Manganese(III) porphyrin oligomers as high-relaxivity MRI contrast agents
Graphical abstract
Introduction
Magnetic resonance imaging (MRI) offers a powerful technique for rapid and precise clinical diagnostic imaging of soft tissue in a noninvasive manner.1, 2 Exploiting the differences (contrast) in longitudinal or transverse relaxation times (T1 or T2) of tissue protons, MRI provides not only morphological, but also anatomical and physiological information of the subject being imaged. One important way to improve the contrast in MRI is to introduce a paramagnetic contrast agent (CA), which can catalytically shorten T1 or T2 of the nearby water protons.3 A parameter termed relaxivity (rn=1,2) is used to quantify the concentration dependence of CAs on proton relaxation rates (mM−1 s−1). Currently, the dominate clinical MRI CAs are based on chelating complexes of paramagnetic gadolinium(III) (GdIII), which produces positive signal enhancement (i.e., brighter image) in T1-weighted (T1w) image.4, 5 However, the relaxivity of GdIII-based CAs (GBCAs) is relatively low and further decreases with increasing magnetic field strength. Moreover, although the indispensable contributions of GBCAs, the previous decade has seen an increase safety concern regarding the severe adverse effect of Gd3+ ion poisoning. It is believed that nephrogenic systemic fibrosis (NSF) is the result of Gd3+ ion release from the conventional GdIII-chelates.6, 7, 8 The imaging ambiguities at high field and health risks of GBCAs makes the developing of new class of CAs with a more biocompatible metal species, ideally with high relaxivity at high field, an urgent task.9, 10
Manganese (Mn), an endogenous MRI-active metal, has been presented as safer alternative to gadolinium. Manganese(III) could chelate with porphyrin ring tightly with high thermodynamic and kinetic stability thus conferring safety. Water soluble manganese(III) porphyrins (MnIIIPs) are found to exhibit high contrast enhancement efficiency (measured as T1 relaxivity or longitudinal r1) at high fields, enabling MR images to be acquired within a shorter time or with higher resolution.11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 It has been proposed that the unique relaxivity of MnIIIPs was due to the electronic and steric effects of this compound,22, 23 thus numerous chemical strategies have been implemented to optimize these parameters for an improved MRI signal. Among them, to prolong the rotational correlation time (τR) of the whole molecule is expected to increase r1 at high fields,12, 17, 24, 25 and MRI CAs based on polymer/ macromolecule platform were a commonly used strategy to slow down the molecular rotation rate (1/τR). However, considering the safety of administration dosage, it should be noted that not only is the high molar relaxivity per paramagnetic metal ion important, but a high relaxivity per molecular mass/ volume is highly preferred.26 Therefore, a CA with many efficient paramagnetic centers confined into a small space is advantageous over a large macromolecule with few paramagnetic metal ions. The reasonable way to achieve this goal is to conjugate several paramagnetic structural units to form one relatively large molecule. Zhang’s group reported two kinds of dimeric MnIIIPs, MnP2 and m-MnP2 with biphenyl linker, favoring high r1 at high magnetic fields.14, 27 It is explicated that covalently coupling the MnIIIP backbones in one molecule could increase the τR of these oligomers due to the limited intramolecular mobility of rigid conformations and steric bulk effects of neighboring porphyrin cores.22 However, the synthetic procedures of MnP2 and m-MnP2 restricted their application in obtaining porphyrin oligomers of various sizes/ shapes. Inspired by these pioneering works and bearing their limitations in mind, herein, two new MnIIIP oligomers (MnPD and MnPT) were designed and synthesized by a more facilely methodology (Scheme 1). The field-dependent relaxation properties of MnPD and MnPT were investigated, and their in vitro/ in vivo MR imaging were also evaluated. Finally, preliminary biosafety studies were assessed by MTT assay and histological analysis.
Section snippets
Preparation and characterization of MnIIIP-based oligomers
In this work, starting from 5-(4-aminophenyl)-10,15,20-tris(4-sulfonatophenyl)porphyrin (ATSP, 1a), MnIIIP dimer (MnPD) could be easily and efficiently synthesized in three steps (Scheme 1). The key process is the high-efficiency coupling reaction between the sulfonated amino MnIIIP (MnATSP, 1b) and the sulfonated isothiocyanate MnIIIP (MnITSP, 1c) to form the thiourea unit under a mild reaction condition. We chose to couple the metalated monomers together to prevent any possible decomposition
Conclusions
In conclusion, two novel MnIIIP-based oligomers, MnPD and MnPT were designed and synthesized as efficient GdIII-free T1 MRI CAs with improved features both in vitro and in vivo. The relative high relaxivity of the two MnIIIPs at high fields could be ascribed to the increase of molecular rotational correlation time (τR) induced by porphyrin conjugation. Due to the high efficiency of isothiocyanate functionary, this work afforded a feasible synthetic strategy to construct porphyrin oligomers.
Materials and compounds synthesis
All the reagents as well as solvents were purchased from commercial suppliers and used without further purification. The detailed synthetic procedures and the characterization of the monomers, manganese(III) 5-(4-aminophenyl)-10,15,20-tris(4-sulfonatophenyl)porphyrin (MnATSP, 1b), manganese(III) 5,10-bis(4-aminophenyl)-15,20-bis(4-sulfonatophenyl)porphyrin (MnBABSP, 2b), manganese(III) 5-(4-isothiocyanatophenyl)-10,15,20-tris (4-sulfonatophenyl)porphyrin (MnITSP, 1c), and the two MnIIIP-based
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by the Hangzhou Science and Technology Bureau of China (Grant No. 20180533B09). The authors also acknowledge Professor Xiao-An Zhang (University of Toronto Scarborough, Canada) and Mr. Han-Lin Liu (University of Toronto Scarborough, Canada) for fruitful discussions.
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