Therapeutic Cardiac Ultrasound Graham Gardner, M.D. Division of Cardiology Beth Israel Deaconess...
-
Upload
garett-dunwell -
Category
Documents
-
view
223 -
download
1
Transcript of Therapeutic Cardiac Ultrasound Graham Gardner, M.D. Division of Cardiology Beth Israel Deaconess...
Therapeutic Cardiac Ultrasound
Graham Gardner, M.D.
Division of Cardiology
Beth Israel Deaconess Medical Center
Harvard Medical School
February 2nd, 2005
Introduction
• Novel Mechanisms for Drug Delivery
• Drug Delivery using Ultrasound
• Advantages and Disadvantages of Cardiac Ultrasound
• Specific Applications – Drug Delivery
– Gene Delivery
• Future Directions
Novel Mechanisms for Drug Delivery
Challenges
• Systemic toxicities
• Degradation (proteins)
• Invasive delivery systems
• Metabolism / time to onset
Solutions
• Local / targeted delivery
• Controlled release / stability
• Non-invasive
• Immediate onset
Novel Mechanisms for Drug Delivery
Innovations
– Nanotechnology
– Controlled-release devices and preparations
– Marriage of pharmaceutical compounds with medical devices
– Ultrasound-enabling
Cardiac Ultrasound Principles
• Creation of microspheres
• Incorporation of drugs (and possibly ligands) within the microspheres
• Distribution of drug-containing microspheres through the vascular system
• Delivery of the drugs to target organs via ultrasound
Microsphere Constituents
• Gas– Air: dissolution in blood is < 1 sec– Perflurocarbons
• Low propensity to diffuse remains in the bubble• Low concentration of saturation in blood prolonged
survival
• Shell– Albumin: flexible and binds to injured endothelium– Acrylates: inflexible and require ultrasound destruction– Polymers: custom-designed
Microsphere Formulation
Microsphere Constituents
• Gas– Room air– Perfluorocarbons
• Shell / surface– Fatty acids– Phospholipids– Albumin– Antibodies– Polymers
Microphere Properties
• Cross-sectional area• Persistence / fragility• Resonance• Attenuation• Adhesion
Microsphere Formulation
Drug and Ligand Formulation
• Microspheres can be formulated with multiple different drugs and act as carrier molecules
• Specific ligands can also be attached to help direct the microspheres to a specific organ or disease process
www.hd.org
Injection of Microspheres
www.ocularvision.comwww.ergonext.com
The microspheres can be introduced into the vascular system through regular intravenous access
Application of Ultrasound
• Ultrasound applied over the skin surface can be used to burst the microbubbles over the target area for drug delivery
• Microspheres themselves act as nuclei for cavitation
EKG-Gating for Coronary Delivery
www.emedhome.com
Destruction of the Microspheres
• Gradual diffusion of gas at low acoustical power
• Formation of shell defect diffusion of gas
• Immediate explosion of the microsphere shell at high acoustical power
• Dispersion of the microspheres into small bubbles
Tsutsui JM, etal. Cardiovascular Ultrasound, 2004.
Additional Effects of Ultrasound
• Creation of extravasation points in skeletal muscle capillaries (micro-fractures)– Microvessels with diameter < 7 um
– Dependent upon ultrasound pulse interval (optimal approx 5 sec)
• Formation of pores in cellular membranes– Best with lower Hz / higher wavelength
• Physical disruption of clot
Tsutsui JM, etal. Cardiovascular Ultrasound, 2004.
Advantages of Ultrasound
• Local or targeted delivery
• Minimize systemic circulation and drug levels
• Delivery of “difficult” compounds– Proteins
– Systemically toxic compounds
• Non-invasive
• Ultrasound facilitation of drug delivery– Microvessel fractures
– Clot dissolution
– Disruption of lipid cellular membranes
Disadvantages of Ultrasound
• “Packaging” requirements– Limitation of total amount
• Cost
• Safety considerations– PVCs
– Disruption of the microvasculature
– Allergy to microsphere preparations or constituents
Specific Applications
• Drug Delivery– Thrombolysis
– Myocarditis
– Angiogenesis
– Restenosis
• Gene Delivery– Cellular transfection
Specific Applications
• Drug Delivery– Thrombolysis
– Myocarditis
– Angiogenesis
– Restenosis
• Gene Delivery– Cellular transfection
Thrombolysis Study: Siegel et al.
