U. Schmidt-Erfurth

Vascular Targeting in Photodynamic Occlusion of Subretinal Vessels

PURPOSEnTo evaluate the potential of photodynamic therapy (PDT) using benzoporphyrin derivative (BPD) for occlusion of subretinal neovascular membranes, the authors studied efficiency and collateral damage of PDT-induced photothrombosis in the rabbit choriocapillary layer.nnnMETHODnBenzoporphyrin derivative, a new photosensitizer, currently in clinical trials for tumor therapy, was used. Low-density lipoprotein served as a carrier to enhance selective targeting of vascular endothelial cells.nnnRESULTSnComplete choriocapillary occlusion was achieved at a BPD dose of 2 mg/kg and a radiant exposure as low as 10 J/cm2. When PDT was performed 3 hours after BPD application, damage to the neural retina was minimal. Only inner photoreceptor segments showed mitochondrial swelling probably secondary to choroidal ischemia. Bruchs membrane remained intact. Retinal pigment epithelium was invariably damaged as seen with other photosensitizers.nnnCONCLUSIONnCompared with photocoagulation BPD-PDT allows endothelial-bound intraluminal photothrombosis, sparing important structures such as neural retina and Bruchs membrane. It may thus provide a more selective treatment of juxtafoveal and subfoveal neovascular membranes.

Photodynamic therapy of subfoveal choroidal neovascularization: clinical and angiographic examples

Abstractu2002· Background: Conventional photocoagulation of subfoveal choroidal neovascularization (CNV) is often accompanied by visual loss due to thermal damage to adjacent retinal structures. Photodynamic therapy (PDT) allows vascular occlusion by selective photochemical destruction of vascular endothelial cells only. In a pilot study we evaluated the use of PDT in CNV. · Methods: In a clinical phase I/II trial, patients with subfoveal CNV were treated with PDT. Benzoporphyrin derivative monoacid ring A (BPD) was used as sensitizer at a drug dose of 6 mg/m2 or 12 mg/m2. Irradiation was performed via a diode laser emitting at 690 nm coupled into a slit lamp. Safe and maximum tolerated light doses were defined by dose escalation from 25 to 150 J/cm2. Photodynamic effects were documented ophthalmoscopically and angiographically.u2002· Results: Sixty-one patients received a single course of BPD-PDT. Preliminary results suggest no damage to retinal structures within the treated area clinically. Retinal perfusion was not altered, while CNV demonstrated immediate absence of fluorescein leakage in the majority of lesions subsequent to PDT. At optimized parameters (6 mg/m2 and 50 J/cm2) complete cessation of leakage from classic CNV occurred in 100% of cases at 1 week and in 50% at week 4. In 70–80% of classic CNV, leakage reappeared at week 12, but markedly less than before treatment.u2002· Conclusion: PDT allows temporary absence of leakage from CNV with preservation of visual acuity. The long-term prognosis of CNV secondary to age-related macular degeneration treated with repeated courses of PDT is being evaluated in a phase III trial.

Photodynamic Therapy of Experimental Choroidal Melanoma Using Lipoprotein-delivered Benzoporphyrin

BACKGROUNDnBenzoporphyrin derivative monoacid (BPD) is a new photosensitizer currently undergoing clinical trial for cutaneous malignancies. Compared with the clinically most frequently used sensitizer, Photofrin, BPD may offer higher tumor phototoxicity, better tissue penetration, and absence of significant skin sensitization. Low-density lipoprotein (LDL) carriers heighten efficiency and selectivity of BPD because neovascular and tumor cells express an increased number of LDL receptors. Hence, in addition to the vaso-occlusive effects similar to most other photosensitizers, LDL-BPD also has been shown to cause direct tumor cell damage.nnnMETHODSnBenzoporphyrin derivative monoacid was complexed with human LDL and used in photodynamic treatment of choroidal melanomas experimentally induced in eight albino rabbits. Five rabbits served as controls. Three hours after intravenous injection of 2 mg/kg body weight of LDL-BPD, eight tumors were irradiated at 692 nm and 100 J/cm2 via an argon-pumped dye laser coupled into a slit lamp.nnnRESULTSnAngiography and histologic findings showed immediate photothrombosis after disintegration of endothelial membranes. After complete necrosis of tumor cells within 24 hours, a small fibrotic scar slowly developed. No tumor regrowth was noted up to 6 weeks when animals were killed.nnnCONCLUSIONnThese data suggest that photodynamic treatment with LDL-BPD may be a promising modality for multiple clinical applications, including tumors and neovascularizations II.

