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Alexander L Klibanov

Publications and source records attributed to Alexander L Klibanov.

27 records · Page 2Linked to original sources
PubMed2003

Targeted in vivo labeling of receptors for vascular endothelial growth factor: approach to identification of ischemic tissue.

BACKGROUND: A method for identifying tissue experiencing hypoxic stress due to atherosclerotic vascular disease would be clinically useful. Vascular endothelial growth factor-121 (VEGF121) is an angiogenic protein secreted in response to hypoxia that binds to VEGF receptors overexpressed by ischemic microvasculature. We tested the hypothesis that VEGF receptors could serve as markers for ischemic tissue and hence provide a target for imaging such tissue with radiolabeled human VEGF121. METHODS AND RESULTS: A rabbit model of unilateral hindlimb ischemia was created by femoral artery excision (n=14). Control rabbits (n=5) underwent identical surgery without femoral excision. On postoperative day 10, rabbits were intravenously administered 100 microCi of 111In-labeled recombinant human VEGF121, and biodistribution studies and planar imaging were conducted at 3, 24, and 48 hours. On postmortem gamma counting, there was greater accumulation of 111In-labeled VEGF121 in ischemic than in control tissue (P<0.02). Differential uptake of isotope by ischemic muscle was not seen in rabbits injected with 125I-labeled human serum albumin (n=6). Radioactivity imaged in hindlimb regions of interest was significantly higher in ischemic muscle than in sham-operated and contralateral nonoperated hindlimb at 3 hours (P<0.02). Immunohistochemical staining confirmed upregulation of VEGF receptors in ischemic skeletal muscle. CONCLUSIONS: Identification of the ischemic state via targeted radiolabeling of hypoxia-induced angiogenic receptors is possible. This approach could be useful for monitoring the efficacy of revascularization strategies such as therapeutic angiogenesis.

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PubMed2003

Noninvasive assessment of angiogenesis by ultrasound and microbubbles targeted to alpha(v)-integrins.

BACKGROUND: Noninvasive methods for characterizing neovessel formation during angiogenesis are currently lacking. We hypothesized that angiogenesis could be imaged with the use of contrast-enhanced ultrasound (CEU) with microbubbles targeted to alpha(v)-integrins. METHODS AND RESULTS: Microbubbles targeted to alpha(v)-integrins were prepared by conjugating echistatin (MB(E)) or monoclonal antibody against murine alpha(v) (MB(alpha)) to their surface. Control microbubbles (MB(c)) were also prepared. The microvascular behavior of these microbubbles was assessed by intravital microscopy of the cremaster muscle in mice treated for 4 days with sustained-release FGF-2. Microvascular retention was much greater (P<0.01) for MB(E) (11+/-6 mm(-3)) and MB(alpha) (10+/-7 mm(-3)) than that for MB(c) (1+/-1 mm(-3)). Retained MB(E) and MB(alpha) attached directly to the microvascular endothelial surface. Microbubble retention in 4 control mice was minimal. Subcutaneous matrigel plugs enriched with FGF-2 were created in 12 mice and studied 10 days later. Neovessels within the matrigel stained positive for alpha(v)-integrins. CEU demonstrated greater (P<0.01) acoustic intensity for MB(E) (16.0+/-5.9 U) and MB(alpha) (17.0+/-5.5 U) compared with MB(c) (5.8+/-2.6 U). The signal from targeted microbubbles (MB(E) and MB(alpha)) correlated well (r=0.90) with the matrigel blood volume determined by CEU perfusion imaging. CONCLUSIONS: CEU with microbubbles targeted for alpha(v)-integrins may provide a noninvasive method for assessing therapeutic angiogenesis.

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PubMed2003

Targeted tissue transfection with ultrasound destruction of plasmid-bearing cationic microbubbles.

The aim of this study was to assess the relative efficacy and mechanism of gene transfection by ultrasound (US) destruction of plasmid-bearing microbubbles. Luciferase reporter plasmid was charge-coupled to cationic lipid microbubbles. Rat hindlimb skeletal muscle was exposed to intermittent high-power US during dose-adjusted intra-arterial (IA) or IV administration of plasmid-bearing microbubbles via the carotid artery or jugular vein, respectively. At 4 days, luciferase activity in US-exposed skeletal muscle was 200-fold greater with IA than with IV administration of plasmid-bearing microbubbles, and was similar to transfection achieved by IM injection of plasmid (positive control). No transfection occurred with US and IA injection of plasmid alone. Intravital microscopy of the cremaster muscle in mice following administration of microbubbles and US exposure demonstrated perivascular deposition of fluorescent plasmid, the extent of which was twofold greater for IA compared to IV injection. Electron microscopy demonstrated a greater extent of myocellular microporations in US-exposed muscle after IA injection of microbubbles. We conclude that muscle transfection by US destruction of plasmid-bearing cationic microbubbles is amplified by IA, rather than IV, injection of microbubbles due to greater extravascular deposition of plasmid and to greater extent of myocellular microporation.

