TY - JOUR
T1 - A rapamycin-binding protein polymer nanoparticle shows potent therapeutic activity in suppressing autoimmune dacryoadenitis in a mouse model of Sjögren's syndrome
AU - Shah, Mihir
AU - Edman, Maria C.
AU - Janga, Srikanth R.
AU - Shi, Pu
AU - Dhandhukia, Jugal
AU - Liu, Siyu
AU - Louie, Stan G.
AU - Rodgers, Kathleen
AU - MacKay, J. Andrew
AU - Hamm-Alvarez, Sarah F.
N1 - Funding Information:
The authors would like to thank Frances Yarber, Hua Pei, Zhen Meng and Anuja Raut for their contributions to this paper. This work was supported by the University of Southern California , NIH grants RO1EY017293-04S1 and RO1EY011386 to S.H.A., R21EB012281 to J.A.M. and P30 CA014089 to the Norris Comprehensive Cancer Center , the Translational Research Laboratory at the School of Pharmacy , and the American Cancer Society IRG-58-007-48 . Histology services were provided by the Cell and Tissue Imaging Core of the USC Research Center for Liver Diseases (supported by P30 DK48522 ) and the Doheny Eye Institute, Advanced Imaging Core .
PY - 2013/11/10
Y1 - 2013/11/10
N2 - 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 polymerbased 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 diabeticmouse (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 drugwith nearly a 5 fold longer terminal half-life of 62.5 h. 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 formulationwas 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.
AB - 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 polymerbased 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 diabeticmouse (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 drugwith nearly a 5 fold longer terminal half-life of 62.5 h. 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 formulationwas 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.
KW - Cathepsin S
KW - Dacryoadenitis
KW - Elastin like-polypeptide
KW - Non obese diabetic mouse
KW - Rapamycin
KW - Sjögren's syndrome
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U2 - 10.1016/j.jconrel.2013.07.016
DO - 10.1016/j.jconrel.2013.07.016
M3 - Article
C2 - 23892265
AN - SCOPUS:84892918737
SN - 0168-3659
VL - 171
SP - 269
EP - 279
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 3
ER -