Porphyrin-Photosensitized Processes: Their Applications in the Prevention of Arterial Restenosis

Abstract

Photodynamic therapy (PDT) is based on the use of a photozensitising compound which is accumulated by rapidly proliferating cells. Subsequent irradiation with light wavelengths specifically absorbed by the photosensitiser promotes the generation of reactive short-lived oxygen species which cause an irreversible and selective damage. Endovascular interventions to correct obstructive arterial disease have been developed worldwide with excellent short term results. However, long term patency is still limited by the onset of restenosis, due to subsequent intimal hyperplasia (IH). IH is characterized by proliferation and migration of smooth muscle cells (SMC) and extracellular matrix production. Targeting of SMC by photozensitisers can be efficiently achieved by taking advantage of the receptors for low density lipoproteins (LDL) expressed by such cells. Thus, preference is given to hydrophobic compounds which readily partition in the lipid matrix of LDL. We developed a liposomal formulation of a highly hydrophobic photozensitising agent, Zn(II)-phthalocyanine (ZnPc). The liposome-delivered ZnPc was readily taken up by cultured SMC cells and preferentially localized in the Golgi apparatus. Red light irradiation of incubated SMC induced cell death. Extension of these investigations to an in vivo rabbit model showed that ZnPc mainly accumulated in the media layer, where PDT induces the main damage through cellular depletion due to apoptosis of SMC, changes in the extracellular matrix with generation of a barrier to cellular migration, and acceleration of re-endothelization. Initial clinical applications showed that PDT safely and effectively prevents restenosis after angioplasty up to a 6 month follow-up.

Photodynamic Therapy Using Novel Zinc Phthalocyanine Derivatives and a Diode Laser for Superficial Tumors in Experimental Animals

“…Zinc Pc derivatives are expected to be second-generation photosensitizers because they have relatively high absorbance at red light, which can reach deep into tissues. However, they show π-π stacking, which results in aggregation in water, and they also have low solubility [11] [12]. To overcome these drawbacks, we synthesized novel zinc Pc derivatives containing fluorine [14] [16] [17] and also conjugate CD molecules.…”

“…Phthalocyanine (Pc) derivatives are being studied intensively as second-generation photosensitizers for PDT owing to their intense absorption in the red visible region, high efficacy in producing singlet oxygen, and ease of chemical modification and formation [11]- [13]. Using Pc derivatives as photosensitizers means that their lipophilic, hydrophilic, and self-aggregation properties can be modulated by modification of the substituents on the periphery of the Pc core.…”

Platelets, photosensitizers, and PDT

“…However, the long term effects are unclear and bypassing the need for cytostatic drugs or invasive modalities would be beneficial [116]. Interestingly, smooth muscle migration and proliferation can be targeted specifically by PDT agents [117]. Likewise, arteriosclerosis has been targeted by PDT with motexafin lutetium with some success in animal studies but is not used clinically [118].…”

“…PDT clearly offers an advantage here as it does not induce teratogenic effects and results in more divers effects [119,120,121]. Current studies often employ liposomal formulations or hydrophobic drugs which can bind to LDLs [117]. For example, photoangioplasty has been suggested as a potential treatment modality as it reduces or inhibits restenosis [122].…”

Novel Insights into the Pathobiology of the Vascular Access – Do They Translate into Improved Care?

“…addition since VSMCs have receptors for low-density lipoproteins, other groups have developed processes of direct photodynamic targeting to prevent neointimal hyperplasia in animal PTFE [147] and angioplasty models [148] . A liposomal formulation of a highly hydrophobic photosensitizing agent, Zn(II)-phthalocyanine, is readily taken up by cultured VSMCs, and subsequent red light irradiation induced cell death and neointimal hyperplasia in rabbits [144] .…”