A Second Generation Mn-Porphyrin Dimer with a Twisted Linker as a Potential Blood Pool Agent for MRI: Tuning the Geometry and Binding with HSA.

Hanlin Liu,Xiao-an Zhang,David Feng Xu,Shili Dong,Weiran Cheng,Keith Tang

doi:10.3390/ph13100282

Hanlin Liu, Xiao-an Zhang + Show 4 more

Open Access

https://doi.org/10.3390/ph13100282

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Journal: Pharmaceuticals	Publication Date: Sep 29, 2020
Citations: 8	License type: CC BY 4.0

Affiliation: The Scarborough Hospital, University of Toronto

Abstract

Blood-pool agents (BPAs) are MRI contrast agents (CAs) characterized by their long circulation in the vascular system to provide an extended time window for high-resolution MR angiography (MRA). Prolonged vascular retention, however, impedes the excretion of BPAs. Therefore, chemical strategy to regulate the balance between retention and clearance is important to reach optimal pharmacokinetics. We recently developed MnP2, the first Mn(III)-porphyrin (MnP) based BPA. MnP2 shows high T1 relaxivity (r1) and high affinity to human serum albumin (HSA) that leads to up to 48-h vascular retention in rats. However, upon albumin binding, the r1 is decreased. To modulate vascular retention time and plasma r1, a regioisomer of MnP2, m-MnP2, was synthesized. The free m-MnP2 exhibits lower r1 than that of MnP2 at magnetic fields above 2 MHz, which agrees with their relative hydrodynamic sizes. The HSA binding of m-MnP2 was evaluated using UV-Vis spectroscopy and found to have tuned-down affinity in comparison with MnP2. Upon HSA binding, the protein complex of m-MnP2 exhibits an r1 of 11.8 mM−1 s−1 at 3 T, which is higher than that of MnP2 bound to HSA. Taken together, this demonstrated the role of molecular geometry in optimizing the pharmacokinetics of albumin-targeting BPAs.

Highlights

Developed for magnetic resonance angiography (MRA) [1], blood-pool agents (BPAs) are used to provide anatomical and functional information of the vascular system and to diagnose vascular related diseases such as atherosclerosis and hemorrhage [2]
Our results demonstrated that the slight change in manganese(III) porphyrins (MnPs) connection at the biphenyl bridge resulted in a significant impact on molecular geometry and on the r1
human serum albumin (HSA) titration studies monitored by UV-visible and circular dichroism (CD) spectra indicated m-MnP2 formed a non-covalent HSA complex, with the interaction tuned down to be less strong in contrast to MnP2, suggesting the modification on biphenyl bridge impacts the interaction with HSA

Summary

Introduction

Developed for magnetic resonance angiography (MRA) [1], blood-pool agents (BPAs) are used to provide anatomical and functional information of the vascular system and to diagnose vascular related diseases such as atherosclerosis and hemorrhage [2]. We chose manganese(III) porphyrins (MnPs) to construct non-Gd BPAs because of their biocompatibility, high stability, high relaxivity especially at high magnetic fields, and versatility for structural modulation [8,9,10,11,12]. The hydrophobic biphenyl linker of MnP2 contributes to strong HSA binding, resulting in a significantly prolonged vascular circulation, relative to other MnPs, such as Mn(III) meso-tetra(4-sulfonato-phenyl)porphine (MnTPPS) and Gd-based CAs [14,15,16]. This r1 trend is consistent with the predicted hydrodynamic sizes, indicating that decreases in molecular tumbling rate of MnPs enhance the r1 As summarized, for both MnP dimers, the high r1 peaks are sustained at higher fields up to 3 T with a moderate decrease, favouring applications at high clinical magnetic fields. Our results demonstrated that the slight change in MnP connection at the biphenyl bridge resulted in a significant impact on molecular geometry and on the r1

Binding Affinity with HSA

Relaxometry Studies with HSA

Findings

Conclusions