Group Metal complexes and MRI Archives | Page 5 of 7 | Centre de Biophysique Moléculaire, CNRS

In Cellulo and In Vivo Comparison of 3 helper lipids for Lipid Nanoparticle Formulation of mRNA

LNPs are a leading class of mRNA delivery systems. LNPs are made of an ionizable lipid, a polyethyleneglycol (PEG)-lipid conjugate and helper lipids. The success of LNPs is due to proprietary ionizable lipids and appropriate helper lipids.

Using a benchmark lipid (D-Lin-MC3) researchers compared the ability of three helper lipids to transfect dendritic cells in cellulo and in vivo. Studies revealed that the choice of helper lipid does not influence the transfection efficiency of immortalized cells but, LNPs prepared with DOPE (dioleylphosphatidylethanolamine) and β-sitosterol were more efficient for mRNA transfection in murine dendritic cells than LNPs containing DSPC (distearoylphosphatidylcholine).

This higher potency of DOPE and β-sitosterol LNPs for mRNA expression was also evident in vivo but only at low mRNA doses.

References of the article published in Nanomaterials:
Ayoub Medjmedj, Albert Ngalle-Loth, Rudy Clemnçon, Josef Hamacek, Chantal Pichon and Federico Perche
In Cellulo and In Vivo Comparison of Cholesterol, Beta-Sitosterol and Dioleylphosphatidylethanolamine for Lipid Nanoparticle Formulation of mRNA
Nanomaterials 2022, 12(14), 2446; https://doi.org/10.3390/nano12142446

Mariano Gago prize awarded to the collaboration between the group of Eva Jakab Toth and the University of Coimbra, Portugal

2022 is the year of the France-Portugal cooperation, organized by the French and Portuguese Ministries for Europe, Foreign Affairs and Culture.

This “France-Portugal 2022” season is an opportunity to highlight many events marking the cooperation between the two countries, including several in the field of Higher Education and Research.

In this context, the Ministry of Higher Education, Research and Innovation and the Academy of Sciences are pleased to propose a scientific prize which distinguishes existing cooperation between French and Portuguese teams, and to offer them an opportunity to deepen the cooperation in the years to come. The four prizes awarded in 2022 cover all scientific disciplines.

In this frame, the collaboration carried out for many years by Eva Jakab Toth with the University of Coimbra has been rewarded with the Mariano Gago Prize. This collaboration concerns the development of imaging agents based on metalloporphyrins for the detection of tissue redox states.

The official award ceremony helded at the Academy of Sciences on Tuesday, June 21, 2022.

The first molecules which really prefer manganese(II) over zinc(II)

Manganese(II) complexes meet increasing interest in biomedical applications, in particular as potential Magnetic Resonance Imaging contrast agents with a better biocompatibility and safety profile than the currently used gadolinium(III) chelates. However, we severely lack chelating ligands that enable high Mn^II complex stability and especially good selectivity for manganese(II) versus zinc(II), the most relevant biological competitor. In an article published in Angewandte Chemie Int. Ed., the “Metal complexes and MRI” group in collaboration with the group of Peter Comba at the University of Heidelberg, has identified novel cage molecules which, for the first time, satisfy these criteria. The bispidine derivative ligands provide rigid and large coordination cavities that perfectly match the slightly larger size of Mn^II, yielding eight-coordinate Mn^II complexes with record stabilities. In contrast, the smaller Zn^II ion cannot accommodate all ligand donors, resulting in highly strained and less stable six-coordinate complexes.

Combined theoretical and experimental data demonstrate unprecedented selectivity, with up to 10 orders of magnitude higher stability for the manganese(II) than for the zinc(II) analogues, in sharp contrast to usual coordination chemistry rules.

https://onlinelibrary.wiley.com/doi/full/10.1002/anie.202115580

Eva Jakab Toth, director of the CBM, received the 2020 Joseph-Achille Le Bel Grand Prix from the Société Chimique de France

A new luminescence for the direct follow-up of drug delivery

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

Angewandte Chemie Int. Ed. 13 août 2021 https://doi.org/10.1002/anie.202109408

See the news on CNRS Chemistry Institute site

Towards new imaging markers for in vivo detection of pathologies such as Alzheimer’s or diabetes

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.

Detection of amyloid peptides: biomarkers for Alzheimer’s Disease and Diabetes

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.

See the article