Novel everolimus-loaded nanocarriers for topical treatment of murine experimental autoimmune uveoretinitis (EAU).

In the present study, therapeutic effect of topically applied everolimus (EV)-loaded methoxy-poly(ethylene-glycol)-hexyl substituted poly (lactic acid) (mPEGhexPLA) nanocarriers on experimental autoimmune uveoretinitis (EAU) were investigated. EAU was induced in B10.RIII mice via immunization with human interphotoreceptor retinoid-binding protein peptide 161-180 (hIRBPp161-180) in complete Freund's adjuvant. Everolimus-loaded mPEGhexPLA (EV/mPEGhexPLA) nanocarriers were prepared by using a solvent evaporation method. On days 12-21 postimmunization (p.i.), the right eyes were treated five times daily either with 10 µl of 0.5% everolimus formulation or PBS (control). The EAU score of the eyes was determined histologically. On day 21 p.i., the peripheral immune responses were measured in serum, cervical lymph nodes (LN), and spleens via hIRBPp161-180-specific serum antibodies, cytokine secretion (ELISA), lymphocyte proliferation, and FoxP3+ regulatory T cells (Treg; flow cytometry). Compared to the PBS-treated mice, unilateral topical everolimus treatment significantly reduced EAU severity in both eyes (p < .05). The treatment reduced the antigen (Ag)-specific hIRBPp161-180-induced proliferation (p < .05), IL-2, IL-17, and IFN-γ secretion from cells isolated from the left and right cervical LN (p < .05). Under everolimus treatment, IL-10 secretion and CD4+CD25+FoxP3+ Treg frequency from cervical LN were enhanced. The proliferative response and cytokine secretion as well as the frequency of splenic Treg were almost unchanged. Topical administration of an everolimus formulation improved EAU in both eyes. The effect might also be related to systemic immunosuppressive effects, as several systemic cellular immune responses were influenced.

Self-assembling polymeric nanocarriers to target inflammatory lesions in ulcerative colitis.

We have developed a self-assembling polymeric nanocarrier to deliver the potent immunosuppressive drug Cyclosporine A (CsA) to inflammatory lesions in ulcerative colitis (UC) patients. Our nanocarrier has a high drug loading capacity and efficiently targets its CsA payload to the diseased tissue after local administration. Tissue drug levels were several orders of magnitude higher in animals suffering from a trinitrobenzene-sulfonic acid (TNBS) - induced colitis, compared to healthy control animals; no drug was detectable in the plasma, underlining the localized delivery strategy. An efficient reduction in inflammation score was obtained with a CsA dose of 1mg/mL. Therapeutic efficacy was comparable to 5-aminosalicylic acid (5-ASA), the positive control treatment in the TNBS-induced colitis model. Repetitive treatment of healthy animals with CsA nanocarriers for seven days was well tolerated with no alterations in colon histology.