Target-oriented delivery of self-assembled immunosuppressant cocktails prolongs allogeneic orthotopic liver transplant survival
2020
Xie, Haiyang | Zhu, Hai | Zhou, Ke | Wan, Jianqin | Zhang, Liang | Yang, Zhentao | Zhou, Liqian | Chen, Xiaona | Xu, Xiao | Zheng, Shusen | Wang, Hangxiang
Organ transplantation remains the gold standard therapeutic option for patients with end-stage organ failure. However, there have been few improvements in the management of post-transplant immunosuppression. As the long-term use of immunosuppressive agents (ISAs) may result in off-target systemic toxicity and complications, minimizing the ISA dosage while preserving the pharmacological efficacy could be a promising solution to address these challenges. Here, we present the design and application of self-assembled prodrug nanoparticles based on chemically derived mycophenolate mofetil, which further provide a hydrophobic core to noncovalently encapsulate additional ISAs such as tacrolimus. The resulting immunosuppressant cocktail nanoparticles are further refined by PEGylation with amphiphilic polymers to form colloidally stable self-assembled immunosuppressant cocktails (SAICs) that are suitable for preclinical studies. In a rat model of allogeneic orthotopic liver transplantation (OLT), administration of SAICs markedly extends graft/recipient survival, retards weight loss and attenuates allograft damage. Furthermore, SAICs significantly abolish intragraft inflammatory cell infiltration and proinflammatory cytokine profiles as well as improve liver graft function. This study demonstrates the superiority of SAICs over traditional ISAs in the treatment of allograft rejection and may support the emerging application of the SAIC platform in clinical settings.
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