© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advhealthmat.de www.MaterialsViews.com wileyonlinelibrary.com 413 REVIEW Adv. Healthcare Mater. 2012, 1, 413–431 Anshuman Jakhmola, Nicolas Anton,* and Thierry F. Vandamme Inorganic Nanoparticles Based Contrast Agents for X-ray Computed Tomography A. Jakhmola, N. Anton, T. F. Vandamme University of Strasbourg Faculté de Pharmacie 74 route du Rhin, BP 60024 F-67401 Illkirch Cedex, France CNRS 7199, Laboratoire de Conception et Application de Molécules Bioactives équipe de Pharmacie Biogalénique E-mail: nanton@unistra.fr DOI: 10.1002/adhm.201200032 1. Introduction The efficient use of X-rays for imaging and computed tomog- raphy applications not only depends on the advancement of diagnostic equipment but also on the contrasting media neces- sary to generate two and three dimensional images for in vivo biomedical applications. Historically, the importance of X-rays in medical diagnosis and imaging was soon recognized after their discovery in 1895 by Rontgen, and research on contrast media and medical imaging was started soon thereafter. The use of the first positive contrast agent most probably dates back to 1896 when barium sulfate was used for investigation of peri- stalsis movement in animals; [1] later in 1921 iodized oil Lipodol (iodized poppy seed oil) was introduced as first suitable X-ray contrast media in myelography. [2] Although X-ray computed tomography is considered as one of the most important imaging techniques for various medical, scientific and technological applications, its use is quite limited as compared to other imaging techniques like MRI or fluorescence imaging. Major limitations are often associated with con- trasting agents approved for medical diag- nosis. Modern X-ray contrasting agents approved for clinical use are either barium sulfate based solution or poly-iodinated aromatic compounds. Conventional ionic contrast media, which are sodium and meglumine salts of tri-iodinated benzoic acid were introduced more than 50 years ago and were quite hyperosmolar and greatly increased toxic and side effects in patients. With new developments, major improvements were achieved in terms of the chemistry and physiological com- patibility of these solutions to reduce the side effects. However, still to date their processing and synthesis require com- plex methodologies that are performed under stringent and toxic conditions. Besides, these tri-iodo- benzene based agents are small molecular weight hydrophilic molecules, which exhibit a rapid renal clearance and vascular permeation. While traditional clinical CT scanners are quite effective for routine diagnosis due to their small response time ( e.g. five seconds to acquire 15 cm thick volume), MicroCT systems tend to be quite slow in comparison ( e.g. ten minutes to scan a mouse); As a result, these are unsuitable for most non preclinical X-ray imaging experiments and analysis. With time many formulation and chemical strategies were under- taken in order to increase the half-life of iodinated contrasting agents. For instance one such development was the introduc- tion of nanoparticle based iodinated molecules as blood pool contrasting agents (BPCA). BPCA are systems which remain in the blood for a prolonged period of time as compared with conventional contrast agents, which diffuse quickly into the interstitial space. These systems, in the form of nanoparticles with a controlled functionalization and surface coating provide significant stealth and antibiofouling properties towards the immune system. In fact this mixed nature of the structure not only increases their residence time in blood but subsequently enhances the contrast. We have recently reviewed iodinated blood pool contrast agents in detail, [3] covering all their chem- ical and physicochemical properties: surface functionalization, stability, toxicology and pharmacokinetics. These contrasting agents which are mainly in the form of colloidal solutions may contain liposomes (encapsulating small molecular weight iodi- nated molecules), nano-emulsions, micelles, dendrimers and Nanomaterials have gained considerable attention and interest in the devel- opment of new and efficient molecular probes for medical diagnosis and imaging. Heavy metal nanoparticles as such are excellent absorber of X-rays and can offer excellent improvement in medical diagnosis and X-ray imaging. Substantial progress has been made in the synthesis protocol and charac- terization studies of these materials but a major challenge still lies in the toxicological studies, which are rather incomplete. The worst known cases were those associated with Thorotrast (suspension of ThO 2 nanoparticles) which resulted in many deaths over years. Properly protected nanomaterials conjugated or coated with biocompatible materials can be used for the fabri- cation of various functional systems with multimodality, targeting properties, reduced toxicity and proper removal from the body. This review aims mainly to provide the advances in the development of inorganic nanoparticle based X-ray contrasting agents with an overview of methods of their preparation, functionalization and applications in medical diagnosis.