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PubMed2002

Noninvasive imaging of myocardial reperfusion injury using leukocyte-targeted contrast echocardiography.

BACKGROUND: We hypothesized that myocardial contrast echocardiography (MCE) with leukocyte-targeted microbubbles could temporally and spatially characterize the severity of postischemic myocardial inflammation. METHODS AND RESULTS: In 9 open-chest dogs, either the left anterior descending or left circumflex coronary artery was occluded for 90 minutes (n=6), while the remaining dogs served as non-ischemic controls. During occlusion, MCE was performed to determine the risk area (RA) and regions supplied by collateral flow. Myocardial inflammation was assessed 5, 60, and 120 minutes after reflow by MCE imaging of leukocyte-targeted (phosphatidylserine-containing) lipid microbubbles. The spatial extent and severity of inflammation were also assessed by radionuclide imaging of the neutrophil-avid tracer 99mTcRP517 and tissue myeloperoxidase activity. Early after reflow, MCE detected inflammation throughout the entire risk area, the extent of which decreased over time due to reduced signal in collateral-supplied regions. The spatial extent of inflammation late after reflow was similar for MCE and radionuclide imaging. The severity of inflammation in the infarct zone, the noninfarcted risk area, and collateral-supplied territories determined by quantitative MCE correlated well with myeloperoxidase activity (r=0.81). CONCLUSIONS: MCE with leukocyte-targeted microbubbles can temporally assess the severity and extent of postischemic myocardial inflammation and could be used to evaluate new treatment strategies designed to limit inflammation in acute coronary syndromes.

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PubMed2002

Modulating targeted adhesion of an ultrasound contrast agent to dysfunctional endothelium.

The early stages of atherosclerosis are characterized by increased endothelial cell (EC) surface expression of leukocyte adhesion molecules (LAMs). Ultrasound detection of acoustically active LAM-targeted microbubbles might provide a means to noninvasively assess the functional status of the endothelium. Toward this end, a lipid-based perfluorobutane-filled microbubble was synthesized with various densities of anti-ICAM-1 monoclonal antibodies conjugated to the bubble shell. We hypothesized that modulating the surface antibody density would permit regulation of the adhesion characteristics of the microbubbles, and that microbubble adhesion would be dependent on local wall shear rate. Coverslips of cultured human coronary artery ECs were exposed to microbubbles with various surface antibody densities (1%, 5%, 10%, 50%, 75%, and 100% of maximum coverage) at various wall shear rates (100, 175, 250, 350, and 500 s-1) in a parallel plate perfusion chamber. ECs were either normal or activated by interleukin-1 beta to overexpress ICAM-1. Adhesion was greater to activated vs. normal ECs (p < 0.001), increased with increasing surface antibody density (p < 0.01), and decreased with increasing wall shear rate (p = 0.02). We conclude that shell antibody density and wall shear rate are critical parameters controlling differential microbubble adhesion. This phenomenon might ultimately permit imaging of clinically relevant LAM expression in vivo.

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PubMedDate not supplied

Microbubbles induce renal hemorrhage when exposed to diagnostic ultrasound in anesthetized rats.

The generation of ultrasound (US) bioeffects using a clinical imaging system is controversial. We tested the hypothesis that the presence of microbubbles in the US field of a medical imager induces biologic effects. Both kidneys of anesthetized rats were insonified for 5 min using a medical imaging system after the administration of microbubbles. One kidney was insonified using a continuous mode (30 Hz) and the opposite kidney was insonified using an intermittent (1 Hz) technique. The microbubbles were exposed to three different transducer frequencies and four transducer output powers. After insonification, the animals were euthanized, the kidneys were removed and their gross appearance scored under "blinded" conditions using a defined scale. After the administration of microbubbles, US imaging of the kidney caused hemorrhage in the renal tissue. The severity and area of hemorrhage increased with an increase in the transducer power and a decrease in the transducer frequency. Intermittent insonification in the presence of microbubbles produced a greater degree of renal hemorrhage than continuous imaging techniques.

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