A Ln(III)-3-hydroxypyridine pH responsive probe optimized by DFT.

Differences in tissue pH can be diagnostic of cancer and other conditions that shift cell metabolism. Paramagnetic probes are promising tools for pH mapping in vivo using magnetic resonance spectroscopy (MRS) as they provide uniquely shifted MR signals that change with pH. Here, we demonstrate a 3-hydroxy-6-methylpyridyl coordinating group as a new pH-responsive reporter group for Ln(III) MRS probes. The pH response of the complex was observed by UV-Vis, fluorescence, and NMR spectroscopies, and modeled using DFT. These results provide insight into the observed pH-dependent NMR spectrum of the complex. The protonation state of the hydroxypyridine changes the coordinating ability of the ligand, affecting the dipolar field of the lanthanide and the chemical shift of nearby reporter nuclei. The favorable pH response and coordination properties of the 3-hydroxypyridyl group indicates its potential for further development as a dual responsive-reporter group. Incorporation into optimized scaffolds for MRS detection may enable sensitive pH-mapping in vivo.

Water-Soluble Nanoconjugate for Enhanced Cellular Delivery of Receptor-Targeted Magnetic Resonance Contrast Agents.

ProGlo is an efficient steroid receptor-targeted magnetic resonance (MR) imaging contrast agent (CA). It has been shown to bind to the progesterone receptor (PR) and produce enhanced image contrast in PR-positive cells and tissues in vitro and in vivo. However, the hydrophobicity of the steroid targeting domain of ProGlo (logP = 1.4) limits its formulation and delivery at clinically relevant doses. In this work, a hydrophobic moiety was utilized to drive efficient adsorption onto nanodiamond (ND) clusters to form a water-soluble nanoconstruct (logP = -2.4) with 80% release in 8 h under biological conditions. In cell culture, the ND-ProGlo construct delivered increased concentrations of ProGlo to target cells compared to ProGlo alone. Importantly, these results were accomplished without the use of solvents such as DMSO, providing a significant advance toward formulating ProGlo for translational applications. Biodistribution studies confirm the delivery of ProGlo to PR(+) tissues with enhanced efficacy over untargeted controls. These results demonstrate the potential for a noncovalent ND-CA construct as a general strategy for solubilizing and delivering hydrophobic targeted MR CAs.