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Multiphase Assembly of Small Molecule Microcrystalline Peptide Hydrogel Allows Immunomodulatory Combination Therapy for Long-Term Heart Transplant Survival

  1. Author:
    Majumder, Poulami [ORCID]
    Zhang, Yichuan
    Iglesias, Marcos
    Fan,Lixin
    Kelley, James A
    Andrews, Caroline
    Patel,Nimit
    Stagno,Jason
    Oh, Byoung Chol
    Furtmüller, Georg J
    Lai,Christopher
    Wang,Yun-Xing
    Brandacher, Gerald
    Raimondi, Giorgio
    Schneider,Joel [ORCID]

  2. Author Address

    Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Building 376, Boyles St, Frederick, MD, 21702, USA., Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA., Basic Science Program, Frederick National Laboratory for Cancer Research, SAXS Core Facility of the National Cancer Institute, Frederick, MD, 21702, USA., Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA., Small Animal Imaging Program, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.,
    1. Year: 2020
    2. Date: Aug 18
    3. Epub Date: 2020 08 18
  2. Journal: Small (Weinheim an der Bergstrasse, Germany)
    1. Pages: e2002791
  4. Type of Article: Article
  5. Article Number: e2002791
  6. ISSN: 1613-6810
  1. Abstract:

    Combination therapies that target multiple pathways involved in immune rejection of transplants hold promise for patients in need of restorative surgery. Herein, a noninteracting multiphase molecular assembly approach is developed to crystallize tofacitinib, a potent JAK1/3 inhibitor, within a shear-thinning self-assembled fibrillar peptide hydrogel network. The resulting microcrystalline tofacitinib hydrogel (MTH) can be syringe-injected directly to the grafting site during surgery to locally deliver the small molecule. The rate of drug delivered from MTH is largely controlled by the dissolution of the encapsulated microcrystals. A single application of MTH, in combination with systemically delivered CTLA4-Ig, a co-stimulation inhibitor, affords significant graft survival in mice receiving heterotopic heart transplants. Locoregional studies indicate that the local delivery of tofacitinib at the graft site enabled by MTH is required for the observed enhanced graft survival. © 2020 Wiley-VCH GmbH.

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External Sources

  1. View Full Text
  2. DOI: 10.1002/smll.202002791
  3. PMID: 32812339
  4. View record in Web of Science®
  5. WOS: 000560351600001

Library Notes

  1. Fiscal Year: FY2019-2020
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