Polyion Complex Micelle as Drug Delivery System for Corneal Neovasuculization

Abstract

Abstract: : Purpose:Corneal neovascularization (NV) is slightly–threatening condition, but there is few effective therapy in the clinical setting. Recently, nanocarriers consisting of polyion complex (PIC) micelles, composed of PEG–b–P(Asp) and the nano–scaled dendrimer porphyrin [NH₂CH₂CH₂NHCO]₃₂DPZn, have been demonstrated to effectively deliver dendrimer porphyrin photosensitizers into cancer cells and produce enhanced photodynamic efficacy. In this study, we examined the accumulation of dendrimer porphyrin photosensitizers in the corneal NV after systemic injection of PIC micelles encapsulating dendrimer porphyrins to investigate the feasibility of drug delivery to corneal NV using PIC nano–micelle. Methods:Corneal NV was induced in C57/B6 mice by placing an intrastromal nylon suture 1 mm away from the limbus. Four days after surgery, PIC micelles were administered by intravenous injection at the dose of 10mg/kg. For a control, the same amount of free dendrimer porphyrin was infused intravenously. To examine the accumulation of dendrimer porphyrin, corneas were excised 1,4,24 and 168 hours after injection, flat–mounted, stained with FITC–labeled BS–1 lectin, and observed with fluorescein microscopy. In the same model, photodynamic therapy was performed. 24 hours after the injection of PIC micelles encapsulating dendrimer porphyrin or free dendrimer porphyrin, 430 nm laser with 0.5 mm diameter was applied over the newly formed vessels in the cornea. The laser energy was 50 Jules/cm². Before and 7 days after the laser treatment, the extent and the density of corneal neovascularization were examined with fluorescein angiography. Results:An hour after administration, fluorescence of dendrimer porphyrin started to accumulate in the vascularized area and enhanced until 24 hours after administration. The accumulation of dendrimer porphyrin decreased but remained after 168 hours. In contrast, dendrimer porphyrin was only vaguely detected in the area of neovascularization in the eyes receiving free dendrimer porphyrin. There was no fluorescence of micelles in normal limbal vessels. After PDT, the density of vessels decreased, but corneal vessels remained in the free dendrimer porphyrin group. In contrast, in the micelled dendrimer porphyrin group, few remaining vessels could be detected after PDT. Conclusions: The results suggest that PDT using dendrimer porphyrin encapsulated in PIC micelles can be an excellent therapy for corneal neovascularization.

Keywords: neovascularization • photodynamic therapy • cornea: basic science