A rapamycin-binding protein polymer nanoparticle shows potent therapeutic activity in suppressing autoimmune dacryoadenitis in a mouse model of Sjögren's syndrome.

Abstract

Sjögren's syndrome (SjS) is a chronic autoimmune disease characterized initially by lymphocytic infiltration and destruction of exocrine glands, followed by systemic organ damage and B-cell lymphoma. Conventional treatment is based on management of symptoms and there is a shortage of therapies that address the underlying causes of inflammation at source exocrine tissue. The aim of this study was to test a novel protein polymer-based platform consisting of diblock copolymers composed from Elastin-like Polypeptides (ELPs) fused with FKBP12, to deliver a potent immunosuppressant with dose-limiting toxicity, rapamycin (Rapa) also known as Sirolimus, and evaluate its effects on the inflamed lacrimal gland (LG) of non-obese diabetic mouse (NOD), a classic mouse model of SjS. Both soluble and diblock copolymer ELPs were fused to FKBP12 and characterized with respect to purity, hydrodynamic radii, drug entrapment and release. Both formulations showed successful association with Rapa; however, the nanoparticle formulation, FSI, released drug with nearly a 5 fold longer terminal half-life of 62.5h. The strong interaction of FSI nanoparticles with Rapa was confirmed in vivo by a shift in the monoexponential pharmacokinetic profile for free drug to a biexponential profile for the nanoparticle formulation. When acutely administered by injection into NOD mice via the tail vein, this FSI formulation significantly suppressed lymphocytic infiltration in the LG relative to the control group while reducing toxicity. There was also a significant effect on inflammatory and mammalian target of Rapamycin (mTOR) pathway genes in the LG and surprisingly, our nanoparticle formulation was significantly better at decreasing a proposed tear biomarker of SjS, cathepsin S (CATS) compared to free drug. These findings suggest that FSI is a promising tool for delivering Rapa for treatment of SjS in a murine model and may be further explored to meet the unmet medical challenge of SjS.

• Authors: Mihir Shah, Maria C Edman, Srikanth R Janga, Pu Shi, Jugal Dhandhukia, Siyu Liu, Stan G Louie, Kathleen Rodgers, J Andrew Mackay, Sarah F Hamm-Alvarez
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 171 Issue 3 Pg. 269-79 (Nov 10 2013) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 23892265 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2013.

Chemical References

• Drug Carriers
• Immunosuppressive Agents
• Peptides
• Recombinant Fusion Proteins
• Elastin
• Tacrolimus Binding Protein 1A
• Sirolimus

Topics

• Amino Acid Sequence
• Animals
• Dacryocystitis (drug therapy, immunology, pathology)
• Drug Carriers (chemistry)
• Elastin (chemistry)
• Female
• Immunosuppressive Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Lacrimal Apparatus (drug effects, immunology, pathology)
• Male
• Mice
• Mice, Inbred NOD
• Molecular Sequence Data
• Nanoparticles (chemistry)
• Peptides (chemistry)
• Recombinant Fusion Proteins (chemistry)
• Sirolimus (administration & dosage, pharmacokinetics, therapeutic use)
• Sjogren's Syndrome (drug therapy, immunology, pathology)
• Tacrolimus Binding Protein 1A (chemistry)