Majumder Poulami, Zhang Yichuan, Iglesias Marcos, Fan Lixin, Kelley James A, Andrews Caroline, Patel Nimit, Stagno Jason R, Oh Byoung Chol, Furtmüller Georg J, Lai Christopher C, Wang Yun-Xing, Brandacher Gerald, Raimondi Giorgio, Schneider Joel P
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.
Small. 2020 Sep;16(38):e2002791. doi: 10.1002/smll.202002791. Epub 2020 Aug 18.
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.
针对移植免疫排斥中多个相关途径的联合疗法，为需要修复性手术的患者带来了希望。在此，我们开发了一种非相互作用的多相分子组装方法，以在剪切变稀的自组装纤维状肽水凝胶网络中使强效JAK1/3抑制剂托法替布结晶。所得的微晶托法替布水凝胶（MTH）可在手术期间直接通过注射器注射到移植部位，以局部递送小分子。从MTH递送药物的速率在很大程度上受包封微晶溶解的控制。单次应用MTH，并联合全身递送共刺激抑制剂CTLA4-Ig，可使接受异位心脏移植的小鼠的移植物显著存活。局部区域研究表明，MTH实现的托法替布在移植部位的局部递送是观察到移植物存活率提高所必需的。
