Cell Labeling via Membrane-Anchored Lipophilic MR Contrast Agents

Abstract

Cell tracking in vivo with MR imaging requires the development of contrast agents with increased sensitivity that effectively label and are retained by cells. Most clinically approved Gd(III)-based contrast agents require high incubation concentrations and prolonged incubation times for cellular internalization. Strategies to increase contrast agent permeability have included conjugating Gd(III) complexes to cell penetrating peptides, nanoparticles, and small molecules which have greatly improved cell labeling but have not resulted in improved cellular retention. To overcome these challenges, we have synthesized a series of lipophilic Gd(III)-based MR contrast agents that label cell membranes in vitro. Two of the agents were synthesized with a multiplexing strategy to contain three Gd(III) chelates (1 and 2) while the third contains a single Gd(III) chelate (3). These new agents exhibit significantly enhanced labeling and retention in HeLa and MDA-MB-231-mcherry cells compared to agents that are internalized by cells (4 and Prohance).

Nanodiscs as a Modular Platform for Multimodal MR-Optical Imaging

“…32 Herein, we incorporate lipophilic contrast agents 1 and 2 into nanodiscs to generate water-soluble, multimodal, and modular platforms for cellular imaging (Figure 1). …”

“…32 Monomeric 2 was synthesized according to Scheme S1. Specifically, 2-decyltetradecan-1-ol was brominated with NBS to yield 11-(bromomethyl)tricosane.…”

“…Complexes 1 , 32 3 , 33 and 4 36 were synthesized according to literature procedures. For a description of synthetic methods for new compounds, see the Supporting Information.…”

A multimeric MR-optical contrast agent for multimodal imaging

“…The observed ionic relaxivities decrease to 4.7 ± 0.3 mM −1 s −1 for 1 and 5.2 ± 0.3 mM −1 s −1 for 2 at 7 T and are consistent with values obtained from agents generated from similar scaffolds. 20,21 …”

Water-soluble lipophilic MR contrast agents for cell membrane labeling

“…Our lab continued the development of lipophilic contrast agents by comparing the labeling and retention of monomeric (contains one Gd(III) complex) and multimeric (contains three Gd(III) complexes) agents. [21] We showed that the monomeric agent had the surprising ability to label cells more effectively and produce more significant contrast enhancement of cells than its multimeric counterpart. Further, the monomeric agent had improved solubility and did not require incubation with detergent in biological media, a limitation of the multimeric design.…”