Microbubble ultrasound contrast agents have now been in use for several decades and their safety and efficacy in a wide range of diagnostic applications have been well established. Recent progress in imaging technology is facilitating exciting developments in techniques such as molecular, 3-D and super resolution imaging and new agents are now being developed to meet their specific requirements. In parallel, there have been significant advances in the therapeutic applications of microbubbles, with recent clinical trials demonstrating drug delivery across the bloodÀbrain barrier and into solid tumours. New agents are similarly being tailored toward these applications, including nanoscale microbubble precursors offering superior circulation times and tissue penetration. The development of novel agents does, however, present several challenges, particularly regarding the regulatory framework. This article reviews the developments in agents for diagnostic, therapeutic and "theranostic" applications; novel manufacturing techniques; and the opportunities and challenges for their commercial and clinical translation.

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Four chiral basic analytes, namely methadone, fluoxetine, venlafaxine, and tramadol, were selected as model compounds for investigating their stereoselective separation with highly sulfated gamma-cyclodextrin (HS gamma-CD) by capillary electrophoresis (CE)-UV and CE-mass spectrometry (MS). At high concentration of chiral selector, the preferentially bonded enantiomer migrated faster in the anodic mode to the detector and high resolutions were obtained for all analytes. In the cathodic mode, at lower highly sulphated cyclodextrin (HS-CD) concentration, basic compounds could be detected, with the weakly bonded enantiomer migrating first (enantiomeric migration order inversion). It was also then possible, at intermediate HS-CD concentration, that only one enantiomer migrated to the detector as cation while the other enantiomer complexed with the CD was negatively charged and presented an opposite mobility. The latter never reached the detector achieving a perfect enantiomeric selectivity. Infinite chiral resolutions were thus achieved by CE-UV as well as by CE-electrospray ionisation (ESI)-MS where concentrations of HS-CD were adapted according to the negative contribution of the nebulization gas pressure of the interface.

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The transition of a targeted ultrasound contrast agent from animal imaging to testing in clinical studies requires considerable chemical development. The nature of the construct changes from an agent that is chemically attached to microbubbles to one where the targeting group is coupled to a phospholipid, for direct incorporation to the bubble surface. We provide an efficient method to attach a heterodimeric peptide to a pegylated phospholipid and show that the resulting construct retains nanomolar affinity for its target, vascular endothelial growth factor receptor 2 (VEGFR2), for both the human (kinase insert domain-containing receptor - KDR) and the mouse (fetal liver kinase 1 - Flk-1) receptors. The purified phospholipid-PEG-peptide isolated from TFA-based eluents is not stable with respect to hydrolysis of the fatty ester moieties. This leads to the time-dependent formation of the lysophospholipid and the phosphoglycerylamide derived from the degradation of the product. Purification of the product using neutral eluent systems provides a stable product. Methods to prepare the lysophospholipid (hydrolysis product) are also included. Biacore binding data demonstrated the retention of binding of the lipopeptide to the KDR receptor. The phospholipid-PEG2000-peptide is smoothly incorporated into gas-filled microbubbles and provides imaging of angiogenesis in a rat tumor model.