July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Development of a targeted carrier for Rapamycin in a murine model of Sjögren’s syndrome
Author Affiliations & Notes
  • Yaping Ju
    Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, California, United States
  • Hao Guo
    Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, California, United States
  • Frances Yarber
    Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, California, United States
  • Maria Edman
    Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, California, United States
  • Santosh Peddi
    Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, California, United States
  • Srikanth Reddy Janga
    Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, California, United States
  • John Andrew MacKay
    Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, California, United States
    Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, California, United States
  • Sarah F Hamm-Alvarez
    Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, California, United States
    Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, California, United States
  • Footnotes
    Commercial Relationships   Yaping Ju, None; Hao Guo, None; Frances Yarber, None; Maria Edman, None; Santosh Peddi, None; Srikanth Reddy Janga, None; John MacKay, None; Sarah Hamm-Alvarez, None
  • Footnotes
    Support  Unrestricted Grant to the Department of Ophthalmology from Research to Prevent Blindness, New York, NY; P30EY029220,EY026635 from NIH
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2822. doi:
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    • Get Citation

      Yaping Ju, Hao Guo, Frances Yarber, Maria Edman, Santosh Peddi, Srikanth Reddy Janga, John Andrew MacKay, Sarah F Hamm-Alvarez; Development of a targeted carrier for Rapamycin in a murine model of Sjögren’s syndrome. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2822.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Sjögren’s syndrome (SS) is a systemic autoimmune disease affecting lacrimal glands (LG) and salivary glands. There is currently no therapy that targets inflammation in affected tissue. Elastin-Like Polypeptides (ELPs) are protein polymers that are thermally-responsive, easy to engineer, and of low immunogenicity, making them ideal candidates for drug carriers. Rapamycin (Rapa), an immunosuppressant, shows promising immunomodulatory effects on autoimmune dacryoadenitis in male NOD mice, a model for SS-associated dacryoadenitis. Since ICAM-1 is elevated in LG of these mice, we developed an ICAM-1-targeted ELP carrier to increase delivery of Rapa to the LG.

Methods : An ICAM-1-binding peptide was fused to the untargeted (VPGAG)192-FKBP fusion protein (AF) and termed IBPAF. The biophysical properties, Rapa binding, and ICAM-1 binding ability of IBPAF and AF purified by inverse transition cycling were determined. Plasma concentrations of fluorescently-labeled ELPs versus time curve were obtained to analyze their pharmacokinetic properties. Biodistribution of fluorescently-labeled ELPs were compared by IVIS and fluorescence intensity in tissue lysates in 14 wk male NOD mice at 2 h, 8 h and 24 h following i.v. injection.

Results : Both AF and IBPAF were purified to >90% homogeneity and formed monodisperse nanoparticles with radius of ~7nm. Both AF and IBPAF efficiently bound Rapa with Kd ~ 5 nM. IBPAF showed significantly higher (4-fold, p<0.05) binding to TNF-α stimulated bENd.3 cells which overexpress ICAM-1. Pharmacokinetics studies in male NOD mice showed no significant differences between AF and IBPAF with respect to t1/2 (8.9 ± 3.2 vs 5.5 ± 2.9 h, respectively), CL (0.179 ± 0.015 vs 0.168 ± 0.026 mL/h, respectively), Vd (2.3 ± 0.4 vs 1.3 ± 0.7 mL, respectively) and AUC (183.8 ± 15.6 vs 196.2 ± 34.3 μM*h, respectively)(mean ± SD, n=5). Both IVIS imaging and analysis of ELP fluorescence in tissue lysates showed that IBPAF had significantly higher LG accumulation in NOD mice when compared with AF (p<0.05, n=5) within 2 h of injection. No significant differences were detected in any other organs between IBPAF and AF at any other time points.

Conclusions : We developed an ICAM-1 targeted protein carrier for Rapa that specifically binds to ICAM-1 in vitro and accumulates in the LG of diseased NOD mice.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

 

Schematic illustration of therapeutic mechanism of ICAM-1 targeted ELP carrier for Rapa

Schematic illustration of therapeutic mechanism of ICAM-1 targeted ELP carrier for Rapa

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