Centro Interdipartimentale di Biotecnologie Molecolari "Guido Tarone"
Enzo Terreno PI
Full Professor of General and Inorganic Chemistry at the Department of Molecular Biotechnology and Health Sciences of the University of Torino
Francesca Garello – Research Fellow
Gianluca Destro – Research Fellow
Martina Capozza – Research Technician
Carla Carrera - Research Technician
Diana Costanzo – PhD student
Rebecca Rizzo – PhD student
Miriam Roberto – PhD student
Alberto Mangia - PhD student
Research activity
The group is strongly committed to the design, in vitro chemical/biological characterization, and in vivo preclinical validation of imaging probes for various in vivo imaging technologies, primarily MRI, Optical, Nuclear Imaging, CT, and multimodal hybrid technologies. These probes are intended for both diagnostic and theranostic applications within the broad field of Molecular Imaging.
In addition to working with small molecules, the team has developed expertise in the preparation of various types of nanoparticles, including phospholipid- and polymer-based micelles, liposomes, nanoemulsions, and inorganic nanoparticles.
As the design of a Molecular Imaging probe typically involves the conjugation of an imaging reporter (dependent on the imaging technology of interest) with a targeting vector, the group has acquired extensive experience in synthesizing different types of vectors. These vectors encompass organic moieties, peptides, proteins, antibodies, and their derivatives.
The main areas of expertise, categorized according to the specific imaging technology, are as follows:
MRI: the team possesses extensive experience in the development and testing of MRI probes. Over the years, we have synthesized and thoroughly characterized various significant metallic probes based on iron oxide, gadolinium, and other lanthanides. These probes have been utilized in T1 or T2 weighted MRI, Dynamic Contrast-Enhanced (DCE) MRI, and Chemical Exchange Saturation Transfer (CEST) applications, both in vitro, within cancer cells, and in vivo using preclinical models. Some of these probes have also been incorporated into nano- or micro-systems to enhance contrast, create multimodal systems (for instance, by decorating particles with fluorescent moieties), and achieve selective delivery through the attachment of targeting vectors, such as peptides or antibodies. This approach allows us to precisely and early detect pathological conditions and monitor disease progression. More recently, we have explored the development of theranostic MRI probes. Theranostic probes have the potential to enable both diagnosis and therapy simultaneously. An example of a theranostic protocol developed by our group involves the use of ultrasound to locally stimulate the release of both the chemotherapeutic drug doxorubicin and an MRI contrast agent from liposomes, in a more specific and efficient manner than the commonly used therapeutic protocols (see Figure 1). Furthermore, our group has also directed its focus towards more biocompatible (non-metallic) probes. This includes the synthesis of highly efficient 19F-based compounds, the development and testing of 19F-loaded nanosystems, which are ideal for imaging inflammatory pathologies, and the use of Chemical Shift Imaging Protocols, which enable the visualization of nanosystems containing highly protonated components without the need for additional metallic contrast agents.
Optical imaging: the team has experience creating targeted fluorescent probes with NIR emission and testing them in cell lines and in tumour bearing mice. These molecules can be used in fluorescence-guided surgery (FGS), which is an excellent option to allow a high spatial resolution discrimination between tumour and healthy tissues. In this area, we also possess expertise in dual-imaging agents and theragnostic, here, we produce new fluorescent probes for Guided Surgery and PhotoDynamic Therapy. The imaging probe is composed by: i) a targeting vector to cancer cells, and ii) a dye that can be detected by NIRF imaging and produce ROS for photodynamic therapy.
Figure 3. In vivo CT imaging after i.v. administration of 5 mmol/kg of Bi-HPDO3A (ref 10).
Nuclear Imaging: In this context, the group is taking its first steps. The main research lines are related to the development of new chemical reactions with potential translatability to radiolabelling with different radionuclides. On the other hand, the design of new chemical probes bearing fluorine-18 and iodine-123 and radiometals to study their behaviour towards cancer is ongoing.
CT: Whereas CT imaging of hard tissues such as bones and cartilages are very sensitive to X-rays, imaging of soft structures (fatty tissues or neoplastic formations) required contrast agents to improve the image performance. Bismuth-based small complex has been recently synthetized and tested in healthy mice showing excellent renal enhancement.
Our future research is dedicated to advancing diagnostic and theranostic tools and exploring novel avenues in various domains. In more detail, our objectives encompass broadening the application of ultrasound technology to trigger the release of nanosystem content, such as drugs, and facilitating cell sonoporation for drug activation in diverse cancer models. Additionally, we are committed to researching and developing environmentally friendly (non-metallic) probes for Magnetic Resonance Imaging (MRI). In this context, we will be investigating the synthesis and application of innovative 19F-based probes, with a particular focus on exploring the 19F Chemical Exchange Saturation Transfer (CEST) properties. We will also continue to refine and optimize new protocols for Chemical Shift Imaging (CSI) of various types of nanosystems without the need for contrast agents.
