This article is part of a special issue on Drug Delivery.
In the course of three generations, ultrasound contrast agents have developed from simple air bubbles without shells to precise imaging devices. Their half-life in the bloodstream has grown from several seconds to longer than 15 minutes. Along with this great improvement, microbubbles have become able to reach not only the heart, but also organs more distant from the injection site such as the brain, the kidneys, and the liver. These advances have inspired the industry to consider using ultrasound contrast agents as targeted drug carriers (1–2).
Ultrasound drug targeting entails an "aim-and-shoot" conception. That is, the target site can be visualized by diagnostic ultrasound imaging before an operator triggers drug administration by increasing the intensity of ultrasound waves, thus destroying the microbubbles and releasing the drug. The cavitation energy released by bursting the microbubbles can render biological barriers such as cell membranes, the capillary endothelium, and the blood-brain barrier temporarily permeable for large and polar drug molecules (3–4). Some of the most promising therapeutic research on microbubbles today involves targeting chemotherapeutics to solid tumors and nucleic acids to cells for gene therapy.One of the major challenges for the development of drug-loaded microbubbles has been to attain high drug-loading amounts. In response to this challenge, scientists have developed new structural designs of ultrasound contrast agents that offer enhanced loading potential.
Structural design of ultrasound-triggered drug carriers
Ultrasound-triggered drug-carrier particles of several distinct structures can achieve targeted drug delivery. The particles' common feature is a great difference between the propagation velocity of ultrasound within the particles and within the surrounding medium.
In general, such great structural diversity of ultrasound-active drug carriers (UAC) exists that the most popular terms in the literature (i.e., "microbubbles" and "ultrasound contrast agents") do not adequately describe them anymore. By way of example, many acoustically active constructs such as phase-shift nanoemulsions do not share the structure of a microbubble. Yet only a few of these constructs can scatter ultrasound, a characteristic that is required of contrast agents.
Drugs and nucleotides may be complexed into nanoparticles (i.e., secondary carriers) that are assembled in their turn onto the microbubble shell (see Figure 1d). The drug also may be encapsulated into a polymeric shell and covered by a layer of biocompatible protein, as is Point Biomedical's (San Carlos, CA) CardioSphere (see Figure 1e). Microcapsules with protein shells may be loaded by surface adsorption, by incorporating the drug into the entire shell, or by the layer-by-layer approach (5).
Microbubbles are appropriate carriers for several drugs. Scientists have loaded the particles with large molecules such as oligonucleutides, plasmids, and proteins, as well as with small molecules such as doxorubicin, docetaxel, and dexamethasone (6–10). Research also has focused on delivering formulations including paclitaxel and resveratrol using acoustically active lipospheres. In addition, secondary-carrier-associated microbubbles have been introduced for the delivery of plasmid DNA and doxorubicin (11–15).