A new ex vivo method to evaluate the performance of candidate MRI contrast agents: a proof-of-concept study.

Ana Paula Candiota,Rui Vasco Simões,Jesús Santamaria,Simó Schwartz,Nuria Miguel-Sancho,Milena Acosta,Soledad Penadés,Ibane Abasolo,Carles Arús,Marco Marradi,Silvia Lope-Piedrafita,Teresa Delgado-Goñi,Ainhoa Irure,Oscar Bomati-Miguel

doi:10.1186/1477-3155-12-12

Abstract

BackgroundMagnetic resonance imaging (MRI) plays an important role in tumor detection/diagnosis. The use of exogenous contrast agents (CAs) helps to improve the discrimination between lesion and neighbouring tissue, but most of the currently available CAs are non-specific. Assessing the performance of new, selective CAs requires exhaustive assays and large amounts of material. Accordingly, in a preliminary screening of new CAs, it is important to choose candidate compounds with good potential for in vivo efficiency. This screening method should reproduce as close as possible the in vivo environment. In this sense, a fast and reliable method to select the best candidate CAs for in vivo studies would minimize time and investment cost, and would benefit the development of better CAs.ResultsThe post-mortem ex vivo relative contrast enhancement (RCE) was evaluated as a method to screen different types of CAs, including paramagnetic and superparamagnetic agents. In detail, sugar/gadolinium-loaded gold nanoparticles (Gd-GNPs) and iron nanoparticles (SPIONs) were tested. Our results indicate that the post-mortem ex vivo RCE of evaluated CAs, did not correlate well with their respective in vitro relaxivities. The results obtained with different Gd-GNPs suggest that the linker length of the sugar conjugate could modulate the interactions with cellular receptors and therefore the relaxivity value. A paramagnetic CA (GNP (E_2)), which performed best among a series of Gd-GNPs, was evaluated both ex vivo and in vivo. The ex vivo RCE was slightly worst than gadoterate meglumine (201.9 ± 9.3% versus 237 ± 14%, respectively), while the in vivo RCE, measured at the time-to-maximum enhancement for both compounds, pointed to GNP E_2 being a better CA in vivo than gadoterate meglumine. This is suggested to be related to the nanoparticule characteristics of the evaluated GNP.ConclusionWe have developed a simple, cost-effective relatively high-throughput method for selecting CAs for in vivo experiments. This method requires approximately 800 times less quantity of material than the amount used for in vivo administrations.

Highlights

Magnetic resonance imaging (MRI) plays an important role in tumor detection/diagnosis
Post mortem ex vivo relative contrast enhancement (RCE) analysis and in vitro 1.4 T and 7.0 T relaxivity measurements were performed for all nanoparticles, while in vivo measurements in mice were restricted to the best performing Gd-complexes containing glyconanoparticles (Gd-GNP) candidate
It should be noted that the value obtained in vitro at 7.0 T for gadoterate meglumine, is in good agreement with literature values obtained in vivo for Gd-DTPA at 6.3 T (3.0 mM−1 s−1) [22], at slightly different temperature (23°C in vitro and 37°C in vivo)

Summary

Introduction

Magnetic resonance imaging (MRI) plays an important role in tumor detection/diagnosis. In a preliminary screening of new CAs, it is important to choose candidate compounds with good potential for in vivo efficiency This screening method should reproduce as close as possible the in vivo environment. In this sense, a fast and reliable method to select the best candidate CAs for in vivo studies would minimize time and investment cost, and would benefit the development of better CAs. Magnetic resonance imaging (MRI) plays an important role in early tumor detection and diagnosis. Contrast agents (CAs) can enhance tissue contrast by shortening longitudinal (T1) and transverse (T2) relaxation times of water The magnitude of this effect is measured as relaxivity (r1 or r2) and it is related to the efficacy of the CAs in accelerating relaxation. Most of the currently available extracellular CAs are non-specific and less efficient than predicted by theory [6], and most of the in vitro strategies used to evaluate their performance are not able to reproduce the in vivo conditions that could modify their ability to generate contrast [5,7,8,9]

Objectives

Methods

Results

Conclusion