Towards Enhanced MRI Performance of Tumor-Specific Dimeric Phenylboronic Contrast Agents

Abstract

It is known that phenylboronic acid (PBA) can target tumor tissues by binding to sialic acid, a substrate overexpressed by cancer cells. This capability has previously been explored in the design of targeting diagnostic probes such as Gd- and 68Ga-DOTA-EN-PBA, two contrast agents for magnetic resonance imaging (MRI) and positron emission tomography (PET), respectively, whose potential has already been demonstrated through in vivo experiments. In addition to its high resolution, the intrinsic low sensitivity of MRI stimulates the search for more effective contrast agents, which, in the case of small-molecular probes, basically narrows down to either increased tumbling time of the entire molecule or elevated local concentration of the paramagnetic ions, both strategies resulting in enhanced relaxivity, and consequently, a higher MRI contrast. The latter strategy can be achieved by the design of multimeric GdIII complexes. Based on the monomeric PBA-containing probes described recently, herein, we report the synthesis and characterization of the dimeric analogues (GdIII-DOTA-EN)2-PBA and (GdIII-DOTA-EN)2F2PBA. The presence of two Gd ions in one molecule clearly contributes to the improved biological performance, as demonstrated by the relaxometric study and cell-binding investigations.

A Gadolinium DO3A Amide m-Phenyl Boronic Acid MRI Probe for Targeted Imaging of Sialated Solid Tumors

“…This study strongly supports the binding of our new probe at earlier time points [25]. In previous studies, DOTA-en-PBA and their dimeric analogs were synthesized, and their binding efficiency was assessed in vivo at 240 min and 1440 min using MRI [27,28]. All the above probes were enhanced in tumors at 240 min and 1440 min.…”

“…The conditional stability constant of the PBA-Sia ester was 11.6 M −1 in homogeneous solution [26]. Several in vivo studies into Gd-DOTA-en-PBA probes and their dimeric forms exhibiting two-site binding occurring through PBA ester formation and an electrostatic interaction that lasted up to 24 h on the tumor site have also been reported [27,28].…”

Advancing cell surface modification in mammalian cells with synthetic molecules

“…47 Consequently, the SA-PBA reaction was commonly employed for tumor cell imaging, targeting, and capturing. 37,[48][49][50][51][52][53][54] Li et al developed self-assembled nanorods of PBA-functionalized pyrene (Py-PBA NRs), which possess a highly efficient and specic imaging feature of SA on the cell membrane. Three cell lines with different expression levels of SA were utilized to demonstrate this imaging ability.…”

MRI Contrast Agents in Glycobiology

“…It should be noted that for the binding of free Neu5Ac by boronic acids at pH < 9, the geminal diol function formed by the undissociated carboxylic OH and the 2-OH groups constitutes a second favorable binding site [ 131 ]. Various boronate-based sensors have been designed for free SA [ 130 ] Conjugates of phenyl boronate with lanthanide and complexes of DTPA and DOTA have been constructed for imaging and radiotherapy of tumors having overexpression of SA on tumor cell surfaces [ 132 , 133 , 134 , 135 , 136 ]. Ammonium groups were incorporated to boost the affinity for SAs through an additional electrostatic interaction with the carboxylate groups of the Neu5Ac substrate.…”

“…Therefore, further studies were performed with the kinetically more stable Gd-DOTA-EN-PBA [ 134 ]. To increase the relaxivity per PBA group, SA-targeted CAs with a payload of two Gd 3+ ions were developed, (Gd-DOTA-EN) 2 -PBA, and (Gd-DOTA-EN) 2 -2,3-difluoroPBA [ 135 , 136 ]. In vitro 1 H NMR longitudinal relaxation rates with Gd-DOTA-EN-PBA correlated very well with the amount of SA on the surface of murine melanoma B16-F10 cells [ 134 ].…”