New Dual Mode Gadolinium Nanoparticle Contrast Agent for Magnetic Resonance Imaging

BACKGROUND: Liposomal-based gadolinium (Gd) nanoparticles have elicited significant interest for use as blood pool and molecular magnetic resonance imaging (MRI) contrast agents. Previous generations of liposomal MR agents contained gadolinium-chelates either within the interior of liposomes (core-encapsulated gadolinium liposomes) or presented on the surface of liposomes (surface-conjugated gadolinium liposomes). We hypothesized that a liposomal agent that contained both core-encapsulated gadolinium and surface-conjugated gadolinium, defined herein as dual-mode gadolinium (Dual-Gd) liposomes, would result in a significant improvement in nanoparticle-based T1 relaxivity over the previous generations of liposomal agents. In this study, we have developed and tested, both in vitro and in vivo, such a dual-mode liposomal-based gadolinium contrast agent. METHODOLOGY/PRINCIPAL FINDINGS: THREE TYPES OF LIPOSOMAL AGENTS WERE FABRICATED: core-encapsulated, surface-conjugated and dual-mode gadolinium liposomes. In vitro physico-chemical characterizations of the agents were performed to determine particle size and elemental composition. Gadolinium-based and nanoparticle-based T1 relaxivities of various agents were determined in bovine plasma. Subsequently, the agents were tested in vivo for contrast-enhanced magnetic resonance angiography (CE-MRA) studies. Characterization of the agents demonstrated the highest gadolinium atoms per nanoparticle for Dual-Gd liposomes. In vitro, surface-conjugated gadolinium liposomes demonstrated the highest T1 relaxivity on a gadolinium-basis. However, Dual-Gd liposomes demonstrated the highest T1 relaxivity on a nanoparticle-basis. In vivo, Dual-Gd liposomes resulted in the highest signal-to-noise ratio (SNR) and contrast-to-noise ratio in CE-MRA studies. CONCLUSIONS/SIGNIFICANCE: The dual-mode gadolinium liposomal contrast agent demonstrated higher particle-based T1 relaxivity, both in vitro and in vivo, compared to either the core-encapsulated or the surface-conjugated liposomal agent. The dual-mode gadolinium liposomes could enable reduced particle dose for use in CE-MRA and increased contrast sensitivity for use in molecular imaging

<i>In vivo</i> comparison of liposomal-Gd contrast agents.

<p>Coronal maximum intensity projection (MIP) images of the head and thorax in mice acquired pre-contrast, post CE-Gd liposomes, post SC-Gd liposomes and post Dual-Gd liposomes. The contrast agents were administered intravenously at a lipid dose of 200 mg/kg. Please note the increased signal in the vessels compared to background and the high vessel conspicuity for smaller vessels (arrows in the Dual-Gd image). All images were acquired in different animals using the 3D-FSPGR sequence. The MIP images are presented at identical gray-scale levels.</p

Characterization of liposomal-Gd formulations.

<p>Characterization of liposomal-Gd formulations.</p

T1 relaxation rates (R1) of liposomal-Gd formulations for different lipid doses.

<p>Measurements were performed at 1.5 Tesla MR field strength in bovine plasma at 37°C. For each lipid dose, the R1 values were significantly different for each of the liposomal-Gd agent (* corresponds to p<0.05).</p

T1 relaxivity of liposomal-Gd formulations on a per nanoparticle basis.

<p>T1 relaxivity of liposomal-Gd formulations on a per nanoparticle basis.</p

Schematic of various liposomal-Gd agents.

<p>Core-encapsulated gadolinium (CE-Gd) liposomes contain conventional low molecular-weight Gd-chelates in the core interior of the liposomes, surface-conjugate gadolinium (SC-Gd) liposomes contain Gd-chelates conjugated on the internal and external surface of the liposome bilayer, Dual-Gd liposomes contain both core-encapsulated and surface-conjugated Gd-chelates. The stars represent Gd-chelates.</p

<i>In vivo</i> comparison of signal to noise ratios (SNR) (Fig. A) and contrast to noise ratios (CNR) (Fig. B) for different liposomal-Gd agents.

<p>Each agent was administered in mice at a lipid dose of 200 mg/kg. There was significant difference within the SNRs and CNRs of various contrast agents (p<0.05).</p