Synopsis
The role of MRI contrast agents is evolving,
from enhancing tissue contrast to sensing physiological changes. New generation
of MRI biosensors can detect and response to biomarkers such as small
molecules, metabolites, metal ions, proteins, enzymes or pH. The major hurdles
in translating these biosensors from bench to bedside are their insufficient
sensitivity and specificity in vivo.
Various biosensors have addressed these issues in specific biomedical applications. In this talk, we will discuss
the frontier MRI biosensor designs for imaging biomarkers in vivo, such as using nanomaterials and MRI contrast mechanisms to
improve the sensitivity and specificity, and their features to overcome
barriers in biomedical applications.
Highlights
· Design principles
for preparing responsive MRI biosensors
· Possible nanocarrier
approaches in the design of MRI biosensors
· Strategies to
overcome physiological and transport barriers
Taget audience
Researchers or clinicians who are interested in imaging biomarkers in vivo using the MRI sensor approach. Purpose
To use
a multidisciplinary approach to develop and apply MRI biosensors for specific
biomedical applications.Syllabus
Imaging biomarkers in vivo is challenging, since barriers exist and most of the
physiochemical changes are dynamic. A typical challenge is the pharmacokinetics
of biosensors, which leads to spatial and temporal fluctuations in tissue
contrast. Thus, to tease out the responsiveness of biosensors towards specific biomarkers,
we need to consider the local concentration of biosensors. Many preclinical
studies have shown that the imaging biomarkers indicate disease status1-6. To allow a
sensitive and specific detection of these biomarkers in vivo, especially to quantify those related to early pathologies,
we need solutions from material design, biosensor fabrication, target delivery,
and amplification of signal readout. Here we review biosensors that response to
enzymes, ions, pH and metabolites in vivo,
and advanced nanocarriers to enhance the specificity and sensitivity. Enzyme is
one of the biomarkers, which responsible for many physiochemical changes at
both cellular and molecular levels. Researchers have devised enzyme targeting
and cleavable biosensors that successfully image enzymes7-11. A common
challenge for translating these biosensors is the detection of the activity
level of a particular enzyme, which is more essential for diagnosis than the
presence of the enzyme. Numerous biosensors have been developed to sensitively
detect endogenous ions, such as Ca(II)12 and Zn(II)13. One of the key issues
is to identify the signal change from abnormal tissues, which can be achieved
by perturbing the system and amplifying signal via macromolecular interaction10. pH biosensors
have been used in detecting the abnormal pH in tumors for imaging metastases
and cancer staging14-17. To facilitate the
mapping of the pH in tumors, pH sensors generate more than one type of signals have
been studied to improve the accuracy of pH imaging in vivo15. In another
biomedical application, a decrease in pH could indicate low cell viability,
thus biosensors to probe local pH changes in cell therapy could help to track
cell status after transplantation18. The use of
various types of nanomaterials could optimize the in vivo performance of biosensors, for examples, using lipid or
polymeric nanocarriers to increase the concentration of biosensors at the
target site19-22, and retain the
biosensors at the site to facilitate the longitudinal assessments. Moreover,
there are emerging contrast mechanisms, such as chemical exchange saturation
transfer (CEST)23-27, to enhance the
sensitivity and specificity. It provides a label-free approach to image
metabolites, such as glucose and glutamate in neurophysiology28-34, however, the
detection of single metabolite is still challenging. These biosensors response
to various biomarkers that indicate pathological changes has demonstrated the
outstanding creativity in the field.Summary
The
development of biosensors has shown the merits of a multidisciplinary approach,
which includes molecular biology, biochemistry, chemistry, engineering and
radiology. The success of sensing biomarkers in vivo depends on the pharmacokinetics of MRI biosensors, percentage
of the dose arrived at target sites, signal attenuations from the
microenvironment, capability of amplifying the signal upon local physiochemical
changes, and retention of biosenosors at target sites. Many more exciting
biomedical applications are expected with the advanced biosensor designs,
including lipid and polymeric nanoparticles, and emerging molecular CEST contrast.
This provides innovations for new biosensors that address the unmet clinical
needs for future endeavors.Acknowledgements
References
1. Aime, S., Castelli, D.D., Crich, S.G., Gianolio, E. &
Terreno, E. Pushing the sensitivity envelope of lanthanide-based magnetic
resonance imaging (MRI) contrast agents for molecular imaging applications. Acc Chem Res 42, 822-831 (2009).
2. Terreno, E., Castelli, D.D., Viale, A.
& Aime, S. Challenges for molecular magnetic resonance imaging. Chem Rev 110, 3019-3042 (2010).
3. Boros, E., Gale, E.M. & Caravan, P.
MR imaging probes: design and applications. Dalton
Trans 44, 4804-4818 (2015).
4. Heffern, M.C., Matosziuk, L.M. &
Meade, T.J. Lanthanide probes for bioresponsive imaging. Chem Rev 114, 4496-4539
(2014).
5. Hingorani, D.V., Bernstein, A.S. &
Pagel, M.D. A review of responsive MRI contrast agents: 2005-2014. Contrast Media Mol Imaging 10, 245-265 (2015).
6. De Leon-Rodriguez, L.M., et al. Responsive MRI agents for
sensing metabolism in vivo. Acc Chem Res
42, 948-957 (2009).
7. Sinharay, S., Fernandez-Cuervo, G.,
Acfalle, J.P. & Pagel, M.D. Detection of Sulfatase Enzyme Activity with a
CatalyCEST MRI Contrast Agent. Chemistry
22, 6491-6495 (2016).
