Therapeutic applications of lipid-coated microbubbles
Section snippets
General properties of microbubbles
Microbubbles are comprised of spherical voids or cavities filled by a gas. Generally, for medical applications, the microbubbles are stabilized by a coating material such as phospholipid, surfactant, denatured human serum albumin or synthetic polymer. Since gas is less dense than liquids or solids, microbubbles comprise a pocket, region or structure of low density. This property of low density of microbubbles has a number of potentially important medical applications, including site-specific
Overview of different kinds of therapeutic microbubbles
Some of the potential therapeutic applications of lipid-coated microbubbles are shown below in Table 2. The design features of the microbubble product will vary depending upon the intended application.
Therapeutic imaging with microbubbles
Ultrasound is a portable imaging modality, the use of which is already well established in the operating room [60], [61], [62], [63]. Microbubble imaging agents enhance visualization of blood flow and as such improve our ability to see changes in blood flow associated with therapy [64], [65]. A number of ablation techniques are currently in use to treat regional cancer disease including alcohol ablation, cryosurgery, radiofrequency ablation and high intensity focused ultrasound (HIFU) [66], [67]
Sonothrombolysis
Thrombosis is the major cause of death in the US. Each year in the US, there are over 1 million cases of myocardial infarction and over 500,000 cases of ischemic stroke [73]. Although atherosclerosis is often the underlying factor, acute thrombosis is the cause of death and morbidity. Plaque rupture and thrombosis may lead to occlusion of critical vessels resulting in significant morbidity and death. While it may be important to treat the underlying lesion, i.e., atherosclerosis, it is of
Blood–brain barrier and delivery to the CNS
The central nervous system poses a challenge to drug delivery. The vessels in the brain are lined by continuous endothelium or blood–brain barrier (BBB). The BBB prevents delivery of most small molecule and macromolecule therapeutic agents to the brain. Hynynen et al. [27] has shown that transcranial application of ultrasound combined with IV administration of microbubbles in rabbits reversibly opened the blood–brain barrier. MR scans were performed on the rabbits' brains after administration
Drug containing microbubbles
For drug delivery applications, it is possible to make therapeutic drug-carrying microbubbles by incorporating the drugs into or onto the bubbles. As shown in Fig. 8, drugs can be incorporated into acoustically active carriers in a number of different ways, ranging from association with the membrane to development of gas/drug-filled microspheres. The presence of gas in the drug delivery vehicles is to confer acoustic activity. The presence of the gas lowers the threshold for cavitation making
Gene delivery with microbubbles
A number of researchers throughout the world have shown that ultrasound and microbubbles may have important applications in gene therapy [31], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [89]. Gene-based medicines are active at very low concentrations if they are effectively delivered to the target cells. Therefore, payload of drug in the microbubble is feasible for gene-based medicines with microbubbles. We have prepared two fundamentally different kinds of
Targeted microbubbles
Targeted microbubbles can be developed by incorporating targeting ligands onto the surface of the microbubbles. Using certain ultrasound imaging techniques (e.g., cavitation imaging), it is possible to detect a single microbubble [88]. In terms of sensitivity to low concentrations of an imaging agent, ultrasound with microbubbles rivals nuclear medicine and exceeds the capabilities of other commonly used imaging techniques such as magnetic resonance imaging and computed tomography. The extreme
Perfluorocarbon nanoemulsions
Liquid PFC can be used to formulate nanoemulsions. Compared to the microbubbles, which have a mean size of around a micron, the PFC nanoemulsions can be much smaller in size, e.g., with mean diameter of about 200 nm. As shown in Table 1, PFC materials have a range of different boiling points and mixed halogenated compounds expand the range even further. It is possible to design nanoemulsion that will undergo the phase transition from liquid to gaseous states at a range of different
Pulmonary delivery with microbubbles
The lungs are an important target for drug delivery. Many chronic diseases such as asthma, cystic fibrosis, interstitial pneumonitis and interstitial fibrosis are diseases of the lungs and airways [108]. Additionally, the alveolar surfaces of the lungs can serve as gateways for systemic delivery of bioactive materials [109], [110], [111]. Conventional aerosol and droplet-based formulations have relatively large hydrodynamic radii and commonly deposit preferentially in the central airways.
Oxygen delivery
Liquid PFC's have been tested in human clinical trials as blood substitutes [117]. On a volume basis, Van Liew [56], [57], [58] has shown that gaseous PFC compounds may deliver more oxygen than liquid PFC's. We prepared oxygen-enriched lipid-coated PFC gas microbubbles for oxygen delivery. In oxygen-enriched aqueous media, these lipid-coated microbubbles appear as micron-sized spherical structures. As the aqueous media is degassed and oxygen content falls, the lipid-coated microbubbles take on
Perspectives
Microbubbles represent a new class of drug delivery/therapeutic products. The microbubbles are activated locally by ultrasound energy. As cavitation occurs, this creates a local shock wave that can be exploited for in vivo therapeutic effects. Potential applications of this technology include treatment of thrombosis and drug delivery. Drug carrying bubbles such as AALs might be used for local delivery of system agents. In the brain, systemic delivery of microbubbles and transcranial application
Acknowledgments
The authors would like to thank Terri New for her help preparing the figures and Anna Vickroy for her help compiling references.
References (123)
- et al.
Gauging the likelihood of cavitation from short-pulse, low-duty cycle diagnostic ultrasound
Ultrasound Med. Biol.
(1991) - et al.
Predicting the acoustic response of a microbubble population for contrast imaging in medical ultrasound
Ultrasound Med. Biol.
(2000) - et al.
Preclinical studies of MRX-115: safety evaluations of a myocardial perfusion agent
Acad. Radiol.
(1996) - et al.
Microvascular rheology of Definity microbubbles after intra-arterial and intravenous administration
J. Am. Soc. Echocardiogr.
(2002) - et al.
Radiofrequency ablation extends the scope of surgery in colorectal liver metastases
Eur. J. Surg. Oncol.
(2003) - et al.
Ultrasonographic detection of focal liver lesions: increased sensitivity and specificity with microbubble contrast agents
Eur. J. Radiol.
(2003) ATL/Philips Ultrasound, Seeking consensus: contrast ultrasound in radiology
Eur. J. Radiol.
(2002)- et al.
Ultrasound, microbubbles, and thrombolysis
Prog. Cardiovasc. Dis.
(2001) - et al.
Thrombolytic enhancement with perfluorocarbon-exposed sonicated dextrose albumin microbubbles
Am. Heart J.
(1996) - et al.
Microbubble-augmented ultrasound declotting of thrombosed arteriovenous dialysis grafts in dogs
J. Vasc. Interv. Radiol.
(2003)