Designed trimer-mimetic TNF superfamily ligands on self-assembling nanocages.
Biomaterials
; 180: 67-77, 2018 10.
Article
em En
| MEDLINE
| ID: mdl-30025246
ABSTRACT
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 trimeric 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 1â¯mo, whereas â¼50% of mTRAIL aggregated within 2â¯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.
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01-internacional
Base de dados:
MEDLINE
Assunto principal:
Biomimética
/
Nanoestruturas
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Ligante Indutor de Apoptose Relacionado a TNF
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Biomaterials
Ano de publicação:
2018
Tipo de documento:
Article