Preparation of targeted microbubbles: ultrasound contrast agents for molecular imaging

Abstract

Targeted ultrasound contrast agents can be prepared by attaching targeting ligands to the lipid, protein or polymer shell coating of gas-filled microbubbles. These materials are stable on storage, fully biocompatible and can be administered parenterally. Detection of microbubble contrast agents by ultrasound is very efficient (single particles with picogram mass can be visualized). Covalent or noncovalent binding techniques can be used to attach targeting ligands. Ligand-carrying microbubbles adhere to the respective molecular targets in vitro and in vivo. Several biomechanical methods are available to improve targeting efficacy, such as the use of a flexible tether spacer arm between the ligand and the bubble, and the use of folds on the microbubble shell, that project out, enhancing the contact area and increasing the length of the lever arm.

Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

“…Since functionalising bubbles with a small, low molecular mass ligand such as biotin ($250 Da) has hardly any effect on the MB response, it is expected that functionalisation of MBs with a peptide also has minimal effect. Polymers are regularly used in MB designs to increase circulation times and to function as a stealth mechanism, mostly in the form of a PEG-lipid [84]. AbouSaleh et al [75] only mentioned a slight increase in elasticity upon PEGylation, but it is not known whether addition of a polymer changes other properties.…”

Molecular Imaging of Tumor Angiogenesis

“…To increase the circulation time of the microbubbles in serum, additional coatings, such as polyethylene glycol polymer arms are added onto the microbubble shell. Additionally these coatings help stabilize the microbubble by providing additional steric protection, preventing aggregation and help escape immune surveillance by the body (Klibanov 2009). …”

Feasibility of Clinical Application of Ultrasound Molecular Imaging

“…To this end, several chemical modifications have been recently applied to targeted bubbles (Klibanov, 2009;Gessner & Dayton, 2010). Firstly, Klibanov et al conjugated clustered polymeric forms of ligands onto the surface of the bubble shell to increase the surface density of ligands (Klibanov et al, 2006b).…”