Chongzhao Ran, Ph.D.
Assistant Professor of Radiology
Harvard Medical School
Athinoula A. Martinos Center for Biomedical Imaging, Mass General Research Institute
Radiology, Massachusetts General Hospital
|PhD Shanghai Institute of Pharmaceutical Industry 2000|
Development of new generations of Amyloid imaging probe
In the past few years, my research has been concentrated on a trilogy of developing “smart” NIRF imaging probes for various amyloid beta (Aβ) species. For this trilogy, in episode (I) we have effectively developed NIRF probes for insoluble Aβs.
In this episode, we have invented a brand-new family of NIR fluorescent dyes CRANAD-X, and some of them are “smart” probes for the insoluble Aβs. In recent years, mounting evidence has driven the evolution of the Aβ hypothesis towards the most toxic soluble Aβs. Although several PET imaging probes for insoluble Aβs have been approved by FDA, and a couple of NIR probes for insoluble Aβs have been reported as well, to the best of my knowledge, none of the imaging probes have the potential to reflect the full spectrum of amyloidosis of AD, which spans from over-accumulated soluble Aβs to predominated insoluble Aβs.
In our episode (II), we have successfully developed NIR probes for both soluble and insoluble Aβ species, and we believe these probes may have the potential to monitoring the full course of the amyloidosis.
The initial stage of amyloidosis pathology is represented by excessive accumulation of Aβ monomers and other soluble species, and this early predominance gradually shifts to the majority of insoluble species with the progression of AD. It is clear that, for early molecular pathology detection, selective imaging probes for soluble Aβs are highly desirable. In our episode (III), we concentrate our efforts on developing imaging probes for soluble Aβs, thus to accomplish early detecting of AD pathology. Our preliminary data indicates that such probes are achievable.
Development of Two-Photon Imaging Probe
In the last two years, my team has been actively developing multifunctional two-photon imaging probes for Ab plaques and CAAs (cerebral amyloid angiopathy). We demonstrated that CRANAD-28, a highly bright bifunctional curcumin analogue, could be used for two-photon imaging of Aβ plaques and CAAs in vivo as well as for inhibiting crosslinking of Aβs.
Compared to other most used two-photon imaging agents for Aβ plaques, this probe has a longer emission wavelength that enables deeper imaging with a thinned skull. The relative quantum yield of CRANAD-28 was near 100% in ethanol (using Rhodamine B as a reference). In addition, using two-photon imaging, we also showed that PiB-C, a conjugate of Pittsburgh compound B (PiB) and 12-crown-4 ether, could readily penetrate the BBB and efficiently label Ab plaques and CAAs in an APP-PS1 transgenic mouse.
New Strategy for AD Drug Development.
In past decades, several categories of Ab-reducing agents have been developed, and some of them had advanced into clinical trials. Unfortunately, all of these clinical trials, by and large, failed to demonstrate their efficacy and safety. All these failures clearly imply that innovative strategies for developing drugs for AD are urgently needed. We reasoned that crown ethers could be used to “neutralize” positive charges of the amino groups of Abs through the formation of hydrogen bonds. We proposed a novel strategy to attenuate the aggregation of Abs through a non-covalent modification at its surface. Our preliminary results demonstrated that 12-crown-4 and its conjugate PiB-C (PiB is the well known PET ligand for Abs) could effectively reduce the aggregation of Ab40, and could rescue the neurotoxicity of Ab42 in cell studies
Developing imaging probes and methods for diabetes and obesity
In the past years, one of my research directions has been focused on the development of probes and technologies for Imaging of Metabolically Abnormal Degeneration (MAD) diseases, which include diabetes and obesity. Based on the structure of streptozotocin (STZ), a beta cell specific small molecule, we have developed two beta-cell specific NIRF probes. More recently, my research has been focused on imaging Brown Adipose Tissue (BAT), which is a re-emerged target for MAD diseases such as diabetes and obesity.
However, highly selective imaging probe for BAT mass is still lack. For this project, my primary contributions include: 1) My research group discovered several NIRF probes suitable for imaging BAT mass through a top-down screening method (Manuscript under revision). 2) My group also demonstrated that Cerenkov Luminescence Imaging (CLI), a newly developed technology, could be used to image BAT with 18F-FDG. Compared to PET imaging, CLI is a much cheaper and faster alternative imaging method for brown adipose tissue.
Development of new optical imaging technology
In addition to the contributions described above, my team has also been worked on Cerenkov Luminescence Imaging, which is a newly emerged imaging technology. In our studies, we demonstrated that Cerenkov Luminescence from 18F-FDG could be used as a UV light source to photoactivate caged compounds.
The obvious advantage of this technique over traditional external UV irradiation is that Cerenkov luminescence is an “internal” UV light source and it has no limitation of photoactivation for deep tissues. In addition, we also demonstrated that Cerenkov Luminescence imaging could be a cheaper alternative imaging method for brown adipose tissue, which is a re-emerged target for obesity and diabetes research.