• Methods– Bilateral Thrombi in the femoral
and coronary arteries of rabbits induced via electrical current
– Thrombosis confirmed via angiography
– Randomization to 2 of several arms• Ultrasound alone (20-37 kHz)• Thrombolytic alone• Microbubbles alone• Thrombolytic and ultrasound• Microbubbles and ultrasound
Siegel RJ, et al. Echocardiography, 2001.
Thrombolysis Study: Siegel et al.
Siegel RJ, et al. Echocardiography, 2001.
Thrombolysis Study: Siegel et al.
• Significantly improved recanalization of femoral arteries with the application of ultrasound to streptokinase or microbubbles compared with streptokinase or microbubbles alone
Siegel RJ, et al. Echocardiography, 2001.
Thrombolysis Study: Siegel et al.
• Results (coronary)– Significantly improved
patency rates at 30 and 90 minutes when TPA combined with ultrasound
– TIMI 2-3 flow seen in 25% of tPA alone vs 92% of ultrasound-tPA combination
– No assessment of LV function
Siegel RJ, et al. Echocardiography, 2001.
Thrombolysis Study: Siegel et al.
Siegel RJ, et al. Echocardiography, 2001.
Specific Applications
• Drug Delivery– Thrombolysis
– Myocarditis
– Angiogenesis
– Restenosis
• Gene Delivery– Cellular transfection
Restenosis
• Synthetic antisense oligonucleotides (c-myc protooncogene) can bind to mRNA and inhibit the synthesis of the protooncogene
• By inhibiting the c-myc protooncogene, these antisense oligonucleotides could inhibit restenosis after vascular injury
Restenosis Study: Porter et al
• Methods– 21 pigs– Injury to the R carotid artery via oversized balloon inflation– Vessel patency confirmed via angiography– Randomized to three arms
• Synthetic oligodeoxynucleaotide to c-myc• Synthetic oligodeoxynucleaotide to c-myc bound with albumin-coated
microbubbles• Control
– Injected at Time 0 and again at 3 days– Ultrasound applied at 20 kHz– Harvesting performed at 30 days
Porter TR, et al. Ultrasound in Med & Biol, 2001.
Restenosis Study: Porter et al
• Results– Lumen area was significantly
larger at the injury site in pigs that received ODN-myc combined with microbubbles (reduction of 8 +/- 2% vs 19% and 28% in the control and antisense alone groups)
Porter TR, et al. Ultrasound in Med & Biol, 2001.
Specific Applications
• Drug Delivery– Thrombolysis
– Myocarditis
– Angiogenesis
– Restenosis
• Gene Delivery– Cellular transfection
Transfection Study: Bekeredjian et al.
• Methods– Albumin microbubbles with a plasmid encoding luciferase
– Injected into internal jugular vein
– Sonos 5500 with S3 transducer applied to chest wall (1.3 MHz)
– Variable transfection and harvesting timepoints
– Hearts dissected
Transfection Study: Bekeredjian et al.
• Results– Highest transfection rate
seen after 4 days but still detectable at 28 days
– Transfection almost exclusively confined to the heart
– Little transfection seen when ultrasound and microbubble injections separated temporally
Transfection Study: Shohet et al.
• Methods– Perfluoropropane-filled albumin microbubbles
– Attached to adenovirus containing cDNA for E coli β-galactosidase gene
– Rats divided into 6 groups• Echocardiographic destruction of microbubbles without gene
• Echocardiographic destruction of microbubbles with gene
• Microbubbles with gene only
• Gene alone
• Echocardiography with gene alone
• Echocardiographic destriction of microbubbles without gene followed by the infusion of gene alone
Transfection Study: Shohet et al.
• Results– Livers of any animal
receiving some adenovirus showed some activity
– All hearts receiving microbubbles, gene, and ultrasound showed uptake
– No skeletal muscles in this experimental group showed uptake
– No uptake was seen in the hearts of any other animals
Transfection Study: Shohet et al.
• Results– β-galactosidase activity was
10-fold higher in the experimental group that received gene-encoated microbubbles and ultrasound simultaneously
– β-galactosidase activity was 2-fold higher in the group that received microbubble and ultrasound destruction first, followed by gene infusion.
Future Directions
• Application to other disease processes– Oncology
• Delivery of chemotherapy
• Delivery of anti-angiogenesis factors
– Musculoskeletal (arthritis)
– GI
– Endocrine (insulin delivery for diabetes)
– Transdermal drug delivery
Future Directions
• Cardiology Applications– Angiogenesis
• Delivery of VEGF
– Enhanced imaging• Ischemic myocardium
– Arrhythmia management• Combination of monitoring and therapy
? Management of Acute Myocardial Infarctions
www.mayoclinic.org