Improvement of pyclen-based manganese complexes relaxivity by using polymer vesicles (polymersomes)
Résumé
Introduction
Magnetic resonance imaging (MRI) is a powerful technique due to its high resolution. Its low
sensitivity can be relieved by a contrast agent, but the commercial contrast agents are
gadolinium complexes which can lead to NSF disease. That is why the synthesis of complexes
based on another cation, like manganese , is interesting because they are potentially less toxic.
To increase their efficacy, their incorporation into a polymersome is envisaged to increase the
rotational correlation time τR . A fluorescent probe will also be incorporated to obtain a bimodal
system active in optical imaging.
Methods
The pyclen macrocycle is obtained by a macrocyclization between an upper part and a lower
part appropriately functionalized to allow selective deprotection steps, as well as the presence of
a limited number of coordinating atoms. An arm present on the pyridine moiety allows the
functionalization of the molecule. The final product is obtained by some deprotection reactions
followed by a coupling reaction on the arm and finally the deprotection of -tBu groups to
complex the ligand with manganese ions. The polymer vesicles also called polymersomes,
composed of a pH sensible diblock PEO-b-PCL, are obtained by the nanoprecipitation route in
the presence in the aqueous phase of ZW800-1, an indocyanine green derivative. They
are then purified by size exclusion chromatography.
Results/Discussion
Each intermediate were completely characterized by NMR and mass spectrometry to attest their
structure. The obtained pyclen based manganese complexes were then fully characterized by
relaxometry to evidence their efficacy. The presence of one fast exchanging water molecule in
the inner coordination sphere of the metal cation was evidenced by O NMR. Their NMRD
profiles were then recorded and fitted with the Solomon and Bloembergen model. This has
allowed to show a slight increase of the relaxivity when the arm is present on the pyridine moiety
due to a slight increase of τR . Polymersomes were prepared in different conditions by varying
the hydrophobic block length of the copolymer. They were then characterized by DLS and MALS
in order to obtain both their hydrodynamic and gyration radii and demonstrate their structure.
The rate of encapsulation of the fluorescent probe was also determined by fluorescence
spectroscopy to optimize it and to perform model drug release experiments.
Conclusions
The pyclen derivatives complexed with manganese cations were obtained and fully
characterized. Their T1 relaxivities are close to that of the Dotarem commercial MR contrast
agent. Fluorescent polymersomes active in optical imaging were also obtained and
characterized. In a near future, the manganese complexes will be incorporated in the
polymersomes to increase their efficacy and obtain a bimodal probe active in both MRI and
optical imaging.