Cell-permeable MR contrast agents with increased intracellular retention

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.