Role of photodynamic therapy in the prevention of intimal hyperplasia

Role of photodynamic therapy in the prevention of intimal hyperplasia.

Endovascular treatment of symptomatic atherosclerotic peripheral artery disease (PAD) is recommended as the primary revascularization strategy in many clinical and anatomic scenarios. Although percutaneous transluminal angioplasty (PTA) has a high initial success rate, restenosis remains the Achilles heel. Restenosis rates up to 60% are reported. Restenosis has a multifactorial etiology including a combination of intimal hyperplasia (IH), matrix deposition and negative geometric remodeling. IH is a complex pathologic process that results from proliferation of smooth muscle cells from the arterial media in response to vessel wall injury. Subsequent migration of smooth muscle cells into the intima and deposition of intracellular matrix lead to vessel narrowing and clinically relevant restenosis. Intimal hyperplasia develops as part of the healing response to the procedure-related vessel wall injury. Self-expanding stents were thought to solve this problem. Randomized trials have demonstrated patency rates with bare metal stents and drug-eluting stents superior to those observed with PTA. In spite of the improved outcomes reported with stenting, in-stent stenosis remains a major issue. Given the limitations of stenting, there has been considerable interest in identifying approaches that could improve patency without the need for a permanent metallic implant.

A new therapeutic approach is photodynamic therapy (PDT). PDT involves the light activation of a photoactivable molecule called a photosensitizer in the presence of oxygen. First there must be an accumulation of photosensitizer in the target tissue. The tissue is photo-illuminated at the wavelength that favors maximal absorption by the photosensitizer. The resultant photobiological response is cell apoptosis and delayed necrosis from neovascular damage.  After light irradiation of the photosensitizer, the energy from the excited photosensitizer can be transferred to surrounding molecules allowing the generation of cytotoxic singlet oxygen. This is a major cytotoxic agent causing severe cellular damage. The cellular damage is only noted in the atheromatous areas after light exposure. Furthermore the elastic lamina and adventitia are preserved, suggesting that the integrity of the vessel is conserved. The absence of mural inflammation, despite extensive cell death, is consistent with the regression of atherosclerotic plaque through a hypothesized mechanism of apoptosis. This suggests that PDT can be an important novel approach to prevent IH.

The use of PDT in the prevention of IH has been reported in different trials but several things remain unclear. Which photosensitizer should we use? How should we administrate the photosensitizer? Is local intravascular administration through a local delivery device possible? What concentration of photosensitizer can we use? What is the appropriate light wavelength? Different trials are needed to answer these questions.

WP1: Search of the literature on ICG

First we need to decide which photosensitizer (PS) is the best. Based on previous reports Indocyanine Green (ICG) is a possible candidate. ICG was approved for clinical use in humans in 1956. It is mainly used for ophthalmologic angiography. It is commercially available at low cost in a pure form. The main features of ICG that make it suitable for bio-imaging applications are its near infrared absorption and its fluorescence. The photodynamic effect of ICG involves cell destruction due to production of reactive oxygen but the mechanisms of action are not clear. But ICG also transforms a part of the light energy into thermal energy. This results in temperature rise in the target tissue also leading to cell necrosis. The question of whether ICG is or is not a good PS for PDT is still controversial. 10 Therefore it is necessary to have a close look at the studies that have been carried out using ICG as a chemical compound for treatment. Different mechanism of action, possible side-effects and complications will be reviewed.

WP2: Selective absorption of ICG in the atherosclerotic plaque: Dosing? Timing? Dose-response curves.

In a first trial we will study the absorption of ICG into the atherosclerotic vessel wall.A rabbit model of lipid-rich atherosclerosis is used. An estimated total of 18 New Zealand white rabbits (3-3.5kg, Charles River) will be used in this first experiment.Rabbits are anesthetized. Through a mid-line abdominal incision the aorta and iliacs are dissected. Heparin is administrated. A barotrauma in the common iliac is performed with a balloon angioplasty. The aorta and iliacs are clamped and ICG is injected in the common iliac at a dose of 1mg/kg.After 270 seconds the non-absorbed ICG is aspirated, the clamps are removed and the circulation is restored. The rabbit is euthanized. The vessels are harvested and send for examination. This first experiment will provide information about what is the best dose for local administration and what is the best time-interval. Other time intervals that can be tested are 180 and 90 seconds. An ICG dose of 100µg/kg is another possibility.

WP3: Local administration of ICG and illumination of the vessel wall.

From the results obtained in the first trial, optimal ICG dose will be locally administrated. Subsequentially the arterial wall is illuminated. The photodynamic effect of ICG, due to the production of singlet oxygen, and thus subsequent photobiological response from the vessel wall is studied. The same model of lipid-rich atherosclerosis in NZ white rabbits is used. The rabbits are anesthetized. Because the tissue destruction will be studied in different time intervals after illumination, the rabbits must be kept alive after illumination of the vessel wall. Therefore we perform a surgical denudation of the external carotid artery instead of a laparotomy. The artery is punctured with an 18g needle, a wire and sheath is introduced. Under fluoroscopy the guide wire is now introduced in the aorta and iliac arteries. Heparin is injected. As in the first experiment, a balloon injury is performed. With the use of two Fogarty balloon catheters the common iliac artery is clamped (for this access from below through the external artery is necessary). Through the double lumen Fogarty catheter ICG is administrated. With the use of a cylindrical light diffuser, illumination of the vessel wall is performed. The exact time of illumination strongly correlates with the used dose of ICG (high dose of ICG, short time of illumination). We can study the effect of illumination in different time intervals e.g. 24hours after illumination.

WP4: Local administration with a specific designed intravascular device.

A specific designed intravascular device will be used to permit the local administration of ICG and subsequent activation of this agent following illumination of the vessel wall. The development of the device will be in cooperation with an external, not yet defined, partner.

WP5: Prevention of IH

Based on the previous trials the hypothesis that PDT plays an important role in the prevention of IH can be tested.In the same rabbit model as previously described ICG is locally administrated and the vessel wall is illuminated. Both doses of ICG and illumination time are based on the results of the previous trials. After this procedure the rabbits are kept alive for at least 4 weeks.The effect of the PDT on the vessel wall will be examined. Different time intervals are possible.

WP6: Trial in man

The ultimate goal is to perform a clinical trial with the specific designed intravascular   catheter for local administration of ICG and illumination of the vessel wall. Is there an important role for photodynamic therapy in the prevention of intimal hyperplasia?