Transcript Echo in Drug Delivery

Therapeutic Cardiac Ultrasound
Graham Gardner, M.D.
Division of Cardiology
Beth Israel Deaconess Medical Center
Harvard Medical School
February 2nd, 2005
Introduction
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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
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Systemic toxicities
Degradation (proteins)
Invasive delivery systems
Metabolism / time to onset
Solutions
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Local / targeted delivery
Controlled release / stability
Non-invasive
Immediate onset
Novel Mechanisms for Drug Delivery
Innovations
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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
Microphere Properties
• Gas
– Room air
– Perfluorocarbons
• Shell / surface
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Fatty acids
Phospholipids
Albumin
Antibodies
Polymers
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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
The microspheres can be
introduced into the
vascular system through
regular intravenous
access
www.ocularvision.com
www.ergonext.com
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
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Thrombolysis
Myocarditis
Angiogenesis
Restenosis
• Gene Delivery
– Cellular transfection
Specific Applications
• Drug Delivery
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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
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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
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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
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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
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Thrombolysis
Myocarditis
Angiogenesis
Restenosis
• Gene Delivery
– Cellular transfection
Transfection Study: Bekeredjian et al.
• Methods
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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 βgalactosidase gene
– Rats divided into 6 groups
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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
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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