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The USFDA-approved immunosuppressive drug Rapamycin (Rapa), despite its potency, is limited by poor bioavailability and a narrow therapeutic index. In this study, we sought to improve bioavailability of Rapa under subcutaneous (SC) administration and to test its therapeutic feasibility and practicality towards Sjögren's Syndrome (SS), which is a systemic autoimmune disease and has no approved therapies. To improve its therapeutic index, we formulated Rapa with a carrier termed FAF, a fusion of the human cytosolic FK506-binding protein 12 (FKBP12) and an Elastin-like polypeptide (ELP). The resulting 97 kDa
i) has minimal burst release; ii) is 'humanized'; iii) is biodegradable; iv) solubilizes two Rapa per FAF; and v) avoids organic solvents or amphiphilic carriers. Demonstrating high stability, FAF remained soluble and monodisperse with a hydrodynamic radius of 8 nm at physiological temperature. A complete pharmacokinetic (PK) analysis of FAF revealed that the bioavailability of subcutaneous (SC) FAF was 60% with increased the mean residence time (MRT) up to 20.3 hrs compared to 10.7 hrs for IV administration. After 24 hrs injection, the plasma concentration of Rapa delivered by FAF was 8 times higher with significantly increased plasma-to-whole blood ratio relative to free Rapa. To evaluate therapeutic effects, FAF-Rapa was administered SC every other day for 2-weeks to non-obese diabetic (NOD) mice that develop lacrimal gland (LG) inflammation with mechanisms comparable to Sjögren's Syndrome (SS). Both FAF-Rapa and free Rapa exhibited immunomodulatory effects by significantly suppressing lymphocytic infiltration, gene expressions of IFN-γ, MHC II, type I collagen and IL-12a, and cathepsin S (CTSS) activity in the LG compared to controls. Serum chemistry and histopathological analyses in major organs revealed no apparent toxicity of FAF-Rapa. Given its improved PK and equipotent therapeutic efficacy compared to free Rapa, FAF-Rapa may be of further interest for systemic treatments for autoimmune diseases like SS.
This article was published in the following journal.
Name: Molecular pharmaceutics
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A serine threonine kinase that controls a wide range of growth-related cellular processes. The protein is referred to as the target of RAPAMYCIN due to the discovery that TACROLIMUS (commonly known as rapamycin) forms an inhibitory complex with TACROLIMUS BINDING PROTEIN 1A that blocks the action of its enzymatic activity.
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