Biocompatible Peptide Coated Ultra-Small Superparamagnetic Iron Oxide Nanoparticles for in vivo Contrast-Enhanced Magnetic Resonance Imaging.

The biocompatibility and performance of reagents for in vivo contrast-enhanced magnetic resonance imag-ing are essential for their translation to the clinic. The quality of the surface coating of nanoparticle-based MRI contrast agents, such as ultra-small superparamagnetic iron oxide nanoparticles (USPIONs), is criti-cal to ensure high colloidal stability in biological environments, improved magnetic performance and dis-persion in circulatory fluids and tissues. Herein, we report the design of a library of 21 peptides and lig-ands and identify highly stable self-assembled monolayers on the USPIONs surface. A total of 86 differ-ent peptide coated USPIONs are prepared and selected using several stringent criteria, e.g., stability against electrolyte-induced aggregation in physiological conditions, prevention of non-specific binding to cells, absence of cellular toxicity and contrast-enhanced in vivo MRI. The bis-phosphorylated peptide 2PG-S*VVVT-PEG4-ol provides highest biocompatibility and performance for USPIONs, with no de-tectable toxicity or adhesion to live cells. The 2PG-S*VVVT-PEG4-ol coated USPIONs show enhanced magnetic resonance properties, r1 (2.4 mM-1.s-1) and r2 (217.8 mM-1.s-1) relaxivities, and greater r2/r1 relaxivity ratios (>90), when compared to commercially available MRI contrast agents. Furthermore, we demonstrate the utility of 2PG-S*VVVT-PEG4-ol coated USPIONs as a T2 contrast agent for in vivo MRI applica-tions. High contrast enhancement of the liver is achieved as well as detection of liver tumors, with signifi-cant improvement of the contrast-to-noise ratio of tumor-to-liver contrast. It is envisaged that the reported peptide coated USPIONs have the potential to allow for the specific targeting of tumors, and hence early detection of cancer by MRI.