There are many potentially treatable ocular diseases that all too often lead to blindness. Bacterial endophthalmitis and fungal endophthalmitis are considered the most disastrous complications of ocular surgery and trauma. Proliferation in the vitreous over and under the retina, is the major cause of failure of retinal detachment surgery. Viral retinitis and uveitis lead to blindness either by destruction of the retina or by creating a secondary complication, such as cataract or glaucoma. Antibiotics, antivirals, antifunagals, and antiproliferative drugs that might successfully treat these diseases are available. However, the blood-retina barrier restricts the concentration of a drug in the globe after systemic injection. Therefore, injection directly into the vitreous has become a method of choice for the treatment of these diseases. The main disadvantage of ineravitreal injection is the rapid drug clearance from the vitreous, necessitating repeated injections to maintain therapeutic levels. In an attempt to maintain therapeutic concentrations for extended periods, drugs have been incorporated into liposomes. However, retarded clearance of the drug from the vitreous does not ensure successful treatment of the disease. The proposed research will determine what factors are most important for the successful treatment of ocular disease using liposome-incorporated drugs. In vitro studies will b=determine the best phospholipid composition and formation methods that will produce stable vesicles with optimal size distributions and leakage rates. The in vivo characteristics of liposome-drug combinations will then be assessed to determine how liposome encapsulation into the aqueous compartment, or intercalation into the bilayer, affects the toxicity, pharmacokinetics, and efficacy of the drug. Then, the roles that decreased clearance, decreased toxicity, and uptake of the vesicle contents by specific cell types play in improved treatment will be determined. Our long range goal is to apply this knowledge of the uptake, breakdown, and clearance of the vesicles and their contents from the vitreous to the improved treatment of human eye disease.
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