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Designed trimer-mimetic TNF superfamily ligands on self-assembling nanocages
Biomaterials ( IF 12.8 ) Pub Date : 2018-07-07 , DOI: 10.1016/j.biomaterials.2018.07.009
Minwoo Kih , Eun Jung Lee , Na Kyeong Lee , Yoon Kyoung Kim , Kyung Eun Lee , Cherlhyun Jeong , Yoosoo Yang , Dong-Hwee Kim , In-San Kim

Presentation of an endogenous bioactive ligand in its native form is a key factor in controlling and determining its bioactivity, stability, and therapeutic efficacy. In this study, we developed a novel strategy for presenting trimeric ligands on nanocages by designing, optimizing and testing based on the rational design, high-resolution structural analysis and agonistic activity assays in vitro and in vivo. We successfully designed a nanocage that presents the TNF superfamily member, TRAIL (TNF-related apoptosis-inducing ligand) in its native-like trimeric structure. The native structure of TRAIL complexes was mimicked on the resulting TRAIL-presenting nanocages (TTPNs) by inserting sufficient spacing, determined from three-dimensional structural models, to provide optimal access to the corresponding receptors. The efficacy of TTPNs as an anti-tumor agent was confirmed in preclinical studies, which revealed up to 330-fold increased affinity, 62.5-fold enhanced apoptotic activity, and improved pharmacokinetic characteristics and stability compared with the monomeric form of TRAIL (mTRAIL). In this latter context, TTPNs exhibited greater than 90% stability over 1 mo, whereas ∼50% of mTRAIL aggregated within 2 d. Consistent with their enhanced stability and ultra-high affinity for the TRAIL receptor, TTPNs effectively induced apoptosis of tumor cells in vivo, leading to effective inhibition of tumor growth. Although TRAIL was used here as a proof-of-concept, all members of the TNF superfamily share the TNF homology domain (THD) and have similar distances between ecto-domain C-termini. Thus, other TNF superfamily ligands could be genetically substituted for the TRAIL ligand on the surface of this biomimetic delivery platform.



中文翻译:

在自组装纳米笼上设计三聚体模拟TNF超家族配体

呈天然形式的内源性生物活性配体的呈递是控制和确定其生物活性,稳定性和治疗功效的关键因素。在这项研究中,我们开发了一种新颖的策略,可通过在合理设计,高分辨率结构分析和体内体外激动活性分析的基础上进行设计,优化和测试,在纳米笼上展示三聚体配。我们成功设计了一个纳米笼,该笼以其天然的三聚体结构展示了TNF超家族成员TRAIL(TNF相关的凋亡诱导配体)。通过插入足够的间距(由三维结构模型确定),可以在生成的TRAIL提呈纳米笼(TTPN)上模拟TRAIL配合物的天然结构,从而提供对相应受体的最佳通道。临床前研究证实了TTPNs作为抗肿瘤药的功效,与TRAIL的单体形式(mTRAIL)相比,它揭示了高达330倍的亲和力提高,62.5倍的凋亡活性提高,药代动力学特性和稳定性的提高。在后一种情况下,TTPN在1个月内表现出大于90%的稳定性,而约50%的mTRAIL在2天内聚集。在体内,导致有效抑制肿瘤生长。尽管在这里使用TRAIL作为概念验证,但TNF超家族的所有成员都共享TNF同源域(THD),并且在外部域C末端之间的距离相似。因此,其他TNF超家族配体可以被该仿生递送平台表面上的TRAIL配体遗传取代。

更新日期:2018-07-08
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