PMID- 23892265
OWN - NLM
STAT- MEDLINE
DCOM- 20140505
LR  - 20211021
IS  - 1873-4995 (Electronic)
IS  - 0168-3659 (Print)
IS  - 0168-3659 (Linking)
VI  - 171
IP  - 3
DP  - 2013 Nov 10
TI  - A rapamycin-binding protein polymer nanoparticle shows potent therapeutic 
      activity in suppressing autoimmune dacryoadenitis in a mouse model of Sjogren's 
      syndrome.
PG  - 269-79
LID - S0168-3659(13)00410-0 [pii]
LID - 10.1016/j.jconrel.2013.07.016 [doi]
AB  - Sjogren'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.
CI  - (c) 2013.
FAU - Shah, Mihir
AU  - Shah M
AD  - Department of Pharmacology and Pharmaceutical Sciences, University of Southern 
      California School of Pharmacy, Los Angeles, USA.
FAU - Edman, Maria C
AU  - Edman MC
FAU - Janga, Srikanth R
AU  - Janga SR
FAU - Shi, Pu
AU  - Shi P
FAU - Dhandhukia, Jugal
AU  - Dhandhukia J
FAU - Liu, Siyu
AU  - Liu S
FAU - Louie, Stan G
AU  - Louie SG
FAU - Rodgers, Kathleen
AU  - Rodgers K
FAU - Mackay, J Andrew
AU  - Mackay JA
FAU - Hamm-Alvarez, Sarah F
AU  - Hamm-Alvarez SF
LA  - eng
GR  - R01 EY017293/EY/NEI NIH HHS/United States
GR  - R01EY017293-04S1/EY/NEI NIH HHS/United States
GR  - P30 CA014089/CA/NCI NIH HHS/United States
GR  - R01 EY011386/EY/NEI NIH HHS/United States
GR  - P30 DK048522/DK/NIDDK NIH HHS/United States
GR  - R21 EB012281/EB/NIBIB NIH HHS/United States
GR  - R01EY011386/EY/NEI NIH HHS/United States
GR  - P30 DK48522/DK/NIDDK NIH HHS/United States
GR  - R21EB012281/EB/NIBIB NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20130725
PL  - Netherlands
TA  - J Control Release
JT  - Journal of controlled release : official journal of the Controlled Release 
      Society
JID - 8607908
RN  - 0 (Drug Carriers)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Peptides)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 9007-58-3 (Elastin)
RN  - EC 5.2.1.- (Tacrolimus Binding Protein 1A)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Dacryocystitis/*drug therapy/immunology/pathology
MH  - Drug Carriers/*chemistry
MH  - Elastin/chemistry
MH  - Female
MH  - Immunosuppressive Agents/*administration & dosage/pharmacokinetics/therapeutic 
      use
MH  - Lacrimal Apparatus/drug effects/immunology/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Molecular Sequence Data
MH  - Nanoparticles/chemistry
MH  - Peptides/*chemistry
MH  - Recombinant Fusion Proteins/chemistry
MH  - Sirolimus/*administration & dosage/pharmacokinetics/therapeutic use
MH  - Sjogren's Syndrome/*drug therapy/immunology/pathology
MH  - Tacrolimus Binding Protein 1A/chemistry
PMC - PMC3796004
MID - NIHMS510048
OTO - NOTNLM
OT  - CATS
OT  - CCH
OT  - CMT
OT  - Cathepsin S
OT  - DLS
OT  - Dacryoadenitis
OT  - ELP
OT  - Elastin like-Polypeptide
OT  - Elastin like-polypeptide
OT  - FK506 binding protein
OT  - FKBP-S48I48
OT  - FKBP12
OT  - FSI
OT  - IFNgamma
OT  - ITC
OT  - LG
OT  - NOD
OT  - Non obese diabetic mouse
OT  - R(h)
OT  - Rapa
OT  - Rapamycin
OT  - SG
OT  - SjS
OT  - Sjogren's syndrome
OT  - Tt
OT  - carbachol
OT  - cathepsin S
OT  - critical micelle temperature
OT  - dynamic light scattering
OT  - hydrodynamic radii
OT  - i.p.
OT  - interferon gamma
OT  - intraperitoneal
OT  - inverse transition cycling
OT  - lacrimal gland
OT  - mTOR
OT  - mammalian target of Rapamycin
OT  - rapamycin
OT  - salivary gland
OT  - transition temperature
EDAT- 2013/07/31 06:00
MHDA- 2014/05/06 06:00
PMCR- 2014/11/10
CRDT- 2013/07/30 06:00
PHST- 2013/03/27 00:00 [received]
PHST- 2013/07/16 00:00 [revised]
PHST- 2013/07/18 00:00 [accepted]
PHST- 2013/07/30 06:00 [entrez]
PHST- 2013/07/31 06:00 [pubmed]
PHST- 2014/05/06 06:00 [medline]
PHST- 2014/11/10 00:00 [pmc-release]
AID - S0168-3659(13)00410-0 [pii]
AID - 10.1016/j.jconrel.2013.07.016 [doi]
PST - ppublish
SO  - J Control Release. 2013 Nov 10;171(3):269-79. doi: 10.1016/j.jconrel.2013.07.016. 
      Epub 2013 Jul 25.