Francis Hane1, Tao Li1, Peter Smylie1, and Mitchell S Albert1
1Lakehead University, Thunder Bay, ON, Canada
Synopsis
We used the MRI
HyperCEST technique to detect the presence of the xenon encapsulating cage
molecule cucurbit[6]uril (CB6) in the abdomen of a rat. We believe that this is
the first in vivo demonstration of a
xenon based biosensor. We were able to observe a HyperCEST signal depletion of
53% within the intraperitoneal space of the rat. Our results demonstrate the
feasibility of HyperCEST biosensors to move from in vitro to in vivo
studies.Audience
& Purpose
Hyperpolarized (HP)
Xenon-129 MRI biosensors have the potential to detect pathological molecules
within the body at extremely low concentrations with MRI-like resolution and
Positron Emission Tomography (PET)-like sensitivity. Combining the increased
sensitivity of hyperpolarization with the Hyperpolarized Chemical Exchange
Saturation Transfer (HyperCEST) technique can provide a sensitivity increase of
a billion times over thermally polarized xenon. In this work we present the
first in vivo HyperCEST spectra of cucurbit[6]uril
(CB6) HyperCEST contrast agent in a live animal. This work is important for
other researchers in the field in translating in vitro testing of HP gas biosensors to preclinical testing and
thence to clinical trials.
Methods
A 10 mL 5.0 mM
solution of CB6 was prepared in a PBS solvent. 83.6% isotopically enriched 129Xe
was hyperpolarized to 30% using a Xemed Xebox polarizer (Durham, NH). 5 mL of
HP 129Xe was introduced into the CB6 solution and shaken for 12
seconds. 5 mL of the CB6 solution containing HP 129Xe was injected
into the intraperitoneal (IP) space of ~400 g male Sprague-Dawley rats. The rats
were placed into a custom RF coil tuned to a Larmor frequency of 129Xe
(35.33 MHz) at 3 T. A HyperCEST pulse sequence (16- 6 ms 3-lobe sinc pulse, 3
ms pulse interval) was applied at the CB6-Xe resonance frequency (+124.3 ppm). NMR
spectra were acquired with both off-resonance control pulses and on-resonance saturation
pulses. MR images were taken with 150 mm x 150 mm FOV, 32x32 voxels, 300 mm
slice thickness. TR=197 ms, TE=0.77 ms.
Results & Discussion
We observed a 53% HyperCEST depletion of the CB6-xenon complex following
the applied saturation pre-pulse. We observed a signal peak at +192.4 ppm with
respect to the xenon gas phase peak corresponding to xenon dissolved in plasma
[1]. We observed a shoulder down field from the peak (+124.3 ppm) which we
assume to be caused by the CB6/Xe complex. However, given the complex
interactions and exchange broadening in vivo,
this peak was not independently resolvable.
Conclusions
We believe that these
data are the first report of in vivo application
of a HP Xe based MRI biosensor in a live animal model. We will continue our
work by obtaining HyperCEST saturation maps in live animals to detect in vivo pathological molecules of
interest.
Acknowledgements
FH would like to acknowledge the generous support of the donors of the BrightFocus Foundation. References
1.
Wang Y, Dmochowski I. Cucurbit[6]uril
is an ultrasensitive 129Xe NMR contrast agent. Chem. Comm. 2015; 51:8982–8985.