Publications

Transcatheter Delivery of Therapeutic Formulations For Percutaneous Intramyocardial Delivery

Mehrdad Rezaee MD, Thomas Quertermous MD, John Altman, Daniel Kayser, Daniel Rosenman, Peter Altman

Stanford University, Mayo Clinic, BioCardia Inc.

Background: There is evidence that intramyocardial delivery of agent(s) may be efficacious in promoting therapeutic angiogenesis. Additionally, the physiology of intramyocardial transport suggests this approach may be an attractive modality to treat both heart failure and restenosis. A catheter system with a hollow helical needle (BioCardia, South San Francisco, California) was developed for safe and routine percutaneous intramyocardial delivery. This catheter was designed to anchor into the myocardium, allowing for controlled rate of delivery, and passage of agent(s) without any significant effect on their composition.

Methods: In order to determine the effects of fluidic shear and catheter interaction, transcatheter passage of an adenoviral vector (AV), plasmid (PL), aortic smooth muscle cells (SMCs), transformed skeletal muscle cells, 15um fluorescent microspheres (15M), 50um microspheres (50M), and 125I labeled bovine serum albumin (125I-BSA) was assessed at two flow rates (1cc/min and 20cc/min). AV and PL were used for transfection of MDCK cells. Transfection efficiency of AV and PL before and after catheter passage was determined using beta-galactosidase (b-gal) marker. Viability of muscle cells after injection through the catheter was determined by Tri-pan blue, and cell count after re-culturing the cells. 15M microspheres were passed through the catheter and quantified using scanning spectral fluorometry. 50M spheres were passed through the catheter and quantified using hemacytometry. Efficiency of 125I-BSA delivery was quantified using a gamma counter. Feasibility of using the catheter system to deliver mammalian cells was first tested in vitro by determining the viability of vascular smooth muscle cells that had been injected through the anchoring infusion system. Subsequently, intramyocardial cell transplantation was performed by delivery of 1x106 porcine skeletal muscle cells through the infusion catheter (n=5). The histological distribution of the transplanted cells and their ability to express exogenous reporter gene were determined acutely (n=3) and after 3 days (n=2).

Results: All formulations were shown to pass through the delivery system with very high efficiencies (98-100 percent for AV, PL, and 15M). In vitro transcatheter viability of mammalian cells at both modest and extremely high flow rates was consistently 95-100%. 50M sphere formulations resulted in catheter occlusion at very high flow rates mostly due to an aggregation phenomenon associated with the core annular flow created. This problem was not present at the lower flow rate. Transcatheter 125I-BSA was initially at 13 +/- 4 percent, but on subsequent deliveries decreased substantially. This may represent a saturable binding to charged elements in the catheter material; flushing the catheter with diluted blood will alleviate this under clinical setting. Histological evaluations demonstrated that three days after the delivery, the transplanted skeletal muscle cells remained viable and were able to express the transfected exogenous gene.

Conclusions: These studies demonstrate the feasibility of this percutaneous intramyocardial delivery system to deliver different therapeutic formulations without altering their intrinsic efficacy.

Molecular Therapy, Vol 13, No 5, Abstract 773, May 2001.