Elsevier

Biomaterials

Volume 31, Issue 24, August 2010, Pages 6249-6268
Biomaterials

Review
Iodinated blood pool contrast media for preclinical X-ray imaging applications – A review

https://doi.org/10.1016/j.biomaterials.2010.04.066Get rights and content

Abstract

The in vivo X-ray micro-computed tomography (micro-CT) is a very powerful and non-invasive tool used to establish high-resolution images with isotropic voxels in typical scan times ranging from minutes to tenths of minutes. This preclinical imaging technology is primarily adapted to visualize bones. X-ray imaging of soft tissues is made possible by using opaque compounds, providing contrast through tissue vascularization. Thus, using control agents with a long-lasting time in the blood, active or passive targeting of soft tissue is made possible in small animals. In this respect, the use of hydrophilic iodinated X-ray contrast media remains limited due to their rapid blood clearance, albeit at a slightly slower pace in humans as compared with rodents. The development of an iodinated contrast medium with increased vascular residence time is thus necessary. This is precisely the scope of the present paper, which will review and compare in detail the different vectors used as long-circulating iodinated contrast agents for micro-CT, i.e. liposomes, nano-emulsions, micelles, dendrimers and other polymeric particles. The discussion is focused, for each of these nanoparticulate systems, on their method of formulation and production, their stability properties, encapsulation properties, release properties, pharmacokinetics, and toxicology. The different aspects relative to the adaptation of these properties and physico-chemical characteristics for blood pool contrast agents aimed at angiographic micro-CT applications are also discussed. The aim of this review is to propose an overview into the formulation and properties of iodinated micro-CT contrast agents for preclinical applications.

Introduction

This review deals specifically with advances in the formulation of contrast agents with a long residence time in the blood pool for preclinical X-ray micro-computed imaging. The main challenges are (i) to provide the highest concentration of contrast agent in the blood (i.e. iodine), (ii) to obtain a stable concentration of this contrast medium in the blood for several hours and (iii) to be able to use passive or active targeting of these contrast agents for tissue or tumor characterization. In this paper we will limit the discussion to iodinated contrast agents, these being the most developed for X-ray CT as they provide a good compromise between contrasting power, safety (reduced toxicity) and cost.

Section snippets

Computed tomography

X-ray computed tomography (CT) is a non-invasive imaging method for which G. Hounsfield and A. Mc Cormack were awarded the Nobel prize in 1979 [1]. It consists in reconstructing tomographic images from the acquisition of 1D (fan beam geometry) or 2D (cone-beam geometry) projections corresponding to the attenuation of X-rays through tissues. Both the X-ray source and opposite detector rotate simultaneously around the subject. The reconstruction of tomographic slices is then achieved by

Definition

Blood pool contrast agents used in X-ray CT consist of a nanometric-scale range of lipid or polymeric particulate systems containing a significant amount of heavy elements like iodine. These heavy atoms confer their contrasting power to the nano-objects. Lipid blood pool contrast agents are basically liposomes and nano-emulsions, while polymeric agents include block-copolymer micelles, dendrimers and classic polymer nanospheres and nanocapsules. Some publications even report nanoparticles

Definition

Liposomes consist of amphiphilic phospholipids self-assembled into vesicular structures [88]. The scope offered by the liposome aqueous core makes these nano-objects prime candidates for carrying and protecting different hydrophilic compounds at the same time, such as both drugs and/or contrast agents [8], [9], [89], [90]. Liposomes are well characterized and biocompatible, which is due to the innocuous nature of their components.

Thus, liposomes have been used as contrast agent carriers since

Definition

Nano-emulsions are nanometric sized emulsions, typically exhibiting diameters ranging from 20 to 200 nm [141]. These emulsions are also frequently known as miniemulsions, fine-dispersed emulsions or submicron emulsions. They are characterized by a great stability in suspension due to their very small size.

Blood pool contrast agents such as nano-emulsions target the liver in a similar way to chylomicrons and may therefore be used to study the liver metabolism [142]. Fenestra LC® is thus used to

Definition

Micelles are self-assembled, mainly spherical shaped, molecular clusters in water [162]. These nanoparticles are formed when the concentration of soap rises above the critical micelle concentration (CMC). When the bulk phase is aqueous, micelles have an inner hydrophobic core and an outer hydrophilic shell, a structure which allows them to carry different hydrophobic compounds. Such micellar systems can be used as blood pool contrast media when their CMC is very low, which is the case for

Definition

Dendrimers are polymeric complexes composed of a series of polymeric branches linked together by an inner core (Fig. 7) [190], [191]. Dendrimer structures are well-controlled and well-defined, potentially exhibiting a high functionality and a low polydispersity (in spite of their large molecular mass). A typical dendrimer is composed of three different topological parts: (i) A focal core which can encapsulate various chemical species. (ii) Several internal layers (called generations) composed

Definition

Nanospheres and nanocapsules are the most common nanometric formulations of polymeric molecules. Nanospheres are solid matrix particles and nanocapsules present a core/shell structure, in which the surrounding shell has a solid polymeric structure and the reservoir core can be a liquid or semisolid core at room temperature [227]. Depending on the hydrophobicity of their core, nanocapsules can solubilize both hydrophilic and lipophilic compounds.

To date, the literature provides two formulations

Conclusion

Over the past few years, major progress in the formulation of nano-delivery systems has made it possible to develop new types of contrast agents. Because of their long residence time in the blood pool, these contrast agents can be used to study or monitor (i) vascular diseases such as pulmonary embolism or atherosclerosis or (ii) pathologies in which the blood flow plays a crucial role: solid tumors, for instance. The main advantages of using CT for these diseases are its high-resolution and

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