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Scientific Report 2007-2009
Condensed matter physics and biophysics
C40. Molecular diffusion and Molecular imaging studies by means of
NMR techniques in materials, tissues, animal models and humans
Diffusion Tensor (DTI) and Diffusion-weighted (DWI)
imaging NMR techniques are the only non-invasive tool
available today to investigate molecular diffusion processes
in vivo. DTI and DWI provide information on
biophysical properties of tissues which influence the diffusion
of water molecules [1]. Molecular imaging is the
non-invasive visualization in space and time of cellular
processes at molecular or genetic level of function.
A key component in molecular imaging is the imaging
probe which homes in on the specific target of interest
in the body providing pharmacokinetic and tracking information.
Using NMR spectroscopic and/or scanning
methods (magnetic resonance spectroscopy, MRS and
imaging, MRI), the probe is labeled with 19F atoms
and it is visualized by 19F-MRS and /or 19F-MRI.
Specifically, target molecules are marked by substitution
of hydrogen atoms with one or more 19F atoms
(usually -CF3 group). Due to the lack of endogenous
background signal in vivo and the high MR sensitivity
of the 19F atoms (83Within the framework of Molecular
Imaging investigations we developed in our laboratory
an in vivo 19F MR Imaging and Spectroscopy
protocol for the optimization of BNCT (Boron Neutron
Capture therapy). BNCT is an experimental binary radiation
therapy based on the cytotoxic effects of high
LET particles released from the 10B(n,alpha)7Li reaction
that occurs when 10B captures a thermal neutron.
For BNCT effectiveness a large amount of 10B atoms (at
least 109 atoms of 10B per targeted cell) should be accumulated
within tumour cells in order to obtain a maximum
tumour-to-brain (T:Br) 10B concentration ratio.
Currently, the therapy is mainly used to treat malignant
brain glioma for which the conventional therapies
do not provide any substantial benefit. The main limitations
for BNCT effectiveness are: 1) the lack of efficient
imaging methods to monitor the bio-distribution of 10Blabeled
drugs in order to estimate the efficiency of the
carrier and the optimal timing of neutron irradiation.
This ideal time is when tumour-to-brain (T:Br) 10B concentration
ratio achieves the maximum value at the lowest
blood concentration; 2) the insufficient intake of 10B
nuclei in the tumour cells. The aim of our study was
to evaluate the boron bio-distribution and pharmacokinetics
of 4-borono-2-fluorophenylalanine (19F-BPA) using
19F-MRI and 19F-MRS in animal model (C6-glioma
rat brain). Moreover, the effect of L-DOPA as potential
enhancer of BPA tumour intake was evaluated. 1H and
19F images were obtained using a 7T MR scanner, to assess
19F-BPA spatial distribution mapping in rat brain.
Images (see upper panels in Figure) were processed in
order to superimpose the 19F image (in colour levels of
low=blue, high=red) on the corresponding anatomical
1H reference (in grey levels). To perform pharmacokinetics
studies 19F spectra from rats blood samples were
collected at 9.4 T at different time delays after BPA infusion
(see a,b and c in Figure). The correlation between
the results obtained by both techniques, showed
the maximum 19F-BPA uptake in C6 tumour-bearing
rats at 2.5h after infusion determining the optimal irradiation
time [2].
Moreover, the effect of L-DOPA as potential enhancer
of 19F-BPA tumour intake was assessed [3,4]. A
significantly higher accumulation of BPA was found in
the tumor tissue of rats pre-treated with L-DOPA as
compared to the control group. Conversely, no significant
difference was found in the normal brain and blood
samples between the two animal groups. Our results
suggest the presence of specific membrane antiport
carriers with an high affinity for L-substrates, such as
L-BPA and L-DOPA to explain the dramatic increase
of BPA concentration in C6-glioma cells pre-treated
with L-DOPA [4]. According to our results, these new
strategies are expected to increase BNCT efficacy in
absence of any additional risk of toxicity.
References
1. C. Rossi et al. J Magn Reson Imag 27, 476 (2008).
2. P. Porcari et al., Phys. Med. Biol. 53, 6979 (2008).
3. S. Capuani et al., Int. J. Radiat. Oncol. Biol. Phys. 72,
562 (2008).
4. P. Porcari et al., Appl. Rad. Isot. 67, S365 (2009).
Authors
S. Capuani 2 ,P. Porcari, C. Rossi, B. Maraviglia.
http://lab-g1/
Sapienza Università di Roma 93 Dipartimento di Fisica