Berunda Polypeptides: Biheaded Rapamycin Carriers for Subcutaneous Treatment of Autoimmune Dry Eye Disease
| Autor: | Santosh Peddi, J. Andrew MacKay, Sarah F. Hamm-Alvarez, Changrim Lee, Stan G. Louie, Frances Yarber, Srikanth Reddy Janga, Siyu Liu, Wannita Klinngam, Nishant Tiwari, Hao Guo, Maria C. Edman |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Drug Compounding Injections Subcutaneous medicine.medical_treatment Pharmaceutical Science Tacrolimus Binding Protein 1A 02 engineering and technology Nod Pharmacology 030226 pharmacology & pharmacy Article Mice 03 medical and health sciences 0302 clinical medicine Therapeutic index Drug Stability Pharmacokinetics Mice Inbred NOD Drug Discovery medicine Animals Potency Cathepsin S Sirolimus Drug Carriers Chemistry 021001 nanoscience & nanotechnology Cathepsins Elastin Bioavailability Disease Models Animal Drug Liberation Sjogren's Syndrome Immunosuppressive drug Toxicity Molecular Medicine Peptides 0210 nano-technology Immunosuppressive Agents |
| Zdroj: | Mol Pharm |
| ISSN: | 1543-8392 1543-8384 |
| Popis: | 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 with subcutaneous (SC) administration and to test its therapeutic feasibility and practicality in a murine model of Sjögren’s syndrome (SS), a systemic autoimmune disease with 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 FAF (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 SC FAF was 60%, with significantly higher blood concentration during the elimination phase compared to IV FAF. The plasma concentration of Rapa delivered by FAF was 8-fold higher with a significantly increased plasma-to-whole blood ratio relative to free Rapa, 24 h after injection. To evaluate therapeutic effects, FAF–Rapa was administered SC every other day for 2 weeks to male non-obese diabetic (NOD) mice, which develop an SS-like autoimmune-mediated lacrimal gland (LG) inflammation and other characteristic features of SS. Both FAF–Rapa and free Rapa exhibited immunomodulatory effects by significantly suppressing lymphocytic infiltration, gene expression of IFN-γ, MHC II, type I collagen and IL-12a, and cathepsin S (CTSS) activity in 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 is of further interest for systemic treatments for autoimmune diseases like SS. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|