Liposomes are nanocapsules widely used for the in vivo transport and delivery of therapeutic or diagnostic agents, or both. The therapeutic agent will only become active upon its release, thus sparing healthy tissues. The follow up of such release process is crucial to understand and control the drug action.
The previously reported approaches are based on optical imaging, using exclusively organic fluorophores or inorganic nanoparticles, co-encapsulated with the drug in the liposome.
The use of luminescent lanthanide complexes is an alternative which offers a number of advantages, including the capacity of those complexes to emit in the near infrared (NIR) region, enabling their detection in biological media.
The CBM research teams have developed an original nanocapsule : a liposome comprising an Ytterbium complex encapsulated with doxorubicin (anticancer agent). The NIR emission of the lanthanide complex is only observed when the drug is encapsulated. This NIR luminescence signal can therefore enable the direct follow-up, and in real time, of the integrity of the liposome, and can thus be used to detect the drug release.
An in vivo proof of concept was performed and the lanthanide luminescent signal could be detected in a mouse model of breast cancer.
Références de l'article :
Doxorubicin-sensitized Luminescence of NIR-emitting Ytterbium Liposomes: Towards Direct Monitoring of Drug Release,
Sara Lacerda, Anthony Delalande, Svetlana V. Eliseeva, Agnès Pallier, Célia S. Bonnet, Frédéric Szeremeta, Sandra Même, Chantal Pichon, Stéphane Petoud, Eva Toth
The accumulation of aggregates of certain non-soluble peptides in tissues is characteristic of several pathologies, such as Alzheimer's and Parkinson's diseases, or diabetes. The detection of these amyloid deposits by in vivo imaging would be very useful for an early diagnostic and a better understanding of the molecular mechanisms of these diseases. Researchers from the Molecular Biophysics Center (CBM) and the Toulouse Coordination Chemistry Laboratory (LCC), in collaboration with Portuguese and Hungarian scientists, have taken an important step forward in the design of imaging agents that specifically recognize these amyloid deposits. This work is on the cover of Chemistry A European Journal.
Metal chelates targeted to amyloid peptides are widely explored as diagnostic tools or therapeutic agents for amyloidogenic diseases. For example, gadolinium complexes can be used as MRI probes, while radiocomplexes (64Cu, 99mTc, etc) can be exploited for nuclear imaging. Other metal complexes capable of preventing aggregate formation are proposed to derive therapeutic strategies.
All these molecules are amphiphilic, composed of a hydrophilic part (containing the metal) and a hydrophobic one (capable of targeting the amyloid aggregates). This particular structure enables the formation of micelles in solution.
The groups of CBM and LCC (Toulouse) have found that this micellisation property has drastic and unexpected consequences on their ability to recognize amyloid peptides and a high impact on their in vivo biodistribution.
The researchers have developed a novel probe with nanomolar affinity towards Aβ and amylin, biomarkers of Alzheimer’s Disease and Ddiabetes, respectively.
This exceptional affinity for a metal complex is only obtained if the complex is present as “single molecule”. Once in the micellar form, this affinity drops by 1000-fold.
These results have a direct consequence for the design of novel imaging and therapeutic probes for amyloidogenic pathologies.
The Board of Directors of the Société Chimique de France awarded the Achille Le Bel 2020 Grand Prize to Eva Jakab Toth, Director of the Center for Molecular Biophysics, for her remarkable role in the development and use of coordination complexes for medical imaging and radio diagnosis.
Gadolinium (Gd3+) complexes have been used as MRI contrast agents for 35 years, but recently the safety of some was questioned. The replacement of Gd3+ by manganese (Mn2+), a biogenic metal, would enable safer complexes.
Nevertheless, the Mn2+ has to be chelated by complexes exhibiting high thermodynamic stability and kinetic inertness (to guarantee that the Mn is not released in vivo) and with a water molecule directly coordinated to the metal, essential for a good MRI efficiency. Combining these two properties is a chemistry challenge.
The “Metal complexes and MRI” team of CBM and their collaborators from IPHC (Strasbourg) have synthesized and studied a bispidine ligand, a molecule which cavity is well adapted for Mn2+ complexation. This Mn2+ complex has an excellent kinetic inertness and its MRI efficiency was validated by preclinical studies.
52Mn is an emergent radionuclide for positron emission tomography (PET). Mn2+ is the only metal enabling both MRI and PET imaging. The use of 52Mn is nevertheless limited by its low availability and lack of appropriate ligand.
For the first time in France, 52Mn was produced at the Orléans’ cyclotron, and 52Mn-bispidine was successfully obtained.
Overall, bispidine is a very promising ligand for the Mn2+ complexation, for MRI and PET. Due to its outstanding kinetic inertness, in vivo use of Mn2+ without toxicity risk can be anticipated.
On January 17, 2020, rich exchanges took place between the thematic group "Metal Complexes and MRI" and students of the first and final European class of the Lycée Pothier in Orleans as part ofDECLICS "Dialogues Entre Chercheurs et Lycéens pour les Intéresser à la Construction des Savoirs" .
