Multimeric and Nanoscale Bioresponsive Probes for Functional MRI

• Applicant: Privatdozent Dr. Goran Angelovski
• Subject Area: Pharmacy ; Biological and Biomimetic Chemistry
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 365513518

• Final Report Year: 2020

Final Report Abstract

The goal of the project was the preparation and characterization of nanosized, target-specific and bioresponsive multifunctional contrast agents that can be used for functional MRI. These probes are capable of reporting on changes in the concentration levels of ions and molecules involved in the neuronal signalling, such as Ca2+ and neurotransmitters (NTs). With their use, the perturbations in the local concentrations of these targets that come as the result of neuronal activity can be translated into the MR signal. Ultimately, this methodology also known as molecular fMRI can help investigating numerous biological processes on molecular and cellular level. The project was divided in three sections. The initial task was the preparation of various bifunctional monomacrocycles, which can respond to Ca2+ or NTs; afterwards, two types of nanosized probes based on liposomes or cyclodextrins should be prepared from these bifunctional molecules. We have successfully developed several procedures for preparation of different types of Ca-, Znor NT-sensitive contrast agents. Having wide number of the bioresponsive probes allowed us detailed investigation of major principles that lead to relaxivity changes, which can potentially lead to development of even more active responsive probes. New synthetic procedures resulted in preparation of different nanosized probes: importantly, they now open a path for the development of diverse types of imaging probes with different nanocarriers. Finally, the properties of several newly developed probes were investigated in vivo by means of MRI. The most important result was application and quantification of the perfluorinated lipid nanoparticle in the rat somatosensory cortex. Namely, we used the quantitative signal of the fluorine to assess its amount in the tissue, which allowed us determination of the Gd3+ content and generation of concentration maps. In summary, this project focused on development of the multimeric and nanoscale bioresponsive probes for functional MRI was concluded very successfully. A few preparation methods and several new probes were developed and thoroughly investigated. Selected examples were characterized in living tissue and used for determination of the probe concentration in vivo. These insights will be very important for the future development of potent bioresponsive probes and their application in the functional molecular imaging studies.

Publications

• “Synergy of Key Properties Promotes Dendrimer Conjugates as Prospective Ratiometric Bioresponsive MRI Probes”. Biomacromolecules 2018, 19, 4668-4676
  L. Connah, G. Angelovski
  
• “A low-molecular weight ditopic MRI probe for ratiometric sensing of zwitterionic amino acid neurotransmitters”. Chem. Commun. 2019, 55, 11924-11927
  Đ. Toljić, G. Angelovski
  
• “In-depth study of a novel class of ditopic gadolinium(III)-based MRI probes sensitive to zwitterionic neurotransmitters”. Front. Chem. 2019, 7, 490
  Đ. Toljić, C. Platas-Iglesias, G. Angelovski
  
• “Investigations into the Effects of Linker Length Elongation on the Behaviour of Calcium-responsive MRI Probes”. Dalton Trans. 2019, 48, 13546-13554
  L. Connah, V. Truffault, C. Platas-Iglesias, G. Angelovski
  
• “Solid-Phase-Supported Approach for the Preparation of Bioresponsive and Multifunctional MRI Probes”. Org. Lett. 2019, 21, 5378-5382
  L. Connah, R. Joshi, S. Vibhute, G. Gambino, J. D. G. Correia, G. Angelovski
  
• “Towards MRI and Optical Detection of Zwitterionic Neurotransmitters: Near- Infrared Luminescent and Magnetic Properties of Macrocyclic Lanthanide(III) Complexes Appended with a Crown Ether and a Benzophenone Chromophore”. Inorg. Chem. 2019, 58, 13619-13630
  F. Oukhatar, S. Eliseeva, C. Bonnet, M. Placidi, N. K. Logothetis, S. Petoud, G. Angelovski, E. Toth
  
• “Translating a low-molecular-weight MRI probe sensitive to amino acid neurotransmitters into a PAMAM dendrimer conjugate: The impact of conjugation”. ChemNanoMat 2019, 5, 1456-1460
  Đ. Toljić, G. Angelovski
  
• “Combination of Bioresponsive Chelates and Perfluorinated Lipid Nanoparticles Enables in vivo MRI Probe Quantification”. Chem. Commun. 2020, 56, 9433-9436
  G. Gambino, T. Gambino, G. Angelovski
  
• “Europium(III) Macrocyclic Chelates Appended with Tyrosine-based Chromophores and Di-(2-picolyl)amine-based Receptors: Turn-On Luminescent Chemosensors Selective to Zinc(II) Ions” ChemPlusChem 2020, 85, 806-814
  G. Wang, C. Platas-Iglesias, G Angelovski
  
• “Ratiometric F MR-based Method for Quantification of Ca 2+ Using Responsive Paramagnetic Probes”. Chem. Commun. 2020, 56, 3492-3495
  G. Gambino, T. Gambino, R. Pohmann, G. Angelovski