title: 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.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, Los Angeles, USA.
authors.forename: Mihir
authors.initials: M
authors.lastname: Shah
authors.forename: Maria C
authors.initials: MC
authors.lastname: Edman
authors.forename: Srikanth R
authors.initials: SR
authors.lastname: Janga
authors.forename: Pu
authors.initials: P
authors.lastname: Shi
authors.forename: Jugal
authors.initials: J
authors.lastname: Dhandhukia
authors.forename: Siyu
authors.initials: S
authors.lastname: Liu
authors.forename: Stan G
authors.initials: SG
authors.lastname: Louie
authors.forename: Kathleen
authors.initials: K
authors.lastname: Rodgers
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Mackay
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Hamm-Alvarez
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003607:Dacryocystitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004337:Drug Carriers / Q000737:chemistry*; D004549:Elastin / Q000737:chemistry; D005260:Female; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007765:Lacrimal Apparatus / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D020123:Sirolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012859:Sjogren's Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D007166:Immunosuppressive Agents; D010455:Peptides; D011993:Recombinant Fusion Proteins; D004549:Elastin; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus
keywords: CATS; CCH; CMT; Cathepsin S; DLS; Dacryoadenitis; ELP; Elastin like-Polypeptide; Elastin like-polypeptide; FK506 binding protein; FKBP-S48I48; FKBP12; FSI; IFNγ; ITC; LG; NOD; Non obese diabetic mouse; R(h); Rapa; Rapamycin; SG; SjS; Sjögren's syndrome; Tt; carbachol; cathepsin S; critical micelle temperature; dynamic light scattering; hydrodynamic radii; i.p.; interferon gamma; intraperitoneal; inverse transition cycling; lacrimal gland; mTOR; mammalian target of Rapamycin; rapamycin; salivary gland; transition temperature
references.citation: Aust Dent J. 2010 Jun;55 Suppl 1:39-47
references.pmid: 20553243
references.citation: Matrix Biol. 2008 Jan;27(1):53-66
references.pmid: 17689946
references.citation: FASEB J. 2012 Apr;26(4):1400-12
references.pmid: 22247332
references.citation: Ophthalmology. 2011 Jul;118(7):1242-52
references.pmid: 21459453
references.citation: Target Oncol. 2011 Mar;6(1):17-27
references.pmid: 21547705
references.citation: Clin Transplant. 2010 Mar-Apr;24(2):149-56
references.pmid: 20236129
references.citation: Ther Drug Monit. 1995 Dec;17(6):666-71
references.pmid: 8588238
references.citation: Exp Eye Res. 2009 Sep;89(3):319-32
references.pmid: 19345210
references.citation: Curr Opin Rheumatol. 2003 May;15(3):219-25
references.pmid: 12707574
references.citation: Exp Eye Res. 2006 Jan;82(1):33-45
references.pmid: 16005870
references.citation: Discov Med. 2010 Mar;9(46):173-8
references.pmid: 20350481
references.citation: Int J Pharm. 2001 Feb 1;213(1-2):25-9
references.pmid: 11165091
references.citation: Clin Rev Allergy Immunol. 2007 Jun;32(3):252-64
references.pmid: 17992592
references.citation: Biomacromolecules. 2013 Apr 8;14(4):976-85
references.pmid: 23406497
references.citation: Expert Opin Drug Saf. 2011 Sep;10(5):727-49
references.pmid: 21557712
references.citation: Arch Immunol Ther Exp (Warsz). 2009 Jan-Feb;57(1):57-66
references.pmid: 19219532
references.citation: J Control Release. 2011 Oct 30;155(2):218-26
references.pmid: 21699930
references.citation: J Clin Invest. 1998 Jun 1;101(11):2351-63
references.pmid: 9616206
references.citation: J Control Release. 2013 Nov 10;171(3):330-8
references.pmid: 23714121
references.citation: Ann N Y Acad Sci. 1993 Jun 23;685:86-113
references.pmid: 8363289
references.citation: Biomacromolecules. 2012 Nov 12;13(11):3439-44
references.pmid: 23088632
references.citation: Biomacromolecules. 2002 Mar-Apr;3(2):357-67
references.pmid: 11888323
references.citation: JAMA. 2010 Jul 28;304(4):452-60
references.pmid: 20664046
references.citation: Biomacromolecules. 2012 Sep 10;13(9):2645-54
references.pmid: 22849577
references.citation: Am J Ophthalmol. 2005 Nov;140(5):898-9
references.pmid: 16310468
references.citation: Nat Rev Drug Discov. 2011 Oct 31;10(11):868-80
references.pmid: 22037041
references.citation: Protein Sci. 2012 Jun;21(6):743-50
references.pmid: 22434766
references.citation: Invest Ophthalmol Vis Sci. 2010 Oct;51(10):5019-29
references.pmid: 20463324
references.citation: FEBS Lett. 2010 Apr 2;584(7):1287-95
references.pmid: 20083114
references.citation: Immunity. 1999 Feb;10(2):197-206
references.pmid: 10072072
references.citation: Neurotherapeutics. 2007 Oct;4(4):654-60
references.pmid: 17920546
references.citation: J Biomed Nanotechnol. 2012 Apr;8(2):193-201
references.pmid: 22515070
references.citation: J Clin Invest. 2002 Aug;110(3):361-9
references.pmid: 12163455
references.citation: J Biomed Biotechnol. 2011;2011:407031
references.pmid: 21660135
references.citation: Int J Nanomedicine. 2012;7:2197-208
references.pmid: 22619555
references.citation: Rheum Dis Clin North Am. 1992 Aug;18(3):517-38
references.pmid: 1323135