Alexander Klibanov | PubMed Health

PubMed2002

Influence of microbubble surface charge on capillary transit and myocardial contrast enhancement.

OBJECTIVE: The goal of the study was to determine whether microbubble charge influences the microvascular retention of microbubble contrast agents. BACKGROUND: Interactions between serum proteins and lipid membranes are greater with anionic compared with neutral membranes. These interactions may influence the microvascular behavior of anionic lipid microbubbles. METHODS: Intravital microscopy of the cremaster muscle was performed in six wild-type mice and three C3-deficient mice during intravenous injection of lipid-shelled microbubbles with either a neutral or a negative charge. Both agents were prepared with and without a protective surface layer of polyethyleneglycol (PEG). Complement attachment to microbubbles was assessed by flow cytometry with flourescein isothiocyanate-conjugated anti-C3b monoclonal antibody. Myocardial contrast echocardiography was performed in six dogs to assess pulmonary and myocardial retention of microbubbles. RESULTS: Size-independent capillary retention of microbubbles, occurring for a few seconds to >10 min, was frequently observed with anionic, but rarely with neutral, microbubbles (4.3 +/- 0.3 vs. 0.4 +/- 0.1 mm(-3), p < 0.01). Anionic microbubble retention was reduced by 70% by surface PEG and was also markedly reduced in C3-deficient mice (1.4 +/- 0.1 mm(-3), p < 0.05 vs. wild-type). Flow cytometry demonstrated complement attachment to only anionic microbubbles. Contrast echocardiography indicated both pulmonary and myocardial retention of only anionic microbubbles, the latter evidenced by persistent opacification >10 min after bolus intravenous injection. CONCLUSIONS: Lipid microbubbles with a net negative charge can be retained within capillaries via complement-mediated attachment to endothelium. This property may be useful for the development of ultrasound contrast agents that can be imaged late after venous injection.

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PubMed2002

Microbubble-endothelial cell interactions as a basis for assessing endothelial function.

Clinical signs and symptoms of coronary artery disease are predated in decades by endothelial dysfunction, an aberration in the vascular lining that permits the development and propagation of atherosclerotic lesions and vasomotor dysfunction in the arterial circulation. These ultimately lead to acute and chronic coronary ischemic syndromes. Other pathophysiologic scenarios encountered in clinical cardiology practice, such as cardiac transplant rejection and the period following coronary angioplasty or cardiac surgery, also are associated with endothelial dysfunction. Endothelial dysfunction parallels coronary risk factors and is potentially reversible, rendering early identification of the phenomenon a clinically important endpoint. Current methods for detecting endothelial dysfunction are limited, however. Myocardial contrast echocardiography using microbubbles targeted to bind to cell surface markers uniquely expressed by dysfunctional endothelial cells may offer an approach to the noninvasive detection of endothelial disease using clinical ultrasound imaging techniques. This article will discuss the concept of targeted ultrasound imaging and present preliminary studies in this area as applied to endothelial assessment. Potential applications to other disease states, both diagnostic and therapeutic, also are discussed.

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