| Project Detail |
All Disciplines (3)
Discipline
Organic Chemistry
Pharmacology, Pharmacy
Cardiovascular Research
Keywords (4)
MRI contrast agents, supramolecular chemistry, atherosclerosis, fullerene
Lay Summary (Italian)
Lead
Bright and intelligent MRI contrast agents
Lay summary
MRI-CAs, commonly used in the clinical field, are very useful for diagnosing diseases and monitoring organic functions. Currently approved MRI-CAs are gadolinium chelates (Gd3 +), which cause side effects in patients with kidney disease due to loss of gadolinium Gd3 +, toxic substance.
One possibility to overcome this limit is the encapsulation of gadolinium Gd3 + within fullerenes. This solution not only eliminates gadolinium Gd3 + loss, but also makes it possible to obtain MRI-CAs characterized by greater relaxation and hence magnetic resonance imaging with better contrast.
The goal of this project is to produce safer and more effective MRI-CAs. For this purpose new derivatives of Gd @ fullerenes will be synthesized, and an activated peptide linker will be used to detect atherosclerosis. Specific matrix metalloprotease peptide sequences (MMP2), overpressured in vulnerable atheromas, will be used to activate the contrast agent.
The synthesized MRI-CAs will be characterized by NMR in collaboration with Prof. Helm at EPFL and in vitro tested using macrophage cell cultures. They will also be investigated for their in vivo distribution and toxicity. Finally, imaging tests on sick mice will be conducted in collaboration with the Molecular Imaging Group of the University of Pennsylvania in the USA.
Direct link to Lay Summary Last update: 04.07.2017
Responsible applicant and co-applicants
Name Institute
Yamakoshi Yoko Laboratory of Organic Chemistry ETH Zurich
Employees
Name Institute
Liosi Korinne
Zirpoli Gabriele
Project partner
Natural persons
Name Institute
Zhou Rong Department of Radiology University of Pennsylvania Medical Center
Helmet Lothar Laboratory of inorganic and bioinorganic chemistry EPFL - SB - ISIC - LCIB
Miyajima Atsuko Cellular and Molecular Toxicology Div. National Institute of Health Sciences
Associated projects
Number Title Start Funding scheme
156097 Synthesis and Study of Photoexcited Fullerenes 01.10.2014 Project support (Dept. I-III)
Abstract
Magnetic resonance imaging contrast agents (MRI-CAs) are very useful for the diagnosis of diseases and monitoring organ functions, and are used routinely in the clinic. Currently approved MRI-CAs are gadolinium-based chelates (Gd3+-chelates), which show serious side effects to the patients with kidney problems due to the trace amount of free Gd3+ leakage from the chelates. Recently Gd@fullerene has been considered as a core for new types of MRI-CAs. Advantages of the use of the Gd@fullerene are no leakage of free Gd3+ due to entrapment inside the fullerene cage, and higher relaxivity compared to the commonly used Gd3+-chelates, providing higher enhancement in the MR images. Barriers to using fullerenes for biological systems include their low water-solubility due to their hydrophobic surface. To solve this problem, many researchers have developed solubilization methods for fullerenes by preparing complexes or derivatives in combination with water-soluble moieties. In this proposal, taking advantages of Gd@fullerene as a MRI-CA core, we aim to design and synthesize a new type of Gd@fullerene-based MRI-CA for selective detection of vulnerable atherosclerosis. We will use peptide sequences specific to the matrix metalloproteinase 2 (MMP2), which is overexpressed in vulnerable types of atheroma, to switch on the MRI contrast. Two types of MMP2-sensitive molecules will be synthesized from Gd3N@C80, a Gd@fullerene, and evaluated by both in vitro enzyme tests in combination with NMR relaxivity measurements, in vitro and in vivo toxicity tests, and in vivo animal tests using model animals. The specific aims of this proposal are described below: Aim 1: To synthesize Gd3N@C80-based supramolecular MRI probes: Two types of Gd3N@C80 supramolecular systems, host-guest-based Gd3N@C80-peptide-cavitand (probe I) and micelle-type with Gd3N@C80–peptide-PEG (probe II) will be synthesized as MMP2-sensitive contrast agents. We expect that in the presence of MMP2, the peptide will be selectively recognized and cleaved to expose Gd3N@C80 to the water molecules, resulting in a higher contrast in the MRI and enabling the selective diagnosis of vulnerable atherosclerosis plaques. Aim 2: Physico-chemical characterization of MRI-CAs and in vitro biological tests: The contrast agents prepared in Aim 1 will be tested in vitro with MMP2. After the selective cleavage is observed, relaxivity change of the probe will be evaluated in detail using NMR facilities in Prof. Helm’s lab (EPFL), a highly known researcher of MRI-CA. Based on these results, we will optimize the initial molecular design. Aim 3: Toxicity test of MRI-CA in vitro and in vivo: The contrast agents prepared in Aim 1 will be subjected to the various in vitro and in vivo toxicity test using in vitro cell culture system and in vivo animal system in collaboration with Dr. Miyajima in Japanese NIH, a world leading center for safety/toxicity of medicines and chemicals. Aim 4: In vivo MR imaging with model mice: In vivo MRI will be carried out in collaboration with Prof. Zhou (University of Pennsylvania), an internationally well-recognized specialist of in vivo MRI with model atherosclerosis mice. The experiments will be carried out in the Small Animal Imaging Facility (SAIF) at the Department of Radiology in the UPenn using knock-out mice with subsequent detailed anatomical analyses. |
