Target-oriented delivery of self-assembled immunosuppressant cocktails prolongs allogeneic orthotopic liver transplant survival
Target-oriented delivery of self-assembled immunosuppressant cocktails prolongs allogeneic orthotopic liver transplant survival
复制标题
自组装免疫抑制剂混合物的靶向递送可延长同种异体原位肝移植的存活率
DOI：
10.1016/j.jconrel.2020.08.043
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发表时间：
2020-12-10
影响因子：
10.8
通讯作者：
Wang, Hangxiang
中科院分区：
文献类型：
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作者：
Xie, Haiyang;Zhu, Hai;Wang, Hangxiang
器官移植仍然是终末期器官衰竭患者的金标准治疗选择。然而，移植后免疫抑制的管理几乎没有改善。由于长期使用免疫抑制剂（ISA）可能会导致脱靶全身毒性和并发症，因此在保持药理功效的同时最大限度地减少 ISA 剂量可能是应对这些挑战的一个有前途的解决方案。在这里，我们介绍了基于化学衍生的吗替麦考酚酯的自组装前药纳米颗粒的设计和应用，该纳米颗粒进一步提供了疏水核心以非共价封装其他 ISA，例如他克莫司。所得的免疫抑制剂混合物纳米颗粒通过两亲性聚合物的聚乙二醇化进一步精制，形成胶体稳定的自组装免疫抑制剂混合物（SAIC），适合临床前研究。在同种异体原位肝移植 (OLT) 大鼠模型中，给予 SAIC 可以显着延长移植物/受体的存活率、延缓体重减轻并减轻同种异体移植物损伤。此外，SAIC 显着消除移植物内炎症细胞浸润和促炎细胞因子谱，并改善肝移植功能。这项研究证明了 SAIC 在治疗同种异体移植排斥反应方面优于传统 ISA，并可能支持 SAIC 平台在临床环境中的新兴应用。
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.