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S. D. Solomon, F. Knezevich, M. Moscaritolo, S. d'Anna, R. Zeimer; Application of Laser-Targeted Drug Delivery Toward the Bench-Top to Bed-Side Transfer of Laser-Targeted Angiography for the Detection of Choroidal Neovascularization - A Phase I Dose Estimate. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3462. doi: https://doi.org/.
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The detection and classification of choroidal neovascularization (CNV) is of paramount importance in assessing the efficacy of existing or new therapies for neovascular age-related macular degeneration (AMD). Presently, this is accomplished with fluorescein angiography. However, conventional angiography only provides information on leakage of dye from CNV. There is a need for a method capable of specifically visualizing the patent vascular lumens of CNV independent of whether or not there is active leakage. We have developed such a method of selective drug delivery that can be applied to perform targeted dynamic angiography. Following successful tests in animal models, a phase I study has been planned in patients with AMD to assess the safety of targeted angiography. This pilot study has been designed to estimate the lowest dose that will yield a visible angiogram.
Our method consists of encapsulating 6-carboxyfluorescein (CF) in thermo-sensitive nanoparticles which are injected intravenously. Due to fluorescence quenching, the nanoparticles are invisible during angiography. A safe, invisible laser beam is then directed to a retinal area suspected of harboring CNV. The laser beam causes the retinal tissues to warm-up, leading to the release of a bolus of dye from the nanoparticles. The progression of this bolus provides selective angiograms that highlight only the choroid, choriocapillaries, and CNV.Pigmented rabbits were injected with different fractions of the intended dose previously derived, and LTA was performed. The blue illumination used for visualization during angiography and the infrared beam used to activate release were set at 20% and 100%, respectively, of the maximal permissible exposure (MPE) set by standards (ANSI) for safe viewing. The digital camera was operated at high gain and a frame size reduced to 696 by 512 pixels.
The dose of CF nanoparticles was reduced gradually from 100% to 13% of the intended dose. The dynamic angiograms acquired clearly showed a bolus progressing in the choroidal arteries, choriocapillaries, and veins. This sequence was visible down to the lowest dose.
This pilot study indicates that the choriocapillaries and small choroidal vessels may be visualized at all the escalation levels of the planned phase I study. Although encouraging, the study does not guarantee the same results in humans, as this pilot study was performed in animal eyes with heavy pigmentation, devoid of CNV or of any scar tissue.
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