suttontalk_AAPM2013_v3.pptx Ultrasound-mediated drug delivery for cardiovascular disease Jonathan T. Sutton1, Kirthi Radhakrishnan1, Jason L. Raymond1, Kenneth J. Bader2, Guillaume Bouchoux2, Kevin J. Haworth1,2, Gail Pyne-Geithman3, Christy K. Holland1,2 1University of Cincinnati; Biomedical Engineering Program, College of Engineering and Applied Science; Cincinnati, OH USA 2University of Cincinnati; Internal Medicine, Division of Cardiovascular Diseases; Cincinnati, OH USA 3University of Cincinnati, College of Medicine, Department of Neurosurgery; Cincinnati, OH USA Acknowledgements: •  NIH RO1 HL059586 •  NIH/NINDS R01 NS047603 •  NIH RO1 HL74002 0 Conventional Drug Delivery Strategy: Perfuse entire vasculature with drug tissue specificity systemic effects Ultrasound-mediated drug delivery: 1.  Target drug/bubbles to pathologic tissue. -  Antibody conjugation -  Molecular image-guidance 2.  Trigger release & penetration -  Permeabilize barriers -  Drive drug penetration 3. Induce bioeffects -  Stabilize plaques -  Inhibit cell proliferation -  Expedite clot lysis 1 CVD Drug Delivery: Strategies SEM: Human Blood Clot Artery Cross Section Holzapfel and Gasser, J Elasticity, 2000. Sutton et al. Exp. Op. Drug Delivery, 2013. 2 Sonothrombolysis Te xa s H ea rt In st itu te , 2 01 3. Ischemic Stroke Cerebral Hemorrhage Deep Vein Thrombosis Myocardial Infarction •  Acute Ischemic Stroke: sudden cerebrovascular stenosis •  Treatment: I.V. recombinant tissue-type plasminogen activator (rt-PA) –  20 – 40% reperfusion, 4-7% hemorrhage, treatment window •  Progress: sonothrombolysis to expedite clot lysis Bubble dynamics Sonothrombolysis: Background 3 Roger et al., Circulation. 2011. Saver et al., J Thromb Hemost, 2011. Datta et al. UMB. 2008 Enzyme penetration: rt-PA 4 Sonothrombolysis: Drug Penetration = Lysis % C lo t M as s Lo ss Implement an accurate transcranial propagation numerical model. Validate experimentally. –  1 cycle, 120 kHz sinusoidal excitation –  Simulations compared with hydrophone measurements –  Degassed human skulls –  15 – 33% pressure reduction (rel. FF) –  Shift in peak pressure position < 2.5 mm –  Homogenous acoustic pressure in MCA Sonothrombolysis: Know Thy Sound Field 5 Bouchoux et al. PMB. 2012. G. Bouchoux, PhD 6 Research Question: Does clot retraction affect extent of sonothrombolysis? Erythrocytotic Fibrin-enriched Liebeskind et al. Stroke, 2011. Borosilicate Strong Retraction Flint Glass Weak Retraction Sonothrombolysis: Barrier Permeability PULSATILE PUMP MEMBRANE OXYGENATOR AFTERLOAD RESERVOIR PRELOAD RESERVOIR EFFLUENT PRESSURE TRANSDUCER INFUSION PUMP 120-kHz Therapy Transducer 2.25-MHz PCD Acoustic Absorber FLOW CLAMP 7 Sonothrombolysis: Ex vivo perfusion model Retracted Clots Unretracted Clots 0 20 40 60 80 P er ce nt M as s Lo ss Plasma Alone ���� ������� ���������� * * * 8 Sutton et al., UMB. 2012. Retracted Clots Unretracted Clots E,F: Bar = 200 µm A-D: Bar = 1 mm Sonothrombolysis: Bioeffects US: 120 kHz, 0.48 MPaPK-PK, CW Ex Vivo Thrombosis System 9 Cardiovascular Drug Delivery: US Contrast Agents Te xa s H ea rt In st itu te , 2 01 3. Drug Targeting & Image-Guidance: ELIP Theragnostic ultrasound contrast agents –  Entrain air to confer echogenicity –  Targeted to pathologic tissue: atherosclerosis, cancer, thrombosis –  Drug loading Proposed schematic of an Echogenic Liposome (ELIP) 10 Gas Hydrophilic drug Antibody Hydrophobic drug J. Raymond Raymond et al. UMB, (Submitted). Drug Targeting & Image-Guidance: ELIP Targeting to Smooth Muscle Laing et al. J. Liposome Res. 2010. Neuroprotection Peripheral vascular disease Atherosclerosis 12 Cardiovascular Drug Delivery: Therapeutics T hom as Jefferson H ospital, 2013. Te xa s H ea rt In st itu te , 2 01 3. Sutton et al. Expert Opinion in Drug Delivery. 2013. 13 PULSATILE PUMP MEMBRANE OXYGENATOR AFTERLOAD RESERVOIR PRELOAD RESERVOIR EFFLUENT PRESSURE TRANSDUCER INFUSION PUMP 120-kHz Therapy Transducer 2.25-MHz PCD Acoustic Absorber FLOW CLAMP 14 Sonothrombolysis: Ex vivo perfusion model Therapy US transducer 1 MHz BEV-ELIP Sham Control BEV-ELIP + US Bioeffects: Drug penetration Bevacizumab (Avastin) Rx: Anti-angiogenesis Size: 149 kDa antibody Form: BEV-ELIP 15 US: 1 MHz, 0.58 MPaPK-PK, CW Bioeffects: Bioactive gas delivery 22G BLUNT HYPO. NEEDLE 16 Force (t) RX Nitric Oxide (NO) Size: Soluble gas, 30 Da Form: NO Liposomes Mechanism: NO + SM = Vasodilation + Permeability Bioeffects: Nitric Oxide 0 200 400 600 −60 −50 −40 −30 −20 −10 0 Time after Treatment (s) P er ce nt T en si on (r el . M ax K C l) A rt er ia l T en si on (% ) Buffer Nitric Oxide Liposomes 17 0 200 400 600 −60 −50 −40 −30 −20 −10 0 Time after Treatment (s) P er ce nt T en si on (r el . M ax K C l) A rt er ia l T en si on (% ) Buffer Nitric Oxide Liposomes Nitric Oxide Liposomes + US 18 US: 1 MHz, 0.18 MPar, 30 cycles, 1% DC Bioeffects: Nitric Oxide 0 200 400 600 −60 −50 −40 −30 −20 −10 0 Time after Treatment (s) P er ce nt T en si on (r el . M ax K C l) A rt er ia l T en si on (% ) + Ctrl: SNP Buffer Nitric Oxide Liposomes Nitric Oxide Liposomes + US 19 US: 1 MHz, 0.18 MPar, 30 cycles, 1% DC Bioeffects: Nitric Oxide Goal of UC IgUTL: Investigate possible role of ultrasound to treat cardiovascular disease –  circulatory stability of drug carriers –  ultrasound image guidance, molecular imaging –  tissue targeting –  promote bioeffects, understand mechanism Current Work: -  Developing/assessing novel drug carrier & US contrast agent (ELIP) -  sonothrombolysis -  drug penetration into tissue & resulting bioeffect •  fibrinolytic enzymes, bevacizumab, nitric oxide 20 CVD Drug Delivery: Summary Thank You Questions, Comments? 21