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Cell-permeable MR contrast agents with increased intracellular retention
Paul J Endres1, Keith W MacRenaris, Stefan Vogt
1Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, USA.
Abstract:
Magnetic resonance imaging (MRI) is a technique used in both clinical and experimental settings to produce high-resolution images of opaque organisms without ionizing radiation. Currently, MR imaging is augmented by contrast agents, and the vast majority these small molecule Gd(III) chelates are confined to the extracellular regions. As a result, contrast agents are confined to vascular regions reducing their ability to provide information about cell physiology or molecular pathology. We have shown that polypeptides of arginine have the capacity to transport Gd(III) contrast agents across cell membranes. However, this transport is not unidirectional, and once inside the cell, the arginine-modified contrast agents efflux rapidly, decreasing the intracellular Gd(III) concentration and corresponding MR image intensity. By exploiting the inherent disulfide reducing environment of cells, thiol compounds, Gd(III)-DOTA-SS-Arg 8 and Gd(III)-DTPA-SS-Arg 8, are cleaved from their cell-penetrating peptide transduction domains upon cell internalization. This reaction prolongs the cell-associated lifetime of the chelated Gd(III) by cleaving it from the cell transduction domain.
Insights
New magnetic resonance imaging (MRI) contrast agents use arginine peptides to enter cells. A disulfide linker releases the contrast agent inside cells, enhancing MRI signal intensity and cellular imaging.
Area of Science:
- Biomedical Imaging
- Molecular Imaging
- Nanotechnology
Background:
- Magnetic resonance imaging (MRI) provides high-resolution images without ionizing radiation.
- Current MRI contrast agents, primarily Gadolinium (Gd(III)) chelates, are confined to extracellular and vascular regions.
- This limitation restricts their ability to provide insights into cellular physiology and molecular pathology.
Purpose of the Study:
- To develop novel MRI contrast agents capable of intracellular delivery and retention.
- To enhance MRI signal intensity and cellular visualization by overcoming extracellular confinement.
- To explore the use of arginine-based peptides for targeted intracellular delivery of contrast agents.
Main Methods:
- Conjugation of Gd(III) contrast agents (Gd(III)-DOTA and Gd(III)-DTPA) to arginine-8 (Arg 8) cell-penetrating peptides via a disulfide bond (SS).
- Synthesis of thiol-cleavable constructs: Gd(III)-DOTA-SS-Arg 8 and Gd(III)-DTPA-SS-Arg 8.
- Evaluation of cellular uptake and intracellular retention of the modified contrast agents in cellular models.
Main Results:
- Arginine peptides facilitated the transport of Gd(III) contrast agents across cell membranes.
- Rapid intracellular efflux of unmodified arginine-modified agents limited intracellular Gd(III) concentration and MRI signal.
- Disulfide bond cleavage within the reducing cellular environment successfully released the Gd(III) chelates from the peptide transduction domains.
- This cleavage prolonged the intracellular retention of Gd(III), increasing associated MRI signal intensity.
Conclusions:
- Thiol-cleavable disulfide linkers enable sustained intracellular retention of arginine-delivered MRI contrast agents.
- This strategy overcomes the limitations of rapid efflux, enhancing intracellular MRI signal.
- The developed contrast agents hold promise for improved cellular imaging and molecular pathology detection using MRI.
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