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
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
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.
So far, no clear nomenclature has emerged that distinguishes ultrasound active particles' application as drug carriers versus
contrast agents and takes their structure into account as well. UACs may be divided into six categories, based on the the
particles' formulation design (see Table I).
Table I: Classification of ultrasound-active drug carriers according to their formulation design.
In the recent past, UACs' structural designs have evolved to incorporate therapeutic molecules with a broad array of physicochemical
properties (see Figure 1). Polar drug molecules, such as small interfering RNA, may be connected to the microbubble shell
through electrostatic interactions or hydrogen bonds (see Figure 1a). Amphiphilic molecules may intercalate between shell
phospholipids (see Figure 1b), and oil-soluble drugs may be included in an oil layer (see Figure 1c).
Figure 1: Structural design of ultrasound active carriers (UACs) and methods of drug incorporation (in red). The drug can
be attached to the outer surface (e.g., by electrostatic interactions or hydrogen bonds) (a), an amphiphilic drug may intercalate
between the monolayer phospholipids (b), a lipophilic drug may be incorporated into an oil layer (c), secondary-carrier associated
microbubbles may carry the drug (d), a drug may be physically encapsulated into a polymeric shell (e), a protein may be surface
loaded onto microcapsules (f), drug may be loaded onto the entire shell volume of protein microcapsules (g), and protein microcapsules
may be loaded layer by layer (h). Adapted from Ref. 33. (IMAGE IS COURTESY OF THE AUTHOR)
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
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