ABSTRACT
PURPOSE: Targeted drug delivery to the ocular tissues remains a challenge. Biodegradable intraocular implants allow prolonged controlled release of drugs directly into the eye. In this study, we evaluated an anterior suprachoroidal polyurethane implant containing dexamethasone polyurethane dispersions (DX-PUD) as a drug delivery system in the rat model of endotoxin-induced uveitis (EIU). METHODS: In vitro drug release was studied using PUD implants containing 8%, 20%, and 30% (wt/wt) DX. Cytotoxicity of the degradation products of DX-PUD was assessed on human ARPE-19 cells using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) test. Short-term ocular biocompatibility of suprachoroidal DX-PUD implants was evaluated in normal rat eyes. Endotoxin-induced uveitis was then induced in rat eyes preimplanted with DX-PUD. Clinical examination was performed at 24 hours; eyes were used to assess inflammatory cell infiltration and macrophage/microglial activation. Cytokine and chemokine expression in the iris/ciliary body and in the retina was investigated using quantitative PCR. Feasibility of anterior suprachoroidal PUD implantation was also tested using postmortem human eyes. RESULTS: A burst release was followed by a sustained controlled release of DX from PUD implants. By-products of the DX-PUD were not toxic to human ARPE-19 cells or to rat ocular tissues. Dexamethasone-PUD implants prevented EIU in rat eyes, reducing inflammatory cell infiltration and inhibiting macrophage/microglial activation. Dexamethasone-PUD downregulated proinflammatory cytokines/chemokines (IL-1ß, IL-6, cytokine-induced neutrophil chemoattractant [CINC]) and inducible nitric oxide synthase (iNOS) and upregulated IL-10 anti-inflammatory cytokine. Polyurethane dispersion was successfully implanted into postmortem human eyes. CONCLUSIONS: Dexamethasone-PUD implanted in the anterior suprachoroidal space may be of interest in the treatment of intraocular inflammation.
Subject(s)
Anti-Inflammatory Agents/administration & dosage , Dexamethasone/administration & dosage , Disease Models, Animal , Drug Delivery Systems , Uveitis/prevention & control , Animals , Anti-Inflammatory Agents/pharmacokinetics , Cell Line , Cell Survival , Ciliary Body/metabolism , Coloring Agents/pharmacology , Cytokines/genetics , Cytokines/metabolism , Dexamethasone/pharmacokinetics , Drug Implants , Extracellular Space , Female , Humans , Iris/metabolism , Lipopolysaccharides/toxicity , Polyurethanes , Rats , Rats, Inbred Lew , Retinal Pigment Epithelium/drug effects , Salmonella typhimurium , Spectroscopy, Fourier Transform Infrared , Tetrazolium Salts/pharmacology , Thiazoles/pharmacology , Uveitis/chemically induced , Uveitis/metabolismABSTRACT
In this study, the effects of the controlled and sustained release of methotrexate from poly(É-caprolactone) implants were evaluated in the solid Ehrlich tumor. The drug locally leached from the implantable devices was capable of reducing the tumor growth and the necrotic areas of the tumor site. Furthermore, the methotrexate exerted its anti-tumor effect probably by the recruitment of neutrophils at the tumor site, which assisted in modulating the growth of the tumor. The polymeric implants containing methotrexate could be a chemotherapic alternative to treat locally solid tumors with lower systemic side effects.
