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

Nicholas G. Fisher, Jonathan P. Christiansen, Alexander Klibanov, Ronald P. Taylor, Sanjiv Kaul, Jonathan Lindner

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)811-819
Number of pages9
JournalJournal of the American College of Cardiology
Volume40
Issue number4
DOIs
StatePublished - Aug 21 2002
Externally publishedYes

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Microbubbles
Lipids
Intravenous Injections
Contrast Media
Abdominal Muscles
Membrane Lipids
Endothelium
Echocardiography
Blood Proteins
Flow Cytometry
Monoclonal Antibodies
Dogs
Lung
Injections
Membranes

ASJC Scopus subject areas

  • Nursing(all)

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Influence of microbubble surface charge on capillary transit and myocardial contrast enhancement. / Fisher, Nicholas G.; Christiansen, Jonathan P.; Klibanov, Alexander; Taylor, Ronald P.; Kaul, Sanjiv; Lindner, Jonathan.

In: Journal of the American College of Cardiology, Vol. 40, No. 4, 21.08.2002, p. 811-819.

Research output: Contribution to journalArticle

Fisher, Nicholas G. ; Christiansen, Jonathan P. ; Klibanov, Alexander ; Taylor, Ronald P. ; Kaul, Sanjiv ; Lindner, Jonathan. / Influence of microbubble surface charge on capillary transit and myocardial contrast enhancement. In: Journal of the American College of Cardiology. 2002 ; Vol. 40, No. 4. pp. 811-819.
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AB - 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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