Tandem Enzymatic Self-Assembly and Slow Release of Dexamethasone Enhances Its Antihepatic Fibrosis Effect.

Many chronic liver diseases will advance to hepatic fibrosis and, if without timely intervention, liver cirrhosis or even hepatocellular carcinoma. Anti-inflammation could be a standard therapeutic strategy for hepatic fibrosis treatment, but a "smart" strategy of hepatic fibrosis-targeted, either self-assembly or slow release of an anti-inflammation drug ( e.g., dexamethasone, Dex), has not been reported. Herein, we rationally designed a hydrogelator precursor Nap-Phe-Phe-Lys(Dex)-Tyr(H2PO3)-OH (1-Dex-P) and proposed a tandem enzymatic strategy of self-assembly and slow release of Dex, with which the precursor exhibited much stronger antihepatic fibrosis effect than Dex both in vitro and in vivo. Enzymatic and cell experiments validated that 1-Dex-P was first dephosphorylated by alkaline phosphatase to yield Nap-Phe-Phe-Lys(Dex)-Tyr-OH (1-Dex), which self-assembled into nanofiber 1-Dex. The nanofiber was then hydrolyzed by esterase to transform into nanofiber 1, accompanied by slow release of Dex. We anticipate that our "smart" tandem enzymatic strategy could be widely employed to design more sophisticated drug delivery systems to achieve enhanced therapeutic efficacy than free drugs in the future.

Immune Responsive Release of Tacrolimus to Overcome Organ Transplant Rejection.

Transplant rejection is the key problem in organ transplantation and, in clinic, immunosuppressive agents such as tacrolimus are directly administered to the recipients after surgery for T-cell inhibition. However, direct administration of tacrolimus may bring severe side effects to the recipients. Herein, by rational design of two hydrogelators NapPhePheGluTyrOH (1) and Nap d-Phe dPheGluTyrOH (2), a facile method of immune responsive release of tacrolimus is developed from their hydrogels to overcome organ transplantation rejection. Upon incubation with protein tyrosine kinase, which is activated in T cells after organ transplantation, the tacrolimus-encapsulating Gel 1 or Gel 2 is disassembled to release tacrolimus. Cell experiments show that both Gel 1 and Gel 2 have better inhibition effect on the activated T cells than free drug tacrolimus. Liver transplantation experiments indicate that, after 7 days of treatment of same dose tacrolimus, the recipient rats in the Gel 2 group show significantly extended median survival time of 22 days while the recipients treated with conventional tacrolimus medication have a median survival time of 13 days. It is expected herein that this "smart" facile method of immune responsive release of tacrolimus can be applied to overcome organ transplantation rejection in clinic in the near future.