Abstract
Abstract: :
Purpose: Local delivery of drugs to the retinal vasculature could open the way for interventions not currently feasible. Laser targeted drug delivery (LTD) has been developed to provide a minimally invasive access to this vasculature. Drugs that are encapsulated in heat–sensitive liposomes and injected intravenously can be released by warming the liposome with a laser pulse directed through the pupil of the eye. Previous studies in rodents have demonstrated the potential benefits of LTD for angiography and safe occlusion of new vessels in a rat model of age related macular degeneration. A dog toxicology study of heat sensitive liposomes containing carboxyfluorescein (CF) was performed. We studied the potential systemic side effects and ocular toxicity of retinal exposure to blue light (used in angiography) in the presence of CF. Methods:Heat sensitive liposomes containing CF were intravenously injected into eight dogs at a dose of 10 ml/kg (10x the intended clinical dose). In each eye, two 20° areas of the fundus were exposed to blue (490 nm) light at the intended power density. In one eye, the procedure was performed once with 3x the maximal intended duration (2 sec). In the opposite eye, blue light exposure was performed 10 times at 2x the intended duration (0.2 sec). Four other dogs were administered CF liposomes and returned to their cages without light exposure. A separate group of 8 dogs was similarly treated except that phosphate buffered saline was injected. All animals were studied for signs of systemic toxicity and underwent ophthalmoscopy. Four of the dogs were sacrificed at day 2 and the remaining four at day 14. Results: There were no adverse findings in clinical pathology, hematology/coagulation, clinical chemistry, urinalysis, cardiovascular evaluations, gross necropsy , histopathology of tissues (including liver and bone marrow) and ophthalmoscopy. Red colored patches on the skin were observed on day 0 following dosing. Anticipated yellowing of the skin and urine, attributed to free CF, was observed during the first week. Conclusions:The lack notable evidence of systemic toxicity, in dogs, following injection of heat sensitive liposomes containing CF at 10x the intended clinical dose, concurs with the findings in rats. These results justify efforts toward a phase I study of LTD for targeted angiography.
Keywords: drug toxicity/drug effects • age–related macular degeneration • imaging methods (CT, FA, ICG, MRI, OCT, RTA, SLO, ultrasound)