Author + information
- Received June 6, 2019
- Revision received September 5, 2019
- Accepted September 5, 2019
- Published online January 27, 2020.
- Patrick H. Kee, MD, PhDa,∗ (, )
- Melanie R. Moody, BSca,
- Shao-Ling Huang, PhDa,
- Hyunggun Kim, PhDa,f,
- Xing Yin, MD, PhDa,
- Tao Peng, MDa,
- Susan T. Laing, MDa,
- Melvin E. Klegerman, PhDa,
- Mohammad H. Rahbar, PhDa,b,
- Deborah Vela, MDe,
- Curtis Genstler, MD, PhDd,
- Kevin J. Haworth, PhDc,
- Christy K. Holland, PhDc and
- David D. McPherson, MDa
- aDepartment of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
- bCenter for Clinical and Translational Sciences, The University of Texas Health Science Center at Houston, Houston, Texas
- cDepartment of Biomedical Engineering, University of Cincinnati, Cincinnati, Ohio
- dEKOS Corporation, Bothell, Washington
- eDepartment of Pathology, Texas Heart Institute, Houston, Texas
- fDepartment of Bio-Mechatronic Engineering, Sungkyunkwan University, Suwon, Republic of Korea
- ↵∗Address for correspondence:
Dr. Patrick H. Kee, Department of Internal Medicine, The University of Texas Health Science Center at Houston, 1881 East Road, 3SCRB 6.4607, Houston, Texas 77054-6011.
• Late in-stent restenosis is a significant problem in the management of atherosclerotic arterial disease that has not been completely ameliorated by the use of drug-eluting stents.
• ELIPs have been developed by our laboratory for specific ligand targeting, payload encapsulation, and ultrasound-activated payload release.
• An EndoSonic endovascular catheter with an ultrasonic core approved by the U.S. Food and Drug Administration for ultrasound-assisted, catheter-directed thrombolysis was harnessed to deliver and activate our ELIP preparations for targeted drug delivery in the peri-stent atheroma.
• Two ELIP preparations, nitric oxide–containing ELIPs and anti–intercellular adhesion molecule-1 antibody-conjugated, pioglitazone-loaded ELIPs, were sequentially delivered and ultrasonically activated by an EKOS catheter in stented arteries in an atherosclerotic miniature swine model.
• This study presents in vivo evidence of ELIP targeting to inflamed arterial wall by anti–intercellular adhesion molecule-1 antibody and ultrasound-driven pioglitazone delivery into deeper layers of the arterial wall. The result is a marked decrease in atheroma formation in the peri-stent region in arteries where the ultrasound-activated therapeutic was administered.
Late in-stent restenosis remains a significant problem. Bare-metal stents were implanted into peripheral arteries in miniature swine, followed by direct intra-arterial infusion of nitric oxide–loaded echogenic liposomes (ELIPs) and anti–intercellular adhesion molecule-1 conjugated ELIPs loaded with pioglitazone exposed to an endovascular catheter with an ultrasonic core. Ultrasound-facilitated delivery of ELIP formulations into stented peripheral arteries attenuated neointimal growth. Local atheroma-targeted, ultrasound-triggered delivery of nitric oxide and pioglitazone, an anti-inflammatory peroxisome proliferator–activated receptor-γ agonist, into stented arteries has the potential to stabilize stent-induced neointimal growth and obviate the need for long-term antiplatelet therapy.
This project was supported by the National Institutes of Health (1R01HL135092). Dr. Huang is a stockholder to Zymo Pharma. Dr. Klegerman reports board service, ownership interest, and stock ownership for Zymo Pharma. Dr. Genstler is an employee and shareholder of EKOS Corporation. Dr. Haworth is a consultant for EKOS Corporation. Dr. Holland is a consultant for BTG/EKOS Corporation on another project. Dr. McPherson is a stockholder in Zymo Pharma. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received June 6, 2019.
- Revision received September 5, 2019.
- Accepted September 5, 2019.
- 2020 The Authors