Miller Joan W
Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
Trans Am Ophthalmol Soc. 2008;106:357-82.
Photodynamic therapy (PDT) using verteporfin was the first pharmacologic therapy for neovascular age-related macular degeneration and changed the treatment paradigm for a major, blinding disease. The experimental work in the nonhuman primate was essential in developing treatment parameters for verteporfin PDT that could successfully occlude choroidal neovascularization with limited injury to the neural retina. Early in the preclinical primate studies, we hypothesized that higher irradiances could be used for ocular PDT than had been used in dermatology and other applications, which typically utilized an irradiance of 150 to 200 mW/cm(2). We set out to test the feasibility of irradiances up to 1800 mW/cm(2).
PDT was applied to normal monkey eyes using verteporfin/benzoporphyrin derivative (BPD) (2 mg/kg) mixed with low-density lipoprotein in DMSO, and 692-nm light, with a spot size 1250mum, fluence approximately 50 J/cm(2), and irradiance varying from 150 (treatment time, 6 minutes) to 1800 mW/cm(2) (treatment time, 30 seconds). Photocoagulation lesions were applied using 514-nm and 692-nm laser light without drug, with irradiance of 18,750 to 200,000 mW/cm(2) and spot size of 500 mum. Treatment effect was evaluated by fundus photography, angiography, and light and electron microscopy with collagen denaturation as a marker of thermal injury.
Verteporfin/BPD PDT at irradiances of 150 to 1800 mW/cm(2) showed no collagen denaturation in contrast to photocoagulation lesions without dye (irradiance 10-fold and higher).
Verteporfin PDT could safely be performed at higher irradiances, permitting a clinically practical therapy. Ultimately, clinical trials demonstrated that verteporfin PDT could limit moderate vision loss in neovascular age-related macular degeneration. Although anti-VEGF therapy has replaced PDT as a first-line therapy, PDT may still have a role, perhaps in combination therapies. Further investigations to optimize drug delivery and to better understand the molecular mechanisms of PDT effects in both choroidal neovascularization and retina will improve its application in macular diseases.
使用维替泊芬的光动力疗法（PDT）是治疗新生血管性年龄相关性黄斑变性的首个药物疗法，改变了这种主要致盲疾病的治疗模式。在非人灵长类动物身上开展的实验工作对于确定维替泊芬PDT的治疗参数至关重要，该治疗参数能够成功封闭脉络膜新生血管，同时对神经视网膜造成的损伤有限。在临床前灵长类动物研究的早期，我们假设眼部PDT可使用比皮肤科及其他应用中更高的辐照度，后者通常使用150至200 mW/cm²的辐照度。我们着手测试高达1800 mW/cm²辐照度的可行性。
将维替泊芬/苯并卟啉衍生物（BPD）（2 mg/kg）与二甲基亚砜中的低密度脂蛋白混合，对正常猴眼进行PDT治疗，使用波长692 nm的光，光斑尺寸1250μm，能量密度约50 J/cm²，辐照度从150 mW/cm²（治疗时间6分钟）至1800 mW/cm²（治疗时间30秒）不等。使用514 nm和692 nm激光且不使用药物进行光凝损伤，辐照度为18750至200000 mW/cm²，光斑尺寸为500μm。通过眼底摄影、血管造影以及以胶原变性作为热损伤标志物的光镜和电镜检查来评估治疗效果。
与未使用染料的光凝损伤（辐照度高10倍及以上）相比，维替泊芬/BPD PDT在150至1800 mW/cm²的辐照度下未显示胶原变性。
维替泊芬PDT可在更高辐照度下安全进行，从而实现临床实用的治疗方法。最终，临床试验表明维替泊芬PDT可限制新生血管性年龄相关性黄斑变性导致的中度视力丧失。尽管抗血管内皮生长因子（VEGF）疗法已取代PDT成为一线治疗方法，但PDT可能仍有作用，或许可用于联合治疗。进一步开展研究以优化药物递送并更好地理解PDT在脉络膜新生血管形成和视网膜中的作用分子机制，将改善其在黄斑疾病中的应用。
