Implants for site-specific drug delivery

No Abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38567/1/770020309_ftp.pd

The efficacy of controlled release -sotalol-polyurethane epicardial implants for ventricular arrhythmias due to acute ischemia in dogs

Epicardially implanted -sotalol polyurethane composite matrices for preventing ischemic ventricular arrhythmias were studied in open chest dogs under general anesthesia. -sotalol was combined with a polyureapolyurethane (3:7) in solvent-cast films, which were characterized in vitro for their drug release at 37[deg]C at pH 7.4 (0.05 M K2HPO4). -sotalol in vitro release occurred rapidly in an initial burst phase, with roughly 20% released within the first five min, and 90% by 60 min. Thereafter, an exponentially decreasing release rate was observed with matrix depletion by five hours. In the animal studies, the left anterior descending coronary artery (LAD) was occluded for 10 min on an hourly basis for up to five occlusions. 10 min prior to the third LAD occlusion, either a -sotalol matrix or a vehicle matrix (control) was placed on either the ischemic or nonischemic left ventricular epicardium. The study was then continued observing the effects of matrix placement on occlusions 3,4, and 5. 200 mg -sotalol matrices, which delivered a net dose of 1.2 mg/kg, effectively inhibited ventricular arrhythmias only if placed on the left ventricular ischemic zone. Placement of 200 mg -sotalol matrices in the nonischemic zone was ineffective for significantly reducing the occurrence of ventricular arrhythmias. Furthermore, -sotalol controlled release matrices were ineffective for preventing ventricular fibrillation (VF) regardless of dose or placement site. 200 mg ischemic zone -sotalol matrices resulted in plasma sotalol levels in regional coronary venous samples ranging from 3.5 [mu]g/ml to 10.4 [mu]g/ml However, peripheral sotalol levels obtained simultaneously ranged from 0.23 [mu]g/ml to 0.78 [mu]g/ ml. It is concluded that epicardial -sotalol controlled release matrices inhibited ischemic ventricular arrhythmias, but not VF, if placed in the left ventricular ischemic zone during repeated LAD occlusions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31043/1/0000720.pd

A DNA controlled-release coating for gene transfer: Transfection in skeletal and cardiac muscle

In this paper we report a novel technique of DNA-polymer coating for gene transfer. A proprietary DNA polymer solution was used for thin-layer coating on a chromic gut suture as a model study. The coated sutures were characterized for physical properties such as coating thickness, mass of the DNA deposited on the suture, surface characteristics as determined by scanning electron microscopy, and in vitro DNA release characteristics under simulated physiologic conditions. The in vivo gene transfection using DNA-coated sutures was demonstrated in rat skeletal muscle and in canine atrial myocardium. A heat-stable human placental alkaline phosphatase (AP) plasmid was used as a marker gene. Incisions of 1 to 1.5 cm were made in the rat skeletal muscles or the canine atrial myocardium. The sites were closed with either the DNA-coated sutures or control sutures. Two weeks after the surgery, the tissue samples adjacent to the suture lines were retrieved and analyzed for AP activity. The DNA-coated sutures demonstrated a sustained release of the DNA under in vitro conditions, with an ∼84% cumulative DNA release occurring in 26 days. An agarose gel electrophoresis of the DNA samples released from the suture demonstrated two bands, with the lower band corresponding to the input DNA (supercoiled). It seems that there was a partial transformation of the DNA from a supercoiled to an open circular form due to the polymer coating. The tissue sites, which received the DNA-coated sutures, demonstrated a significantly higher AP activity compared with the tissue sites that received control sutures. In the rat studies, the mean AP activity (square root of cpm/ µg protein) was 43.6 ± 3.3 vs 20.6 ± 2.1 ( p = 0.001) at the control sites. Similarly, in the canine studies, the AP activity was 73.6 ± 7.4 Vs 21.6 ± 1.4 ( p = 0.0009) at the control sites. Thus, our studies demonstrated a successful gene transfer using our DNA-polymer coating technique. This technique could be useful for coating sutures used in vascular and general surgery, and also for coating medical devices, such as stents, catheters, or orthopedic devices, to achieve a site-specific gene delivery.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34492/1/14_ftp.pd