Treatment of Experimental Autoimmune Uveoretinitis with Intravitreal Injection of Tacrolimus (FK506) Encapsulated in Liposomes

Abstract

PURPOSE. To evaluate the effects of intravitreal injection of liposomes encapsulating tacrolimus (FK506) on experimental autoimmune uveoretinitis (EAU) in Lewis rats. METHODS. Liposomes containing tacrolimus were prepared by reverse-phase evaporation vesicles. EAU was induced in Lewis rats by subcutaneous injection of interphotoreceptor retinoid-binding protein R16 peptide emulsified in adjuvant. Ten days later, rats were intravitreally injected with saline, tacrolimus, tacrolimus-loaded liposomes, or unloaded liposomes. Clinical signs of inflammation and ocular histologic sections were observed and graded. Retinal function was evaluated by electroretinography (ERG). Tacrolimus concentration was determined in the vitreous body and serum by ELISA. Ocular biodistribution of rhodamine-conjugated liposomes containing tacrolimus (tacrolimus-Rh-lip) was analyzed with a laser scanning confocal microscope. To evaluate the systemic effect of intravitreally injected tacrolimus, delayed-type hypersensitivity (DTH) and lymphocyte proliferation assay (LPA) responses were detected. RESULTS. Treatment of EAU with intravitreal injection of liposomal tacrolimus significantly reduced intraocular inflammation and markedly inhibited the development of EAU, as determined in clinical and histopathologic analyses. No toxic effects could be detected as evaluated by ERG. The concentration of tacrolimus in ocular fluids remained for as long as 14 days after liposomal injection of tacrolimus. Confocal microscopy showed a transretinal distribution of the liposomal particles. DTH and LPA responses were not impaired in liposomal tacrolimus-treated rats. CONCLUSIONS. Intravitreal injection of liposomal tacrolimus was highly effective in suppressing the process of EAU without any side effects on retinal function or systemic cellular immunity. This treatment may represent a new option for the management of intraocular inflammation.

Advance of the application of nano-controlled release system in ophthalmic drug delivery

“…It is supposed that the liposome increase the liquidity of bacterial cell membrane. In another study, the Tacrolimus formulated by liposome has less toxic effect towards internal retinal cells (Zhang et al, 2010), compared with the non-liposome formulated Tacrolimus. After intravitreal injection, the concentrate of tacrolimus in vitreous body kept in 50 ng/mL for 14 days.…”

Immunosuppressive and Anti-Inflammatory Properties of Engineered Nanomaterials

“…Cyclosporine Liposomes (Freise et al, 1994;Shah et al, 2006); polymeric NP (Gref et al, 2001;Italia et al, 2007;Azzi et al, 2010;Tang et al, 2012); lipid NP (Muller et al, 2008) Preclinical Tacrolimus Lipid NP (Pople and Singh, 2012); polymeric NP (Tammam et al, 2012); liposomes (Erdogan et al, 2002;Zhang et al, 2010) Preclinical Rapamycin/sirolimus Polymeric NP (Yuan et al, 2008;Woo et al, 2012;Shah et al, 2013); micelles (Yanez et al, 2008;Chen et al, 2013); liposomes (Rouf et al, 2009;Ghanbarzadeh et al, 2013) Preclinical Mycophenolic acid Polymeric NP (Shirali et al, 2011); nanogels (Look et al, 2013); dendrimers (Hu et al, 2009) Preclinical Corticosteroids Liposomes Linker et al, 2008;Schweingruber et al, 2011;Ulmansky et al, 2012); polymeric NP (Ishihara et al, 2005;Matsuo et al, 2009); solid lipid NP (Jensen et al, 2010;Zhang and Smith, 2011); dendrimers (Khandare et al, 2005) Preclinical Non-steroidal anti-inflammatory Dendrimers (Chauhan et al, 2004;Na et al, 2006;Chandrasekar et al, 2007;Cheng et al, 2007); nanocolloid (Milkova et al, 2013); lipid NP (Castelli et al, 2005); liposomes (Paavola et al, 2000;Srinath et al, 2000;Turker et al, 2008)…”

Liposomes and nanotechnology in drug development: focus on ocular targets

“…33 The stability of the drug inside the vitreous body can be improved even further by adding polyethylene glycol (PEG) to the surface of the liposomes, since PEG-modification of liposomes sterically stabilizes them by covering the liposomal surface with a fixed aqueous layer. 31 Other reports have also demonstrated the usefulness of liposomal formulations after intravitreal injection (Table 1), and the drugs delivered in these studies have included amikacin, 34 amphotericin B, 35 a model antisense oligonucleotide, 31,36 bevacizumab, 37 cyclosporine, 38 5-fluorouridine 5′-monophosphate, 39,40 fluconazole, 41 GCV, gentamicin, 28 tacrolimus, 42 tobramycin, 43 vasoactive intestinal peptide, 44 an angiogenesis inhibitor, 45 tilisolol, 46 and ofloxacin. 47 The toxicity of various doses of intravitreal amphotericin B deoxycholate, amphotericin B lipid complexes (ABLC), and liposomal amphotericin B (L-AmB) (AmBisome ® ; Astellas Pharma Inc, Tokyo, Japan) in rabbits was examined by Cannon et al 35 Eye examination was performed before and after injection, and at the designated times, the vitreous humor was aspirated, and amphotericin B concentrations were determined, followed by enucleation for histological studies.…”