@article{f228fe8ac8094f4e8936e8dc3771db10,
title = "Multiphase Assembly of Small Molecule Microcrystalline Peptide Hydrogel Allows Immunomodulatory Combination Therapy for Long-Term Heart Transplant Survival",
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.",
keywords = "hydrogels, immunotherapy, peptides, self-assembly, transplants",
author = "Poulami Majumder and Yichuan Zhang and Marcos Iglesias and Lixin Fan and Kelley, {James A.} and Caroline Andrews and Nimit Patel and Stagno, {Jason R.} and Oh, {Byoung Chol} and Furtm{\"u}ller, {Georg J.} and Lai, {Christopher C.} and Wang, {Yun Xing} and Gerald Brandacher and Giorgio Raimondi and Schneider, {Joel P.}",
note = "Funding Information: This research was supported by the Center for Cancer Research Intramural Research Program of the National Cancer Institute, National Institutes of Health, by the Department of Plastic and Reconstructive Surgery at Johns Hopkins School of Medicine, and by the USAMRAA through the FY17 Reconstructive Transplant Research Program under Award No. W81XWH1810789. The authors acknowledge Dr. Cory Brayton (Director, Phenotypic Core facility, Johns Hopkins Medicine) for histological evaluation of transplanted heart tissues, Dr. Galit Fichman (Chemical Biology Laboratory, NCI Frederick), and Dr. Ziqiu Wang (Electron Microscopy Laboratory, Leidos Biomedical Research Inc.) for help with transmission electron microscopy. Dr. Joseph D. Kalen and Lisa Riffle (Small Animal Imaging Program, Leidos Biomedical Research Inc.) are acknowledged for help with ultrasound imaging. For the SAXS experiments, the authors acknowledge the SAXS core facility at the Center for Cancer Research, National Cancer Institute (NCI). The shared scattering beamline 12ID‐B resource is allocated under the PUP‐24152 agreement between the National Cancer Institute and Argonne National Laboratory (ANL). Use of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility, was operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE‐AC02‐06CH11357. Funding Information: This research was supported by the Center for Cancer Research Intramural Research Program of the National Cancer Institute, National Institutes of Health, by the Department of Plastic and Reconstructive Surgery at Johns Hopkins School of Medicine, and by the USAMRAA through the FY17 Reconstructive Transplant Research Program under Award No. W81XWH1810789. The authors acknowledge Dr. Cory Brayton (Director, Phenotypic Core facility, Johns Hopkins Medicine) for histological evaluation of transplanted heart tissues, Dr. Galit Fichman (Chemical Biology Laboratory, NCI Frederick), and Dr. Ziqiu Wang (Electron Microscopy Laboratory, Leidos Biomedical Research Inc.) for help with transmission electron microscopy. Dr. Joseph D. Kalen and Lisa Riffle (Small Animal Imaging Program, Leidos Biomedical Research Inc.) are acknowledged for help with ultrasound imaging. For the SAXS experiments, the authors acknowledge the SAXS core facility at the Center for Cancer Research, National Cancer Institute (NCI). The shared scattering beamline 12ID-B resource is allocated under the PUP-24152 agreement between the National Cancer Institute and Argonne National Laboratory (ANL). Use of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility, was operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Publisher Copyright: {\textcopyright} 2020 Wiley-VCH GmbH",
year = "2020",
month = sep,
day = "1",
doi = "10.1002/smll.202002791",
language = "English (US)",
volume = "16",
journal = "Small",
issn = "1613-6810",
publisher = "Wiley-VCH Verlag",
number = "38",
}