Photodynamic targeting of human retinoblastoma cells using covalent low-density lipoprotein conjugates.

Combination of photosensitizers with carrier molecules has been shown to enhance the efficiency of photodynamic therapy (PDT). Owing to an increased expression of their receptors on some malignant and proliferating cells, low-density lipoproteins (LDLs) are potential endogenous carriers. A photosensitizer, chlorin e6 (Ce6), was covalently bound to LDL via carbodiimide activation. The Ce6-LDL conjugate was evaluated on a fibroblast cell line with defined LDL receptor expression and a retinoblastoma cell line (Y79). Uptake of free Ce6 and Ce6 either covalently bound to or complexed with LDL was measured by spectrofluorimetry. Phototoxicity after irradiation at 660 nm was determined by a mitochondrial activity assay (MTT). Covalent binding to LDL significantly increased the uptake of Ce6 for both cell lines by a factor of 4-5. A Ce6: LDL binding ratio of 50:1 was optimal. A receptor-mediated uptake was demonstrated by saturability and competitive inhibition by free LDL. Binding also occurred at 2 degrees C and was attributed to non-specific associations. Irradiation with 10 J cm-2 of 660 nm light after treatment of cells with Ce6-LDL conjugate reduced the MTT activity by 80%, while free or mixed Ce6 induced a maximum of 10% reduction in the MTT activity following identical treatment conditions. These data suggest that targeting of LDL receptor-bearing cells using covalently bound carriers, such as LDL, might increase the efficiency and selectivity of PDT. Intraocular tumours such as retinoblastomas could be appropriate targets for such an approach owing to the ease of access of light sources and the need for non-invasive approaches in sensitive ocular sites.

Macular injury by a military range finder.

OBJECTIVEnThe authors report the clinical findings of a civilian patient who unintentionally looked into the laser beam of a military range finder. Detailed information on the range finder is given. The objective is to illustrate the potential danger of such devices and to give detailed information on the device, the clinical findings associated with exposure, and the laser-tissue interaction mechanism.nnnMETHODSnThe patient was examined with fluorescein angiography, indocyanine green angiography, microperimetry, and optical coherence tomography, both in the acute stage (2 hours) and 4 weeks later. Fluorescein angiography was performed again 4 months later. A total of 100 mg prednisone tapered over 9 days was prescribed. Additionally, 50 microg tissue plasminogen activator (TPA) and 0.5 mL pure C2F6 were injected in the vitreous.nnnRESULTSnIn the acute phase, hemorrhage was located beneath the retina, primarily beneath the retinal pigment epithelium. Retinal defects as seen initially over the subretinal blood were reduced after 4 weeks, but a retinal defect ranging from the lasered site toward the fovea remained. Visual acuity slightly increased from 20/100 to 20/63 after 4 weeks. Indocyanine green angiography showed a large hypofluorescent spot in the macula. Four months after the accident, a classic choroidal neovascularization developed, originating from the lasered site. The technical parameters of the range finder were: Nd:YAG laser (1,064 nm), pulse duration 10 ns, beam divergence 1.5 mrad, energy 10 mJ.nnnCONCLUSIONnA range finder can produce severe macular injury. The primary laser-tissue interaction mechanism seems to be explosive disruption of choroidal tissue. Intravitreal injection of TPA and C2F6 did not show a clear benefit to such laser lesions. A late complication can be secondary choroidal neovascularization.

Functional topographic imaging of the human retina by confocal scanning laser angiography

We present a new method for processing confocal fluorescence angiographies in order to extract the topography of the perfused surface. The topographies extracted for various normal and pathologic conditions agree well with morphological and functional conditions. They allow, for example, the quantification of leakage and the verification of treatment success in photodynamic therapy and provide thus a new valuable tool for analyzing the topography of functional pathologies.