To evaluate the feasibility, efficacy, and selectivity of photodynamictherapy (PDT) using targeted delivery of verteporfin to choroidal neovascularization(CNV) in the rat laser-injury model of CNV.
We performed PDT in rat eyes on experimental CNV and normal retina andchoroid using verteporfin conjugates. A targeted verteporfin conjugate wasmade by conjugating verteporfin (after isolation from its liposomal formulation)to a modified polyvinyl alcohol (PVA) polymer (verteporfin-PVA) followed bylinkage to the peptide ATWLPPR known to bind the receptor for vascular endothelialgrowth factor, VEGFR2. The verteporfin-PVA conjugate served as a control.We performed fluorescent fundus angiography to determine the optimal timingof light application for PDT using the conjugates. Closure of CNV was assessedangiographically and graded in a masked standardized fashion. We used standardizedhistological grading to compare the effects on normal retina and choroid.
The verteporfin-PVA conjugation ratio was on average 28:1. The conjugateretained typical emission/excitation spectra and photosensitizing activityand was as efficient as an equivalent amount of verteporfin. Peak intensityof targeted verteporfin in CNV was detected angiographically at 1 hour afterintravenous injection. Photodynamic therapy using targeted verteporfin (3or 4.5 mg/m2) with light application 1 hour after drug injectionshowed angiographic closure of all treated CNV (17/17) 1 day after treatment.Photodynamic therapy using verteporfin-PVA at the same drug dose achievedclosure in 18 of 20 CNV. Histological examination after PDT of normal retinaand choroid using targeted verteporfin and irradiation at 1 hour showed minimaleffect on retinal pigment epithelium and no injury to photoreceptors, whereasPDT using verteporfin-PVA resulted in retinal pigment epithelium necrosisand mild damage to photoreceptors.
Verteporfin bound to the targeting peptide, ATWLPPR, retained its spectraland photosensitizing properties. Angiography demonstrated localization ofthe targeted verteporfin 1 hour after injection. Photodynamic therapy usingtargeted verteporfin and the control conjugate were more effective in causingCNV closure than standard liposomal verteporfin. The targeted verteporfinresulted in more selective treatment than the control conjugate or standardverteporfin. These results suggest that targeted PDT strategies based on selectiveexpression of receptors on CNV vasculature may improve current therapy.
Targeted PDT for CNV is feasible and may offer a qualitative improvementin current treatments for patients with age-related macular degeneration.This study provides the basis for further preclinical studies of targetedPDT strategies and subsequent clinical trials.