A novel elastin-like polypeptide drug carrier for cyclosporine A improves tear flow in a mouse model of Sjögren's syndrome.

摘要: Abstract As a potent macrolide immunosuppressant, cyclosporine A (CsA) is used to treat multiple autoimmune diseases, including non-autoimmune and autoimmune-mediated dry eye disease, rheumatoid arthritis psoriasis. Despite its potency, CsA has poor solubility, bioavailability, can cause serious adverse reactions such as nephrotoxicity neurotoxicity. To overcome these limitations, we invented new strategy carry by fusing cognate human receptor, cyclophilin (CypA), 73 kDa elastin-like polypeptide (ELP) termed A192 using recombinant protein expression. Derived from tropoelastin, ELPs are characterized the ability phase separate above temperature that function of variables concentration, molecular weight, hydrophobicity. The resultant fusion protein, CA192, which assembles into dimeric species in solution, effectively binds solubilizes with Kd 189 nM, comparable endogenous CypA 35.5 nM. release profile CA192 follows one decay model half-life 957.3 h without burst stage. Moreover, CA192-CsA inhibited IL-2 expression induced Jurkat cells through calcineurin-NFAT signaling pathway an IC50 1.2 nM, free 0.5 nM. intravenous pharmacokinetics followed two-compartment mean residence time 7.3 h. Subcutaneous administration revealed bioavailability 30% 15.9 h. When given subcutaneously for 2 weeks starting at 14 weeks male non-obese diabetic (NOD) mice, dacryoadenitis study Sjogren's syndrome (SS), (2.5 mg/kg, every other day) significantly (p = 0.014) increased tear production relative alone. delivery reduced indications CsA. represents viable approach deliver this effective but nephrotoxic agent modality preserves therapeutic efficacy suppresses drug toxicity.