8. Sinharay, S., et al. Noninvasive detection of enzyme activity in tumor models
of human ovarian cancer using catalyCEST MRI. Magn Reson Med (2016).
9. Gounis, M.J., et al. MR imaging of myeloperoxidase activity in a model of the
inflamed aneurysm wall. AJNR Am J
Neuroradiol 36, 146-152 (2015).
10. Moon, S.H., et al. Development of a complementary PET/MR dual-modal imaging
probe for targeting prostate-specific membrane antigen (PSMA). Nanomedicine 12, 871-879 (2016).
11. Loving, G.S. & Caravan, P. Activation
and retention: a magnetic resonance probe for the detection of acute
thrombosis. Angew Chem Int Ed Engl 53, 1140-1143 (2014).
12. Hagberg, G.E., et al. Diffusion properties of conventional and calcium-sensitive
MRI contrast agents in the rat cerebral cortex. Contrast Media Mol Imaging 9,
71-82 (2014).
13. Clavijo Jordan, M.V., et al. Zinc-sensitive MRI contrast agent detects differential
release of Zn(II) ions from the healthy vs. malignant mouse prostate. Proc Natl Acad Sci U S A 113, E5464-5471 (2016).
14. Longo, D.L., et al. In Vivo Imaging of Tumor Metabolism and Acidosis by
Combining PET and MRI-CEST pH Imaging. Cancer
Res 76, 6463-6470 (2016).
15. Jones, K.M., et al. Clinical Translation of Tumor Acidosis Measurements with
AcidoCEST MRI. Mol Imaging Biol
(2016).
16. Wu, Y.,
et al. pH imaging of mouse kidneys in vivo using a frequency-dependent
paraCEST agent. Magn Reson Med 75, 2432-2441 (2016).
17. Wang, X., et al. A pH-Responsive MRI Agent that Can Be Activated Beyond the
Tissue Magnetization Transfer Window. Angew
Chem Int Ed Engl 54, 8662-8664
(2015).
18. Chan, K.W., et al. MRI-detectable pH nanosensors incorporated into hydrogels
for in vivo sensing of transplanted-cell viability. Nat Mater 12, 268-275
(2013).
19. Wu, Y., Evbuomwan, M., Melendez, M.,
Opina, A. & Sherry, A.D. Advantages of macromolecular to nanosized
chemical-exchange saturation transfer agents for MRI applications. Future Med Chem 2, 351-366 (2010).
20. Castelli, D.D., Terreno, E., Longo, D.
& Aime, S. Nanoparticle-based chemical exchange saturation transfer (CEST)
agents. NMR Biomed 26, 839-849 (2013).
21. Chan, K.W., Bulte, J.W. & McMahon,
M.T. Diamagnetic chemical exchange saturation transfer (diaCEST) liposomes:
physicochemical properties and imaging applications. Wiley Interdiscip Rev Nanomed Nanobiotechnol 6, 111-124 (2014).
22. Mao, X., Xu, J. & Cui, H. Functional
nanoparticles for magnetic resonance imaging. Wiley Interdiscip Rev Nanomed Nanobiotechnol 8, 814-841 (2016).
23. van Zijl, P.C. & Yadav, N.N. Chemical
exchange saturation transfer (CEST): what is in a name and what isn't? Magn Reson Med 65, 927-948 (2011).
24. Ward, K.M., Aletras, A.H. & Balaban,
R.S. A new class of contrast agents for MRI based on proton chemical exchange
dependent saturation transfer (CEST). J
Magn Reson 143, 79-87 (2000).
25. Ward, K.M. & Balaban, R.S.
Determination of pH using water protons and chemical exchange dependent
saturation transfer (CEST). Magn Reson
Med 44, 799-802 (2000).
26. Vinogradov, E., Sherry, A.D. &
Lenkinski, R.E. CEST: from basic principles to applications, challenges and
opportunities. J Magn Reson 229, 155-172 (2013).
27. Terreno, E., Castelli, D.D. & Aime, S.
Encoding the frequency dependence in MRI contrast media: the emerging class of
CEST agents. Contrast Media Mol Imaging
5, 78-98 (2010).
28. Akhenblit, P.J., et al. Assessing Metabolic Changes in Response to mTOR Inhibition
in a Mantle Cell Lymphoma Xenograft Model Using AcidoCEST MRI. Mol Imaging 15(2016).
29. Ren, J., Trokowski, R., Zhang, S., Malloy,
C.R. & Sherry, A.D. Imaging the tissue distribution of glucose in livers
using a PARACEST sensor. Magn Reson Med
60, 1047-1055 (2008).
30. Chan, K.W., et al. Natural D-glucose as a biodegradable MRI contrast agent
for detecting cancer. Magn Reson Med 68, 1764-1773 (2012).
31. Nasrallah, F.A., Pages, G., Kuchel, P.W.,
Golay, X. & Chuang, K.H. Imaging brain deoxyglucose uptake and metabolism
by glucoCEST MRI. J Cereb Blood Flow
Metab 33, 1270-1278 (2013).
32. Yadav, N.N., et al. Natural D-glucose as a biodegradable MRI relaxation agent.
Magn Reson Med 72, 823-828 (2014).
33. Walker-Samuel, S., et al. In vivo imaging of glucose uptake and metabolism in
tumors. Nat Med 19, 1067-1072 (2013).
34. Cai, K.,
et al. Magnetic resonance imaging of glutamate. Nat Med 18, 302-306
(2012).