In the realm of nuclear medicine, we aim to expand our scope of work. We intend to implement our novel radiolabeling strategies for creating new vectors and deepen our understanding of theranostics.
For our optical imaging initiatives, we have plans to enhance our library of compounds, with a focus on targeting a broader range of tumour types. Furthermore, we will employ ultrasound-guided techniques to facilitate the release of photosensitizers, thus enhancing the uptake and efficacy of photodynamic agents.
By pursuing these multifaceted research objectives, we aspire to contribute to the advancement of diagnostic and therapeutic approaches across various medical disciplines.
FOE MUR: ERIC Eurobioimaging - Coordination of the Multi Modal Molecular Imaging Italian Node
COST Action CA15209 (”European Network on NMR Relaxometry”)
AIRC IG 2018 - n. 22041 “Boosting the efficacy of liposomal doxorubicin against ovarian cancer by local ultrasound stimulation under MRI guidance”
PRIN 2018: “Rationally designed nanogels embedding paramagnetic ions as MRI probes”
PNRR-4.2-3.1: Project “SEE LIFE - StrEngthEning the ItaLIan InFrastructure of Euro-bioimaging”
PNC-E3: Project “INNOVA - Italian network of excellence for advanced diagnosis”
PRIN 2022: Project “Design of paramagnetic metal complexes for improved MRI-guided drug-release applications”
Terreno E, Uggeri F, Aime S. Image guided therapy: the advent of theranostic agents. J Control Release. 2012 Jul 20;161(2):328-37. doi: 10.1016/j.jconrel.2012.05.028.
Filippi M, Martinelli J, Mulas G, Ferraretto M, Teirlinck E, Botta M, Tei L, Terreno E. Dendrimersomes: a new vesicular nano-platform for MR-molecular imaging applications. Chem Commun (Camb). 2014 Apr 4;50(26):3453-6. doi: 10.1039/c3cc49584a. Epub 2014 Feb 19. PMID: 24553970.
Pagoto A, Stefania R, Garello F, Arena F, Digilio G, Aime S, Terreno E. Paramagnetic Phospholipid-Based Micelles Targeting VCAM-1 Receptors for MRI Visualization of Inflammation. Bioconjug Chem. 2016 Aug 17;27(8):1921-30. doi: 10.1021/acs.bioconjchem.6b00308. Link Scopus
Rizzitelli S, Giustetto P, Faletto D, Delli Castelli D, Aime S, Terreno E. The release of Doxorubicin from liposomes monitored by MRI and triggered by a combination of US stimuli led to a complete tumor regression in a breast cancer mouse model. J Control Release. 2016 May 28;230:57-63. doi: 10.1016/j.jconrel.2016.03.040.
Capozza M, Blasi F, Valbusa G, Oliva P, Cabella C, Buonsanti F, Cordaro A, Pizzuto L, Maiocchi A, Poggi L. Photoacoustic imaging of integrin-overexpressing tumors using a novel ICG-based contrast agent in mice. Photoacoustics 11, 36-45 (2018). https://doi.org/10.1016/j.pacs.2018.07.007
Filippi M, Garello F, Pasquino C, Arena F, Giustetto P, Antico F, Terreno E. Indocyanine green labeling for optical and photoacoustic imaging of mesenchymal stem cells after in vivo transplantation. J Biophotonics. 2019 May;12(5):e201800035. doi: 10.1002/jbio.201800035.
Garello F, Boido M, Miglietti M, Bitonto V, Zenzola M, Filippi M, Arena F, Consolino L, Ghibaudi M, Terreno E. Imaging of Inflammation in Spinal Cord Injury: Novel Insights on the Usage of PFC-Based Contrast Agents. Biomedicines. 2021 Apr 3;9(4):379. doi: 10.3390/biomedicines9040379.
Capozza M, Stefania R, Dinatale V, Bitonto V, Conti L, Grange C, Skovronova R, Terreno E. A Novel PSMA-Targeted Probe for NIRF-Guided Surgery and Photodynamic Therapy: Synthesis and Preclinical Validation. Int J Mol Sci 23 (2022). https://doi.org/10.3390/ijms232112878
Capozza M, Anemone A, Dhakan C, Della Peruta M, Bracesco M, Zullino S, Villano D, Terreno E, Longo D, Aime S.. GlucoCEST MRI for the Evaluation Response to Chemotherapeutic and Metabolic Treatments in a Murine Triple-Negative Breast Cancer: A Comparison with[(18)F]F-FDG-PET. Mol Imaging Biol 24, 126-134 (2022). https://doi.org/10.1007/s11307-021-01637-6
Rizzo, R., Capozza, M., Carrera, C. & Terreno, E. Bi-HPDO3A as a novel contrast agent for X-ray computed tomography. Sci Rep 13, 16747 (2023). https://doi.org/10.1038/s41598-023-43031-y
