinium chloride yielded the desired product (Scheme
5
). However, the imaging
and PDT efficacy of the Gd-complexes are under investigation.
2.3 PET/Fluorescence Imaging and PDT
In recent years, multimodality systems for in vivo imaging of small animals have
become important tools for modern biomedical research, as they offer advantages
of combining complimentary characteristics of different modalities. Representative
examples of multimodality system are the combination of MRI and CT (computed
tomography), CT and fluorescence, and CT and positron emission tomography
(PET). A system with PET or SPECT and fluorescence offers advantages because
the co-registration of PET and fluorescence images is quite convenient. In recent
years, several agents combining both fluorescence and PET-imaging abilities have
been developed in various laboratories and have definite advantages over the use of
two independent agents with different pharmacokinetic profiles. However, in
developing nuclear imaging agents, the selection of radionuclide plays very impor-
tant role, and it should coincide with the pharmacokinetic properties of the mole-
cule in which the radionuclide is attached.
