Responsabile Scientifico

• TEI Lorenzo (DiSIT)

Titolo del progetto

• Design of paramagnetic metal complexes for improved MRI-guided drug-release applications

Ente finanziatore

• 
  MUR - Ministero dell'Università e Ricerca

Programma di finanziamento

• PRIN - Progetti di Ricerca di Rilevante Interesse Nazionale (dal 2020)

Bando di riferimento

• PRIN 2022

Anno di presentazione del progetto

• 2022

Anno di approvazione del progetto

• 2023

Project ID / numero contratto

• 20224B4285

Durata del progetto

• 24 mesi

Inizio del progetto

• 16/10/2023

Fine del progetto

• 28/02/2026

Progetto approvato - Contributo unità di ricerca del Dipartimento

• €101.874,00

Sustainable Development Goals - Agenda 2030

Keyword

• liposomes
• Coordination Chemistry
• Bioinorganic Chemistry
• Paramagnetic metal complexes
• MRI contrast agents
• Drug delivery nanocarriers

Stato del progetto

• Approvato

Abstract

• This project aims at developing new highly clinically translatable paramagnetic metal complexes for improving MRI-guided theranostic procedures for the in vivo visualization of drug release processes from smart nanocarriers. Smart therapeutic nanocarriers, where the release of the drug is locally triggered by endogenous (chemical) or externally applied (physical) stimuli, represent one of the new frontiers of chemotherapy. Imaging technologies may offer a very valuable support to monitor in vivo, and with a limited invasiveness, the effective release of the drug from the nanocarrier, thus allowing to predict the therapeutic response, on a personalized basis, without waiting for the onset of the therapeutic outcome. Liposomes are by far the most important class of nanocarriers, and several liposomal formulations are already successfully used in clinical practice. Interestingly, the co-encapsulation of a paramagnetic metal complex in the aqueous core of liposomes allows the development of MRI-guided procedures where the stimulated release of the drug is accompanied by the detection of a contrast in the lesion. The contrast mechanism is based on the removal of the “contrast quenching” that occurs when the agent is released (along with the drug) from the nanocarrier. Of course, the detection sensitivity of the overall procedure, and consequently its theranostic performance, is strongly affected by the difference in the contrast efficacy of the agent between the “encapsulated” and the “released” states. Thus, the most straightforward way to enhance this difference is the design of neutral paramagnetic metal complexes with high encapsulation efficiency and high relaxivity when they are released from the nanocarrier. Different strategies will be adopted to reach this objective: i) the use of a neutral monometallic agent with very high relaxivity, ii) the use of neutral oligometallic complexes, and iii) complexes designed to bind proteins present in the nanocarrier microenvironment. In addition to ligands for Gd(III) ion, also ligands for Mn(II) will be considered. The synthesized agents will be characterized in terms of their relaxometric properties, ability to be encapsulated in liposomes, and biocompatibility towards selected cell lines (tumor and immune cells). Finally, the lead compounds will be tested in vivo with a MRI-guided theranostic protocol on a mouse model of breast cancer, and the performance compared with liposomes loaded with the standard MRI agent gadoteridol.