Gene-based therapies for restenosis

Labhasetwar, Vinod; Chen, Borong; Muller, David W.M.; Bonadio, Jeffrey; Ciftci, Kadriye; March, Keith L.; Levy, Robert J.

doi:10.1016/s0169-409x(96)00485-1

Cited by 14 publications

(5 citation statements)

References 71 publications

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“…We have also demonstrated gene expression in the rabbit iliac arterial wall following a local infusion of PLGA nanospheres containing AP plasmid DNA. 30 Our coating technique could be useful for medical devices such as stents, catheters, or orthopedic devices, to deliver therapeutic genes locally at the site of implant. Stents coated with a therapeutic gene could be useful for preventing restenosis.…”

Section: Discussionmentioning

confidence: 99%

A DNA Controlled-Release Coating for Gene Transfer: Transfection in Skeletal and Cardiac Muscle

Labhasetwar¹,

Bonadio²,

Goldstein³

et al. 1998

Journal of Pharmaceutical Sciences

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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 approximately 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/microgram 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.

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Section: Discussionmentioning

confidence: 99%

A DNA Controlled-Release Coating for Gene Transfer: Transfection in Skeletal and Cardiac Muscle

Labhasetwar¹,

Bonadio²,

Goldstein³

et al. 1998

Journal of Pharmaceutical Sciences

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“…[13][14][15][16] The main focus of this study was to investigate various agents (see Table 1) for nanoparticle surface modification to enhance their arterial wall uptake. Polylactic polyglycolic acid copolymer (PLGA) was used to formulate nanoparticles using U-86983, a 2-aminochromone (U-86), as a model antiproliferative agent (Pharmacia & Upjohn, Kalamazoo, MI).…”

Section: Introductionmentioning

confidence: 99%

Arterial Uptake of Biodegradable Nanoparticles: Effect of Surface Modifications

Labhasetwar¹,

Song²,

Humphrey³

et al. 1998

Journal of Pharmaceutical Sciences

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172

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Restenosis is the reobstruction of an artery following interventional procedures such as balloon angioplasty or stenting. Local pharmacotherapeutic approaches using controlled release systems are under investigation to inhibit the regional pathophysiologic process of restenosis. We have been investigating biodegradable nanoparticles (100 +/- 39 nm in diameter, mean +/- sd) for the local intra-arterial drug delivery. The purpose of this study was to investigate nanoparticle surface modifications (see Table 1) to enhance their arterial uptake. The PLGA (polylactic polyglycolic acid copolymer) nanoparticles were formulated by an oil-in-water emulsion solvent evaporation technique using a 2-aminochromone (U-86983, Upjohn and Pharmacia) (U-86) as a model antiproliferative agent. The various formulations of nanoparticles were evaluated for the arterial wall uptake by using an ex-vivo dog femoral artery model. The selected formulations were then tested in vivo in acute dog femoral artery and pig coronary artery models. The nanoparticles surface modified with a cationic compound, didodecyldimethylammonium bromide (DMAB), demonstrated 7-10-fold greater arterial U-86 levels compared to the unmodified nanoparticles in different ex-vivo and in-vivo studies. The mean U-86 levels were 10.7 +/- 1.7 microg/10 mg (dog) and 6.6 +/- 0.6 microg/10 mg (pig) in the artery segments ( approximately 2 cm) which were infused with the nanoparticles. The pig coronary studies further demonstrated that the infusion of nanoparticles with higher U-86 loading reduced the arterial U-86 levels, whereas increasing the nanoparticle concentration in the infusion solutions increased the arterial U-86 levels. The biodistribution studies in pigs following coronary arterial administration of nanoparticles demonstrated disposition of U-86 in the myocardium and distally in the liver and the lung. The mechanism of enhanced arterial uptake of the DMAB surface modified nanoparticles seems to be due to the alteration in the nanoparticle surface charge. The unmodified nanoparticles had a zeta potential of -27.8 +/- 0.5 mV (mean +/- sem, n = 5), whereas the DMAB modified nanoparticles demonstrated a zeta potential of +22.1 +/- 3.2 mV (mean +/- sem, n = 5). The adsorption of DMAB to the nanoparticle surface followed the Freundlich isotherm with binding capacity k = 28.1 microg/mg and affinity constant p = 2. 33. In conclusion, surface modified nanoparticles have potential applications for intra-arterial drug delivery to localize therapeutic agents in the arterial wall to inhibit restenosis.

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“…liposomes, were first described by Bangham in the 1960's [54], and liposomes have been tested for gene and drug delivery to prevent or treat restenosis for more than 20 years [55,56]. Liposomes are closed vesicles, composed of membrane-like lipid bilayers capable of incorporating both hydrophobic and hydrophilic drugs.…”

Section: Liposomesmentioning

confidence: 99%